Conditions: Biliary Tract Cancer
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 162
Healthy volunteers: no

Brief summary:
This study will evaluate the efficacy and safety of atezolizumab with bevacizumab in combination with cisplatin and gemcitabine(CisGem), compared with atezolizumab in combination with CisGem, in participants with advanced biliary tract cancer (BTC) who have not received prior systemic therapy. Treatment will consist of a chemotherapy combination phase followed by a cancer immunotherapy (CIT)/placebo phase.

Detailed description:

Arms:
arm 1: Participants will receive atezolizumab intravenously 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, and clinical status. Participants will receive bevacizumab intravenously on Day 1 of each 21-day cycle. Participants will receive cisplatin intravenously followed by gemcitabine on Days 1 and 8 of each 21-day cycle for Cycles 1-8. arm 2: Participants will receive atezolizumab intravenously 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, and clinical status. Participants will receive placebo matching bevacizumab intravenously on Day 1 of each 21-day cycle. Participants will receive cisplatin intravenously followed by gemcitabine on Days 1 and 8 of each 21-day cycle for Cycles 1-8.

Interventions: intervention 1: Atezolizumab intervention 2: Bevacizumab intervention 3: Placebo intervention 4: Cisplatin intervention 5: Gemcitabine
Intervention descriptions: intervention 1: Atezolizumab will be administered intravenously at a fixed dose of 1200 mg on Day 1 of each 21-day cycle. intervention 2: Bevacizumab will be administered at a dose of 15 mg/kg intravenously on Day 1 of each 21-day cycle after atezolizumab. intervention 3: Placebo matching bevacizumab will be administered intravenously on Day 1 of each 21-day cycle after atezolizumab. intervention 4: Cisplatin will be administered intravenously at a dose of 25 mg/m\^2 on Days 1 and 8 of each 21-day cycle for Cycles 1-8. intervention 5: Gemcitabine will be administered intravenously at a dose of 1000 mg/m\^2 on Days 1 and 8 of each 21-day cycle for Cycles 1-8.

Protocol document:
Prot_SAP_000.pdf: 
 
Official Title: 
A Phase II, Randomized, Double-Blind Placebo-Controlled Study of 
Atezolizumab With or Without Bevacizumab in Combination With 
Cisplatin Plus Gemcitabine in Patients With Untreated, Advanced 
Biliary Tract Cancer 
NCT Number: 
NCT04677504 
Document Date: 
Protocol Amendment Version 6: 03-February-2023 
 
 
 


CONFIDENTIAL 
This clinical study is being sponsored globally by F. Hoffmann-La Roche Ltd of Basel, 
Switzerland.  However, it may be implemented in individual countries by Roche's local affiliates, 
including Genentech, Inc. in the United States.  The information contained in this document, especially 
any unpublished data, is the property of F. Hoffmann-La Roche Ltd (or under its control) and therefore 
is provided to you in confidence as an investigator, potential investigator, or consultant, for review by 
you, your staff, and an applicable Ethics Committee or Institutional Review Board.  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 persons to whom the drug may be administered. 
 
Atezolizumab and Bevacizumab—F. Hoffmann-La Roche Ltd 
Protocol GO42661, Version 6 
PROTOCOL 
TITLE: 
A PHASE II, RANDOMIZED, DOUBLE-BLIND 
PLACEBO-CONTROLLED STUDY OF 
ATEZOLIZUMAB WITH OR WITHOUT 
BEVACIZUMAB IN COMBINATION WITH 
CISPLATIN PLUS GEMCITABINE IN PATIENTS 
WITH UNTREATED, ADVANCED BILIARY 
TRACT CANCER 
PROTOCOL NUMBER: GO42661 
STUDY NAME 
IMbrave151 
VERSION NUMBER: 
6 
EUDRACT NUMBER: 
2020-003759-14 
IND NUMBER: 
152,455 
NCT NUMBER: 
NCT04677504 
TEST PRODUCTS: 
Atezolizumab (RO5541267) 
Bevacizumab (RO4876646) 
MEDICAL MONITOR: 
 M.D., Ph.D. 
SPONSOR: 
F. Hoffmann-La Roche Ltd 
APPROVAL: 
See electronic signature and date stamp on the 
final page of this document. 


Atezolizumab and Bevacizumab—F. Hoffmann-La Roche Ltd 
2/Protocol GO42661, Version 6 
PROTOCOL HISTORY 
Protocol 
Version 
Date Final 
6 
See electronic date stamp on the 
final page of this document. 
5 
23 June 2022 
4 
14 December 2021 
3 
3 March 2021 
2 
7 October 2020 
1 
27 August 2020 


Atezolizumab and Bevacizumab—F. Hoffmann-La Roche Ltd 
3/Protocol GO42661, Version 6 
PROTOCOL AMENDMENT, VERSION 6:  
RATIONALE 
Protocol GO42661 has primarily been amended to update risks and adverse event 
management guidelines for atezolizumab to align with the Atezolizumab Investigator's 
Brochure, Version 19 and Addenda 1 and 2.  Substantive changes to the protocol, along 
with a rationale for each change, are summarized below:  
 
The medical term "Wegener granulomatosis" has been replaced by the 
term "granulomatosis with polyangiitis" to align with the updated preferred term 
in MedDRA (Section 4.1.2 and Appendix 12). 
 
The list of identified risks for atezolizumab has been revised to include pericardial 
disorders, myelitis, and facial paresis (Section 5.1.1). 
 
Hemophagocytic lymphohistiocytosis has been updated from a potential risk to an 
identified risk associated with atezolizumab, and language has been revised 
accordingly (Section 5.1.1). 
 
The list of adverse events of special interest has been revised to include myelitis 
and facial paresis (Section 5.2.3). 
 
A description of the technical and organizational security measures taken to 
protect personal data has been added to align with Clinical Trials Regulation 
requirements (Section 8.4). 
 
Appendix 12 has been revised to indicate that caution should be used when 
considering atezolizumab for patients who have previously experienced a 
pericardial disorder while receiving another immunostimulatory anti-cancer agent. 
 
Appendix 12 has been revised to include autoimmune myelitis. 
 
The adverse event management guidelines have been updated to align with the 
Atezolizumab Investigator's Brochure, Version 19 and Addenda 1 and 2 
(Appendix 15). 
 
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. 


Atezolizumab and Bevacizumab—F. Hoffmann-La Roche Ltd 
4/Protocol GO42661, Version 6 
 
TABLE OF CONTENTS 
PROTOCOL AMENDMENT ACCEPTANCE FORM .......................................... 11 
PROTOCOL SYNOPSIS .................................................................................... 12 
1. 
BACKGROUND ............................................................................ 28 
1.1 
Background on Biliary Tract Cancer ........................................ 28 
1.2 
Treatment of Advanced Biliary Tract Cancer ........................... 28 
1.2.1 
Anti-Vascular Endothelial Growth Factor Treatments in 
Biliary Tract Cancer ................................................................. 29 
1.2.2 
Cancer Immunotherapy in Biliary Tract Cancer ....................... 29 
1.3 
Background on Atezolizumab .................................................. 30 
1.4 
Background on Bevacizumab .................................................. 31 
1.5 
Study Rationale and BenefitRisk Assessment ....................... 31 
1.5.1 
Rationale for Combining Chemotherapy with AntiPD-
1/PD-L1 Antibodies .................................................................. 31 
1.5.2 
Rationale for Combined Inhibition of PD-L1 and VEGF ........... 32 
1.5.3 
Rationale for Combining AntiPD-L1, Anti-VEGF, and 
Chemotherapy ......................................................................... 33 
1.5.4 
Benefit-Risk Assessment during the COVID-19 Pandemic ...... 33 
2. 
OBJECTIVES AND ENDPOINTS ................................................. 35 
3. 
STUDY DESIGN ........................................................................... 38 
3.1 
Description of the Study ........................................................... 38 
3.2 
End of Study and Length of Study ........................................... 42 
3.3 
Rationale for Study Design ...................................................... 42 
3.3.1 
Rationale for Atezolizumab Dose and Schedule ...................... 42 
3.3.2 
Rationale for Bevacizumab Dose and Schedule ...................... 42 
3.3.3 
Rationale for Patient Population .............................................. 42 
3.3.4 
Rationale for Treatment Arms .................................................. 43 
3.3.5 
Rationale for Continued Treatment of 
Atezolizumab/Bevacizumab and Atezolizumab/Placebo 
after Chemotherapy ................................................................. 43 
3.3.6 
Rationale for Progression-Free Survival as the Primary 
Endpoint .................................................................................. 44 
3.3.7 
Rationale for Stratification Factors ........................................... 44 


Atezolizumab and Bevacizumab—F. Hoffmann-La Roche Ltd 
5/Protocol GO42661, Version 6 
3.3.8 
Rationale for Atezolizumab Treatment beyond Initial 
Radiographic Progression........................................................ 45 
3.3.9 
Rationale for Biomarker Assessments ..................................... 45 
3.3.10 
Rationale for Non-Standard Clinical Outcome 
Assessments ........................................................................... 46 
4. 
MATERIALS AND METHODS ...................................................... 47 
4.1 
Patients .................................................................................... 47 
4.1.1 
Inclusion Criteria ...................................................................... 47 
4.1.2 
Exclusion Criteria ..................................................................... 51 
4.2 
Method of Treatment Assignment and Blinding ....................... 55 
4.2.1 
Blinding .................................................................................... 55 
4.3 
Study Treatment and Other Treatments Relevant to the 
Study Design ........................................................................... 56 
4.3.1 
Study Treatment Formulations and Packaging ........................ 57 
4.3.1.1 
Atezolizumab ........................................................................... 57 
4.3.1.2 
Bevacizumab and Placebo ...................................................... 57 
4.3.1.3 
Cisplatin and Gemcitabine ....................................................... 57 
4.3.2 
Study Treatment Dosage, Administration, and Compliance .... 57 
4.3.2.1 
Atezolizumab ........................................................................... 58 
4.3.2.2 
Bevacizumab and Placebo ...................................................... 58 
4.3.3 
Chemotherapy (Cisplatin and Gemcitabine) ............................ 59 
4.3.4 
Investigational Medicinal Product Handling and 
Accountability ........................................................................... 60 
4.3.5 
Continued Access to Atezolizumab and Bevacizumab ............ 61 
4.4 
Concomitant Therapy .............................................................. 61 
4.4.1 
Permitted Therapy ................................................................... 62 
4.4.2 
Cautionary Therapy ................................................................. 64 
4.4.2.1 
Corticosteroids, Immunosuppressive Medications, and 
TNF- Inhibitors ....................................................................... 64 
4.4.2.2 
Herbal Therapies ..................................................................... 65 
4.4.3 
Prohibited Therapy .................................................................. 65 
4.4.3.1 
Prohibited and Cautionary Therapy for Gemcitabine-
Treated Patients ...................................................................... 66 
4.4.3.2 
Prohibited and Cautionary Therapy for Cisplatin-Treated 
Patients .................................................................................... 66 


Atezolizumab and Bevacizumab—F. Hoffmann-La Roche Ltd 
6/Protocol GO42661, Version 6 
4.5 
Study Assessments ................................................................. 66 
4.5.1 
Informed Consent Forms and Screening Log .......................... 67 
4.5.2 
Medical History, Baseline Conditions, Concomitant 
Medication, and Demographic Data ......................................... 67 
4.5.3 
Physical Examinations ............................................................. 67 
4.5.4 
Vital Signs ................................................................................ 67 
4.5.5 
Tumor and Response Evaluations ........................................... 68 
4.5.6 
Laboratory, Biomarker, and Other Biological Samples ............ 69 
4.5.7 
Electrocardiograms .................................................................. 72 
4.5.8 
Clinical Outcome Assessments ............................................... 72 
4.5.8.1 
Data Collection Methods for Clinical Outcome 
Assessments ........................................................................... 73 
4.5.8.2 
Description of Clinical Outcome Assessment Instruments ....... 74 
4.5.9 
Blood Samples for Whole Exome Sequencing (Patients at 
Participating Sites) ................................................................... 75 
4.5.10 
Optional Tumor Biopsies ......................................................... 76 
4.5.11 
Optional Stool Samples ........................................................... 76 
4.5.12 
Study Treatment Discontinuation ............................................. 77 
4.5.13 
Patient Discontinuation from the Study .................................... 78 
4.5.14 
Study Discontinuation .............................................................. 79 
4.5.15 
Site Discontinuation ................................................................. 79 
5. 
ASSESSMENT OF SAFETY ......................................................... 79 
5.1 
Safety Plan .............................................................................. 79 
5.1.1 
Risks Associated with Atezolizumab ........................................ 80 
5.1.2 
Risks Associated with Bevacizumab ........................................ 80 
5.1.3 
Risks Associated with Combination Use of Atezolizumab 
and Bevacizumab .................................................................... 80 
5.1.4 
Risks Associated with Cisplatin or Gemcitabine ...................... 80 
5.1.5 
Cisplatin and Gemcitabine Dose Modifications ........................ 81 
5.2 
Safety Parameters and Definitions .......................................... 81 
5.2.1 
Adverse Events ........................................................................ 81 
5.2.2 
Serious Adverse Events (Immediately Reportable to the 
Sponsor) .................................................................................. 82 


Atezolizumab and Bevacizumab—F. Hoffmann-La Roche Ltd 
7/Protocol GO42661, Version 6 
5.2.3 
Adverse Events of Special Interest (Immediately 
Reportable to the Sponsor) ...................................................... 82 
5.3 
Methods and Timing for Capturing and Assessing 
Safety Parameters ................................................................... 84 
5.3.1 
Adverse Event Reporting Period .............................................. 84 
5.3.2 
Eliciting Adverse Event Information ......................................... 84 
5.3.3 
Assessment of Severity of Adverse Events ............................. 84 
5.3.4 
Assessment of Causality of Adverse Events............................ 85 
5.3.5 
Procedures for Recording Adverse Events .............................. 86 
5.3.5.1 
Infusion-Related Reactions and Cytokine Release 
Syndrome ................................................................................ 86 
5.3.5.2 
Diagnosis versus Signs and Symptoms ................................... 87 
5.3.5.3 
Adverse Events That Are Secondary to Other Events ............. 87 
5.3.5.4 
Persistent or Recurrent Adverse Events .................................. 87 
5.3.5.5 
Abnormal Laboratory Values ................................................... 88 
5.3.5.6 
Abnormal Vital Sign Values ..................................................... 89 
5.3.5.7 
Abnormal Liver Function Tests ................................................ 89 
5.3.5.8 
Deaths ..................................................................................... 89 
5.3.5.9 
Preexisting Medical Conditions ................................................ 90 
5.3.5.10 
Lack of Efficacy or Worsening of Biliary Tract Cancer ............. 90 
5.3.5.11 
Hospitalization or Prolonged Hospitalization ............................ 90 
5.3.5.12 
Cases of Accidental Overdose or Medication Error ................. 91 
5.3.5.13 
Patient-Reported Outcome Data .............................................. 92 
5.3.5.14 
Safety Biomarker Data ............................................................. 92 
5.4 
Immediate Reporting Requirements from Investigator to 
Sponsor ................................................................................... 92 
5.4.1 
Medical Monitors and Emergency Medical Contacts ............... 93 
5.4.2 
Reporting Requirements for Serious Adverse Events and 
Adverse Events of Special Interest .......................................... 93 
5.4.2.1 
Events That Occur prior to Study Treatment Initiation ............. 93 
5.4.2.2 
Events That Occur after Study Treatment Initiation ................. 94 
5.4.3 
Reporting Requirements for Pregnancies ................................ 94 
5.4.3.1 
Pregnancies in Female Patients .............................................. 94 
5.4.3.2 
Pregnancies in Female Partners of Male Patients ................... 95 


Atezolizumab and Bevacizumab—F. Hoffmann-La Roche Ltd 
8/Protocol GO42661, Version 6 
5.4.3.3 
Abortions.................................................................................. 95 
5.4.3.4 
Congenital Anomalies/Birth Defects ........................................ 95 
5.5 
Follow-Up of Patients after Adverse Events............................. 96 
5.5.1 
Investigator Follow-Up ............................................................. 96 
5.5.2 
Sponsor Follow-Up .................................................................. 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 ............... 96 
6. 
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN ......... 97 
6.1 
Determination of Sample Size ................................................. 98 
6.2 
Summaries of Conduct of Study .............................................. 99 
6.3 
Summaries of Demographic and Baseline Characteristics ...... 99 
6.4 
Efficacy Analyses ..................................................................... 99 
6.4.1 
Primary Efficacy Endpoint ........................................................ 99 
6.4.2 
Secondary Efficacy Endpoints ............................................... 100 
6.4.2.1 
Overall Survival ...................................................................... 100 
6.4.2.2 
Confirmed Objective Response Rate ..................................... 100 
6.4.2.3 
Duration of Response ............................................................ 101 
6.4.2.4 
Disease Control Rate ............................................................. 101 
6.4.2.5 
Time to Confirmed Deterioration ............................................ 101 
6.4.3 
Exploratory Efficacy Endpoints .............................................. 101 
6.4.3.1 
Exploratory Progression-Free Survival .................................. 101 
6.4.3.2 
Exploratory Overall Survival ................................................... 101 
6.4.3.3 
Exploratory Patient-Reported Outcome Endpoints ................ 102 
6.5 
Safety Analyses ..................................................................... 102 
6.5.1 
Analyses of Exposure, Adverse Event, Laboratory, Vital 
Sign, and ECG Data .............................................................. 102 
6.5.2 
Exploratory Analyses of PRO-CTCAE Data .......................... 103 
6.6 
Pharmacokinetic Analyses ..................................................... 103 
6.7 
Immunogenicity Analyses ...................................................... 103 
6.8 
Biomarker Analyses ............................................................... 104 
6.9 
Interim Analyses .................................................................... 104 
6.9.1 
Planned Interim Analysis ....................................................... 104 


Atezolizumab and Bevacizumab—F. Hoffmann-La Roche Ltd 
9/Protocol GO42661, Version 6 
6.9.2 
Optional Interim Analyses ...................................................... 104 
7. 
DATA COLLECTION AND MANAGEMENT ............................... 105 
7.1 
Data Quality Assurance ......................................................... 105 
7.2 
Electronic Case Report Forms ............................................... 105 
7.3 
Electronic Patient-Reported Outcome Data ........................... 105 
7.4 
Source Data Documentation .................................................. 106 
7.5 
Use of Computerized Systems .............................................. 106 
7.6 
Retention of Records ............................................................. 107 
8. 
ETHICAL CONSIDERATIONS .................................................... 107 
8.1 
Compliance with Laws and Regulations ................................ 107 
8.2 
Informed Consent .................................................................. 107 
8.3 
Institutional Review Board or Ethics Committee .................... 108 
8.4 
Confidentiality ........................................................................ 109 
8.5 
Financial Disclosure ............................................................... 110 
9. 
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION ..................................................................... 110 
9.1 
Study Documentation ............................................................ 110 
9.2 
Protocol Deviations ................................................................ 110 
9.3 
Management of Study Quality ................................................ 110 
9.4 
Site Inspections ..................................................................... 111 
9.5 
Administrative Structure ......................................................... 111 
9.6 
Dissemination of Data and Protection of Trade Secrets ........ 111 
9.7 
Protocol Amendments ........................................................... 112 
10. 
REFERENCES............................................................................ 113 
 
 
LIST OF TABLES 
Table 1 
Objectives and Corresponding Endpoints ................................... 36 
Table 2 
Study Treatment ......................................................................... 39 
Table 3 
Administration of First and Subsequent Atezolizumab 
Infusions...................................................................................... 58 
Table 4 
Administration of First and Subsequent 
Bevacizumab/Placebo Infusions ................................................. 59 


Atezolizumab and Bevacizumab—F. Hoffmann-La Roche Ltd 
10/Protocol GO42661, Version 6 
Table 5 
Timing for Vital Sign Measurements for First and 
Subsequent Infusions ................................................................. 68 
Table 6 
Dose-Modification Levels for Cisplatin and Gemcitabine ............ 81 
Table 7 
Adverse Event Severity Grading Scale for Events Not 
Specifically Listed in NCI CTCAE ............................................... 85 
Table 8 
Causal Attribution Guidance ....................................................... 86 
Table 9 
Operating Characteristics for Proposed Study Design for 
Several Possible True Underlying PFS Hazard Ratio Values ..... 98 
 
 
LIST OF FIGURES 
Figure 1 
Study Schema ............................................................................. 41 
 
 
LIST OF APPENDICES 
Appendix 1 
Schedule of Activities ................................................................ 120 
Appendix 2 
Schedule of Patient-Reported Outcome Assessments ............. 127 
Appendix 3 
Schedule of Pharmacokinetic, Immunogenicity, and 
Biomarker Samples ................................................................... 129 
Appendix 4 
Staging Criteria for Advanced Biliary Cancers .......................... 130 
Appendix 5 
Response Evaluation Criteria in Solid Tumors, 
Version 1.1 (RECIST v1.1)........................................................ 131 
Appendix 6 
European Organisation for the Research and Treatment of 
Cancer Quality-of-Life Questionnaire (EORTC QLQ-C30) ........ 140 
Appendix 7 
European Organisation for Research and Treatment of 
Cancer Quality-of-Life Questionnaire for 
Cholangiocarcinoma and Cancer of the Gallbladder (EORTC 
QLQ-BIL21) ............................................................................... 142 
Appendix 8 
European Organisation for Research and Treatment of 
Cancer Item Library 77 (EORTC IL77) ...................................... 143 
Appendix 9 
Patient Global Impression of Change and Its Importance 
(PGI-CI)..................................................................................... 144 
Appendix 10 
Patient Global Impression of Severity (PGI-S) .......................... 145 
Appendix 11 
Patient-Reported Outcome Common Terminology Criteria for 
Adverse Events (PRO-CTCAE) ................................................ 146 
Appendix 12 
Preexisting Autoimmune Diseases and Immune Deficiencies .. 147 
Appendix 13 
Anaphylaxis Precautions ........................................................... 148 
Appendix 14 
Overall Guidelines for Management of Patients Who 
Experience Adverse Events ...................................................... 149 
Appendix 15 
Risks Associated with Atezolizumab and Guidelines for 
Management of Adverse Events Associated with 
Atezolizumab ............................................................................ 164 


Atezolizumab and Bevacizumab—F. Hoffmann-La Roche Ltd 
11/Protocol GO42661, Version 6 
PROTOCOL AMENDMENT ACCEPTANCE FORM 
TITLE: 
A PHASE II, RANDOMIZED, DOUBLE-BLIND 
PLACEBO-CONTROLLED STUDY OF 
ATEZOLIZUMAB WITH OR WITHOUT 
BEVACIZUMAB IN COMBINATION WITH 
CISPLATIN PLUS GEMCITABINE IN PATIENTS 
WITH UNTREATED, ADVANCED BILIARY TRACT 
CANCER 
PROTOCOL NUMBER: GO42661 
STUDY NAME 
IMbrave151 
VERSION NUMBER: 
6 
EUDRACT NUMBER: 
2020-003759-14 
IND NUMBER: 
152,455 
NCT NUMBER: 
NCT04677504 
TEST PRODUCTS: 
Atezolizumab (RO5541267) 
Bevacizumab (RO4876646) 
MEDICAL MONITOR: 
 M.D., Ph.D. 
SPONSOR: 
F. Hoffmann-La Roche Ltd 
 
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 as instructed by your local study monitor. 
 


 
Atezolizumab and Bevacizumab—F. Hoffmann-La Roche Ltd 
12/Protocol GO42661, Version 6 
PROTOCOL SYNOPSIS 
TITLE: 
A PHASE II, RANDOMIZED, DOUBLE-BLIND 
PLACEBO-CONTROLLED STUDY OF ATEZOLIZUMAB WITH OR 
WITHOUT BEVACIZUMAB IN COMBINATION WITH CISPLATIN 
PLUS GEMCITABINE IN PATIENTS WITH UNTREATED, 
ADVANCED BILIARY TRACT CANCER 
PROTOCOL NUMBER: 
GO42661 
STUDY NAME 
IMbrave151 
VERSION NUMBER: 
6 
EUDRACT NUMBER: 
2020-003759-14 
IND NUMBER: 
152,455 
NCT NUMBER: 
NCT04677504 
TEST PRODUCTS: 
Atezolizumab (RO5541267) 
Bevacizumab (RO4876646) 
PHASE: 
II 
INDICATION: 
Biliary tract cancer 
SPONSOR: 
F. Hoffmann-La Roche Ltd 
 
OBJECTIVES AND ENDPOINTS 
This study will evaluate the efficacy and safety of atezolizumab with bevacizumab in 
combination with cisplatin and gemcitabine (CisGem), compared with atezolizumab in 
combination with CisGem, in patients with advanced biliary tract cancer (BTC) (i.e., intrahepatic 
cholangiocarcinoma [iCCA], extrahepatic CCA [eCCA], or gallbladder cancer [GBC]) who have 
not received prior systemic therapy.  Specific objectives and corresponding endpoints for the 
study are outlined in Table 1. 
In this protocol, study treatment refers to the combination of treatments assigned to patients 
as part of this study.  Patients will receive one of the following combinations of treatments: 
 
Atezolizumab  Bevacizumabchemotherapy (CisGem), followed by 
Atezolizumab  Bevacizumab 
 
Atezolizumab  Placebochemotherapy (CisGem), followed by Atezolizumab  Placebo 


 
Atezolizumab and Bevacizumab—F. Hoffmann-La Roche Ltd 
13/Protocol GO42661, Version 6 
TABLE 1 
OBJECTIVES AND CORRESPONDING ENDPOINTS 
Primary Efficacy Objective 
Corresponding Endpoint 
 To evaluate the efficacy of 
Atezo  Bev  CisGem compared 
with Atezo  PBO  CisGem 
 PFS, defined as the time from randomization to the first 
occurrence of disease progression as determined by 
the investigator according to RECIST v1.1 or death 
from any cause (whichever occurs first) 
Secondary Efficacy Objective 
Corresponding Endpoints 
 To evaluate the efficacy of 
Atezo  Bev  CisGem compared 
with Atezo  PBO  CisGem 
 OS, defined as the time from randomization to death 
from any cause 
 Confirmed ORR, defined as the proportion of patients 
with a CR or PR on two consecutive occasions 
 4 weeks apart, as determined by the investigator 
according to RECIST v1.1 
 DOR, defined as the time from the first occurrence of 
a confirmed objective response to disease progression 
as determined by the investigator according to 
RECIST v1.1 or death from any cause 
(whichever occurs first) 
 DCR, defined as the proportion of patients with a CR or 
a PR on two consecutive occasions 4 weeks apart or 
SD with a minimum duration of 9 weeks, as determined 
by the investigator according to RECIST v1.1 
 TTCD in patient-reported physical functioning, role 
functioning, and quality of life, as measured by the 
respective scales of the EORTC QLQ-C30 and/or 
EORTC IL77, and defined as the time from 
randomization to the first clinically meaningful 
deterioration that is either maintained for 
two consecutive assessments or followed by death 
from any cause within 3 weeks 
Exploratory Efficacy Objective 
Corresponding Endpoints 
 To evaluate the efficacy of 
Atezo  Bev  CisGem compared 
with Atezo  PBO  CisGem 
 PFS rates at specified timepoints (e.g., 6 months and 
12 months), defined as the probability that a patient will 
be alive without experiencing disease progression, as 
determined by the investigator according to 
RECIST v1.1, at specified timepoints 
 OS rates at specific timepoints (e.g., 6 months and 
12 months), defined as the probability that a patient will 
be alive at specified timepoints 
 Mean scores and changes in mean scores from 
baseline in all scales of the EORTC QLQ-C30, EORTC 
IL77, and EORTC QLQ-BIL21 
 Proportion of responses on the PGI-CI and PGI-S 
Safety Objective 
Corresponding Endpoints 
 To evaluate the safety of 
Atezo  Bev  CisGem compared 
with Atezo  PBO  CisGem 
 Incidence and severity of adverse events, with severity 
determined according to NCI CTCAE v5.0 
 Change from baseline in targeted vital signs 
 Change from baseline in targeted clinical laboratory 
test results 
 
 


 
Atezolizumab and Bevacizumab—F. Hoffmann-La Roche Ltd 
14/Protocol GO42661, Version 6 
TABLE 1 
OBJECTIVES AND CORRESPONDING ENDPOINTS (CONT.) 
Exploratory Safety Objective 
Corresponding Endpoints 
 To evaluate the treatment-related 
tolerability of Atezo  Bev  CisGem 
compared with Atezo  PBO  CisGem 
from the patient perspective 
 Frequency, severity, interference, and/or presence 
of select symptomatic treatment toxicities, as 
determined through use of the PRO-CTCAE 
 Change from baseline in select symptomatic 
treatment toxicities, as determined by the 
PRO-CTCAE 
 Overall troublesomeness with treatment, as 
determined by the treatment side effects single 
item of the EORTC QLQ-BIL21 
Pharmacokinetic Objective 
Corresponding Endpoint 
 To characterize the pharmacokinetics 
of atezolizumab when given in 
combination with bevacizumab and/or 
gemcitabine/cisplatin 
 Serum concentration of atezolizumab at specified 
timepoints 
Immunogenicity Objective 
Corresponding Endpoint 
 To evaluate the immune response to 
atezolizumab 
 Prevalence of ADAs to atezolizumab at baseline 
and incidence of ADAs to atezolizumab during the 
study 
Exploratory Immunogenicity 
Objective 
Corresponding Endpoint 
 To evaluate potential effects of ADAs  Relationship between ADA status and efficacy, 
safety, or PK endpoints 
Exploratory Biomarker Objective 
Corresponding Endpoint 
 To identify and/or evaluate 
biomarkers that are predictive of 
response to study treatment 
(i.e., predictive biomarkers), are early 
surrogates of efficacy, are associated 
with progression to a more severe 
disease state (i.e., prognostic 
biomarkers), are associated with 
acquired resistance to study 
treatment, are associated with 
susceptibility to developing adverse 
events or can lead to improved 
adverse event monitoring or 
investigation (i.e., safety biomarkers), 
can provide evidence of study 
treatment activity 
(i.e., pharmacodynamic biomarkers), 
or can increase the knowledge and 
understanding of disease biology and 
drug safety 
 Relationship between biomarkers in blood, serum, 
plasma, and tumor tissue and efficacy, safety, PK, 
immunogenicity, or other biomarker endpoints 
 
 


 
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TABLE 1 
OBJECTIVES AND CORRESPONDING ENDPOINTS (CONT.) 
ADA  anti-drug antibody; Atezo  atezolizumab; Bev  bevacizumab; CisGem  cisplatin and 
gemcitabine; CR  complete response; DCR  disease control rate; DOR  duration of response; 
EORTC  European Organisation for Research and Treatment of Cancer; IL  Item Library; 
NCI CTCAE  National Cancer Institute Common Terminology Criteria for Adverse Events; 
ORR  objective response rate; OS  overall survival; PBO  placebo; PFS  progression-free 
survival; PGI-CI  Patient Global Impression of Change, Importance; PGI-S  Patient Global 
Impression of Severity; PK  pharmacokinetic; PR  partial response; 
PRO-CTCAE  Patient-Reported Outcome Common Terminology Criteria for Adverse Events; 
QLQ-BIL21  Quality-of-Life Questionnaire for Cholangiocarcinoma and Cancer of the 
Gallbladder; QLQ-C30  Quality-of-Life Questionnaire for Cancer; RECIST  Response 
Evaluation Criteria in Solid Tumors; SD  stable disease; TTCD  time to confirmed 
deterioration. 
 
STUDY DESIGN 
DESCRIPTION OF STUDY 
This is a Phase II, randomized, double-blind, placebo-controlled, multicenter study designed to 
evaluate the efficacy and safety of atezolizumab with bevacizumab in combination with CisGem, 
compared with atezolizumab in combination with CisGem, in patients with advanced BTC 
(i.e., iCCA, eCCA, or GBC) who have not received prior systemic therapy. 
The study will enroll globally approximately 150 patients, who will be randomized in a 1:1 ratio 
to one of two treatment arms.  The number of patients with either eCCA or GBC will be capped 
at a maximum of 50% of the total number of patients enrolled. 
Treatment will consist of a chemotherapy combination phase followed by a cancer 
immunotherapy (CIT)/placebo phase as outlined in Table 2. 
TABLE 2 
STUDY TREATMENT 
Treatment 
Arm 
Dose, Route, and Regimen 
(Drugs Listed in Order of Administration) 
Chemotherapy Combination Phase a 
Cycles 18 
(21-Day Cycles) 
CIT/Placebo Phase 
Cycles 9 and Beyond  
(21-Day Cycles) 
Arm A 
AtezoBevCisGem 
 Atezolizumab 1200 mg IV on Day 1 
 Bevacizumab 15 mg/kg IV on Day 1 
 Cisplatin 25 mg/m2 IV on Days 1 and 8 
 Gemcitabine 1000 mg/m2 IV on Days 1 
and 8 
AtezoBev 
 Atezolizumab 1200 mg IV on Day 1 
 Bevacizumab 15 mg/kg IV on Day 1 
Arm B 
AtezoPBOCisGem 
 Atezolizumab 1200 mg IV on Day 1 
 Placebo IV on Day 1 
 Cisplatin 25 mg/m2 IV on Days 1 and 8 
 Gemcitabine 1000 mg/m2 IV on Days 1 
and 8 
AtezoPBO 
 Atezolizumab 1200 mg IV on Day 1 
 Placebo IV on Day 1 
Atezo  atezolizumab; Bev  bevacizumab; CisGem  cisplatin and gemcitabine; CIT  cancer 
immunotherapy; PBO  placebo. 
a Treatment during the chemotherapy combination phase will be administered on a 21-day 
cycle until completion of eight cycles, loss of clinical benefit, or unacceptable toxicity, 
whichever occurs first. 
 
Randomization will be stratified according to the following stratification factors: 
 
Location of primary tumor (iCCA vs. eCCA vs. GBC) 
 
Metastatic disease (yes vs. no) 
 
Geographic region (Asia vs. rest of the world) 


 
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Patients who do not meet the criteria for participation in this study (screen failure) may qualify 
for one re-screening opportunity (for a total of two screenings per participant) at the 
investigator's discretion.  Patients are not required to re-sign the Informed Consent Form if they 
are re-screened within 60 days after previously signing the Informed Consent Form.  
The investigator will record reasons for screen failure in the screening log. 
Patients will continue treatment as indicated in Table 2 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 (as assessed by the investigator according to Response Evaluation Criteria 
in Solid Tumors, Version 1.1 [RECIST v1.1]) while receiving atezolizumab 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, such as new or worsening 
hypercalcemia) indicating unequivocal progression of disease 
 
Absence of decline in Eastern Cooperative Oncology Group (ECOG) Performance Status 
that can be attributed to disease progression 
 
Absence of tumor progression at critical anatomical sites (e.g., leptomeningeal disease) that 
cannot be managed by protocol-allowed medical interventions 
 
Patients who transiently withhold or permanently discontinue one component of their treatment 
(i.e., either atezolizumab, bevacizumab/placebo, or chemotherapy) because of toxicity may 
continue with the other components of study treatment, as long as the patients are experiencing 
clinical benefit in the opinion of the investigator.  However, bevacizumab/placebo should not be 
continued as a single agent. 
Patients will undergo tumor assessments every 9 (1) weeks following treatment initiation.  
Sites will collect and send imaging used for tumor assessments to an independent review 
facility to enable potential centralized, independent review of response and progression 
endpoints. 
Following disease progression or loss of clinical benefit, patients will be followed for survival and 
subsequent anti-cancer therapies until death, loss to follow-up, withdrawal of consent, or study 
termination by the Sponsor, whichever occurs first. 
Patient-reported outcome (PRO) assessments will be completed before starting treatment, at 
specified timepoints during treatment, and at treatment discontinuation. 
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 (NCI CTCAE), Version 5.0.  Laboratory safety assessments will include the 
regular monitoring of hematology and blood chemistry.  Serum samples will be collected to 
monitor the pharmacokinetics of atezolizumab when administered in combination with 
bevacizumab and/or CisGem.  Patient samples, including archival tumor tissues, as well as 
serum and plasma, will be collected for future exploratory biomarker assessments. 
NUMBER OF PATIENTS 
Approximately 150 patients with unresectable, recurrent, or metastatic BTC will be enrolled in 
this study. 
TARGET POPULATION 
Inclusion Criteria 
Patients must meet the following criteria for study entry: 
 
Signed Informed Consent Form 
 
Age  18 years at the time of signing the Informed Consent Form 
 
Ability to comply with the study protocol 
 
Considered to be eligible to receive platinum-based chemotherapy, in the investigator’s 
judgment 


 
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 
Documentation of recurrent/metastatic or locally advanced unresectable disease based on 
computed tomography (CT) or magnetic resonance imaging (MRI) scans 
 
Histologically or cytologically confirmed diagnosis of iCCA, eCCA, or GBC 
For patients with recurrent BTC, histologic confirmation of BTC at the time of resection is 
acceptable 
 
No prior systemic therapy (including systemic investigational agents) for advanced BTC 
Prior chemotherapy or radiotherapy (with or without radio-sensitizing chemotherapy) 
in the neoadjuvant or adjuvant setting is permitted provided this is completed at least 
6 months prior to Day 1 of Cycle 1. 
Prior treatment with gemcitabine administered as a radiation sensitizer in the 
neoadjuvant and adjuvant settings surrounding surgery, during and up to 4 weeks after 
radiation therapy is allowed, provided all toxicities have returned to baseline, or Grade 1 
or better. 
Previous use of herbal therapies and traditional Chinese medicines with anti-cancer 
activity included in the label is allowed, provided that these medications are discontinued 
prior to Day 1 of Cycle 1. 
The following prior interventions are permitted, provided the patient has fully recovered: 
– 
Surgery:  Non-curative resection with macroscopic residual disease or palliative 
bypass surgery.  Patients who have previously undergone curative surgery must 
have evidence of non-resectable disease requiring systemic chemotherapy. 
– 
Photodynamic therapy:  Prior photodynamic therapy for localized disease with no 
evidence of metastatic disease or for localized disease to relieve biliary obstruction 
in the presence of metastatic disease, provided patient has clear evidence of 
disease progression requiring systemic chemotherapy. 
– 
Palliative radiotherapy:  Palliative radiotherapy, provided that all adverse events 
have resolved and the patient has measurable disease outside the field of 
radiation. 
 
At least one measurable untreated lesion (per RECIST v1.1) 
 
Adequate biliary drainage with no evidence of ongoing infection 
If applicable, treatable and clinically relevant biliary duct obstruction must be relieved by 
internal endoscopic drainage/stenting at least 2 weeks prior to Day 1 of Cycle 1 or by 
palliative bypass surgery or percutaneous drainage prior to Day 1 of Cycle 1, and the 
patient has no active or suspected uncontrolled infection. 
Patients fitted with a biliary stent should be clinically stable and free of signs of infection 
and have total bilirubin  2 upper limit of normal (ULN) and AST/ALT  5ULN for 
 2 weeks prior to Day 1 of Cycle 1.  Patients with improving biliary function who meet all 
other inclusion criteria may be re-tested during the screening window. 
 
Availability of a representative tumor specimen that is suitable for determination of PD-L1 
status via central testing 
A formalin-fixed, paraffin-embedded (FFPE) tumor specimen in a paraffin block 
(preferred) or at least 16 slides containing unstained, freshly cut, serial sections should 
be submitted along with an associated pathology report within 4 weeks of randomization. 
If FFPE specimens described above are not available, any type of specimen (including 
fine-needle aspiration, cell pellet specimens [e.g., from pleural effusion], and lavage 
samples) are also acceptable.  This specimen should be accompanied by the associated 
pathology report. 
If archival tissue is either insufficient or unavailable, a core-needle biopsy specimen 
should be collected during the screening period, if clinically feasible.  Trans-jugular 
biopsy tissue sample collections for patients who are at high risk of bleeding may be 
allowed. 
If archival tissue is either insufficient or unavailable and a fresh biopsy is not 
clinically feasible, the patient may still be eligible. 


 
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 
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/L, and have an undetectable viral load 
 
Documented virology status of hepatitis, as confirmed by screening hepatitis B virus (HBV) 
or hepatitis C virus (HCV) tests 
– 
For patients with active HBV:  HBV DNA  500 IU/mL during screening, initiation of 
anti-HBV treatment at least 14 days prior to Day 1 of Cycle 1 and willingness to 
continue anti-HBV treatment during the study (per local standard of care [e.g., 
entecavir]) 
– 
Patients with HCV, either with resolved infection (as evidenced by detectable 
antibody) or chronic infection (as evidenced by detectable HCV RNA), are eligible 
 
Eastern Cooperative Oncology Group Performance Status of 0 or 1 
 
Life expectancy of  3 months 
 
Adequate hematologic and end-organ function, defined by the following laboratory test 
results, obtained within 7 days prior to Day 1 of Cycle 1 unless otherwise specified: 
– 
AST and ALT  2.5  ULN with the following exceptions: 
Patients with documented liver metastases:  AST and ALT  5ULN. 
– 
Serum bilirubin  2  ULN 
– 
Albumin  28 g/L ( 2.8 g/dL) 
– 
Creatinine clearance  60 mL/min (calculated using the Cockcroft-Gault formula) 
– 
Hemoglobin  90 g/L ( 9 g/dL) 
Patients may be transfused to meet this criterion. 
– 
Platelet count  100109/L ( 100,000/L) without transfusion 
– 
Lymphocyte count 0.5109/L ( 500/L) 
– 
ANC  1.5109/L (1500/L) without granulocyte colony-stimulating factor support 
– 
For patients not receiving therapeutic anticoagulation:  INR or aPTT  2 ULN 
– 
Proteinuria  2 on dipstick analysis (within 7 days prior to Day 1 of Cycle 1) 
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. 
 
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 or CisGem, whichever is later.  Women must refrain from donating eggs 
during this same period. 
A woman is considered to be of childbearing potential if she is postmenarchal, has not 
reached a postmenopausal state (12 continuous months of amenorrhea with no 
identified cause other than menopause), and 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).  The definition of 
childbearing potential may be adapted for alignment with local guidelines or 
regulations. 
Examples of contraceptive methods with a failure rate of 1% per year include bilateral 
tubal ligation, male sterilization, hormonal contraceptives that inhibit ovulation, 
hormone-releasing intrauterine devices, and copper intrauterine devices. 


 
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The reliability of sexual abstinence should be evaluated in relation to the duration of 
the clinical trial and the preferred and usual lifestyle of the patient.  Periodic abstinence 
(e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal 
are not adequate methods of contraception.  If required per local guidelines or 
regulations, locally recognized adequate methods of contraception and information 
about the reliability of abstinence will be described in the local Informed Consent Form. 
 
For men:  agreement to remain abstinent (refrain from heterosexual intercourse) or use 
a condom, and agreement to refrain from donating sperm, as defined below: 
With a female partner of childbearing potential or pregnant female partner, men must 
remain abstinent or use a condom during the treatment period and for 6 months after 
the final dose of bevacizumab or CisGem, whichever is later, to avoid exposing the 
embryo.  Men must refrain from donating sperm during this same period. 
The reliability of sexual abstinence should be evaluated in relation to the duration of 
the clinical trial and the preferred and usual lifestyle of the patient.  Periodic abstinence 
(e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal 
are not adequate methods of preventing drug exposure.  If required per local 
guidelines or regulations, locally recognized adequate methods of contraception and 
information about the reliability of abstinence will be described in the local 
Informed Consent Form. 
 
Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from study entry: 
 
Recurrent disease  6 months after curative surgery or 6 months after the completion of 
adjuvant therapy (chemotherapy and/or radiation) 
 
Prior local regional therapy such as radioembolization 
 
Combined or mixed hepatocellular/CCA 
 
Clinically significant hepatic encephalopathy within the 12 months prior to Day 1 of Cycle 12 
 
National Cancer Institute Common Terminology Criteria for Adverse Events Grade  2 
peripheral neuropathy 
 
Prior bleeding event due to untreated or incompletely treated esophageal and/or gastric 
varices within 6 months prior to Day 1 of Cycle 1 
Patients at high risk of esophageal varices are required to undergo an 
esophagogastroduodenoscopy (EGD) during screening or must have undergone an 
EGD within 6 months of Day 1 of Cycle 1.  All size of varices (small to large) must be 
assessed and treated per local standard of care prior to Day 1 of Cycle 1.  Patients at 
high-risk of esophageal varices who have had an EGD within 6 months of Day 1 of 
Cycle 1 do not need to repeat EGD at screening.  Criteria for high-risk varices include 
at least one of the following: 
– 
Presence or history of cirrhosis 
– 
Presence or history of portal hypertension 
– 
Presence or history of primary biliary cirrhosis, or primary sclerosing cholangitis 
– 
HBV or HCV infection 
– 
Evidence of gross vascular invasion (portal vein, hepatic vein or collateral 
vessels) 
– 
Evidence of splenomegaly 
– 
Platelet count  120  109/L (120,000/L) and albumin  36 g/L (3.6 g/dL) 
– 
Evidence of portal vein occlusion due to malignant invasion or constriction 
– 
Evidence of varices by imaging 


 
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 
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, 
granulomatosis with polyangiitis, 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. 
– 
There is 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 12 months prior to Day 1 of Cycle 1. 
 
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 CT scan 
 
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 
Day 1 of Cycle 1, unstable arrhythmia, or unstable angina 
 
History of malignancy other than BTC within 5 years prior to screening, with the exception 
of malignancies with a negligible risk of metastasis or death (e.g., 5-year overall survival 
[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 
 
Symptomatic, untreated, or actively progressing 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 hemorrhage or spinal cord hemorrhage. 
– 
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 within 7 days prior to 
initiation of study treatment, whole-brain radiotherapy within 14 days prior to 
initiation of study treatment, and neurosurgical resection within 28 days prior to 
initiation of study treatment. 
– 
The patient has no ongoing requirement for corticosteroids as therapy for CNS 
disease.  Anticonvulsant therapy at a stable dose is permitted. 
– 
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. 


 
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 
For patients with lung metastases, if one of the following criteria applies: 
– 
Large, centrally located pulmonary metastases 
– 
Clear tumor infiltration into the thoracic great vessels seen on imaging 
– 
Clear cavitation of pulmonary lesions seen on imaging 
 
Active tuberculosis 
 
Severe infection within 4 weeks prior to Day 1 of Cycle 1, including, but not limited to, 
hospitalization for complications of infection, bacteremia, or severe pneumonia, or any 
active infection that, in the opinion of the investigator, could impact patient safety 
 
Treatment with therapeutic oral or IV antibiotics within 2 weeks prior to Day 1 of Cycle 1 
Patients receiving prophylactic antibiotics (e.g., to prevent a urinary tract infection or 
chronic obstructive pulmonary disease [COPD] exacerbation) are eligible for the study, 
provided the signs of active infection have resolved. 
 
Prior allogeneic stem cell or solid organ transplantation 
 
On the waiting list for liver 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 
 
Pregnant or breastfeeding, or intending to become pregnant during the study or within 
5 months after the final dose of atezolizumab or within 6 months after the final dose of 
bevacizumab or CisGem 
Women of childbearing potential must have a negative serum pregnancy test result 
within 14 days prior to Day 1 of Cycle 1. 
 
Co-infection with HBV and HCV 
Patients with a history of HCV infection but who are negative for HCV RNA by 
polymerase chain reaction will be considered to be negative for HCV infection. 
 
Uncontrolled or symptomatic hypercalcemia (ionized calcium  1.5 mmol/L, 
calcium  12 mg/dL, or corrected serum calcium  ULN) 
 
History of severe allergic anaphylactic reactions to chimeric or humanized antibodies or 
fusion proteins 
 
History of allergic reactions to cisplatin or other platinum-containing compounds 
 
Known hypersensitivity to gemcitabine 
 
Known hypersensitivity to Chinese hamster ovary cell products or to any component of the 
atezolizumab or bevacizumab formulations 
 
Treatment with a live, attenuated vaccine within 4 weeks prior to Day 1 of Cycle 1 or 
anticipation of need for such a vaccine during atezolizumab treatment or within 5 months 
after the final dose of atezolizumab 
 
Treatment with investigational therapy within 4 weeks prior to Day 1 of Cycle 1 
 
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) within 4 weeks or 5 drug-elimination half-lives (whichever is longer) prior 
to Day 1 of Cycle 1 
 
Treatment with systemic immunosuppressive medication (including, but not limited to, 
corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide, and 
antiTNF- agents) within 2 weeks prior to Day 1 of Cycle 1 or anticipation of need for 
systemic immunosuppressive medication during study treatment, with the following 
exceptions: 


 
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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 
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 BP 100 mmHg), based on an average of at least 3 BP 
readings at 2 or more sessions 
Anti-hypertensive therapy to achieve these parameters is allowed. 
 
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 Day 1 of Cycle 1 
 
History of hemoptysis (2.5 mL of bright red blood per episode) within 1 month prior to 
Day 1 of Cycle 1 
 
Evidence of bleeding diathesis or significant coagulopathy (in the absence of therapeutic 
anticoagulation) 
 
Current or recent (within 10 days of Day 1 of Cycle 1) use of aspirin (325 mg/day) or 
current or recent treatment with dipyridamole, ticlopidine, clopidogrel, and cilostazol 
 
Current or recent (within 10 days prior to Day 1 of Cycle 1) 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 is within 
normal limits (according to institutional standards) within 14 days prior to Day 1 of 
Cycle 1. 
Prophylactic use of low-molecular-weight heparin (i.e., 40 mg/day enoxaparin) is 
allowed.  However, the use of direct oral anticoagulant therapies such as dabigatran 
(Pradaxa®) and rivaroxaban (Xarelto®) is not recommended due to bleeding risk. 
 
Core biopsy or other minor surgical procedure, excluding placement of a vascular access 
device, within 3 days prior to Day 1 of Cycle 1 
 
History of abdominal or tracheoesophageal fistula, gastrointestinal (GI) perforation, or 
intra-abdominal abscess within 6 months prior to Day 1 of Cycle 1 
 
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 
 
Major surgical procedure within 4 weeks prior to Day 1 of Cycle 1 or anticipation of need for 
a major surgical procedure during the study 
 
History of clinically significant and uncontrolled intra-abdominal inflammatory disease within 
6 months prior to Day 1 of Cycle 1, including, but not limited to, peptic ulcer disease, 
diverticulitis, or colitis 
 
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. 
 
Preexisting renal impairment, myelosuppression, or hearing impairment 
 
END OF STUDY 
The end of this study is defined as the date at which the last data required for study analysis are 
collected.  The end of study will occur once the last patient, last visit occurs following the final 
OS analysis.  


 
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LENGTH OF STUDY 
The total length of the study, from screening of the first patient to the end of the study, is 
expected to be approximately 35 years. 
In addition, the Sponsor may decide to terminate the study at any time. 
If the Sponsor decides to terminate the study, patients who are still receiving study treatment or 
undergoing survival follow-up may be enrolled in an extension study or a non-interventional 
study, if available. 
INVESTIGATIONAL MEDICINAL PRODUCTS 
The investigational medicinal products (IMPs) for this study are atezolizumab and 
bevacizumab/placebo.  Cisplatin and gemcitabine are considered non-IMPs. 
TEST PRODUCTS (INVESTIGATIONAL DRUGS) 
Atezolizumab will be administered by IV infusion at a fixed dose of 1200 mg every 3 weeks 
(Q3W) 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, and clinical status. 
Bevacizumab (Arm A) at a dose of 15 mg/kg or matching placebo (Arm B) will be administered 
after atezolizumab by IV infusion on Day 1 of each 21-day cycle.  There will be a minimum 
5-minute gap between administration of atezolizumab and bevacizumab/placebo. 
NON-INVESTIGATIONAL MEDICINAL PRODUCTS 
Cisplatin will be administered by IV infusion at a dose of 25 mg/m2 followed by gemcitabine at 
a dose of 1000 mg/m2 on Days 1 and 8 of each 21-day cycle. 
STATISTICAL METHODS 
PRIMARY ANALYSIS 
The primary efficacy endpoint is investigator-assessed PFS according to RECIST v1.1. 
Investigator-assessed PFS is defined as the time from randomization to the occurrence of 
disease progression as determined by investigator according to RECIST v1.1, or death from 
any cause, whichever occurs first.  Patients who have not experienced disease progression or 
death at the time of the clinical cutoff date will be censored at the time of the last tumor 
assessment at which they were known to be progression-free with radiographic evidence as of 
the clinical cutoff date.  Patients with no postbaseline tumor assessment will be censored at the 
date of randomization. 
A stratified Cox proportional-hazards model will be used to estimate the PFS HR and its 95% 
CI.  A stratified two-sided log-rank test will be used to compare the investigator-assessed PFS 
between Arm A and Arm B at the two-sided significance level of 0.05.  The stratification factors 
for these stratified analyses are location of primary tumor (iCCA vs. eCCA vs. GBC), metastatic 
disease (yes vs. no), and geographic region (Asia vs. rest of the world).  However, if at least 
one stratum has fewer than 10 events at the time of analysis, the level of stratification factor that 
contains the smallest number of events will be combined with other levels of the same 
stratification factor for the stratified analysis.  The final set of stratification factors used in the 
primary endpoint analysis will be applied to all other endpoints where stratified analyses are 
performed.  The stratification information will be obtained from the IxRS at the time of 
randomization.  Results from an unstratified analysis will also be provided.  The Kaplan-Meier 
method will be used to estimate median PFS for each treatment arm.  The Brookmeyer-Crowley 
methodology will be used to calculate the 95% CI for the median PFS of each treatment arm. 
To assess the homogeneity of the treatment effect with respect to the primary efficacy endpoint 
of PFS, forest plots (including the estimated HRs) for clinically relevant subgroups will be 
provided. 
To assess the robustness of the primary PFS analysis, a sensitivity analysis will be performed 
by incorporating an additional censoring rule for patients who take new anti-cancer therapy prior 
to occurrence of radiographic progression.  These patients will be censored at the last tumor 
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DETERMINATION OF SAMPLE SIZE 
The purpose of this Phase II study is estimation and hypothesis generation regarding the effect 
of atezolizumab with bevacizumab in combination with CisGem (Arm A) on PFS relative to 
atezolizumab in combination with CisGem (Arm B).  Point and CI estimates of the true 
underlying HR of comparing PFS between Arm A and Arm B will be calculated.  A total of 
approximately 150 patients will be randomized at a 1:1 randomization ratio to either Arm A or 
Arm B.  It is assumed that the median duration of PFS in the control arm (Arm B) is 9 months.  
Operating characteristics (statistical power based on a two-sided significance level of 0.05 and 
expected total number of events) at the time of the final PFS analysis will occur when 
approximately 90 PFS events have been observed.  The planned sample size of 150 patients, 
targeting approximately 90 PFS events at the time of the final PFS analysis, is considered to 
provide sufficient data and precision for the purpose of estimation of the HR point estimate and 
its 95% CI. 
INTERIM ANALYSES 
One interim analysis of PFS and objective response rate will be performed at the time when 
100 patients have been followed for at least 6 months, and is estimated to occur at 
approximately 12 months after the first patient is enrolled.  All of the planned 150 patients are 
expected to have been randomized in the study at the time of this planned interim analysis.  
The interim analysis will be performed and interpreted by Sponsor study team personnel, who 
will have full access to unblinded data at the time of analysis.  Access to treatment assignment 
information will follow the Sponsor's standard procedures and will not be given to the Sponsor 
until the first interim analysis within this study is being conducted. 
 


 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Definition 
ADA 
anti-drug antibody 
BP 
blood pressure 
BTC 
biliary tract cancer 
CCA 
cholangiocarcinoma 
CisGem 
cisplatin and gemcitabine 
CIT 
cancer immunotherapy 
COPD 
chronic obstructive pulmonary disease 
COVID-19 
coronavirus disease 2019 
CR 
complete response 
CRS 
cytokine release syndrome 
CT 
computed tomography (scan) 
DCR 
disease control rate 
DOR 
duration of response 
EC 
Ethics Committee 
eCCA 
extrahepatic cholangiocarcinoma 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic Case Report Form 
EDC 
electronic data capture 
EGD 
esophagogastroduodenoscopy 
EORTC 
European Organisation for Research and Treatment of Cancer 
Fc 
fragment crystallizable 
FDA 
(U.S.) Food and Drug Administration 
FFPE 
formalin-fixed, paraffin-embedded 
GBC 
gallbladder cancer 
GHS/QoL 
Global Health Status/Quality of Life 
GI 
gastrointestinal 
HBcAb 
hepatitis B core antibody 
HBsAb 
hepatitis B surface antibody 
HBsAg 
hepatitis B surface antigen 
HBV 
hepatitis B virus 
HCC 
hepatocellular carcinoma 
HCV 
hepatitis C virus 
HIPAA 
Health Insurance Portability and Accountability Act 
HLH 
hemophagocytic lymphohistiocytosis 
HR 
hazard ratio 
iCCA 
intrahepatic cholangiocarcinoma 
ICH 
International Council for Harmonisation 


 
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Abbreviation 
Definition 
IL 
item library 
IMP 
investigational medicinal product 
IND 
Investigational New Drug (Application) 
IRB 
Institutional Review Board 
IRF 
independent review facility 
IRR 
infusion-related reaction 
LMWH 
low molecular weight heparin 
ITT 
intent-to-treat 
IxRS 
interactive voice or Web-based response system 
MAS 
macrophage activation syndrome 
MDSC 
myeloid-derived suppressor cell 
MRI 
magnetic resonance imaging 
NCI CTCAE 
National Cancer Institute Common Terminology Criteria for 
Adverse Events 
NSAID 
non-steroidal anti-inflammatory 
NSCLC 
nonsmall-cell lung cancer 
ORR 
objective response rate 
OS 
overall survival 
PFS 
progression-free survival 
PGI-CI 
Patient-Reported Global Impression of Change and 
Its Importance 
PGI-S 
Patient-Reported Global Impression of Severity 
PK 
pharmacokinetics 
PR 
partial response 
PRO 
patient-reported outcome 
PRO-CTCAE 
Patient-Reported Outcome Common Terminology Criteria for 
Adverse Events 
Q3W 
every 3 weeks 
QLQ-BIL21 
Quality-of-Life Questionnaire for Cholangiocarcinoma and 
Cancer of the Gallbladder 
RCC 
renal cell carcinoma 
RECIST 
Response Evaluation Criteria in Solid Tumors 
SARS-CoV-2 
severe acute respiratory syndrome coronavirus 2 
SD 
stable disease 
T3 
free triiodothyronine 
T4 
free thyroxine 
TAM 
tumor-associated macrophage 
TME 
tumor microenvironment 
Treg 
regulatory T-cell 


 
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Abbreviation 
Definition 
TTCD 
time to confirmed deterioration 
ULN 
upper limit of normal 
VEGF 
vascular endothelial growth factor 
WES 
whole exome sequencing 
 
 


 
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1. 
BACKGROUND 
1.1 
BACKGROUND ON BILIARY TRACT CANCER 
Biliary tract cancers (BTCs) represent a heterogeneous group of epithelial malignancies 
developing in the biliary tree.  Biliary tract cancers include cholangiocarcinoma (CCA) as 
well as gallbladder cancer (GBC) and ampulla of Vater cancer.  Classification of CCA is 
based on the anatomical site of origin and can be subdivided into intrahepatic CCA 
(iCCA), arising from the liver, and extrahepatic CCA (eCCA), arising from the 
extrahepatic bile ducts.  Extrahepatic CCA can be further segmented into perihilar and 
distal subtypes. 
Cholangiocarcinoma currently accounts for approximately 15% of all primary liver 
cancers and approximately 3% of gastrointestinal (GI) malignancies 
(Banales et al. 2020).  Globally, the incidence and mortality rates of BTC show 
substantial geographical variation, presumably reflecting differences in geographical risk 
factors and possibly genetic determinants.  The incidence of CCA is manifold higher in 
Asia compared with Western countries.  Both the incidence and mortality of CCA are 
increasing, primarily because of a global rise in iCCA.  The incidence of GBC is highest 
in Asian countries, as well as countries in Latin America. 
At the time of diagnosis, 70%90% of patients with BTC present with unresectable 
locally advanced or metastatic disease.  Cholangiocarcinomas are usually asymptomatic 
in early stages and are therefore often diagnosed when the disease is already in 
advanced stages, resulting in a dismal prognosis. 
A silent early presentation, coupled with a highly aggressive nature and refractoriness to 
chemotherapy, contribute to a poor prognosis.  Even for patients with resectable 
disease, postoperative recurrence in  60% of cases is reported within the first or second 
year following surgery (Jung et al. 2012) regardless of adjuvant treatment.  
Unresectable, recurrent, or metastatic BTCs are collectively termed advanced BTC. 
1.2 
TREATMENT OF ADVANCED BILIARY TRACT CANCER 
The current first-line standard of care for advanced BTC is the combination of cisplatin 
and gemcitabine (hereafter referred to as CisGem) based on the results of the 
ABC-02 Phase III study (Valle et al. 2010).  Compared with single-agent gemcitabine, 
CisGem conferred a statistically significant overall survival (OS) advantage (hazard ratio 
[HR]: 0.64; 95% CI: 0.52 to 0.80; p 0.001; median OS 11.7 vs. 8.1 months).  In addition, 
CisGem also significantly improved progression-free survival (PFS) and disease control 
rate (DCR).  These data have been conﬁrmed in subsequent randomized studies 
(Okusaka et al. 2010; Sakai et al. 2018; Morizane et al. 2019). 
The limited benefit of first-line treatment with CisGem highlights the need for more 
effective agents and treatment combinations to improve patient outcomes.  
Comprehensive genomic profiling has identified several potentially actionable oncogenic 


 
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alterations in patients with CCA, notably FGFR2 and IDH, leading to the development of 
molecularly targeted agents in biomarker-selected patients (Lamarca et al. 2020).  
However, FGFR2 and IDH mutations are largely confined to  20% patients with iCCA 
and are far less common in eCCA or GBC BTC malignancies.  Therefore, there remains 
a significant unmet need for more effective treatments for advanced BTC. 
1.2.1 
Anti-Vascular Endothelial Growth Factor Treatments in Biliary 
Tract Cancer 
Vascular endothelial growth factor (VEGF), a primary growth factor regulating 
angiogenesis, is over-expressed in 45%75% of BTCs.  Vascular endothelial growth 
factor expression is associated with the presence of metastases in iCCA; poorer 
prognosis in eCCA, and increased microvascular density in both CCA and GBC.  
These observations have made VEGF-driven angiogenesis a logical target in BTC. 
Despite the strong associations between angiogenesis and BTC, a series of randomized 
Phase II trials in which anti-VEGF agents were added to first-line chemotherapy have 
failed to demonstrate improved clinical benefit.  The ABC-03 study evaluated the effect 
of adding cediranib (an oral VEGFR1, VEGFR2, and VEGFR3 tyrosine kinase inhibitor, 
with additional activity against PDGF receptors and c-KIT) to CisGem on PFS in patients 
with advanced BTC (Valle et al. 2015).  The study failed to meet its primary PFS 
endpoint (HR: 0.93; 80% CI: 0.74 to 1.19; p  0.72), although the objective response rate 
(ORR), a secondary endpoint, was significantly increased in the cediranib arm 
(44% vs. 19%; p  0.0036).  Study I3O-MC-JSBF evaluated the addition of ramucirumab 
(a VEGFR2 antibody) to CisGem in patients with advanced BTC.  The addition of 
ramucirumab to CisGem did not improve the primary endpoint of PFS (HR: 1.123, 
p  0.4821), or OS or ORR, both secondary endpoints (Valle et al. 2020).  Gemcitabine 
combined with sorafenib (a multikinase inhibitor targeting proliferative and angiogenic 
pathways) failed to improve PFS compared with gemcitabine alone 
(Moehler et al. 2014). 
Bevacizumab-based chemotherapy combinations have been studied in patients with 
advanced BTC in a series of single-arm Phase II studies.  The combination of 
bevacizumab with gemcitabine/oxaliplatin resulted in an ORR of 40%, a median PFS of 
7 months, and a median OS of 12.7 months (Zhu et al. 2010).  The combination of 
bevacizumab, gemcitabine, and capecitabine led to an ORR of 24%, a median PFS of 
8.1 months, and a median OS of 10.2 months (Iyer et al. 2018).  In both studies, the 
addition of bevacizumab to chemotherapy did not improve outcomes in patients with 
advanced BTC, compared with historical controls.  Both studies concluded that the 
respective bevacizumab combinations were associated with manageable toxicity. 
1.2.2 
Cancer Immunotherapy in Biliary Tract Cancer 
Cancer immunotherapy (CIT) with antibodies targeting the PD-1/PD-L1 axis has 
changed the standard of care in multiple cancers, including hepatocellular carcinoma 
(HCC).  Cancer immunotherapy approaches have garnered significant interest in BTC, 


 
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given their etiologic association with inflammation as well as relatively high levels of 
expression of PD-L1.  However, the role of PD-1/PD-L1 inhibition in BTC remains to be 
established and existing clinical data are limited to small single-arm studies and 
sub-analyses of basket trials.  To date, the efficacy of single-agent antiPD-1/PD-L1 
antibodies has been disappointing and, in most cases, reported ORRs are 
10% (Kelley et al. 2020).  In the largest study published to date (KEYNOTE-158), the 
ORR was 5.8% in 104 patients with advanced, previously treated BTC 
(Bang et al. 2019).  Currently, the role of antiPD-L1 antibodies in BTC is limited to 
patients with deficient mismatch repair and microsatellite instabilityhigh, which 
represent  5% of all patients (Lamarca et al. 2020a). 
Relatedly, antiPD-1 antibodies given as monotherapy have failed to improve OS in 
unresectable HCC, and a retrospective series indicate that liver metastases are less 
responsive to PD-1 inhibition compared with other anatomic sites (Tumeh et al. 2017; 
Yau et al. 2019; Finn et al. 2020).  These observations point to the highly 
immunosuppressed nature of the liver tumor microenvironment (TME) in the setting of 
primary or secondary hepatic tumors. 
Given the apparent limitations of antiPD-L1 antibody monotherapy in BTC, there is 
strong interest in developing combination immunotherapy strategies in order to abrogate 
immune-suppressive mechanisms and promote anti-cancer immunity. 
Cancers harness several mechanisms of immune escape to restrain or evade antitumor 
immune responses, including modulation of the TME to create an immunosuppressive 
milieu that dictates responsiveness to CIT. 
In most BTCs, the TME is frequently characterized by poor cytotoxic T-cell infiltration 
and overexpression of immunosuppressive cell types such as tumor-associated 
macrophages (TAMs), myeloid-derived suppressor cells (MDSCs), regulatory T-cells 
(Tregs), and immature dendritic cells.  These TME components are believed to be 
essential in restraining anti-cancer immunity and fostering BTC progression through 
various mechanisms such as angiogenesis (Loeuillard et al. 2019; Fabris et al. 2020).  
Infiltration of immunosuppressive cells such as TAMs and MDSCs is associated with 
poor patient outcomes. 
PD-L1 blockade, in combination with agents targeting immune suppressive mechanisms 
within the TME, is a rational approach, including with both chemotherapy and anti-VEGF 
drugs, to promote a more immune-permissive TME. 
1.3 
BACKGROUND ON ATEZOLIZUMAB 
Atezolizumab is a humanized IgG1 monoclonal antibody that targets PD-L1 and inhibits 
the interaction between PD-L1 and its receptors, PD-1 and B7-1 (also known as CD80), 
both of which function as inhibitory receptors expressed on T cells.  Therapeutic 
blockade of PD-L1 binding by atezolizumab has been shown to enhance the magnitude 


 
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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 fragment crystallizable (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 patients with 
cancer and is being investigated as a potential therapy in a wide variety of malignancies.  
Atezolizumab is being studied as a single agent treatment in the advanced cancer and 
adjuvant therapy settings, as well as in combination with chemotherapy, targeted 
therapy, and CIT. 
Atezolizumab is approved for the treatment of urothelial carcinoma, nonsmall-cell lung 
cancer (NSCLC), small-cell lung cancer, triple-negative breast cancer, hepatocellular 
carcinoma, and melanoma. 
See the Atezolizumab Investigator's Brochure for details on nonclinical and clinical 
studies. 
1.4 
BACKGROUND ON BEVACIZUMAB 
Bevacizumab is a recombinant humanized monoclonal IgG1 antibody that binds to and 
inhibits the biologic activity of human VEGF in in vitro and in vivo assay systems. 
Bevacizumab was first granted marketing approval in the United States on 
26 February 2004 in combination with IV 5fluorouracil-based chemotherapy for the 
first-line treatment of patients with metastatic carcinoma of the colon or rectum.  
Bevacizumab is approved in over 100 countries for one or more of the following 
indications:  breast cancer, NSCLC, renal cell cancer, glioblastoma multiforme, cervical 
cancer, epithelial ovarian cancer, primary peritoneal cancer, and fallopian tube cancer. 
See the Bevacizumab Investigator's Brochure for details on nonclinical and 
clinical studies. 
1.5 
STUDY RATIONALE AND BENEFITRISK ASSESSMENT 
1.5.1 
Rationale for Combining Chemotherapy with AntiPD-1/PD-L1 
Antibodies 
Chemotherapy can induce a number of positive immunomodulatory effects in the TME, 
such as induction of immunogenic cell death and/or depleting immunosuppressive cells 
(Galluzzi et al. 2015; Heinhuis et al. 2019), providing a rationale to combine with 
antiPD-1/PD-L1 antibodies.  Multiple clinical studies have demonstrated that 
chemotherapy, including CisGem, can be effectively and safely combined with 
antiPD-1/PD-L1 antibodies in patients with cancer (Galsky et al. 2020).  
The immunomodulatory effects of chemotherapy differ according to the type of drug 
used (Wu and Waxman 2018).  Both cisplatin and gemcitabine have been shown to 
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immunogenic cell death (Hato et al. 2014; Galluzi et al. 2017).  This latter observation 
may limit the immune-potentiating effect of CisGem. 
To date, antiPD-L1 antibodies in combination with CisGem have been studied in small 
single-arm studies in BTC (Ueno et al. 2019; Feng et al. 2020).  Despite encouraging 
response rates, PFS and OS in these non-randomized studies were disappointing, 
relative to the data for CisGem alone from randomized studies.  This observation may 
suggest that additional treatment modalities may be required to further amplify the 
immune response. 
1.5.2 
Rationale for Combined Inhibition of PD-L1 and VEGF 
Many immune-suppressive components of the BTC TME are thought to be regulated by 
VEGF, providing a therapeutic rationale to explore dual blockade of PD-L1 and VEGF 
pathways in order to promote anti-cancer immunity.  Excessive levels of VEGF within the 
TME can induce tumor-associated immunosuppression either directly or indirectly by 
means of 4 principal mechanisms:  1) inhibition of dendritic cell maturation and antigen 
presentation; 2) inhibition of cytotoxic T-cell proliferation, trafficking, and infiltration; 
3) promotion of an aberrant tumor vasculature; and 4) recruitment and proliferation of 
MDSCs, Tregs, and pro-tumor M2-TAMs (Fukumura et al. 2018).  Therefore, 
T cellmediated cancer-cell killing by PD-L1 blockade could be enhanced through the 
reversal of VEGF-mediated immunosuppression mechanisms by the addition of 
anti-VEGF therapy.  Combination treatment with antiPD-L1 and anti-angiogenic agents 
is now a standard of care in renal cell carcinoma (RCC), NSCLC, and HCC, based on 
the results of Phase III studies. 
Combined PD-L1 and VEGF inhibition with atezolizumab and bevacizumab in patients 
with HCC was studied in 2 randomized studies.  In Arm F of Study GO30140, 
119 patients with unresectable HCC were randomly assigned in a 1:1 ratio to receive 
either atezolizumab alone or atezolizumab in combination with bevacizumab.  
A statistically and clinically significant improvement in independent review facility 
(IRF)-assessed PFS per Response Evaluation Criteria in Solid Tumors, Version 1.1 
(RECIST v1.1) was observed in the combination arm versus atezolizumab monotherapy 
(HR0.55; 80% CI: 0.40 to 0.74; p  0·0108) (Lee et al. 2020).  Study YO40245 
(IMbrave150) was a randomized Phase III study in which 501 patients with unresectable 
HCC were randomly assigned in a 2:1 ratio to receive either atezolizumab plus 
bevacizumab or sorafenib.  Combination treatment with atezolizumab plus bevacizumab 
resulted in a statistically and clinically significant improvement in OS (HR: 0.58; 
95% CI: 0.42 to 0.79; p  0.0006), PFS (HR0.59; 95% CI: 0.47 to 0.76; p 0.0001), and 
ORR (27% vs. 12%; p 0.0001) compared with sorafenib (Finn et al. 2020).  In 
a post-hoc analysis of Study GO30140, the PFS benefit of atezolizumab and 
bevacizumab compared with atezolizumab alone was enhanced in patients with HCC 
harboring myeloid, Treg, and VEGFR2 immunosuppressive gene signatures (Zhu et al. 
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The effectiveness of combined PD-1/PD-L1 and VEGF inhibition in BTC is yet to be 
established, with available data limited to small Phase I studies (Arkenau et al. 2018; 
Lin et al. 2018). 
1.5.3 
Rationale for Combining AntiPD-L1, Anti-VEGF, and 
Chemotherapy 
The highly immunosuppressed nature of the TME in BTC, coupled with the limited 
clinical activity of PD-1 antibodies combined with either anti-VEGF drugs or CisGem, 
suggest that more active treatment combinations are needed to unlock an anti-cancer 
immune response.  Combining atezolizumab with bevacizumab along with CisGem, all 
of which have immunomodulatory effects, is one such approach.  This combination has 
yet to be evaluated in BTC. 
Published Phase III data in other tumor types such as NSCLC support the rationale for 
the combination of platinum-based chemotherapy, atezolizumab and bevacizumab in 
BTC.  In patients with metastatic non-squamous NSCLC, the addition of atezolizumab to 
bevacizumab plus chemotherapy significantly improved PFS and OS compared with 
bevacizumab plus chemotherapy (Socinski et al. 2018).  Importantly, in a pre-specified 
analysis of patients with baseline liver metastases, atezolizumab plus bevacizumab and 
chemotherapy significantly improved OS and PFS in patients with liver metastases.  
Conversely, neither atezolizumab plus chemotherapy nor bevacizumab combined with 
chemotherapy prolonged OS or PFS in patients with liver metastases (Reck et al. 2019).  
This finding indicates that the dual targeting of PD-L1 and VEGF with a chemotherapy 
backbone may be needed to induce clinically meaningful antitumor immunity in hepatic 
tumors.  These data provide clinical proof of principle to evaluate the atezolizumab, 
bevacizumab, and CisGem combination regimen in BTC. 
On the basis of the compelling rationale described above and expected clinical benefit 
with the combination of atezolizumab, bevacizumab, and CisGem and the well-defined 
safety profile of each approved drug as single agent and in combination, the Sponsor 
believes that the potential benefits of the combination outweigh its risks in the treatment 
of advanced-stage BTC, which remains an incurable disease with a high unmet medical 
need. 
The overall benefitrisk ratio for atezolizumab in combination bevacizumab and CisGem 
is expected to be acceptable in this setting. 
1.5.4 
Benefit-Risk Assessment during the COVID-19 Pandemic 
In the setting of the coronavirus disease 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. 


 
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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 the outcome from SARS-CoV-2 infection is altered by CIT. 
Severe SARS-CoV-2 infection appears to be associated with a cytokine release 
syndrome (CRS) involving the inflammatory cytokines IL-6, IL-10, IL-2, and interferon- 
(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. 
Neutropenia and lymphopenia associated with chemotherapy may increase the risk of 
developing an infection in patients receiving atezolizumab in combination with 
chemotherapy. 
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 
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 
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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. 
The 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 efficacy and safety of atezolizumab with bevacizumab in 
combination with CisGem, compared with atezolizumab in combination with CisGem, in 
patients with advanced BTC (i.e., iCCA, eCCA, or GBC) who have not received prior 
systemic therapy.  Specific objectives and corresponding endpoints for the study are 
outlined in Table 1. 
In this protocol, study treatment refers to the combination of treatments assigned 
to patients as part of this study.  Patients will receive one of the following combinations 
of treatments (see Section 3.1 for details): 
 
Atezolizumab  Bevacizumab  chemotherapy (CisGem), followed by 
Atezolizumab  Bevacizumab 
 
Atezolizumab  Placebo  chemotherapy (CisGem), followed by 
Atezolizumab  Placebo 
 


 
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Table 1 
Objectives and Corresponding Endpoints 
Primary Efficacy Objective 
Corresponding Endpoint 
 To evaluate the efficacy of 
Atezo  Bev  CisGem compared 
with Atezo  PBO  CisGem 
 PFS, defined as the time from randomization to the first 
occurrence of disease progression as determined by 
the investigator according to RECIST v1.1 or death 
from any cause (whichever occurs first) 
Secondary Efficacy Objective 
Corresponding Endpoints 
 To evaluate the efficacy of 
Atezo  Bev  CisGem compared 
with Atezo  PBO  CisGem 
 OS, defined as the time from randomization to death 
from any cause 
 Confirmed ORR, defined as the proportion of patients 
with a CR or PR on two consecutive occasions 
 4 weeks apart, as determined by the investigator 
according to RECIST v1.1 
 DOR, defined as the time from the first occurrence of 
a confirmed objective response to disease progression 
as determined by the investigator according to 
RECIST v1.1 or death from any cause 
(whichever occurs first) 
 DCR, defined as the proportion of patients with a CR or 
a PR on two consecutive occasions  4 weeks apart or 
SD with a minimum duration of 9 weeks, as determined 
by the investigator according to RECIST v1.1 
 TTCD in patient-reported physical functioning, role 
functioning, and quality of life, as measured by the 
respective scales of the EORTC QLQ-C30 and/or 
EORTC IL77, and defined as the time from 
randomization to the first clinically meaningful 
deterioration that is either maintained for 
two consecutive assessments or followed by death 
from any cause within 3 weeks 
Exploratory Efficacy Objective 
Corresponding Endpoints 
 To evaluate the efficacy of 
Atez  Bev  CisGem compared 
with Atezo  PBO  CisGem 
 PFS rates at specified timepoints (e.g., 6 months and 
12 months), defined as the probability that a patient will 
be alive without experiencing disease progression, as 
determined by the investigator according to 
RECIST v1.1, at specified timepoints 
 OS rates at specific timepoints (e.g., 6 months and 
12 months), defined as the probability that a patient will 
be alive at specified timepoints 
 Mean scores and changes in mean scores from 
baseline in all scales of the EORTC QLQ-C30, EORTC 
IL77, and EORTC QLQ-BIL21 
 Proportion of responses on the PGI-CI and PGI-S 


 
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Table 1 
Objectives and Corresponding Endpoints (cont.) 
Safety Objective 
Corresponding Endpoints 
 To evaluate the safety of 
Atezo  Bev  CisGem compared 
with Atezo  PBO  CisGem 
 Incidence and severity of adverse events, with severity 
determined according to NCI CTCAE v5.0 
 Change from baseline in targeted vital signs 
 Change from baseline in targeted clinical laboratory 
test results 
Exploratory Safety Objective 
Corresponding Endpoints 
 To evaluate the treatment-related 
tolerability of Atezo  Bev  CisGem 
compared with 
Atezo  PBO  CisGem from the 
patient perspective 
 Frequency, severity, interference, and/or presence of 
select symptomatic treatment toxicities, as determined 
through use of the PRO-CTCAE 
 Change from baseline in select symptomatic treatment 
toxicities, as determined by the PRO-CTCAE 
 Overall troublesomeness with treatment, as determined 
by the treatment side effects single item of the 
EORTC QLQ-BIL21 
Pharmacokinetic Objective 
Corresponding Endpoint 
 To characterize the 
pharmacokinetics of atezolizumab 
when given in combination with 
bevacizumab and/or CisGem 
 Serum concentration of atezolizumab at specified 
timepoints 
Immunogenicity Objective 
Corresponding Endpoint 
 To evaluate the immune response 
to atezolizumab 
 Prevalence of ADAs to atezolizumab at baseline and 
incidence of ADAs to atezolizumab during the study 
Exploratory Immunogenicity 
Objective 
Corresponding Endpoint 
 To evaluate potential effects of 
ADAs 
 Relationship between ADA status and efficacy, safety, 
or PK endpoints 


 
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Table 1 
Objectives and Corresponding Endpoints (cont.) 
Exploratory Biomarker Objective 
Corresponding Endpoint 
 To identify and/or evaluate biomarkers 
that are predictive of response to study 
treatment (i.e., predictive biomarkers), 
are early surrogates of efficacy, are 
associated with progression to a more 
severe disease state (i.e., prognostic 
biomarkers), are associated with 
acquired resistance to study treatment, 
are associated with susceptibility to 
developing adverse events or can lead to 
improved adverse event monitoring or 
investigation (i.e., safety biomarkers), 
can provide evidence of study treatment 
activity (i.e., pharmacodynamic 
biomarkers), or can increase the 
knowledge and understanding of disease 
biology and drug safety 
 Relationship between biomarkers in blood, 
serum, plasma, and tumor tissue and efficacy, 
safety, PK, immunogenicity, or other biomarker 
endpoints 
ADA  anti-drug antibody; Atezo  atezolizumab; Bev  bevacizumab; CisGem  cisplatin and 
gemcitabine; CR  complete response; DCR  disease control rate; DOR  duration of response; 
EORTC  European Organisation for Research and Treatment of Cancer; IL  Item Library; 
NCI CTCAE  National Cancer Institute Common Terminology Criteria for Adverse Events; 
ORR  objective response rate; OS  overall survival; PBO  placebo; PFS  progression-free 
survival; PGI-CI  Patient Global Impression of Change, Importance; PGI-S  Patient Global 
Impression of Severity; PK  pharmacokinetic; PR  partial response; 
PRO-CTCAE  Patient-Reported Outcome Common Terminology Criteria for Adverse Events; 
QLQ-BIL21  Quality-of-Life Questionnaire for Cholangiocarcinoma and Cancer of the 
Gallbladder; RECIST  Response Evaluation Criteria in Solid Tumors; SD  stable disease; 
TTCD  time to confirmed deterioration. 
 
3. 
STUDY DESIGN 
3.1 
DESCRIPTION OF THE STUDY 
This is a Phase II, randomized, double-blind, placebo-controlled, multicenter study 
designed to evaluate the efficacy and safety of atezolizumab with bevacizumab in 
combination with CisGem, compared with atezolizumab in combination with CisGem, in 
patients with advanced BTC (i.e., iCCA, eCCA, or GBC) who have not received prior 
systemic therapy. 
The study will enroll globally approximately 150 patients, who will be randomized in 
a 1:1 ratio to one of two treatment arms.  The number of patients with either eCCA or 
GBC will be capped at a maximum of 50% of the total number of patients enrolled. 
Treatment will consist of a chemotherapy combination phase followed by a CIT/placebo 
phase as outlined in Table 2. 


 
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Table 2 
Study Treatment 
Treatment 
Arm 
Dose, Route, and Regimen 
(Drugs Listed in Order of Administration) 
Chemotherapy Combination Phase a 
Cycles 18 
(21-Day Cycles) 
CIT/Placebo Phase 
Cycles 9 and Beyond 
(21-Day Cycles) 
Arm A 
Atezo  Bev  CisGem 
 Atezolizumab 1200 mg IV on Day 1 
 Bevacizumab 15 mg/kg IV on Day 1 
 Cisplatin 25 mg/m2 IV on Days 1 and 8 
 Gemcitabine 1000 mg/m2 IV on Days 1 
and 8 
Atezo  Bev 
 Atezolizumab 1200 mg IV on Day 1 
 Bevacizumab 15 mg/kg IV on Day 1 
Arm B 
Atezo  PBO  CisGem 
 Atezolizumab 1200 mg IV on Day 1 
 Placebo IV on Day 1 
 Cisplatin 25 mg/m2 IV on Days 1 and 8 
 Gemcitabine 1000 mg/m2 IV on Days 1 
and 8 
Atezo  PBO 
 Atezolizumab 1200 mg IV on Day 1 
 Placebo IV on Day 1 
Atezo  atezolizumab; Bev  bevacizumab; CisGem  cisplatin and gemcitabine; CIT  cancer 
immunotherapy; PBO  placebo. 
a Treatment during the chemotherapy combination phase will be administered on a 21-day 
cycle until completion of 8 cycles, loss of clinical benefit, or unacceptable toxicity, whichever 
occurs first. 
 
Randomization will be stratified according to the following stratification factors: 
 
Location of primary tumor (iCCA vs. eCCA vs. GBC) 
 
Metastatic disease (yes vs. no) 
 
Geographic region (Asia vs. rest of the world) 
 
Patients who do not meet the criteria for participation in this study (screen failure) may 
qualify for 1 re-screening opportunity (for a total of 2 screenings per participant) at the 
investigator's discretion.  Patients are not required to re-sign the Informed Consent Form 
if they are re-screened within 60 days after previously signing the 
Informed Consent Form.  The investigator will record reasons for screen failure in the 
screening log (see Section 4.5.1). 
Patients will continue treatment as indicated in Table 2 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 the criteria for disease progression (as assessed by the investigator according 


 
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to RECIST v1.1; see Appendix 5) while receiving atezolizumab 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, such as new or 
worsening hypercalcemia) indicating unequivocal progression of disease 
 
Absence of decline in Eastern Cooperative Oncology Group (ECOG) Performance 
Status that can be attributed to disease progression 
 
Absence of tumor progression at critical anatomical sites (e.g., leptomeningeal 
disease) that cannot be managed by protocol-allowed medical interventions 
 
Patients who transiently withhold or permanently discontinue one component of their 
treatment (i.e., either atezolizumab, bevacizumab/placebo, or chemotherapy) because of 
toxicity may continue with the other components of study treatment, as long as the 
patients are experiencing clinical benefit in the opinion of the investigator.  However, 
bevacizumab/placebo should not be continued as a single agent. 
Patients will undergo tumor assessments every 9 ( 1) weeks following treatment 
initiation, as outlined in Section 4.5.5 and Appendix 1.  Sites will collect and send 
imaging used for tumor assessments to an IRF to enable potential centralized, 
independent review of response and progression endpoints. 
Following disease progression or loss of clinical benefit, patients will be followed for 
survival and subsequent anti-cancer therapies until death, loss to follow-up, withdrawal 
of consent, or study termination by the Sponsor, whichever occurs first. 
Patient-reported outcome (PRO) assessments will be completed before starting 
treatment, at specified timepoints during treatment, and at treatment discontinuation. 
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 (NCI CTCAE), Version 5.0.  Laboratory safety 
assessments will include the regular monitoring of hematology and blood chemistry.  
Serum samples will be collected to monitor the pharmacokinetics (PK) of atezolizumab 
when administered in combination with bevacizumab and/or CisGem.  Patient samples, 
including archival of tumor tissues, as well as serum and plasma, will be collected for 
future exploratory biomarker assessments. 
An overview of the study design is presented in Figure 1.  A schedule of activities is 
provided in Appendix 1.


 
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Figure 1 Study Schema 
 
CIT  cancer immunotherapy; eCCA  extrahepatic cholangiocarcinoma; ECOG PS  Eastern Cooperative Oncology Group Performance Status; 
GBC  gallbladder cancer; iCCA  intrahepatic cholangiocarcinoma; R  randomization; RECIST  Response Evaluation Criteria in Solid Tumors; 
ROW  rest of the world. 


 
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3.2 
END OF STUDY AND LENGTH OF STUDY 
The end of this study is defined as the date at which the last data required for study 
analysis are collected.  The end of study will occur once the last patient, last visit occurs 
following the final OS analysis.  The total length of the study, from screening of the first 
patient to the end of the study, is expected to be approximately 35 years. 
In addition, the Sponsor may decide to terminate the study at any time. 
If the Sponsor decides to terminate the study, patients who are still receiving study 
treatment or undergoing survival follow-up may be enrolled in an extension study or 
a non-interventional study, if available. 
3.3 
RATIONALE FOR STUDY DESIGN 
3.3.1 
Rationale for Atezolizumab Dose and Schedule 
Atezolizumab will be administered at a fixed dose of 1200 mg every 3 weeks (Q3W) 
(1200 mg on Day 1 of each 21-day cycle), which is an approved dosage for 
atezolizumab, as outlined in the prescribing information.  Anti-tumor activity has been 
observed across doses, ranging from 120 mg/kg Q3W.  In Study PCD4989g, the 
maximum tolerated dose of atezolizumab was not reached and no dose-limiting toxicities 
were observed at any dose.  The fixed dose of 1200 mg Q3W (equivalent to an average 
body weightbased dose of 15 mg/kg Q3W) was selected on the basis of both 
nonclinical studies (Deng et al. 2016) and available clinical PK, efficacy, and safety data 
(see the Atezolizumab Investigator's Brochure for details). 
3.3.2 
Rationale for Bevacizumab Dose and Schedule 
Bevacizumab will be administered at a 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 and was the 
dose used in combination with atezolizumab in the GO30140, IMbrave150, and 
IMpower150 studies.  In these studies, the combination of atezolizumab plus 
bevacizumab was generally safe and well-tolerated and no new safety signals related to 
the combination therapy were identified beyond the established safety profile for each 
individual agent.  The results of the IMpower150 study showed that the addition of 
platinum-based chemotherapy to atezolizumab and bevacizumab was also generally 
safe, well-tolerated, and consistent with previously reported safety risks of the individual 
drugs. 
3.3.3 
Rationale for Patient Population 
This study will enroll patients with advanced BTC who have not been previously treated 
for advanced disease.  Consistent with other trials in BTC, the patient population will 
include patients with iCCA, eCCA and GBC.  Patients with ampullary tumors will be 
excluded as these are thought to behave differently to other BTCs. 


 
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The prognosis for patients with advanced BTC is poor, with median survival rarely 
exceeding 1 year.  As a result, a significant unmet need exists for new and effective 
treatments. 
3.3.4 
Rationale for Treatment Arms 
The standard of care for first-line treatment for most patients with advanced BTC is 
CisGem.  In this study, patients in both arms will receive this standard chemotherapy 
regimen in combination with either atezolizumab plus bevacizumab or atezolizumab plus 
placebo.  Despite the failure of anti-VEGF agents combined with chemotherapy in 
advanced BTC, VEGF remains a rational target given its multifaceted role in maintaining 
an immunosuppressive TME.  Immunotherapy with drugs targeting PD-1/PD-L1 has 
transformed cancer treatment, but this approach has not been well-studied in BTC.  
Preliminary data indicate limited clinical activity of single-agent antiPD-1/PD-L1 
antibodies, including atezolizumab, highlighting the need for combination regimens to 
augment anti-cancer immunity in patients with BTC.  Biliary tract cancer has an 
unfavorable TME that is dominated by immunosuppressive elements, many of which are 
known to be regulated by VEGF.  Collectively, these observations provide a compelling 
rationale to study atezolizumab in combination with bevacizumab and chemotherapy in 
patients with advanced BTC. 
In this study, both treatment arms are considered experimental.  This randomized 
Phase II study aims to assess the relative merits of both experimental regimens in order 
to inform the design of future studies in BTC. 
The study does not include a CisGem-only treatment arm, given that this regimen has 
been well-characterized in previous randomized clinical trials (see Section 1.5.3). 
3.3.5 
Rationale for Continued Treatment of 
Atezolizumab/Bevacizumab and Atezolizumab/Placebo after 
Chemotherapy 
The ability to treat patients on a continuous basis with platinum-based chemotherapy 
regimens is limited because of the risk of cumulative toxicity.  In BTC, CisGem 
administration is typically limited to a maximum of 24 weeks or 8 cycles, and for most 
patients, clinical response is noted by 24 weeks (Furuse et al. 2011). 
The toxicity profile and response for antiPD-1/PD-L1 agents differ from chemotherapy 
and permit longer treatment durations.  The incidence and nature of toxicities associated 
with immunotherapy is different from platinum-based chemotherapy regimens and 
PD-1/PD-L1 antibodies are generally considered to be more easily tolerated than 
chemotherapies.  The combination of atezolizumab, bevacizumab, and 
carboplatin/paclitaxel was successfully evaluated by the Sponsor in patients with NSCLC 
adenocarcinoma in the IMpower150 Phase III study.  This study protocol allowed for the 
continuation of atezolizumab, with or without bevacizumab, following the cessation of 
induction chemotherapy.  In this study, the rate of serious adverse events with 


 
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atezolizumab either alone or in combination with bevacizumab during the maintenance 
phase were low and clinically manageable.  Furthermore, the median durations of 
treatment with atezolizumab and bevacizumab were longer than the duration of 
chemotherapy; 8.2 months for atezolizumab (range:  026 months), 6.7 months for 
bevacizumab (range:  026 months), and 2.2 months for chemotherapy 
(range:  05 months; Socinski et al. 2018).  The patterns of response to either PD-1 or 
PD-L1 inhibitors are different than that of chemotherapies, with clinical responses 
occurring in a delayed fashion or converting from either stable disease (SD) to RECIST-
defined partial response (PR) or complete response (CR) or from PR to CR.  Delayed 
initial anti-tumor response or late conversion to CR may occur sometime after stopping 
treatment with CisGem.  For these reasons, continued treatment with atezolizumab or 
atezolizumab plus bevacizumab/placebo following cessation of chemotherapy may be 
clinically beneficial to patients with BTC. 
3.3.6 
Rationale for Progression-Free Survival as the Primary 
Endpoint 
In this study, the primary efficacy endpoint will be investigator-assessed PFS.  In BTC, 
PFS has been shown to strongly correlate with OS in a systematic review of data from 
104 trials and is considered to be an appropriate surrogate endpoint of clinical benefit in 
BTC (Eckel and Schmid 2007).  In addition, PFS is not generally confounded by 
subsequent therapies.  Progression-free survival has been used successfully as 
a surrogate endpoint of benefit for advanced BTC to guide follow-on Phase III studies 
(Valle et al. 2009). 
3.3.7 
Rationale for Stratification Factors 
Patients will be stratified according to anatomic subtype, presence of metastatic disease, 
and geographic region in order to balance key prognostic variables between treatment 
arms: 
 
Anatomic subtype:  Each anatomic subtype of BTC has a distinct epidemiology, 
pathobiology, and prognosis (Rizvi et al. 2018).  For example, iCCA has a better 
prognosis than other BTC subtypes, whereas GBC has a poorer prognosis 
(Furuse et al. 2011).  Anatomic subtypes of BTC are also heterogeneous with 
respect to genetic background and TME composition, which may impact response 
to immunotherapy (Rizvi et al. 2018). 
 
Extent of disease:  This study will enroll patients with either locally advanced tumors 
not amenable to surgical resection or metastatic disease.  The presence of distant 
metastases is a poor prognostic factor (Park et al. 2009; Kim et al. 2017). 


 
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 
Geographic region:  Differences exist with respect to patient characteristics, 
treatment strategies, and clinical outcomes between Eastern and Western patients 
with BTC (Marcano-Bonilla et al. 2016; Olthof et al. 2019).  The prevalence of risk 
factors such as fluke infestation and viral hepatitis varies by geographic region, 
which may contribute to a differential response to immunotherapy (Khan et al. 2019; 
Kelley et al. 2020). 
 
3.3.8 
Rationale for Atezolizumab Treatment beyond Initial 
Radiographic Progression 
In studies of immunotherapeutic agents, CR, PR, and SD 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 
tumor-infiltrating immune cells and no viable cancer cells.  Because of the potential for 
a response after pseudoprogression, this study will allow all patients to continue 
treatment after apparent radiographic progression per RECIST v1.1, provided the 
benefitrisk ratio is determined to be favorable by the investigator (for the criteria, see 
Section 3.1).  Patients should be discontinued in the event of 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 for details). 
3.3.9 
Rationale for Biomarker Assessments 
Published results suggest that the expression of PD-L1 in tumors correlates with 
response to antiPD-1 and antiPD-L1 therapy (Topalian et al. 2012; Herbst et al. 2014; 
Borghaei et al. 2015; Fehrenbacher et al. 2016; Herbst et al. 2016; 
Rosenberg et al. 2016).  In this study, archival or newly collected tumor tissue will be 
obtained at baseline.  If archival tumor tissue is not available, or is determined to be 
unsuitable for required testing, a pretreatment tumor biopsy is required, if deemed 
clinically feasible by the investigator.  Archival or baseline tumor specimens will be 
tested for PD-L1 expression retrospectively by a central laboratory.  In addition to the 
assessment of PD-L1 status, other exploratory biomarkers, such as potential predictive 
and prognostic biomarkers related to the clinical benefit of atezolizumab, bevacizumab, 
CisGem, and combinations of these therapies; or tumor immunobiology, mechanisms of 
resistance, or tumor type may be analyzed. 
Tissue samples will be collected for DNA extraction to enable whole exome sequencing 
(WES) to identify variants that are predictive of response to study drug, are associated 
with progression to a more severe disease state, are associated with acquired 
resistance to study drug, are associated with susceptibility to developing adverse events, 
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knowledge and understanding of disease biology and drug safety.  Genomics is 
increasingly informing researchers’ understanding of disease pathobiology.  
WES provides a comprehensive characterization of the exome, and, along with clinical 
data collected in this study, may increase the opportunity for developing new therapeutic 
approaches or new methods for monitoring efficacy and safety or predicting which 
patients are more likely to respond to a drug or develop adverse events.  Data will be 
analyzed in the context of this study but may also be explored in aggregate with data 
from other studies.  The availability of a larger dataset will assist in identification and 
characterization of important biomarkers and pathways to support future drug 
development. 
Blood samples will be collected at baseline and during the study to evaluate changes in 
circulating biomarkers.  Changes in biomarkers, such as cytokines associated with T-cell 
activation and lymphocyte subpopulations may provide evidence of biologic activity of 
atezolizumab, bevacizumab, CisGem, and combinations in patients with BTC.  
Correlations between these biomarkers and safety and efficacy endpoints will be 
explored to identify blood-based biomarkers that might predict which patients are more 
likely to benefit from the combination treatment. 
Exploratory research on safety biomarkers may be conducted to support future drug 
development.  Research may include further characterization of a safety biomarker or 
identification of new safety biomarkers that are associated with susceptibility to 
developing adverse events or can lead to improved adverse event monitoring or 
investigation.  Adverse event reports will not be derived from safety biomarker data by 
the Sponsor, and safety biomarker data will not be included in the formal safety analyses 
for this study.  In addition, safety biomarker data will not inform decisions on patient 
management. 
3.3.10 
Rationale for Non-Standard Clinical Outcome Assessments 
Patient experience with advanced BTC is complex and impacted by both disease- and 
treatment-related symptoms.  Patients with advanced BTC present with a number of 
disease-related symptoms, which can differ according to the anatomic subtype and can 
include yellowing of the skin and eyes, itching, abdominal pain, appetite loss, weight 
loss, or fatigue, which negatively affect their daily functioning and health-related quality 
of life (Koeberle et al. 2008; Zabernigg et al. 2012).  Such concepts are best 
documented through PRO instruments, which uniquely and directly capture patients’ 
perspective of their disease, and ultimately provide clinicians with valuable information to 
support decision-making. 
Cancer treatments, particularly combination therapies, can also produce significant 
symptomatic adverse events, some of which can overlap with disease-related 
symptoms.  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; 


 
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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 the study 
treatments, patients will be asked to report on their experience related to four 
treatment-related symptoms selected from the validated PRO-Common Terminology 
Criteria for Adverse Events (PRO-CTCAE) item bank (see Appendix 11).  Because there 
may be an overlap in these symptoms with those associated with advanced BTC, only 
symptoms that are uniquely associated with the study treatments were chosen from the 
PRO-CTCAE.  The 4 symptoms were identified as being salient to patients' experience 
with the study treatments, on the basis of known adverse drug reactions, mechanism of 
action, and recent work to identify common adverse events associated with 
immunotherapies (King-Kallimanis et al. 2019; Hansen et al. 2020). 
4. 
MATERIALS AND METHODS 
4.1 
PATIENTS 
Approximately 150 patients with unresectable, recurrent or metastatic BTC will be 
enrolled in this study. 
4.1.1 
Inclusion Criteria 
Patients must meet the following criteria for study entry: 
 
Signed Informed Consent Form 
 
Age  18 years at the time of signing the Informed Consent Form 
 
Ability to comply with the study protocol 
 
Considered to be eligible to receive platinum-based chemotherapy, in the 
investigator’s judgment 
 
Documentation of recurrent/metastatic or locally advanced unresectable disease 
based on computed tomography (CT) or magnetic resonance imaging (MRI) scans 
(see Appendix 4) 
 
Histologically or cytologically confirmed diagnosis of iCCA, eCCA, or GBC 
– 
For patients with recurrent BTC, histologic confirmation of BTC at the time of 
resection is acceptable 
 
No prior systemic therapy (including systemic investigational agents) for advanced 
BTC 
– 
Prior chemotherapy or radiotherapy (with or without radio-sensitizing 
chemotherapy) in the neoadjuvant or adjuvant setting is permitted provided this 
is completed at least 6 months prior to Day 1 of Cycle 1 
– 
Prior treatment with gemcitabine administered as a radiation sensitizer in the 
neoadjuvant and adjuvant settings surrounding surgery, during and up to 
4 weeks after radiation therapy is allowed, provided all toxicities have returned 
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– 
Previous use of herbal therapies and traditional Chinese medicines with 
anti-cancer activity included in the label is allowed, provided that these 
medications are discontinued prior to Day 1 of Cycle 1 
– 
The following prior interventions are permitted, provided the patient has fully 
recovered: 
Surgery:  Non-curative resection with macroscopic residual disease or 
palliative bypass surgery.  Patients who have previously undergone 
curative surgery must have evidence of non-resectable disease requiring 
systemic chemotherapy. 
Photodynamic therapy:  Prior photodynamic therapy for localized disease 
with no evidence of metastatic disease or for localized disease to relieve 
biliary obstruction in the presence of metastatic disease, provided patient 
has clear evidence of disease progression requiring systemic 
chemotherapy. 
Palliative radiotherapy:  Palliative radiotherapy, provided that all adverse 
events have resolved and the patient has measurable disease outside the 
field of radiation. 
 
At least one measurable untreated lesion (per RECIST v1.1) 
 
Adequate biliary drainage with no evidence of ongoing infection 
– 
If applicable, treatable and clinically relevant biliary duct obstruction must be 
relieved by internal endoscopic drainage/stenting at least 2 weeks prior to 
Day 1 of Cycle 1 or by palliative bypass surgery or percutaneous drainage prior 
to Day 1 of Cycle 1, and the patient has no active or suspected uncontrolled 
infection 
– 
Patients fitted with a biliary stent should be clinically stable and free of signs of 
infection and have total bilirubin  2upper limit of normal (ULN) and AST/ALT 
 5ULN for  2 weeks prior to Day 1 of Cycle 1.  Patients with improving biliary 
function who meet all other inclusion criteria may be re-tested during the 
screening window. 
 
Availability of a representative tumor specimen that is suitable for determination of 
PD-L1 status via central testing 
– 
A formalin-fixed, paraffin-embedded (FFPE) tumor specimen in a paraffin block 
(preferred) or at least 16 slides containing unstained, freshly cut, serial sections 
should be submitted along with an associated pathology report within 4 weeks 
of randomization 
– 
If FFPE specimens described above are not available, any type of specimen 
(including fine-needle aspiration, cell pellet specimens [e.g., from pleural 
effusion], and lavage samples) are also acceptable.  This specimen should be 
accompanied by the associated pathology report. 
If archival tissue is either insufficient or unavailable, a core-needle biopsy 
specimen should be collected during the screening period, if clinically 


 
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feasible.  Trans-jugular biopsy tissue sample collections for patients who 
are at high risk of bleeding may be allowed. 
If archival tissue is either insufficient or unavailable and a fresh biopsy is 
not clinically feasible, the patient may still be eligible. 
 
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/L, and have an undetectable viral load 
 
Documented virology status of hepatitis, as confirmed by screening hepatitis B virus 
(HBV) or hepatitis C virus (HCV) tests 
– 
For patients with active HBV:  HBV DNA  500 IU/mL during screening, initiation 
of anti-HBV treatment at least 14 days prior to Day 1 of Cycle 1 and willingness 
to continue anti-HBV treatment during the study (per local standard of care 
[e.g., entecavir]) 
– 
Patients with HCV, either with resolved infection (as evidenced by detectable 
antibody) or chronic infection (as evidenced by detectable HCV RNA), are 
eligible 
 
Eastern Cooperative Oncology Group Performance Status of 0 or 1 
 
Life expectancy of  3 months 
 
Adequate hematologic and end-organ function, defined by the following laboratory 
test results, obtained within 7 days prior to Day 1 of Cycle 1 unless otherwise 
specified: 
– 
AST and ALT  2.5  ULN with the following exceptions: 
Patients with documented liver metastases:  AST and ALT  5  ULN. 
– 
Serum bilirubin  2  ULN 
– 
Albumin  28 g/L ( 2.8 g/dL) 
– 
Creatinine clearance  60 mL/min (calculated using the Cockcroft-Gault 
formula) 
– 
Hemoglobin  90 g/L ( 9 g/dL) 
Patients may be transfused to meet this criterion. 
– 
Platelet count  100  109/L ( 100,000/L) without transfusion 
– 
Lymphocyte count  0.5  109/L ( 500/L) 
– 
ANC  1.5  109/L (1500/L) without granulocyte colony-stimulating factor 
support 
– 
For patients not receiving therapeutic anticoagulation:  INR or aPTT  2  ULN 
– 
Proteinuria  2  on dipstick analysis (within 7 days prior to Day 1 of Cycle 1) 
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. 


 
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 
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 or CisGem, whichever is later.  Women must refrain from 
donating eggs during this same period. 
– 
A woman is considered to be of childbearing potential if she is postmenarchal, 
has not reached a postmenopausal state ( 12 continuous months of 
amenorrhea with no identified cause other than menopause), and 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).  The definition of childbearing potential may be 
adapted for alignment with local guidelines or regulations. 
– 
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 adequate methods of contraception.  
If required per local guidelines or regulations, locally recognized adequate 
methods of contraception and information about the reliability of abstinence will 
be described in the local Informed Consent Form. 
 
For men:  Agreement to remain abstinent (refrain from heterosexual intercourse) or 
use a condom, and agreement to refrain from donating sperm, as defined below: 
– 
With a female partner of childbearing potential or pregnant female partner, men 
must remain abstinent or use a condom during the treatment period and for 
6 months after the final dose of bevacizumab or CisGem, whichever is later, to 
avoid exposing the embryo.  Men must refrain from donating sperm during this 
same period. 
– 
The reliability of sexual abstinence should be evaluated in relation to the 
duration of the clinical trial and the preferred and usual lifestyle of the patient.  
Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation 
methods) and withdrawal are not adequate methods of preventing drug 
exposure.  If required per local guidelines or regulations, locally recognized 
adequate methods of contraception and information about the reliability of 
abstinence will be described in the local Informed Consent Form. 
 


 
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4.1.2 
Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from study entry: 
 
Recurrent disease  6 months after curative surgery or  6 months after the 
completion of adjuvant therapy (chemotherapy and/or radiation) 
 
Prior local regional therapy such as radioembolization 
 
Combined or mixed hepatocellular/CCA 
 
Clinically significant hepatic encephalopathy within the 12 months prior to Day 1 of 
Cycle 1 
 
National Cancer Institute Common Terminology Criteria for Adverse Events Grade 
 2 peripheral neuropathy 
 
Prior bleeding event due to untreated or incompletely treated esophageal and/or 
gastric varices within 6 months prior to Day 1 of Cycle 1 
Patients at high risk of esophageal varices are required to undergo an 
esophagogastroduodenoscopy (EGD) during screening or must have 
undergone an EGD within 6 months of Day 1 of Cycle 1.  All size of varices 
(small to large) must be assessed and treated per local standard of care prior to 
Day 1 of Cycle 1.  Patients at high-risk of esophageal varices who have had an 
EGD within 6 months of Day 1 of Cycle 1 do not need to repeat EGD at 
screening.  Criteria for high-risk varices include at least one of the following: 
– 
Presence or history of cirrhosis 
– 
Presence or history of portal hypertension 
– 
Presence or history of primary biliary cirrhosis, or primary sclerosing 
cholangitis 
– 
HBV or HCV infection 
– 
Evidence of gross vascular invasion (portal vein, hepatic vein or collateral 
vessels) 
– 
Evidence of splenomegaly 
– 
Platelet count  120  109/L (120,000/L) and albumin  36 g/L (3.6 g/dL) 
– 
Evidence of portal vein occlusion due to malignant invasion or constriction 
– 
Evidence of varices by imaging 
 
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, granulomatosis with polyangiitis, Sjögren syndrome, Guillain-
Barré syndrome, or multiple sclerosis (see Appendix 12 for a more comprehensive 
list of autoimmune diseases and immune deficiencies), with the following 
exceptions: 
– 
Patients with a history of autoimmune-related hypothyroidism who are on 
thyroid-replacement hormone are eligible for the study 


 
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– 
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. 
There is 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 12 months prior to Day 1 of Cycle 1. 
 
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 CT scan 
 
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 Day 1 of Cycle 1, unstable arrhythmia, or unstable angina 
 
History of malignancy other than BTC 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 
 
Symptomatic, untreated, or actively progressing 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 hemorrhage or spinal cord 
hemorrhage. 
– 
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 within 7 days prior 
to initiation of study treatment, whole-brain radiotherapy within 14 days 
prior to initiation of study treatment, and neurosurgical resection within 
28 days prior to initiation of study treatment. 
– 
The patient has no ongoing requirement for corticosteroids as therapy for 
CNS disease.  Anticonvulsant therapy at a stable dose is permitted. 


 
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– 
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. 
 
For patients with lung metastases, if one of the following criteria applies: 
– 
Large, centrally located pulmonary metastases 
– 
Clear tumor infiltration into the thoracic great vessels seen on imaging 
– 
Clear cavitation of pulmonary lesions seen on imaging 
 
Active tuberculosis 
 
Severe infection within 4 weeks prior to Day 1 of Cycle 1, including, but not limited 
to:  hospitalization for complications of infection, bacteremia, or severe pneumonia, 
or any active infection that, in the opinion of the investigator, could impact patient 
safety 
 
Treatment with therapeutic oral or IV antibiotics within 2 weeks prior to Day 1 of 
Cycle 1 
Patients receiving prophylactic antibiotics (e.g., to prevent a urinary tract infection 
or chronic obstructive pulmonary disease [COPD] exacerbation) are eligible for 
the study, provided the signs of active infection have resolved 
 
Prior allogeneic stem cell or solid organ transplantation 
 
On the waiting list for liver 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 
 
Pregnant or breastfeeding, or intending to become pregnant during the study or 
within 5 months after the final dose of atezolizumab or within 6 months after the final 
dose of bevacizumab and/or CisGem 
– 
Women of childbearing potential must have a negative serum pregnancy test 
result within 14 days prior to Day 1 of Cycle 1 
 
Co-infection with HBV and HCV 
– 
Patients with a history of HCV infection but who are negative for HCV RNA by 
polymerase chain reaction will be considered to be negative for HCV infection 
 
Uncontrolled or symptomatic hypercalcemia (ionized calcium  1.5 mmol/L, 
calcium  12 mg/dL, or corrected serum calcium  ULN) 
 
History of severe allergic anaphylactic reactions to chimeric or humanized 
antibodies or fusion proteins 
 
History of allergic reactions to cisplatin or other platinum-containing compounds 
 
Known hypersensitivity to gemcitabine 
 
Known hypersensitivity to Chinese hamster ovary cell products or to any component 
of the atezolizumab or bevacizumab formulations 


 
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 
Treatment with a live, attenuated vaccine within 4 weeks prior to Day 1 of Cycle 1 or 
anticipation of need for such a vaccine during atezolizumab treatment or within 
5 months after the final dose of atezolizumab 
 
Treatment with investigational therapy within 4 weeks prior to Day 1 of Cycle 1 
 
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 IL-2) within 4 weeks or 5 drug-elimination half-lives (whichever is 
longer) prior to Day 1 of Cycle 1 
 
Treatment with systemic immunosuppressive medication (including, but not limited 
to, corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide, and 
antiTNF- agents) within 2 weeks prior to Day 1 of Cycle 1 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 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 BP  100 mmHg), based on an average of at least 
3 BP readings at 2 or more sessions 
– 
Anti-hypertensive therapy to achieve these parameters is allowed 
 
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 Day 1 of Cycle 1 
 
History of hemoptysis ( 2.5 mL of bright red blood per episode) within 1 month prior 
to Day 1 of Cycle 1 
 
Evidence of bleeding diathesis or significant coagulopathy (in the absence of 
therapeutic anticoagulation) 
 
Current or recent (within 10 days of Day 1 of Cycle 1) use of aspirin ( 325 mg/day) 
or current or recent treatment with dipyridamole, ticlopidine, clopidogrel, and 
cilostazol 
 
Current or recent (within 10 days prior to Day 1 of Cycle 1) 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 


 
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aPTT is within normal limits (according to institutional standards) within 14 days 
prior to Day 1 of Cycle 1 
– 
Prophylactic use of low-molecular-weight heparin (i.e., 40 mg/day enoxaparin) 
is allowed.  However, the use of direct oral anticoagulant therapies such as 
dabigatran (Pradaxa) and rivaroxaban (Xarelto) is not recommended due to 
bleeding risk 
 
Core biopsy or other minor surgical procedure, excluding placement of a vascular 
access device, within 3 days prior to Day 1 of Cycle 1 
 
History of abdominal or tracheoesophageal fistula, GI perforation, or intra-abdominal 
abscess within 6 months prior to Day 1 of Cycle 1 
 
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 
 
Major surgical procedure within 4 weeks prior to Day 1 of Cycle 1 or anticipation of 
need for a major surgical procedure during the study 
 
History of clinically significant and uncontrolled intra-abdominal inflammatory 
disease within 6 months prior to Day 1 of Cycle 1, including, but not limited to, peptic 
ulcer disease, diverticulitis, or colitis 
 
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 
 
Preexisting renal impairment, myelosuppression, or hearing impairment 
 
4.2 
METHOD OF TREATMENT ASSIGNMENT AND BLINDING 
This is a randomized, double-blind study.  After written informed consent has been 
obtained, all screening procedures and assessments have been completed, and 
eligibility has been established for a patient, the study site will obtain the patient's 
identification number and treatment assignment from the interactive voice or Web-based 
response system (IxRS). 
Patients will be randomly assigned in a 1:1 ratio to one of two treatment arms: 
 
Arm A (Atezolizumab  Bevacizumab  CisGem) 
 
Arm B (Atezolizumab  Placebo  CisGem) 
 
Randomization will occur through use of a permuted-block randomization method to 
ensure a balanced assignment to each treatment arm.  Randomization will be stratified 
through an IxRS according to the stratification factors outlined in Section 3.1. 
4.2.1 
Blinding 
Study site personnel and patients will be blinded to treatment assignment during the 
study.  The Sponsor and its agents will also be blinded to treatment assignment, with the 


 
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exception of individuals who require access to patient treatment assignments to fulfill 
their job roles during a clinical trial.  These roles include the unblinding group 
responsible, clinical supply chain managers, sample handling staff, operational assay 
group personnel, and IxRS service provider. 
The Sponsor will remain blinded to treatment assignment until the time of the first interim 
analysis of PFS.  Investigators and patients will remain blinded to treatment assignment 
until the time of the final analysis of OS, except in cases for which single-patient 
unblinding is necessary, as outlined below. 
If unblinding is necessary for a medical emergency (e.g., in the case of a serious 
adverse event for which patient management might be affected by knowledge of 
treatment assignment), the investigator will be able to break the treatment code by 
contacting the IxRS.  The investigator is not required to contact the Medical Monitor prior 
to breaking the treatment code; however, the treatment code should not be broken 
except in emergency situations.  The investigator should inform the Medical Monitor that 
the treatment code has been broken. 
If the investigator wishes to know the identity of the study drug for any reason other than 
a medical emergency, he or she should contact the Medical Monitor directly.  Unblinding 
may be permitted if an investigator is deciding whether a patient should withdraw from 
the study and initiate treatment with a proven therapy.  However, unblinding will not be 
permitted if an investigator is deciding whether a patient should withdraw from the study 
and initiate treatment with an unproven therapy.  The investigator should document and 
provide an explanation for any non-emergency unblinding.  If the Medical Monitor agrees 
to patient unblinding, the investigator will be able to break the treatment code by 
contacting the IxRS. 
As per health authority reporting requirements, the Sponsor's Drug Safety representative 
will break the treatment code for all serious, unexpected suspected adverse reactions 
(see Section 5.7) that are considered by the investigator or Sponsor to be related to 
study drug.  The patient may continue to receive treatment, and the investigator, patient, 
and Sponsor personnel, with the exception of the Drug Safety representative and 
personnel who must have access to patient treatment assignments to fulfill their roles 
(as defined above), will remain blinded to treatment assignment. 
4.3 
STUDY TREATMENT AND OTHER TREATMENTS RELEVANT 
TO THE STUDY DESIGN 
The investigational medicinal products (IMPs) for this study are atezolizumab and 
bevacizumab/placebo.  Cisplatin and gemcitabine are considered non-IMPs. 


 
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4.3.1 
Study Treatment Formulations 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 and Placebo 
Bevacizumab will be supplied by the Sponsor as a sterile liquid in single-use, 16-mL, 
preservative-free glass vials that contain 400 mg of bevacizumab (25 mg/mL). 
For information on the formulation and handling of bevacizumab, see the pharmacy 
manual and the Bevacizumab Investigator's Brochure. 
Matching placebo will be provided by the Sponsor.  Placebo will be supplied as a sterile 
liquid in single-use, 16-mL, preservative-free glass vials that contain the vehicle without 
active ingredient.  Further details are provided in the pharmacy manual. 
4.3.1.3 
Cisplatin and Gemcitabine 
For information on the formulation and packaging of CisGem, see the local prescribing 
information for these drugs. 
4.3.2 
Study Treatment Dosage, Administration, and Compliance 
The treatment regimens are summarized in Section 3.1. 
Treatment must be initiated no later than 3 business days after randomization, with the 
exception of the emergence of an adverse event for which dosing may be postponed. 
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, with one exception:  
If treatment was postponed for fewer than 3 days, the patient can resume the original 
schedule. 
See 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 14 and Appendix 15. 


 
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4.3.2.1 
Atezolizumab 
Atezolizumab will be administered by IV infusion at a fixed dose of 1200 mg Q3W 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, and clinical status (see Section 3.1 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 13.  
Atezolizumab infusions will be administered per the instructions outlined in Table 3. 
Table 3 
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. 
 Atezolizumab should be infused over 
60 ( 15) minutes. 
 If clinically indicated, vital signs should be 
measured every 15 ( 5) minutes during the 
infusion and at 30 ( 10) minutes after the 
infusion. 
 Patients should be informed about the 
possibility of delayed post-infusion 
symptoms and instructed to contact their 
study physician if they develop such 
symptoms. 
 If the patient experienced an 
infusion-related reaction with any previous 
infusion, premedication with 
antihistamines, antipyretics, and/or 
analgesics may be administered for 
subsequent doses at the discretion of the 
investigator. 
 Vital signs should be measured within 
60 minutes prior to the infusion. 
 Atezolizumab should be infused over 
30 ( 10) minutes if the previous infusion 
was tolerated without an infusion-related 
reaction, or 60 ( 15) minutes if the patient 
experienced an infusion-related reaction 
with the previous infusion. 
 If the patient experienced an 
infusion-related reaction with the previous 
infusion or if clinically indicated, vital signs 
should be measured during the infusion 
and at 30 ( 10) minutes after the infusion. 
 
Guidelines for medical management of infusion-related reactions (IRRs) are provided in 
Appendix 14. 
No dose modification for atezolizumab is allowed. 
4.3.2.2 
Bevacizumab and Placebo 
Bevacizumab (Arm A) at a dose of 15 mg/kg or matching placebo (Arm B) will be 
administered after atezolizumab by IV infusion on Day 1 of each 21-day cycle.  
There will be a minimum 5-minute gap between administration of atezolizumab and 
bevacizumab/placebo.  Treatment duration is described in Section 3.1. 


 
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The dose of bevacizumab will be based on the patient's weight (in kilograms) measured 
 14 days prior to Day 1 of Cycle 1 and will remain the same throughout the study unless 
there is a weight change of  10% from the baseline body weight, in which case the 
bevacizumab dose should be modified. 
Administration of bevacizumab/placebo 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 13.  
Bevacizumab/placebo infusions will be administered per the instructions outlined in 
Table 4. 
Table 4 
Administration of First and Subsequent Bevacizumab/Placebo 
Infusions 
First Infusion 
Subsequent Infusions 
 
No premedication is permitted prior to the 
bevacizumab/placebo infusion. 
 
Vital signs (pulse rate, respiratory rate, 
blood pressure, and temperature) should 
be measured within 60 minutes prior to the 
infusion. 
 
Bevacizumab/placebo should be infused 
over 90 ( 15) minutes. 
 
Vital signs should be measured at the end 
of the infusion and 2 ( 1) hours after the 
infusion. 
 
Patients should be informed about the 
possibility of delayed post-infusion 
symptoms and instructed to contact their 
study physician if they develop such 
symptoms. 
 
If the patient experienced an 
infusion-related reaction with any 
previous infusion, premedication with 
antihistamines, antipyretics, and/or 
analgesics may be administered for 
subsequent doses at the discretion of the 
investigator. 
 
Vital signs should be measured within 
60 minutes prior to the infusion. 
 
Bevacizumab/placebo should be infused 
over 60 ( 10) minutes if the previous 
infusion was tolerated without an 
infusion-related reaction, or 
90 ( 15) minutes if the patient 
experienced an infusion-related reaction 
with the previous infusion.  If the 
60-minute infusion was well-tolerated, 
bevacizumab/placebo may be infused 
over 30 ( 15) minutes thereafter. 
 
Vital signs should be measured at the 
end of the infusion and 2 ( 1) hours after 
the infusion. 
 
Guidelines for medical management of IRRs are provided in Appendix 14. 
No dose modifications are permitted for bevacizumab/placebo aside from weight-based 
dose changes as outlined in the protocol. 
4.3.3 
Chemotherapy (Cisplatin and Gemcitabine) 
Cisplatin will be administered by IV infusion at a dose of 25 mg/m2 followed by 
gemcitabine at a dose of 1000 mg/m2 on Days 1 and 8 of each 21-day cycle. 


 
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Gemcitabine and cisplatin and accompanying supportive care will be administered 
according to the local prescribing information.  In general, sites should also follow their 
institutional guidelines and local standard of care for determining dose adjustments in 
the event of changes in patient weight.  Cisplatin will be administered after completion of 
the bevacizumab/placebo infusion, and gemcitabine will be administered after 
completion of the cisplatin infusion. 
Dose modification guidelines are provided in Section 5.1.4 and Appendix 14. 
4.3.4 
Investigational Medicinal Product Handling and Accountability 
All IMPs required for completion of this study (atezolizumab and bevacizumab/placebo) 
will be provided by the Sponsor.  The study site (i.e., investigator or other authorized 
personnel [e.g., pharmacist or mobile nurse]) 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, 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 accordance with the labeled 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. 
Investigational medicinal products 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 
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. 
See the pharmacy manual and/or the applicable Investigator's Brochure for information 
on IMP handling, including preparation, storage, and accountability. 


 
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4.3.5 
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 BTC 
 
The Sponsor has reasonable safety concerns regarding the IMP as treatment for 
BTC 
 
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 from the following website: 
https://www.roche.com/policy_continued_access_to_investigational_medicines.pdf 
4.4 
CONCOMITANT THERAPY 
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 Day 1 Cycle 1 to the treatment discontinuation visit.  All such medications should 
be reported to the investigator and recorded on the Concomitant Medications eCRF. 


 
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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 
 
Prophylactic use of low-dose anti-coagulation, unfractionated heparin, or low 
molecular weight heparin (LMWH) 
– 
The preferred choice for anti-coagulation treatment is LMWH as per American 
Society of Clinical Oncology guidelines (Lyman et al. 2013) 
 
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) 
 
Corticosteroids administered for COPD or asthma 
 
Low-dose corticosteroids administered for orthostatic hypotension or adrenocortical 
insufficiency 
 
Palliative radiotherapy (e.g., treatment of known bony metastases or symptomatic 
relief of pain)  7 days prior to Day 1 of Cycle 1 of the chemotherapy combination 
phase and during the CIT/placebo phase, 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 
continued during palliative radiotherapy.  Bevacizumab/placebo must be held 
during palliative radiotherapy treatment.  Upon completion of palliative 
radiotherapy treatment, continuation of bevacizumab/placebo treatment may be 
allowed. 
 
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 3 or fewer brain metastases 
may receive radiotherapy to the brain (either stereotactic radiosurgery or whole 
brain radiotherapy) and continue on study treatment, provided that all of the 
following criteria are met: 
The patient has no evidence of progression or hemorrhage 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 


 
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Note:  Treatment with atezolizumab and bevacizumab/placebo 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 
3 or fewer lesions may still be eligible to continue study treatment at the 
investigator’s discretion.  The Medical Monitor is available to advise as needed.  
Patients who receive local therapy directed at a target lesion will no longer be 
evaluable for radiographic response but will remain evaluable for progression. 
 
Relief of biliary tract obstruction during study treatment 
– 
In the event of the development of obstructive jaundice due to biliary tract 
obstruction, appropriate measures will be undertaken to diagnose (e.g., by 
ultrasound and/or CT scan) and relieve the obstruction (e.g., by Endoscopic 
retrograde cholangiopancreatography [ERCP]/Percutaneous transhepatic 
cholangiography [PTC]  stent insertion/drainage) in accordance with institutional 
standards of care. 
– 
Protocol treatment should be deferred until the liver function tests have 
sufficiently resolved to permit safely restarting study treatment in the opinion of 
the investigator. 
– 
Biliary tract obstruction by itself shall not constitute evidence of disease 
progression. 
– 
Imaging will be performed at the planned time points according to the protocol. 
 
On study tissue biopsies 
– 
The following precautions should be considered by the investigator with regard 
to the administration of bevacizumab or bevacizumab placebo after tumor 
biopsies; they are not expected to supersede institutional guidelines 
– 
Bevacizumab/placebo should not be administered until  3 days following 
the procedure and evidence of adequate wound healing is observed. 
– 
For patients undergoing needle biopsies of deep-seated lesions (e.g., liver 
or renal), hemoglobin, and hematocrit will be checked at the time of biopsy 
and prior to restarting bevacizumab/placebo, as clinically indicated. 
– 
Suggested post-biopsy hematocrit/hemoglobin thresholds include: 
For patients who have a  2 unit decrease in hemoglobin (g/dL) or a  6% 
decrease in hematocrit following the biopsy, bevacizumab may be restarted 
with appropriate clinical monitoring 
For patients who have a  2 but  3 unit decrease in hemoglobin (g/dL) or a 
 6% but  9% decrease in hematocrit, bevacizumab may be restarted at 
the discretion of the investigator 
Patients who have a  3 unit decrease in hemoglobin (g/dL) or a  9% 
decrease in hematocrit should be evaluated (e.g., by means of CT scan or 


 
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ultrasound), and bevacizumab may be restarted once the levels improve at 
the discretion of the investigator 
 
Premedication with antihistamines, antipyretic medications, and/or analgesics may be 
administered for the second and subsequent atezolizumab infusions only, at the 
discretion of the investigator. 
Anti-emetic prophylaxis may be administered at the treating physician’s discretion 
according to local practice. 
In general, investigators should manage a patient's care (including preexisting 
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 dyspnea, 
hypotension, wheezing, bronchospasm, tachycardia, reduced oxygen saturation, or 
respiratory distress should be managed with supportive therapies as clinically indicated 
(e.g., supplemental oxygen and 2-adrenergic agonists; see Appendix 13). 
4.4.2 
Cautionary Therapy 
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 (see Section 5.1 and Appendix 15 for details). 


 
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4.4.2.2 
Herbal Therapies 
Concomitant use of herbal therapies is not recommended because their PK, 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 
Any concomitant therapy intended for the treatment of cancer, whether health 
authority-approved or experimental, is prohibited for various time periods prior to Day 1 
of Cycle 1 (depending on the anticancer agent; see Section 4.1.2) and during study 
treatment until disease progression is documented and patient has discontinued study 
treatment.  This includes, but is not limited to, the following: 
 
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, 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 and local therapy under certain circumstances 
(see Section 4.4.1 for details) 
 
Concomitant use of herbal therapies and traditional Chinese medicine with 
anti-cancer activity included in the label 
 
Investigational therapy within 4 weeks prior to Day 1 of Cycle 1 and during study 
treatment 
 
Live, attenuated vaccines (e.g., FluMist) within 4 weeks prior to Day 1 of Cycle 1, 
during atezolizumab treatment, and for 5 months after the final dose of atezolizumab 
 
Systemic immunostimulatory agents (including, but not limited to, interferons and 
IL-2) within 4 weeks or 5 drug-elimination half-lives (whichever is longer) prior to 
Day 1 of Cycle 1 and during study treatment because these agents could potentially 
increase the risk of autoimmune conditions when given in combination with 
atezolizumab 
 
Current use of full dose oral or parenteral anticoagulants or thrombolytic agents for 
therapeutic (as opposed to prophylactic) purposes or anti-platelet therapy are 
prohibited within 10 days prior to Day 1 of Cycle 1 and during study treatment 
– 
Local label recommended doses for prophylactic use of anticoagulants or 
thrombolytic therapies are allowed. 
– 
Low-dose aspirin ( 325 mg/day) is permitted.  Coadministration of proton-pump 
inhibitors is strongly recommended to reduce potential GI damage. 
– 
If a patient experiences a venous thromboembolism event while still receiving 
study treatment, it may still be possible for the patient to continue study 
treatment despite anticoagulation treatment (see Section 4.1.2). 


 
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 
Use of warfarin or warfarin-like products is not permitted (includes for prophylactic 
use) 
 
Concomitant chronic use of NSAIDs while receiving study treatment 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), sporadic or 
short-term intake of oral NSAIDs is allowed, when coadministered with proton-pump 
inhibitors to reduce potential GI damage 
 
4.4.3.1 
Prohibited and Cautionary Therapy for Gemcitabine-Treated 
Patients 
Gemcitabine is not indicated for use in combination with radiotherapy.  Patients should 
not receive gemcitabine within 7 days before or after radiotherapy.  Concurrent therapy 
(given together or  7 days apart) with gemcitabine and thoracic radiation has led to 
life-threatening mucositis, especially esophagitis and pneumonitis.  Excessive toxicity 
has not been observed when gemcitabine is administered more than 7 days before or 
after radiation.  Radiation recall has been reported in patients who receive gemcitabine 
after prior radiation. 
4.4.3.2 
Prohibited and Cautionary Therapy for Cisplatin-Treated 
Patients 
Simultaneous use of myelosuppressive agents or radiation will boost the effects of 
cisplatin's myelosuppressive activity.  The occurrence of nephrotoxicity caused by 
cisplatin may be intensified by concomitant treatment with antihypertensive agents 
containing furosemide, hydralazine, diazoxide, and propranolol. 
Concomitant administration of ototoxic (e.g., aminoglycosides, loop diuretics) medicinal 
products will potentiate the toxic effect of cisplatin on auditory function. 
Simultaneous use of antihistamines, buclizine, cyclizine, loxapine, meclizine, 
phenothiazines, thioxanthenes, or trimethobenzamides may mask ototoxic symptoms 
(such as dizziness and tinnitus). 
In the event of the simultaneous use of oral anticoagulants, it is advisable to more 
frequently check the INR. 
4.5 
STUDY ASSESSMENTS 
The schedule of activities to be performed during the study is provided in Appendix 1.  
The schedule of activities related to PRO assessments is provided in Appendix 2.  
All activities should be performed and documented for each patient. 
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. 


 
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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 and, to document eligibility or record reasons for screening failure, 
as applicable.  Patients who do not initially meet all eligibility criteria for participation in 
this study (screen failure) may qualify for one re-screening opportunity (for a total of two 
screenings per patient) at the discretion of the investigator.  Patients are not required to 
re-sign the Informed Consent Form if they are re-screened within 60 days after 
previously signing the Informed Consent Form.  The investigator will record reasons for 
screen failure in the screening log. 
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, 
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 Day 1 of Cycle 1 will be recorded.  At the time of each follow-up physical examination, 
an interval medical history should be obtained and any changes in medications and 
allergies should be recorded. 
Demographic data will include age, sex, and self-reported race/ethnicity. 
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 
cardiovascular, dermatologic, musculoskeletal, respiratory, GI, 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 
postbaseline visits and as clinically indicated.  Changes from baseline abnormalities 
should be recorded in patient notes.  New or worsened clinically significant abnormalities 
should be recorded as adverse events on the Adverse Event eCRF. 
4.5.4 
Vital Signs 
Vital signs will include measurements of respiratory rate, pulse rate, systolic and 
diastolic BP, and temperature.  Record abnormalities observed at baseline on the 


 
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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 5, 
and at other specified timepoints as outlined in the schedule of activities 
(see Appendix 1). 
Table 5 
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/ 
placebo 
 Within 60 minutes prior to the 
bevacizumab/placebo infusion 
 Within 60 minutes prior to the 
bevacizumab/placebo infusion 
 At the end of infusion and 
2 ( 1) hours after the 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 and every 9 ( 1) weeks thereafter, 
regardless of dose delays, until radiographic disease progression per RECIST v1.1 or 
(for patients who continue atezolizumab plus bevacizumab or placebo, after radiographic 
disease progression) loss of clinical benefit, as determined by the investigator 
(see Section 3.1 for details).  Thus, tumor assessments are to continue according to 
schedule in patients who discontinue treatment for reasons other than disease 
progression or loss of clinical benefit, even if they start a new anti-cancer therapy.  At the 
investigator's discretion, tumor assessments may be repeated at any time if progressive 
disease is suspected. 
All measurable and evaluable lesions should be assessed and documented at 
screening.  Tumor assessments performed as standard of care prior to obtaining 
informed consent and within 28 days prior to Day 1 of Cycle 1 do not have to be 
repeated at screening. 
Screening assessments must include CT scans (with oral or IV contrast) or MRI scans of 
the chest, abdomen, 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 
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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 measurable and evaluable lesions identified at baseline should be re-assessed at 
each subsequent tumor evaluation.  The same radiographic procedures used to assess 
disease sites at screening should be used for subsequent tumor assessments (e.g., the 
same contrast protocol for CT scans). 
Objective response at a single timepoint will be determined by the investigator according 
to RECIST v1.1 (see Appendix 5).  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: 
 
Hematology:  RBC count, hemoglobin, hematocrit, WBC count with differential 
(neutrophils, lymphocytes, eosinophils, monocytes, basophils), and platelet count 
 
Chemistry panel (serum or plasma):  bicarbonate or total carbon dioxide 
(if considered standard of care for the region), magnesium, sodium, potassium, 
chloride, glucose, BUN or urea, creatinine, total protein, albumin, phosphate, 
calcium, total bilirubin, ALP, ALT, AST, and LDH 
 
Coagulation:  INR and aPTT 
 
Thyroid-function testing:  thyroid-stimulating hormone, free triiodothyronine (T3) 
(or total T3 for sites where free T3 is not performed), and free thyroxine (also known 
as T4) 
 
HIV serology 
 
HBV serology:  hepatitis B surface antigen (HBsAg), hepatitis B surface antibody, 
total hepatitis B core antibody (HBcAb), and HBV DNA 
If a patient has a positive HBsAg test and/or a positive total HBcAb test at 
screening, an HBV DNA test and a quantitative HBsAg test must also be 
performed during screening to determine if the patient has an HBV infection, as 
well as at Cycles 5 and 9, and at the discontinuation visit.  If local quantitative 
HBsAg test is not available, a qualitative HBsAg followed by a quantitative HBV 
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 
HCV serology:  HCV antibody and (if HCV antibody test is positive) HCV RNA 
If a patient has a positive HCV antibody test at screening, an HCV RNA test must 
also be performed to determine if the patient has an HCV infection. 
 
C-reactive protein 
 
CA19-9 
 
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 postmenarchal, 
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 sent to one or several central laboratories or to the 
Sponsor or a designee for analysis: 
 
Serum samples for atezolizumab PK analysis through use of a validated assay 
 
Serum samples for assessment of anti-drug antibodies (ADAs) to atezolizumab 
through use of a validated assay 
 
Blood, serum, plasma, and peripheral blood mononuclear cell (PBMC) samples for 
exploratory research on biomarkers and biomarker assay development 
 
Whole metagenomics sequencing and comprehensive analysis of the microbiome 
will be performed on stool samples for exploratory microbiome research 
 
A representative tumor specimen that is suitable for determination of PD-L1 status 
via central testing 
A FFPE tumor specimen in a paraffin block (preferred) or at least 16 slides 
containing unstained, freshly cut, serial sections should be submitted along with 
an associated pathology report within 4 weeks of randomization 
If FFPE specimens described above are not available, any type of specimen 
(including fine-needle aspiration, cell pellet specimens [e.g., from pleural 
effusion], and lavage samples) are also acceptable.  This specimen should be 
accompanied by the associated pathology report. 
If archival tissue is either insufficient or unavailable, a core-needle biopsy 
specimen should be collected during the screening period, if clinically 
feasible.  Transjugular biopsy tissue sample collections for patients who 
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If archival tissue is either insufficient or unavailable and a fresh biopsy is 
not clinically feasible, the patient may still be eligible. 
Tumor tissue should be of good quality based on total and viable tumor content.  
Samples must contain a minimum of 50 viable tumor cells that preserve cellular 
context and tissue architecture regardless of needle gauge or retrieval method.  
Samples collected via resection, core-needle biopsy (at least 3 cores, embedded 
in a single paraffin block), or excisional, incisional, punch, or forceps biopsy are 
acceptable. 
If archival tumor tissue is unavailable or is determined to be unsuitable for 
required testing, a pretreatment tumor biopsy is required, if clinically feasible.  
A pretreatment tumor biopsy may also be performed if a patient's archival tissue 
test results do not meet eligibility criteria. 
 
Exploratory biomarker research may include, but will not be limited to, analysis of genes 
or gene signatures associated with tumor immunobiology, PD-L1, immune cell 
subpopulations, T cellreceptor repertoire, or cytokines associated with T-cell activation.  
Research may involve extraction of DNA, cell-free DNA, or RNA; analysis of mutations, 
single nucleotide polymorphisms, and other genomic variants; and genomic profiling 
through use of next-generation sequencing of a comprehensive panel of genes.  
DNA extracted from blood may be compared with DNA extracted from tissue to identify 
somatic variants by distinguishing germline variants from somatic variants.  
Next-generation sequencing methods will include WES of tissue and blood samples, but 
WES of blood samples will be performed only at participating sites (see Section 4.5.9). 
Screening blood and tumor tissue samples, including those collected from patients who 
do not enroll in the study, may be used for future research and/or development of 
disease-related tests or tools. 
For sampling procedures, storage conditions, and shipment instructions, see the 
laboratory manual. 
Biological samples will be destroyed no later than the time of completion of the final 
Clinical Study Report, with the following exceptions: 
 
Plasma and/or Serum samples collected for PK or immunogenicity analysis may be 
needed for additional immunogenicity characterization and for PK or immunogenicity 
assay development and validation; therefore, these samples will be destroyed no 
later than 5 years after the final Clinical Study Report has been completed 
 
Blood, plasma, serum, PBMC, and tumor tissue samples collected for biomarker 
research will be destroyed no later than 5 years after the final Clinical Study Report 
has been completed.  However, the storage period will be in accordance with the 
Institutional Review Board (IRB)/Ethics Committee (EC)-approved Informed 
Consent Form and applicable laws (e.g., health authority requirements) 
 
For enrolled patients, remaining archival tissue blocks will be returned to the site 
upon request or no later than the time of final closure of the study database, 


 
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whichever occurs first.  For patients who are not enrolled, remaining archival tissue 
blocks will be returned to the site no later than 6 weeks after eligibility determination 
 
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, including data on genomic variants, 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. 
4.5.7 
Electrocardiograms 
An ECG is required at screening and when clinically indicated.  Electrocardiograms for 
each patient should be obtained from the same machine wherever possible.  
Lead placement should be as consistent as possible.  Electrocardiogram 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 instruments will be completed to more fully characterize the 
clinical profile of Atezolizumab  Bevacizumab  CisGem compared with 
Atezolizumab  Placebo  CisGem.  Patient-reported outcome data will be 
collected through use of the following instruments: 
 
European Organisation for Research and Treatment of Cancer (EORTC) 
quality-of-life questionnaire (QLQ-C30) 
 
European Organisation for Research and Treatment of Cancer quality-of-life 
questionnaire for cholangiocarcinoma and cancer of the gallbladder (QLQ-BIL21) 
 
Selected items from the EORTC Item Library (IL) 77 
 
Patient Global Impression of Change and its Importance (PGI-CI) 
 
Patient Global Impression of Severity (PGI-S) 
 
Patient-Reported Outcome Common Terminology Criteria for Adverse Events 
(PRO-CTCAE) 


 
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4.5.8.1 
Data Collection Methods for Clinical Outcome Assessments 
Patient-reported outcome instruments will be completed at home or the clinic at specified 
timepoints during the study (see schedule of activities in Appendix 2).  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, unless otherwise specified. 
Patient-reported outcome instruments, translated into the local language as appropriate, 
will be completed during clinic visits through use of an electronic device provided by the 
Sponsor when possible.  The device will be pre-programmed to enable the appropriate 
instruments to be administered in the correct order at each specified timepoint.  The 
electronic device and instructions for completing the instruments electronically will be 
provided by the site staff.  The data will be transmitted to a centralized database 
maintained by the electronic device vendor.  The data will be available for access by 
appropriate study personnel.  In circumstances when the electronic device is not 
available (e.g., device failure or due to supply issues), a backup data collection method 
(e.g., web backup) will be used.  Cycles 15 Day 15 PRO assessments will be 
completed at home via telephone interview with patient responses collected on the 
device (or web backup) by site staff. 
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 
 
During clinic visits, PRO instruments should be administered as outlined below: 
 
Patients' health status should not be discussed prior to administration of the 
instruments 
 
Sites must administer the official version of each instrument, as provided by the 
Sponsor.  Instruments must not be copied from the protocol 
 
Sites should allow sufficient time for patients to complete the instruments, estimated 
to be 20 minutes at each specified visit 
 
Sites should administer the instruments in a quiet area with minimal distractions and 
disruptions 
 
Patients should be instructed to answer questions to the best of their ability; there 
are no right or wrong answers 
 
Site staff should not interpret or explain questions, but may read questions verbatim 
upon request 


 
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 
Patients should not obtain advice or help from others (e.g., family members or 
friends) when completing the instruments 
 
4.5.8.2 
Description of Clinical Outcome Assessment Instruments 
EORTC QLQ-C30 
The EORTC QLQ-C30 is a validated and reliable self-reported measure 
(Aaronson et al. 1993; Fayers et al. 2001); see Appendix 6).  It consists of 30 questions 
that assess 5 aspects of patient functioning (physical, emotional, role, cognitive, 
and social), Global Health Status and Quality of Life (GHS/QoL), and 9 symptoms 
(fatigue, nausea and vomiting, pain, dyspnea, insomnia, appetite loss, constipation, 
diarrhea, and financial difficulties) with a recall period of the previous week.  The 
functioning and symptoms items are scored on a 4-point scale that ranges from not at 
all to very much, and the GHS/QoL items are scored on a 7-point scale that ranges 
from very poor to excellent. 
EORTC QLQ-BIL21 
The EORTC QLQ-BIL21 is a validated and reliable self-reported measure that serves as 
a modular supplement to the QLQ-C30 for use in patients with CCA and cancer of the 
gallbladder (Kaupp-Roberts et al. 2016; see Appendix 7).  It consists of 21 questions that 
assess 8 symptoms (eating, jaundice, tiredness, pain, anxiety, treatment side effects, 
difficulties with draining bags/tube, and concerns regarding weight loss) with a recall 
period of the previous week.  The scoring for the QLQ-BIL21 follows that of the 
QLQ-C30. 
EORTC IL77 
The EORTC IL77 is a reduced version of the QLQ-C30 that was created specifically for 
this study from the EORTC Quality of Life Group IIL (https://www.eortc.be/itemlibrary/).  
It consists of 12 questions that assess 2 aspects of patient functioning (physical and 
role), GHS/QoL, and 2 symptoms (nausea and vomiting, and appetite loss) with a recall 
period of the previous week (see Appendix 8).  The scoring for the IL77 follows that of 
the QLQ-C30. 
PGI-CI 
The PGI-CI is a 2-item, self-reported measure used to assess patients’ impression about 
changes to their overall health because of their cancer and the associated importance 
compared with when they began the study (see Appendix 9).  In the first item, the PGI-CI 
utilizes a 7-point response scale that ranges from very much worse to very much 
improved (adapted from Guy et al. 1976).  In the second item, the PGI-CI utilizes 
a 3-point response scale (yes, no, and not applicable) for patients to indicate if the 
change they experienced (and reported in the first item) was important to them. 
PGI-S 
The PGI-S is a 1-item, self-reported measure used to assess patients’ impression about 
how severely their overall health has been impacted because of their cancer during the 


 
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preceding week (see Appendix 10).  The PGI-S utilizes a 5-point response scale that 
ranges from very severe to none (adapted from Guy et al. 1976). 
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 4 symptoms deemed most applicable to the current treatments has been 
selected for this study (see Appendix 11).  Symptoms have been selected on the basis 
of known adverse drug reactions, mechanism of action of the treatments under 
investigation, and recent work to identify common adverse events associated with 
immunotherapies (King-Kallimanis et al. 2019; Hansen et al. 2020). 
4.5.9 
Blood Samples for Whole Exome Sequencing (Patients at 
Participating Sites) 
At participating sites, blood samples will be collected for DNA extraction to enable WES 
to identify variants that are predictive of response to study drug, are associated with 
progression to a more severe disease state, are associated with acquired resistance to 
study drug, are associated with susceptibility to developing adverse events, can lead to 
improved adverse event monitoring or investigation, or can increase the knowledge and 
understanding of disease biology and drug safety.  DNA extracted from blood may be 
compared with DNA extracted from tissue to identify somatic variants by distinguishing 
germline variants from somatic variants.  The samples may be sent to one or more 
laboratories for analysis. 
Collection and submission of blood samples for WES is contingent upon the review and 
approval of the exploratory research by each site's IRB or EC and, if applicable, an 
appropriate regulatory body.  If a site has not been granted approval for WES, this 
section of the protocol (Section 4.5.9) will not be applicable at that site. 
Genomics is increasingly informing researcher's understanding of disease pathobiology.  
WES provides a comprehensive characterization of the exome, and, along with clinical 
data collected in this study, may increase the opportunity for developing new therapeutic 
approaches or new methods for monitoring efficacy and safety or predicting which 
patients are more likely to respond to a drug or develop adverse events.  Data will be 
analyzed in the context of this study but may also be explored in aggregate with data 
from other studies.  The availability of a larger dataset will assist in identification and 


 
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characterization of important biomarkers and pathways to support future drug 
development. 
For sampling procedures, storage conditions, and shipment instructions, see the 
laboratory manual. 
Blood samples collected for WES are to be stored no later than 5 years after the final 
Clinical Study Report has been completed.  However, the storage period will be in 
accordance with the IRB/EC-approved Informed Consent Form and applicable laws 
(e.g., health authority requirements). 
See Section 4.5.6 for details on use of samples after patient withdrawal, confidentiality 
standards for data, and availability of data from biomarker analyses. 
4.5.10 
Optional Tumor Biopsies 
Consenting patients will undergo optional tumor biopsies at 24 weeks after treatment 
initiation, at disease progression, and may undergo additional on-treatment biopsies at 
any other time at the investigator's discretion (if deemed clinically feasible by the 
investigator).  Samples collected via resection, core-needle biopsy (at least 3 cores 
preferred), or excisional, incisional, punch, or forceps biopsy are preferred. 
The Informed Consent Form will contain a separate section that addresses optional 
biopsies.  A separate, specific signature will be required to document a patient's 
agreement to undergo optional biopsies.  The investigator should document whether or 
not the patient has given consent to participate and (if applicable) the date(s) of consent, 
by completing the Optional Biopsy Sample Informed Consent eCRF. 
Samples may be used for exploratory biomarker research as described in Section 4.5.6.  
For sampling procedures, storage conditions, and shipment instructions, see the 
laboratory manual.  See Section 4.5.6 for details on duration of sample storage, use of 
samples after patient withdrawal, confidentiality standards for data, and availability of 
data from biomarker analyses. 
4.5.11 
Optional Stool Samples 
Patients will be given the option of consenting to provide stool samples.  Optional stool 
samples will be collected at baseline and one additional timepoint between Cycle 2 and 
Cycle 3. 
The Informed Consent Form will contain a separate section that addresses optional stool 
samples.  A separate, specific signature will be required to document a patient's 
agreement to provide optional stool samples.  The investigator should document 
whether or not the patient has given consent to participate and (if applicable) the date(s) 
of consent, by completing the Optional Stool Sample Informed Consent eCRF. 


 
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The gut microbiome has been shown to be a key determinant in immune regulation in 
cancer, in part by influencing T-cell driven anti-tumor responses (Routy et al. 2018).  
For example, antibiotic treatment is associated with poor survival outcomes to antiPD-1 
therapy in NSCLC, RCC, and urothelial carcinoma (Elkrief et al. 2019).  Conversely, the 
risk of colitis with CITs may be predicted based on a patient’s pretreatment microbiome 
(Dubin et al. 2016; Chaput et al. 2017).  Thus, heterogeneity in microbiome composition 
across patients may be a key driver of safety events in addition to efficacy.  Whereas gut 
bacteria have been implicated in the development of liver cancer, their impact on the 
efficacy of CIT is still unknown. 
This study will examine whether a patient’s microbiome can determine response to a CIT 
combination, and conversely, whether a CIT combination can alter the microbiome to 
such an extent that on-treatment changes to the microbiome could be early predictors of 
adverse events, including colitis.  Analyzing the microbiome in BTC may provide the 
opportunity to discover systemic effects on distal cancers. 
Samples may be used for exploratory biomarker research as described in Section 4.5.6.  
See Section 4.5.6 for details on sample storage, use of samples after patient withdrawal, 
confidentiality standards for data, and availability of data from biomarker analyses. 
For sampling procedures, storage conditions, and shipment instructions, see the 
laboratory manual. 
4.5.12 
Study Treatment Discontinuation 
Patients must permanently discontinue study treatment (atezolizumab, 
bevacizumab/placebo, and chemotherapy) if they experience any of the following: 
 
Intolerable toxicity related to study treatment, including development of an 
immune-mediated adverse event determined by the investigator to be unacceptable 
given the individual patient's potential response to therapy and severity of the event 
 
Any medical condition that may jeopardize the patient's safety if he or she continues 
study treatment 
 
Investigator or Sponsor determination that treatment discontinuation is in the best 
interest of the patient 
 
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 for details) 
 
If one component of study treatment is transiently withheld or permanently discontinued 
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 


 
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clinical benefit in the opinion of the investigator.  However, bevacizumab/placebo should 
not be continued as a single agent. 
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 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). 
4.5.13 
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 
 
Study termination or site closure 
 
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. 


 
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4.5.14 
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. 
4.5.15 
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) 
 
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 Sections 5.1.1, 5.1.2, 5.1.3, and 5.1.4). 
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/placebo 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 14, and Appendix 15.  See Sections 5.2, 5.3, 5.4, 5.5, and 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). 


 
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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 lead to hemophagocytic lymphohistiocytosis (HLH).  Refer to 
Appendix 15 of the protocol and Section 6 of the Atezolizumab Investigator's Brochure 
for a detailed description of anticipated safety risks for atezolizumab. 
5.1.2 
Risks Associated with Bevacizumab 
Bevacizumab has been associated with risks such as the following:  GI perforations, 
hemorrhage, arterial thromboembolic events, fistulae, wound-healing complications, 
hypertension, venous thromboembolism, and proteinuria. 
See Appendix 14 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, based on the known safety profile of each agent and available data from 
clinical studies.  Nevertheless, the attribution and management of certain adverse events 
that have been associated with each agent separately (e.g., hemorrhage, 
hypothyroidism, and GI toxicity) may be ambiguous 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. 
5.1.4 
Risks Associated with Cisplatin or Gemcitabine 
For adverse reactions, warnings, and precautions for CisGem, see the local prescribing 
information.  See Section 5.1.5 for dose modifications and Appendix 14 for management 
of risks associated with CisGem. 


 
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5.1.5 
Cisplatin and Gemcitabine Dose Modifications 
The investigator may attribute toxicity to cisplatin or gemcitabine and use stepwise dose 
modifications according to Table 6.  Dose modifications for hematologic toxicity will be 
based on blood counts obtained within 1 day prior to Days 1 and 8 of each cycle of 
therapy.  Dose re-escalations are only permitted for the Day 8 gemcitabine dose 
adjustment for hematologic parameters.  Treatment with filgrastim or pegfilgrastim may 
be used if needed.  Investigators may follow institutional guidelines of local standard 
of care if they conflict with these recommendations, however treatment with 
sargramostim is not allowed. 
Table 6 
Dose-Modification Levels for Cisplatin and Gemcitabine 
Treatment 
Starting 
Dose 
Dose 
Level 1 
Dose  
Level 2 
Dose  
Level 3 
Dose  
Level 4 
Cisplatin a 
25 mg/m2 
20 mg/m2 
15 mg/m2 
Discontinue 
 
Gemcitabine b 
1000 mg/m2 
800 mg/m2 
600 mg/m2 
Discontinue 
 
a No dose re-escalation of cisplatin is allowed after a dose reduction to a lower dose level. 
b Dose re-escalations are only permitted for the Day 8 gemcitabine dose adjustment for 
hematologic parameters. 
 
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. 
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 Sections 5.3.5.9 
and 5.3.5.10 for more information) 
 
Recurrence of an intermittent medical condition (e.g., headache) not present at 
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 
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; 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; 


 
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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, IRRs, CRS, HLH, and MAS 
 
Nephritis 
 
Ocular toxicities (e.g., uveitis, retinitis, optic neuritis) 
 
Grade  2 cardiac disorders  
 
Vasculitis 
 
Autoimmune hemolytic anemia 
 
Severe cutaneous reactions (e.g., Stevens-Johnson syndrome, dermatitis bullous, 
toxic epidermal necrolysis) 
 
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 
– 
Any grade CNS bleeding 
– 
Grade  2 hemoptysis 
– 
Other Grade  3 hemorrhagic event 
 
Any arterial thromboembolic event 
 
Grade  3 venous thromboembolic event 
 
Any grade posterior reversible encephalopathy syndrome 
 
Grade  3 congestive heart failure 
 
Myelitis 
 
Facial paresis 


 
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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, 5.5, and 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 on Day 1 of Cycle 1, 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. 
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. 


 
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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:  
https://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. 
 
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 


 
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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. 
Only 1 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 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 (occurring 
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 of an IRR should be recorded on 
the dedicated Infusion-Related Reaction eCRF. 
If a patient experiences both a local and systemic reaction to a single administration of 
study treatment, each reaction should be recorded separately on the 


 
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Adverse Event eCRF, with associated signs and symptoms of an IRR also recorded 
separately on the dedicated Infusion-Related Reaction 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 14. 
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. 
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 GI hemorrhage 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 


 
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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 
 
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 judgment 
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 
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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. 
If a clinically significant vital sign abnormality is a sign of a disease or syndrome 
(e.g., high BP), 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ULN) 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ULN in combination with total bilirubin 
 2ULN 
 
Treatment-emergent ALT or AST  3ULN 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 BTC 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 


 
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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). 
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 preexisting 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 preexisting 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 preexisting condition has changed by including applicable descriptors 
(e.g., more frequent headaches). 
5.3.5.10 
Lack of Efficacy or Worsening of Biliary Tract Cancer 
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.  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. 


 
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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) 
 
Hospitalization for a preexisting 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. 
 
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 bevacizumab (or matching placebo), 
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. 


 
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 
Medication error that qualifies as an overdose:  Enter the adverse event term.  
Check the Accidental overdose and Medication error boxes. 
 
In addition, all special situations associated with atezolizumab and bevacizumab 
(or matching placebo), 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. 
 
As an example, an accidental overdose that resulted in a headache would require 
2 entries on the Adverse Event eCRF, 1 entry to report the accidental overdose and 
1 entry to report the headache.  The Accidental overdose and Medication error 
boxes would need to be checked for both entries. 
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 the PRO-CTCAE) with investigator reports of adverse 
events.  Sites are not expected to review the PRO-CTCAE data for adverse events. 
5.3.5.14 
Safety Biomarker Data 
Adverse event reports will not be derived from safety biomarker data by the Sponsor, 
and safety biomarker data will not be included in the formal safety analyses for this 
study.  In addition, safety biomarker data will not inform decisions on patient 
management. 
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 


 
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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) 
 
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 
Contact Information for Sites in North, South America and Europe 
Medical Monitor/Roche Medical Responsible}: 
 M.D., Ph.D. (Primary) 
Telephone No.: 
Mobile Telephone No.: 
  1 (650) 580-7063 
 
Medical Monitor/Emergency Medical Contact: 
 Pharm.D. (Secondary) 
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.  


 
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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. 
5.4.2.2 
Events That Occur after Study Treatment Initiation 
After initiation of study treatment on Day 1 of Cycle 1, 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 final dose of atezolizumab or 6 months after the final dose of 
bevacizumab or chemotherapy (CisGem).  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. 


 
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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 or chemotherapy (CisGem).  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.  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. 
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). 


 
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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, the event is assessed as stable by the investigator, 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 study period, 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. 
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 
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. 


 
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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 
The statistical considerations and analysis plan are summarized below. 
Efficacy analyses will be performed based on the intent-to-treat (ITT) principle that all 
randomized patients, regardless of whether they receive the assigned treatment or not, 
will be included for analyses with patients grouped according to the treatment assigned 
at randomization.  The ITT population will be used for the efficacy endpoints, including 
ORR, PFS, and OS.  Duration of response (DOR) will be assessed in the 
DOR-evaluable population, a subset of the ITT population who achieve the best overall 
response as CR or PR.  The PRO analyses of time to confirmed deterioration (TTCD) 
will be conducted based on the ITT population, and the remaining PRO analyses will be 
conducted in the PRO-evaluable population, which is a subset of the ITT patients with 
a non-missing baseline PRO assessment and at least 1 postbaseline PRO assessment. 
Safety analyses will be conducted for all randomized patients who receive any amount of 
any component of study treatment, defined as safety-evaluable population, with patients 
grouped according to actual treatment received.  The full set of the safety-evaluable 
patients will be included in analyses where applicable.  For analyses that assess 
postbaseline changes compared with baseline values, a subset of the safety-evaluable 
population who do not have missing data at baseline and have at least one postbaseline 
value will be included for the analyses. 
Pharmacokinetic and ADA analyses will be performed in all patients with at least 1 PK 
assessment and all patients with at least 1 postbaseline ADA assessment, respectively. 
The final PFS analysis will be performed at the time when approximately 90 PFS events, 
as assessed by the investigator per RECIST v1.1, have been observed.  The final OS 


 
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analysis will be performed when approximately 90 OS events have been observed or 
when all patients have been followed for a minimum of 2 years, whichever occurs first. 
6.1 
DETERMINATION OF SAMPLE SIZE 
The purpose of this Phase II study is estimation and hypothesis generation regarding the 
effect of atezolizumab with bevacizumab in combination with CisGem (Arm A) on PFS 
relative to atezolizumab in combination with CisGem (Arm B).  Point and CI estimates of 
the true underlying HR of comparing PFS between Arm A and Arm B will be calculated.  
A total of approximately 150 patients will be randomized at a 1:1 randomization ratio to 
either Arm A or Arm B.  It is assumed that the median duration of PFS in the control arm 
(Arm B) is 9 months.  Operating characteristics (statistical power based on a two-sided 
significance level of 0.05 and expected total number of events) at the time of the final 
PFS analysis for true underlying HR values of 0.55, 0.60, and 0.70 are provided in 
Table 9.  The final PFS analysis will occur when approximately 90 PFS events have 
been observed.  The planned sample size of 150 patients, targeting approximately 
90 PFS events at the time of the final PFS analysis, is considered to provide sufficient 
data and precision for the purpose of estimation of the HR point estimate and its 95% CI. 
Table 9 
Operating Characteristics for Proposed Study Design for Several 
Possible True Underlying PFS Hazard Ratio Values 
 
True Underlying HR 
0.55 
0.60 
0.70 
Expected number of 
events  
90 
90 
90 
Power a 
81% 
68% 
39% 
95% CI for true HR b 
(0.36, 0.83) 
(0.40, 0.91) 
(0.46, 1.06) 
HR  hazard ratio; PFS  progression-free survival. 
Note:  Operating characteristics are based on the following assumptions:  PFS event times are 
exponentially distributed and median PFS in Arm B is 9 months. 
a Two-sided   0.05. 
b Confidence intervals are based on the assumption that the PFS HR point estimate is equal to 
the true underlying value of the HR in each column. 
 
It should be noted that the study is underpowered for detection of minimal clinically 
meaningful differences under an assumed true HR of 0.60 and above (see second and 
third columns of Table 9).  Therefore, a clinically meaningful HR point estimate may not 
be statistically significant due to a low power. 


 
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6.2 
SUMMARIES OF CONDUCT OF STUDY 
Enrollment, study drug administration, and discontinuation from the study will be 
summarized by treatment arm.  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 by treatment arm. 
Descriptive statistics will be used in these summary tables.  Continuous variables will be 
summarized using means, standard deviations, medians and ranges.  Categorical 
variables will be summarized using counts and percentages. 
6.3 
SUMMARIES OF DEMOGRAPHIC AND BASELINE 
CHARACTERISTICS 
Demographic and baseline characteristics (including age, sex, race/ethnicity, 
stratification factors, etc.) will be summarized using means, standard deviations, 
medians, and ranges for continuous variables and counts and percentages for 
categorical variables, as appropriate.  Summaries will be presented overall and by 
treatment arm. 
6.4 
EFFICACY ANALYSES 
The primary analysis population for the efficacy analyses will be the ITT population and 
will consist of all randomized patients, with patients grouped according to their assigned 
treatment, regardless of whether they received any assigned study treatment or not. 
6.4.1 
Primary Efficacy Endpoint 
The primary efficacy endpoint is investigator-assessed PFS according to RECIST v1.1. 
Investigator-assessed PFS is defined as the time from randomization to the occurrence 
of disease progression as determined by investigator according to RECIST v1.1, or 
death from any cause, whichever occurs first.  Patients who have not experienced 
disease progression or death at the time of the clinical cutoff date will be censored at the 
time of the last tumor assessment at which they were known to be progression-free with 
radiographic evidence as of the clinical cutoff date.  Patients with no postbaseline tumor 
assessment will be censored at the date of randomization. 
A stratified Cox proportional-hazards model will be used to estimate the PFS HR and 
its 95% CI.  A stratified two-sided log-rank test will be used to compare the 
investigator-assessed PFS between Arm A and Arm B at the two-sided significance level 
of 0.05.  The stratification factors for these stratified analyses are location of primary 
tumor (iCCA vs. eCCA vs. GBC), metastatic disease (yes vs. no), and geographic region 
(Asia vs. rest of the world).  However, if at least one stratum has fewer than 10 events at 
the time of analysis, the level of stratification factor that contains the smallest number of 
events will be combined with other levels of the same stratification factor for the stratified 
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be applied to all other endpoints where stratified analyses are performed.  
The stratification information will be obtained from the IxRS at the time of randomization.  
Results from an unstratified analysis will also be provided.  The Kaplan-Meier method 
will be used to estimate median PFS for each treatment arm.  The Brookmeyer-Crowley 
methodology will be used to calculate the 95% CI for the median PFS of each treatment 
arm. 
To assess the homogeneity of the treatment effect with respect to the primary efficacy 
endpoint of PFS, forest plots (including the estimated HRs) for clinically relevant 
subgroups will be provided. 
To assess the robustness of the primary PFS analysis, a sensitivity analysis will be 
performed by incorporating an additional censoring rule for patients who take new 
anti-cancer therapy prior to occurrence of radiographic progression.  These patients will 
be censored at the last tumor assessment before start of the new treatment, regardless 
of progression or death afterwards. 
6.4.2 
Secondary Efficacy Endpoints 
The secondary efficacy endpoints are OS, investigator-assessed confirmed ORR, DOR, 
and DCR, and TTCD in patient-reported physical functioning, role functioning, and 
quality of life. 
6.4.2.1 
Overall Survival 
Overall survival is defined as the time from randomization to death from any cause.  
Data for patients who are not reported as having died at the time of the clinical cutoff 
date will be censored at the date last known to be alive.  Data for patients who do not 
have postbaseline information will be censored at the date of randomization. 
The analysis methods for OS will be similar to those described for PFS. 
6.4.2.2 
Confirmed Objective Response Rate 
Confirmed ORR is defined as the proportion of patients with a CR or PR on two 
consecutive occasions  4 weeks apart, as determined by the investigator according to 
RECIST v1.1.  Patients without any postbaseline tumor assessments will be considered 
as non-responders. 
The confirmed ORRs for each treatment arm will be calculated based on the 
ITT population, and the respective 95% CIs will be estimated using the Clopper-Pearson 
method.  The confirmed ORRs will be compared between Arm A and Arm B using the 
stratified Cochran-Mantel-Haenszel test, and the ORR difference between these 2 arms 
will be also calculated with 95% CI being computed using the normal approximation to 
the binomial distribution. 


 
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6.4.2.3 
Duration of Response 
Duration of response is defined as the time from the first occurrence of a confirmed 
objective response to disease progression as determined by the investigator according 
to RECIST v1.1 or death from any cause (whichever occurs first).  Data for patients who 
are alive and who have not experienced disease progression at the time of the clinical 
cutoff date will be censored at the date of the last tumor assessment at which they were 
known to be progression-free. 
The DOR will be analyzed for the subset of ITT patients who have the best confirmed 
response as PR or CR.  The median DOR and its 95% CI for each treatment arm will be 
estimated by Kaplan-Meier methodology. 
6.4.2.4 
Disease Control Rate 
Disease control rate is defined as the proportion of patients with CR or PR on two 
consecutive occasions  4 weeks apart, or SD with a minimum duration of 9 weeks, as 
determined by the investigator according to RECIST v1.1. 
The DCR for each treatment arm will be calculated based on the ITT population, with the 
respective 95% CIs being estimated using the Clopper-Pearson method. 
6.4.2.5 
Time to Confirmed Deterioration 
Time to confirmed deterioration in patient-reported physical functioning, role functioning, 
and quality of life, as measured by the respective scales of the EORTC QLQ-C30 and/or 
EORTC IL77, is defined as the time from randomization to the first clinically meaningful 
deterioration that is either maintained for two consecutive assessments or followed by 
death from any cause within 3 weeks.  Clinically meaningful deterioration will be defined 
using anchor-based analyses, details for which will be pre-specified in a separate 
statistical analysis plan. 
The TTCD analyses will be conducted in the ITT population, and the analysis methods 
will be similar to those described for PFS. 
6.4.3 
Exploratory Efficacy Endpoints 
6.4.3.1 
Exploratory Progression-Free Survival 
Progression-free survival rates at specified timepoints (e.g., 6 and 12 months), defined 
as the probability that a patient will be alive without experiencing disease progression, as 
determined by the investigator according to RECIST v1.1, at specified timepoints.  
The PFS rates will be estimated using the Kaplan-Meier methodology. 
6.4.3.2 
Exploratory Overall Survival 
Overall survival rates at specific timepoints (e.g., 6 months and 12 months), defined as 
the probability that a patient will be alive at specified timepoints will be estimated using 
the Kaplan-Meier methodology. 


 
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6.4.3.3 
Exploratory Patient-Reported Outcome Endpoints 
Completion rates and reasons for missing data will be summarized for the 
EORTC QLQ-C30, EORTC QLQ-BIL21, EORTC IL77, PGI-CI, and PGI-S at each 
treatment cycle by treatment arm and within the ITT population. 
Visit mean summary and change from baseline analyses will be performed for all scales 
of the EORTC QLQ-C30, EORTC QLQ-BIL21, and EORTC IL77.  Summary statistics 
(e.g., number of patients, mean, standard deviation, median, minimum, maximum, 
95% CI) of linearly transformed scores (per the EORTC scoring manual) will be 
calculated at all assessment timepoints for each study arm.  These analyses will be 
performed in the PRO-evaluable population. 
Summary statistics (e.g., number of patients, proportions) will be calculated for the 
PGI-CI and PGI-S in the PRO-evaluable population. 
6.5 
SAFETY ANALYSES 
The safety analysis population will consist of all randomized patients who received any 
amount of any component of study treatment, with patients grouped according to 
treatment received. 
6.5.1 
Analyses of Exposure, Adverse Event, Laboratory, Vital Sign, 
and ECG Data 
Safety will be assessed through summaries of exposure to study treatment, adverse 
events, changes in laboratory test results, and changes in vital signs and ECGs. 
Study treatment exposure (such as treatment duration, number of cycles, and dose 
intensity) will be summarized with descriptive statistics. 
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 of special interest, and adverse events leading 
to study treatment discontinuation that occur on or after the first dose of study treatment 
or worsen after the first dose of study treatment for existing baseline conditions 
(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 and cause of death will be 
summarized. 
Relevant laboratory, vital sign (pulse rate, respiratory rate, BP, pulse oximetry, 
and temperature), and ECG data will be displayed by time, with grades identified where 
appropriate.  Additionally, a shift table of selected laboratory tests will be used to 
summarize the baseline and maximum postbaseline severity grades.  Changes in vital 
signs and ECGs will be summarized. 


 
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6.5.2 
Exploratory Analyses of PRO-CTCAE Data 
Patient-reported outcome-CTCAE analyses will be 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.  Patient-reported outcome-CTCAE data will be analyzed at the 
item level in line with current NCI CTCAE recommendations for data handling 
(Basch et al. 2014). 
Patient-reported outcome-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 (presence, 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 postbaseline score and change from baseline will 
be summarized by treatment arm. 
Graphical representation of PRO-CTCAE data over time may also be provided. 
6.6 
PHARMACOKINETIC ANALYSES 
The PK analysis population will consist of all patients with at least 1 PK assessment. 
Samples will be collected for PK analyses and serum concentrations of atezolizumab will 
be reported as individual values and summarized (mean, standard deviation, coefficient 
of variation, median, range, geometric mean, and geometric mean coefficient of 
variation) by treatment arm and cycle, when appropriate and as data allow.  Individual 
and median serum atezolizumab concentrations will be plotted for PK-evaluable patients 
by day. 
Atezolizumab concentration data may be pooled with data from other studies using an 
established population PK model to derive PK parameters such as clearance, volume of 
distribution, and area under the curve, as warranted by the data.  Potential correlations 
of relevant PK parameters with dose, safety, efficacy, or biomarker outcomes may be 
explored. 
Additional PK and pharmacodynamic analyses will be conducted as appropriate. 
6.7 
IMMUNOGENICITY ANALYSES 
Immunogenicity analysis in this study will be based on ADAs to atezolizumab.  
The immunogenicity analysis population will consist of all patients with at least 
1 postbaseline ADA assessment.  Patients will be grouped according to treatment 
received. 


 
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The numbers and proportions of ADA-positive patients and ADA-negative patients at 
baseline (baseline prevalence) and after drug administration (postbaseline incidence) 
will be summarized for ADA-evaluable patients.  When determining postbaseline 
incidence, patients are considered to be ADA-positive if they are ADA-negative or have 
missing data at baseline but develop an ADA response following study drug exposure 
(treatment-induced ADA response), or if they are ADA-positive at baseline and the titer 
of one or more postbaseline samples is at least 0.60 titer unit greater than the titer of the 
baseline sample (treatment-enhanced ADA response).  Patients are considered to be 
post-treatment ADA-negative if they are ADA-negative or have missing data at baseline 
and all postbaseline samples are negative, or if they are ADA-positive at baseline but do 
not have any postbaseline samples with a titer that is at least 0.60 titer unit greater than 
the titer of the baseline sample (treatment unaffected). 
The relationship between ADA status and safety, efficacy, PK, and biomarker endpoints 
may be analyzed and reported. 
6.8 
BIOMARKER ANALYSES 
Exploratory biomarker data may be analyzed in the context of this study and in 
aggregate with data from other studies. 
6.9 
INTERIM ANALYSES 
6.9.1 
Planned Interim Analysis 
One interim analysis of PFS and ORR will be performed at the time when 100 patients 
have been followed for at least 6 months, and is estimated to occur at approximately 
12 months after the first patient is enrolled.  All of the planned 150 patients are expected 
to have been randomized in the study at the time of this planned interim analysis.  
The interim analysis will be performed and interpreted by Sponsor study team personnel, 
who will have full access to unblinded data at the time of analysis.  Access to treatment 
assignment information will follow the Sponsor's standard procedures and will not be 
given to the Sponsor until the first interim analysis within this study is being conducted. 
6.9.2 
Optional Interim Analyses 
Given the hypothesis-generating nature of this study, the Sponsor may choose to 
conduct additional interim efficacy analyses.  The decision to conduct an optional interim 
analysis and the timing of the analysis will be documented in the Sponsor's trial master 
file prior to the conduct of the interim analysis.  The optional interim analysis will be 
performed and interpreted by Sponsor study team personnel, who will have full access 
to unblinded data at the time of analysis.  Access to treatment assignment information 
will follow the Sponsor's standard procedures and will not be given to the Sponsor until 
the first interim analysis within this study is being conducted. 


 
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7. 
DATA COLLECTION AND MANAGEMENT 
7.1 
DATA QUALITY ASSURANCE 
The Sponsor 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 Sponsor will request data clarification from the sites, which the sites 
will resolve electronically in the EDC system. 
The Sponsor will produce an EDC Study Specification document that describes the 
quality checking to be performed on the data.  Central laboratory data and any other 
externally generated electronic study data will be sent directly to the Sponsor, using the 
Sponsor's standard procedures to handle and process the electronic transfer of these 
data. 
Electronic Case Report Forms and correction documentation will be maintained in the 
EDC system's audit trail.  System backups for data stored by the Sponsor and records 
retention for the study data will be consistent with the Sponsor's standard procedures. 
7.2 
ELECTRONIC CASE REPORT FORMS 
Electronic Case Report Forms 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.  Electronic Case Report Forms 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.  Electronic Case Report 
Forms 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. 
7.3 
ELECTRONIC PATIENT-REPORTED OUTCOME DATA 
An electronic device will be used to capture PRO data when possible 
(see Section 4.5.8.1).  The device is designed for entry of data in a way that is 
attributable, secure, and accurate, in compliance with U.S. Food and Drug 
Administration (FDA) regulations for electronic records (21 CFR Part 11).  The data will 
be transmitted to a centralized database maintained by the electronic device vendor. 
The electronic data will be available for view access only, via a secure method.  
Only identified and trained users may view the data, and their actions will become part of 
the audit trail.  The Sponsor will have view access only.  System backups for data stored 


 
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by the Sponsor and records retention for the study data will be consistent with the 
Sponsor's standard procedures. 
Once the study is complete, the data, audit trail, and trial and system documentation will 
be archived.  The investigator will receive patient data for the site in both human- and 
machine-readable formats that must be kept with the study records as source data.  
Acknowledgement of receipt of the data is required.  In addition, the Sponsor will receive 
all data in a machine-readable format. 
7.4 
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, PROs, 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. 
7.5 
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 


 
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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. 
7.6 
RETENTION OF RECORDS 
Records and documents pertaining to the conduct of this study and the distribution of 
IMP, including eCRFs, electronic PRO data, Informed Consent Forms, laboratory test 
results, medication inventory records, and images must be retained by the 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. 
The Sponsor 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 United States or under a 
U.S. Investigational New Drug (IND) Application will comply with FDA regulations and 
applicable local, state, and federal laws.  Studies conducted in the European Union or 
European Economic Area will comply with the E.U. Clinical Trials Directive (2001/20/EC) 
or Clinical Trials Regulation (536/2014) 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. 


 
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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. 
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) while 
a patient is participating 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. 
For sites in the United States, each Consent Form may also include patient authorization 
to allow use and disclosure of personal health information in compliance with the 
U.S. Health Insurance Portability and Accountability Act (HIPAA) of 1996.  If the site 
utilizes a separate Authorization Form for patient authorization for use and disclosure of 
personal health information under the HIPAA regulations, the review, approval, 
and other processes outlined above apply except that IRB review and approval may not 
be required per study site policies. 
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. 


 
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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 9.6). 
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. 
8.4 
CONFIDENTIALITY 
Information technology systems used to collect, process, and store study-related data 
are secured by technical and organizational security measures designed to protect such 
data against accidental or unlawful loss, alteration, or unauthorized disclosure or 
access.  In the event of a data security breach, appropriate mitigation measures will be 
implemented. 
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 9.5). 
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. 


 
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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 9.5). 
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). 
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 will implement 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 will identify potential risks associated with critical 
trial processes and data and will implement plans for evaluating and controlling these 
risks.  Risk evaluation and control will include the selection of risk-based parameters 


 
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(e.g., adverse event rate, protocol deviation rate) and the establishment of quality 
tolerance limits for these parameters prior to study initiation.  Detection of deviations 
from quality tolerance limits will trigger an evaluation to determine if action is needed.  
Details on the establishment and monitoring of quality tolerance limits will be provided in 
a Quality Tolerance Limit Management Plan. 
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 F. Hoffmann-La Roche Ltd.  The Sponsor 
will provide clinical operations management, data management, and medical monitoring. 
Approximately 75 sites globally will participate to randomize approximately 150 patients.  
Screening and enrollment will occur through an IxRS. 
Central facilities will be used for certain study assessments throughout the study 
(e.g., specified laboratory tests, biomarker analyses, and PK analyses), as specified in 
Section 4.5.6.  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 summaries 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, see the Roche Global 
Policy on Sharing of Clinical Study Information at the following website: 
https://www.roche.com/innovation/process/clinical-trials/data-sharing/ 
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 


 
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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. 
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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10. 
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Appendix 1  
Schedule of Activities 
Day 
Screening a 
Treatment Cycles (21-Day Cycles) b 
Treatment 
Discontinuation 
Visit c 
 30 Days after 
Final Dose 
Follow-Up 
Chemotherapy 
Combination Phase 
(Cycles 18) 
CIT/Placebo 
Phase 
(Cycles 9 and 
Beyond) 
Days –28 
to –1 
Day 1  
Day 8 
Day 1  
(Window) 
( 3 Days) 
Informed consent d 
x 
 
 
 
 
 
Baseline tumor tissue sample e 
x 
 
 
 
 
 
Demographic data 
x 
 
 
 
 
 
Medical history, including cancer, and baseline 
conditions f 
x 
 
 
 
 
 
PRO assessments g 
 
See Appendix 2 
 
Vital signs j 
x 
x 
 
x 
x 
 
Weight k 
x 
x k 
x k 
x k 
 
 
Height 
x 
 
 
 
 
 
Complete physical examination l 
x 
 
 
 
 
 
Limited physical examination l 
 
x m 
 
x m 
x 
 
ECOG Performance Status 
x 
x m 
 
x m 
x 
 
ECG n 
x 
If clinically indicated 
 
EGD o 
x 
 
 
 
 
 
Hematology p 
x q 
x  
x  
x m 
x 
 
Chemistry profile (serum or plasma)  r 
x q 
x m 
 
x m 
x 
 


Appendix 1: 
Schedule of Activities 
  
Atezolizumab and Bevacizumab—F. Hoffmann-La Roche Ltd 
121/Protocol GO42661, Version 6 
Day 
Screening a 
Treatment Cycles (21-Day Cycles) b 
Treatment 
Discontinuation 
Visit c 
 30 Days after 
Final Dose 
Follow-Up 
Chemotherapy 
Combination Phase 
(Cycles 18) 
CIT/Placebo 
Phase 
(Cycles 9 and 
Beyond) 
Days –28 
to –1 
Day 1  
Day 8 
Day 1  
(Window) 
( 3 Days) 
Coagulation tests:  INR and aPTT 
x q 
 
 
 
x 
 
Pregnancy test  s 
x 
x 
 
x 
x 
 
TSH, free T3, and free T4 t 
x 
x t 
x 
 
CA 19-9 
x 
x 
 
x 
x 
 
C-reactive protein 
 
x 
 
x 
x 
 
HIV, HBV, HCV serology u 
x 
 
 
 
 
 
Quantitative HBsAg, HBV DNA, HCV RNA v 
x 
 
 
x 
x 
 
Urinalysis  w 
x 
x m 
 
x m 
 
 
Atezolizumab IV infusion x 
 
x 
 
x 
 
 
Bevacizumab/placebo IV infusion x 
 
x 
 
x 
 
 
Cisplatin and gemcitabine IV infusions x 
 
x 
x 
 
 
 
Concomitant medications y 
x 
x 
 
x 
x 
 
Tumor assessment z, aa 
x z 
x aa 
Adverse events bb 
 
x 
x 
x 
x 
x 
Serum sample for ADA and PK assessment cc 
 
See Appendix 3  
Blood samples for biomarkers (central laboratory) cc 
 
See Appendix 3 
Fresh tumor tissue biopsy sample (optional)  
 
See Appendix 3 
 


Appendix 1: 
Schedule of Activities 
  
Atezolizumab and Bevacizumab—F. Hoffmann-La Roche Ltd 
122/Protocol GO42661, Version 6 
Day 
Screening a 
Treatment Cycles (21-Day Cycles) b 
Treatment 
Discontinuation 
Visit c 
 30 Days after 
Final Dose 
Follow-Up 
Chemotherapy 
Combination Phase 
(Cycles 18) 
CIT/Placebo 
Phase 
(Cycles 9 and 
Beyond) 
Days –28 
to –1 
Day 1  
Day 8 
Day 1  
(Window) 
( 3 Days) 
Stool sample (optional)  
x 
See Appendix 3 
 
 
 
Survival and anti-cancer therapy follow-up dd 
 
 
 
 
 
x 


Appendix 1: 
Schedule of Activities 
  
Atezolizumab and Bevacizumab—F. Hoffmann-La Roche Ltd 
123/Protocol GO42661, Version 6 
ADA  anti-drug antibody; CIT  cancer immunotherapy; CT  computed tomography; ECOG  Eastern Cooperative Oncology Group; 
EGD  esophagogastroduodenoscopy; EORTC  European Organisation for Research and Treatment of Cancer; FFPE  formalin-fixed, 
paraffin-embedded; 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; PK  pharmacokinetic; PRO  patient-reported outcome; RECIST v1.1  Response 
Evaluation Criteria in Solid Tumors, Version 1.1; T3  free triiodothyronine; T4  free thyroxine. 
Notes:  All assessments will be performed on the day of the specified visit unless a time window is specified.  On treatment days, all assessments 
should be performed prior to dosing, unless otherwise specified.  If scheduled dosing and study assessments are precluded because of a holiday, 
weekend, or other event, dosing may be postponed to the soonest following date, with subsequent dosing continuing on a 21-day schedule.  
If treatment was postponed for fewer than 3 days, the patient can resume the original schedule.  Screening local laboratory assessments 
obtained  96 hours prior to the initiation of study treatment do not have to be repeated for Cycle 1. 
a Results of standard of care tests or examinations performed prior to obtaining informed consent and within 28 days prior to Day 1 of Cycle 1 may 
be used; such tests do not need to be repeated for screening. 
b During the study treatment period, assessments scheduled on the days of study treatment infusions, should be performed before the infusion 
unless otherwise noted. 
c Patients will be asked to return to the clinic no more than 30 days after the final dose of study treatment for a treatment discontinuation visit. 
d Informed consent must be documented before any study-specific screening procedure is performed. 
e Representative tumor specimens in formalin fixed paraffin-embedded (FFPE) blocks (preferred) or at least 16 unstained slides with an 
associated pathology report should be submitted within 4 weeks of randomization.  A patient with insufficient or unavailable archival tissue or 
without a fresh biopsy sample may be eligible.  See Section 4.1.1 for tissue sample requirements. 
f Medical history, including clinically significant diseases, surgeries, reproductive status, smoking history, and use of alcohol, will be recorded at 
screening.  Cancer history includes stage, date of diagnosis, and prior cancer therapies and procedures. 
g The  3-day window only applies to visit scheduling.  PROs should 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 ( 3-day window).  In scenarios 
where laboratory assessments (e.g., blood draws) are done at a different location than the one providing treatment or when they are done on a 
different day than study treatment administration, laboratory assessments can be completed before the completion of PROs ( 3 days) as long as 
results have not been discussed with patients. 
j Vital signs include respiratory rate, pulse rate, systolic and diastolic blood pressure, and temperature.  Vital signs should be recorded as 
described in Section 4.5.4. 
k The dose of bevacizumab/placebo 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 body weight, in which 
case the bevacizumab dose should be modified.  Body weight will be re-baselined at the time of dose change, and dose modifications should 
occur if the patient’s weight changes  10% from the new baseline.  In general, sites should also follow their institutional guidelines and local 
standard of care for determining chemotherapy dose adjustments in the event of changes in patient weight. 


Appendix 1: 
Schedule of Activities 
  
Atezolizumab and Bevacizumab—F. Hoffmann-La Roche Ltd 
124/Protocol GO42661, Version 6 
l Complete and limited physical examinations are defined in Section 4.5.3. 
m ECOG Performance Status, limited physical examination, local laboratory assessments, and PRO assessments may be obtained 96 hours 
before Day 1 of each cycle. 
n An ECG is required at screening and when clinically indicated.  Electrocardiograms for each patient should be obtained from the same machine 
wherever possible.  Lead placement should be as consistent as possible.  Electrocardiogram recordings must be performed after the patient has 
been resting in a supine position for at least 10 minutes. 
o Patients at high risk of esophageal varices are required to undergo an EGD during screening or must have undergone an EGD within 6 months 
of Day 1 of Cycle 1.  Please refer to Section 4.1.2 for risk criteria. 
p Hematology consists of CBC, including RBC count, hemoglobin, hematocrit, WBC count with differential (neutrophils, lymphocytes, eosinophils, 
monocytes, basophils), and platelet count. 
q At screening, patients must have adequate hematologic and end-organ function defined by laboratory results obtained within 7 days prior to 
Day 1 of Cycle 1, as described in Section 4.1.1.  Screening local laboratory assessments obtained  96 hours prior to the initiation of study 
treatment do not have to be repeated for Cycle 1. 
r Chemistry panel (serum or plasma) includes bicarbonate or total carbon dioxide (if considered standard of care for the region), magnesium, 
sodium, potassium, chloride, glucose, BUN or urea, creatinine, total protein, albumin, phosphate, calcium, total bilirubin, ALP, ALT, AST, and 
LDH. 
s All women of childbearing potential (including those who have had a tubal ligation) must have a serum pregnancy test performed at screening 
and documented as negative within 14 days prior to Day 1 of Cycle 1.  During the study, urine pregnancy tests will be performed on Day 1 of 
every cycle.  If a urine pregnancy test is positive, it must be confirmed by a serum pregnancy test. 
t TSH, free T3 (or total T3 at sites where free T3 is not performed), and free T4 will be collected at screening, on Day 1 of Cycle 1, and every 
fourth cycle thereafter (e.g., Cycles 1, 5, 9, 13, and so forth). 
u During screening, patients will be tested for HIV, HBsAg, HBsAb, total HBcAb, and HCV antibody.  HBV DNA test must be performed during 
screening in patients who have positive serology for HBsAg and/or positive serology for HBcAb.  If a patient has a positive HCV antibody test 
during screening, an HCV RNA test must also be performed. 
v If a patient tests positive for HBsAg and/or HBcAb, quantitative HBsAg and HBV DNA will be tested during screening, Day 1 of Cycles 5 and 9, 
and at the discontinuation visit.  If a patient tests positive for HCV antibody during screening, quantitative HCV RNA must be tested locally during 
screening, on Day 1 of Cycles 5 and 9, and at the discontinuation visit.  If local quantitative HBsAg test is not available, a qualitative HBsAg 
followed by quantitative HBV DNA can be performed as an alternative.  Study treatment and procedures may proceed while HBV DNA is being 
processed, but results should be reviewed by the investigator as soon as they are available.  If HBV DNA increases to  500 IU/mL, consultation 
with a hepatologist or gastroenterologist with specialty in HBV is recommended.  The Medical Monitor is available to advise as needed. 


Appendix 1: 
Schedule of Activities 
  
Atezolizumab and Bevacizumab—F. Hoffmann-La Roche Ltd 
125/Protocol GO42661, Version 6 
w Urinalysis includes PH, specific gravity, glucose, protein, ketones, and blood.  Dipstick is permitted.  Urine dipstick for proteinuria at screening 
must be  2   within 7 days prior to Day 1 of Cycle 1.  Patients discovered to have  2+ proteinuria on dipstick urinalysis at baseline should 
undergo a 24-hour urine collection and must demonstrate  1 g of protein in 24 hours.  Urinalysis/urine dipstick should be repeated before every 
cycle during treatment. 
x Atezolizumab will be administered prior to bevacizumab/placebo.  Patients will receive atezolizumab by continuous IV infusion every 21 days on 
Day 1 of each 21-day cycle as indicated.  For atezolizumab, the initial dose will be delivered over 60 ( 15) minutes.  Subsequent infusions will 
be delivered over 30 ( 10) minutes if the previous infusion was tolerated without infusion-associated adverse events, or 60 ( 15) minutes if the 
patient experienced an infusion-associated adverse event with the previous infusion.  Following atezolizumab, patients will receive 
bevacizumab/placebo by continuous IV infusion every 21 days on Day 1 of each 21-day cycle as indicated.  The initial dose of 
bevacizumab/placebo will be delivered over 90 ( 15) minutes.  Subsequent infusions will be delivered over 60 ( 10) minutes if the previous 
continuous IV infusion was tolerated without infusion-associated adverse events, or 90 ( 15) minutes if the patient experienced an 
infusion-associated adverse event with the previous infusion.  Subsequent infusions will be delivered over 30 ( 10) minutes if the previous 
infusion was tolerated without infusion-associated adverse events, or 60 ( 15) minutes if the patient experienced an infusion-associated adverse 
event with the previous infusion.  During the chemotherapy combination phase, patients will receive cisplatin at a dose of 25 mg/m2 IV followed 
by gemcitabine at a dose of 1000 mg/m2 by continuous IV infusion on Days 1 and 8 of each 21-day cycle.  Cisplatin will be administered after 
completion of the bevacizumab/placebo infusion, and gemcitabine will be administered after completion of the cisplatin infusion.  Dosing of all 
study drugs will occur only if the clinical assessment and local laboratory test results are acceptable.  If a tumor assessment was performed, 
results must be reviewed by the investigator before dosing of study treatment. 
y 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 Day 1 of Cycle 1 should be documented until the treatment 
discontinuation visit.  At study visits, changes to current medications or medications used since the last documentation will be recorded. 
z All measurable and evaluable lesions should be assessed and documented at screening.  Tumor assessments performed as a standard of care 
prior to obtaining informed consent and within 28 days prior to Day 1 of Cycle 1 do not have to be repeated at screening.  Screening 
assessments must include CT scans (with oral or IV contrast) or MRI scans of the chest, abdomen, 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. 


Appendix 1: 
Schedule of Activities 
  
Atezolizumab and Bevacizumab—F. Hoffmann-La Roche Ltd 
126/Protocol GO42661, Version 6 
aa Patients will undergo tumor assessments at baseline and every 9 ( 1) weeks thereafter, regardless of dose delays, until radiographic disease 
progression per RECIST v1.1 or (for patients who continue atezolizumab plus bevacizumab or placebo, after radiographic disease progression) 
loss of clinical benefit as determined by the investigator (see Section 3.1 for details).  Thus, tumor assessments are to continue according to 
schedule in patients who discontinue treatment for reasons other than disease progression or loss of clinical benefit, even if they start new 
anti-cancer therapy.  At the investigator's discretion, tumor assessments may be repeated at any time if progressive disease is suspected.  All 
measurable and evaluable lesions should be re-assessed at each subsequent tumor evaluation.  The same radiographic procedures used to 
assess disease sites at screening should be used for subsequent tumor assessments (e.g., the same contrast protocol for CT scans). 
bb After informed consent has been obtained, but prior to Day 1 of Cycle 1, only serious adverse events caused by a protocol-mandated 
intervention should be reported.  After initiation of study treatment, all adverse events will be reported until 30 days after the final dose of study 
treatment or until initiation of 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 final dose of study treatment or until initiation of a new systemic anti-cancer therapy, 
whichever occurs first.  After this period, all deaths, regardless of cause, should be reported.  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 adverse event should be reported (see 
Section 5.6). 
cc See Appendix 3 for details of the PK, immunogenicity, and biomarker collection schedule.  Blood samples may be processed at sites to obtain 
serum and plasma, as described in the laboratory manual. 
dd After treatment discontinuation, information on survival follow-up and new anti-cancer therapy (including targeted therapy and immunotherapy) 
will be collected via telephone calls, patient medical records, and/or clinic visits approximately every 3 months until death (unless the patient 
withdraws consent or the Sponsor terminates the study).  If a patient requests to be withdrawn from follow-up, this request must be documented 
in the source documents and signed by the investigator.  If the patient withdraws from the study, the study staff may use a public information 
source (e.g., county records) to obtain information about survival status. 
 


 
Atezolizumab and Bevacizumab—F. Hoffmann-La Roche Ltd 
127/Protocol GO42661, Version 6 
Appendix 2  
Schedule of Patient-Reported Outcome Assessments 
Day 
All Treatment Cycles (21-Day Cycles) a 
Treatment Discontinuation 
Visit b 
 30 Days after 
Final Dose 
Chemotherapy Combination Phase 
CIT/Placebo Phase 
Cycles 12 
Cycles 35 
Cycles 
68 
Cycles 9 and 
Beyond 
Day 1 
Day 8 
Day 15 c 
Day 1 
Day 15 c 
Day 1 
Day 1 
(Window) 
( 3 Days) 
EORTC QLQ-C30 
x 
 
 
 
 
 
x 
(Cycles 9 and 11 
only) 
x 
EORTC IL77 
 
 
 
x 
 
x 
x 
(Odd cycles 
13   only) 
 
EORTC QLQ-BIL21 
x 
 
 
x 
 
x 
x 
(Odd cycles 9   only) 
x 
PGI-CI 
 
 
 
x 
(Cycle 3 
only) 
 
x 
(Cycle 6 
only) 
x 
(Cycle 9 only) 
x 
PGI-S 
x 
 
 
x 
(Cycle 3 
only) 
 
x 
(Cycle 6 
only) 
x 
(Cycle 9 only) 
x 
PRO-CTCAE 
x 
x 
x c 
x 
x c 
x 
x 
(Odd cycles 9   only) 
x 


Appendix 2 
Schedule of Patient-Reported Outcome Assessments 
  
Atezolizumab and Bevacizumab—F. Hoffmann-La Roche Ltd 
128/Protocol GO42661, Version 6 
CIT  cancer immunotherapy; EORTC  European Organisation for Research and Treatment of Cancer; IL  item library; PGI-CI  Patient Global 
Impression of Change and its Importance; PGI-S  Patient Global Impression of Severity; PRO  patient-reported outcome; 
PRO-CTCAE  Patient-Reported Outcome Common Terminology Criteria for Adverse Events; QLQ-BIL21  Quality-of-Life Questionnaire for 
Cholangiocarcinoma and Cancer of the Gallbladder. 
a All PRO assessments will be completed at the clinic, except for the Day 15 PRO-CTCAE which will be completed from home.  The  3-day 
window only applies to visit scheduling.  PROs should 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 ( 3-day window).  In scenarios where laboratory 
assessments (e.g., blood draws) are done at a different location than the one providing treatment or when they are done on a different day than 
study treatment administration, laboratory assessments can be completed before the completion of PROs ( 3 days) as long as results have not 
been discussed with patients. 
b Patients will be asked to return to the clinic not more than 30 days after the final dose of study treatment for a treatment discontinuation visit. 
c These PRO assessments will be completed at home via telephone call. 
 


 
Atezolizumab and Bevacizumab—F. Hoffmann-La Roche Ltd 
129/Protocol GO42661, Version 6 
Appendix 3  
Schedule of Pharmacokinetic, Immunogenicity, and 
Biomarker Samples 
Visit 
Timepoint 
Sample Type 
 
Screening and between 
Cycle 2 and Cycle 3 
(optional) 
 
 
Stool sample (optional) 
 
Day 1 of Cycle 1 
 
Prior to any drug 
administration 
 
Atezolizumab PK (serum) 
 
Atezolizumab ADA 
(serum) 
 
Blood biomarker (PBMC) 
 
Serum biomarker 
 
Plasma biomarker 
 
Blood (WES) a 
 
30 ( 10) minutes after 
end of atezolizumab 
infusion 
 
Atezolizumab PK (serum) 
 
Day 1 of Cycles 2, 3, 4, 8, 
12, and 16 
 
Prior to any drug 
administration 
 
Atezolizumab PK (serum) 
 
Atezolizumab ADA 
(serum) 
 
Blood biomarker (PBMC) 
 
Serum biomarker 
 
Plasma biomarker 
 
24 weeks after treatment 
initiation and at disease 
progression 
(optional) 
 
 
Fresh tumor tissue biopsy 
sample (optional) b 
 
Treatment discontinuation 
visit ( 30 days after final 
dose) c 
 
At visit 
 
Atezolizumab PK (serum) 
 
Atezolizumab ADA 
(serum) 
 
Blood biomarker (PBMC) 
 
Serum biomarker 
 
Plasma biomarker 
ADA  anti-drug antibody; PBMC  peripheral blood mononuclear cell; PK  pharmacokinetic; 
WES  whole exome sequencing. 
a Blood sample for WES to be collected at Day 1 of Cycle 1, or as soon as possible after 
enrollment.  Collection for participating sites only. 
b For patients who consent to collection of optional biopsies, optional tumor biopsy samples 
may be collected by core-needle or excisional or punch biopsy at the investigator’s discretion.  
Preferably, growing lesions should be selected. 
c If biomarker samples have been collected or will be collected at a visit within 7 days of the 
biopsy procedure date, an additional biomarker sample collection is not required 
 


 
Atezolizumab and Bevacizumab—F. Hoffmann-La Roche Ltd 
130/Protocol GO42661, Version 6 
Appendix 4  
Staging Criteria for Advanced Biliary Cancers 
BTC subtype 
Locally advanced 
Metastatic 
Extrahepatic 
(Biliary confluence 
involvement) 
 
Bilateral extension to second-
order biliary radicles 
 
Encasement or occlusion of 
hepatic artery (or bilateral 
involvement of hepatic arteries) 
 
Encasement or occlusion of portal 
vein 
 
Atrophy of one liver lobe with 
contralateral portal branch or 
hepatic artery involvement 
 
Extrahepatic adjacent local 
invasion (vessels or organs) 
 
Multifocal masses within 
different liver segments 
 
Metastatic lymph nodes 
beyond the 
hepatoduodenal ligament 
 
Extrahepatic 
disseminated disease 
(e.g., lung, bone, 
peritoneum) 
Intrahepatic 
(Hepatic mass 
without biliary 
confluence 
involvement) 
 
Hepatic artery involvement 
 
Multifocal masses within the same 
liver segment 
 
Extrahepatic adjacent local 
invasion (vessels or organs) 
Gallbladder 
 
Large intrahepatic adjacent local 
invasion 
 
Extrahepatic adjacent local 
invasion (vessels, bile ducts or 
organs) 
BTC  biliary tract cancer. 
 
REFERENCE 
Malka D, Cervera P, Foulon S, et al. Gemcitabine and oxaliplatin with or without 
cetuximab in advanced biliary-tract cancer (BINGO): a randomised, open-label, 
non-comparative phase 2 trial. Lancet Oncol 2014;15:819828. 
 


 
Atezolizumab and Bevacizumab—F. Hoffmann-La Roche Ltd 
131/Protocol GO42661, Version 6 
Appendix 5  
Response Evaluation Criteria in Solid Tumors, 
Version 1.1 (RECIST v1.1) 
Selected sections from the Response Evaluation Criteria in Solid Tumors, Version 1.1 
(RECIST v1.1) (Eisenhauer et al. 2009), are presented below, with slight modifications 
from the original publication and the addition of explanatory text as needed for clarity.1 
TUMOR MEASURABILITY 
At baseline, tumor lesions/lymph nodes will be categorized as measurable or 
non-measurable as described below.  All measurable and non-measurable lesions 
should be assessed at screening and at subsequent protocol-specified tumor 
assessment timepoints.  Additional assessments may be performed as clinically 
indicated for suspicion of progression. 
DEFINITION OF MEASURABLE LESIONS 
Tumor Lesions 
Tumor lesions must be accurately measured in at least one dimension (longest diameter 
in the plane of measurement is to be recorded) with a minimum size as follows: 
 
10 mm by computed tomography (CT) or magnetic resonance imaging (MRI) scan 
(CT/MRI scan slice thickness/interval  5 mm) 
 
10-mm caliper measurement by clinical examination (lesions that cannot be 
accurately measured with calipers should be recorded as non-measurable) 
 
20 mm by chest X-ray 
 
Malignant Lymph Nodes 
To be considered pathologically enlarged and measurable, a lymph node must be 
 15 mm in the short axis when assessed by CT scan (CT scan slice thickness 
recommended to be  5 mm).  At baseline and follow-up, only the short axis will be 
measured and followed.  Additional information on lymph node measurement is provided 
below (see Identification of Target and Non-Target Lesions and Calculation of Sum of 
Diameters). 
                                            
 
1 For clarity and for consistency within this document, the section numbers and cross-references 
to other sections within the article have been deleted and minor changes have been made. 


Appendix 5:  Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST v1.1) 
  
Atezolizumab and Bevacizumab—F. Hoffmann-La Roche Ltd 
132/Protocol GO42661, Version 6 
DEFINITION OF NON-MEASURABLE LESIONS 
Non-measurable tumor lesions encompass small lesions (longest diameter  10 mm or 
pathological lymph nodes with short axis  10 mm but  15 mm) as well as truly 
non-measurable lesions.  Lesions considered truly non-measurable include 
leptomeningeal disease, ascites, pleural or pericardial effusion, inflammatory breast 
disease, lymphangitic involvement of skin or lung, peritoneal spread, and abdominal 
mass/abdominal organomegaly identified by physical examination that is not measurable 
by reproducible imaging techniques. 
SPECIAL CONSIDERATIONS REGARDING LESION MEASURABILITY 
Bone lesions, cystic lesions, and lesions previously treated with local therapy require 
particular comment, as outlined below. 
Bone Lesions: 
 
Technetium-99m bone scans, sodium fluoride positron emission tomography scans, 
and plain films are not considered adequate imaging techniques for measuring bone 
lesions.  However, these techniques can be used to confirm the presence or 
disappearance of bone lesions. 
 
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 
 


Appendix 5:  Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST v1.1) 
  
Atezolizumab and Bevacizumab—F. Hoffmann-La Roche Ltd 
133/Protocol GO42661, Version 6 
METHODS FOR ASSESSING LESIONS 
All measurements should be recorded in metric notation, using calipers if clinically 
assessed.  All baseline evaluations should be performed as close as possible to the 
treatment start and never more than 4 weeks before the beginning of the treatment. 
The same method of assessment and the same technique should be used to 
characterize each identified and reported lesion at baseline and during the study.  
Imaging-based evaluation should always be the preferred option. 
CLINICAL LESIONS 
Clinical lesions will only be considered measurable when they are superficial and 
 10 mm in diameter as assessed using calipers (e.g., skin nodules).  For the case of 
skin lesions, documentation by color photography, including a ruler to estimate the size 
of the lesion, is suggested. 
CHEST X-RAY 
Chest CT is preferred over chest X-ray, particularly when progression is an important 
endpoint, since CT is more sensitive than X-ray, particularly in identifying new lesions.  
However, lesions on chest X-ray may be considered measurable if they are clearly 
defined and surrounded by aerated lung. 
CT AND MRI SCANS 
Computed tomography 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 a 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.  Magnetic resonance 
imaging 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 (without IV contrast) will be used to evaluate the patient at 
baseline and during the study should be guided by the tumor type under investigation 
and the anatomic location of the disease.  For patients who develop contraindications to 
contrast after baseline contrast CT is done, the decision as to whether non-contrast CT 
or MRI (enhanced or non-enhanced) will be performed should also be based on the 
tumor type and the anatomic location of the disease, and should be optimized to allow 
for comparison with the prior studies if possible.  Each case should be discussed with 
the radiologist to determine if substitution of these other approaches is possible and, 
if not, the patient should be considered not evaluable from that point forward.  Care must 
be taken in measurement of target lesions and interpretation of non-target disease or 


Appendix 5:  Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST v1.1) 
  
Atezolizumab and Bevacizumab—F. Hoffmann-La Roche Ltd 
134/Protocol GO42661, Version 6 
new lesions on a different modality, since the same lesion may appear to have 
a different size using a new modality. 
ENDOSCOPY, LAPAROSCOPY, ULTRASOUND, TUMOR MARKERS, 
CYTOLOGY, HISTOLOGY 
Endoscopy, laparoscopy, ultrasound, tumor markers, cytology, and histology cannot be 
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 5 lesions total (and a maximum of 2 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 1 or 
2 organ sites involved, a maximum of 2 lesions (1 site) and 4 lesions (2 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 


Appendix 5:  Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST v1.1) 
  
Atezolizumab and Bevacizumab—F. Hoffmann-La Roche Ltd 
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but  15 mm) should be considered non-target lesions.  Nodes that have a short axis of 
 10 mm are considered non-pathological and should not be recorded or followed. 
All lesions (or sites of disease) not selected as target lesions (measurable or 
non-measurable), including pathological lymph nodes, should be identified as non-target 
lesions and should also be recorded at baseline.  Measurements are not required.  It is 
possible to record multiple non-target lesions involving the same organ as a single item 
on the Case Report Form (CRF) (e.g., multiple enlarged pelvic lymph nodes or 
multiple liver metastases). 
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 CR criteria are met, since a normal lymph node is defined as having a short axis of 
 10 mm. 
Measuring Lesions That Become Too Small to Measure 
During the study, all target lesions (lymph node and non-lymph node) recorded at 
baseline should have their actual measurements recorded at each subsequent 
evaluation, even when very small (e.g., 2 mm).  However, sometimes lesions or lymph 
nodes that are recorded as target lesions at baseline become so faint on the CT scan 
that the radiologist may not feel comfortable assigning an exact measurement and may 
report them as being too small to measure.  When this occurs, it is important that a value 
be recorded on the CRF, as follows: 
 
If it is the opinion of the radiologist that the lesion has likely disappeared, the 
measurement should be recorded as 0 mm. 
 
If the lesion is believed to be present and is faintly seen but too small to measure, 
a default value of 5 mm should be assigned and too small to measure should be 
ticked.  (Note:  It is less likely that this rule will be used for lymph nodes since they 
usually have a definable size when normal and are frequently surrounded by fat 
such as in the retroperitoneum; however, if a lymph node is believed to be present 
and is faintly seen but too small to measure, a default value of 5 mm should be 
assigned in this circumstance as well and too small to measure should also be 
ticked). 
 


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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 on Treatment 
When non-lymph node lesions fragment, the longest diameters of the fragmented 
portions should be added together to calculate the sum of diameters.  Similarly, as 
lesions coalesce, a plane between them may be maintained that would aid in obtaining 
maximal diameter measurements of each individual lesion.  If the lesions have truly 
coalesced such that they are no longer separable, the vector of the longest diameter in 
this instance should be the maximum longest diameter for the coalesced lesion. 
EVALUATION OF NON-TARGET LESIONS 
Measurements are not required for non-target lesions, except that malignant lymph node 
non-target lesions should be monitored for reduction to  10 mm in short axis.  
Non-target lesions should be noted at baseline and should be identified as present or 
absent and (in rare cases) may be noted as indicative of progression at subsequent 
evaluations.  In addition, if a lymph node lesion shrinks to a non-malignant size 
(short axis  10 mm), this should be captured on the CRF as part of the assessment of 
non-target lesions. 
RESPONSE CRITERIA 
CRITERIA FOR TARGET LESIONS 
Definitions of the criteria used to determine objective tumor response for target lesions 
are provided below: 
 
Complete response:  Disappearance of all target lesions 
Any pathological lymph nodes must have reduction in short axis to  10 mm. 
 
Partial response:  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 
 


Appendix 5:  Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST v1.1) 
  
Atezolizumab and Bevacizumab—F. Hoffmann-La Roche Ltd 
137/Protocol GO42661, Version 6 
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. 
 
Complete response:  Disappearance of all non-target lesions and (if applicable) 
normalization of tumor marker level 
All lymph nodes must be non-pathological in size ( 10 mm short axis). 
 
Non-CR/Non-PD:  Persistence of one or more non-target lesions and/or 
(if applicable) maintenance of tumor marker level above the normal limits 
 
Progressive disease:  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. 


Appendix 5:  Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST v1.1) 
  
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If a new lesion is equivocal, for example because of its small size, continued therapy and 
follow-up evaluation will clarify if it represents truly new disease.  If repeat scans confirm 
there is definitely a new lesion, progression should be declared using the date of the 
initial scan. 
CRITERIA FOR OVERALL RESPONSE AT A SINGLE TIMEPOINT 
Table 1 provides a summary of the overall response status calculation at each response 
assessment timepoint for patients who have measurable disease at baseline. 
Table 1 
Criteria for Overall Response at a Single Timepoint:  Patients 
with Target Lesions (with or without Non-Target Lesions) 
Target Lesions 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
CR 
No 
CR 
CR 
Non-CR/non-PD 
No 
PR 
CR 
Not all evaluated 
No 
PR 
PR 
Non-PD or not all 
evaluated 
No 
PR 
SD 
Non-PD or not all 
evaluated 
No 
SD 
Not all evaluated 
Non-PD 
No 
NE 
PD 
Any 
Yes or no 
PD 
Any 
PD 
Yes or no 
PD 
Any 
Any 
Yes 
PD 
CR  complete response; NE  not evaluable; PD  progressive disease; PR  partial response; 
SD  stable disease. 
 
MISSING ASSESSMENTS AND NOT-EVALUABLE DESIGNATION 
When no imaging/measurement is done at all at a particular timepoint, the patient is not 
evaluable at that timepoint.  If measurements are made on only a subset of target 
lesions at a timepoint, usually the case is also considered not evaluable at that 
timepoint, unless a convincing argument can be made that the contribution of the 
individual missing lesions would not change the assigned timepoint response.  This 
would be most likely to happen in the case of PD.  For example, if a patient had 
a baseline sum of 50 mm with 3 measured lesions and during the study, only 2 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. 


Appendix 5:  Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST v1.1) 
  
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139/Protocol GO42661, Version 6 
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 therapy.  
The objective response status of such patients is to be determined by evaluation of 
target and non-target lesions as shown in Table 1. 
For equivocal findings of progression (e.g., very small and uncertain new lesions; cystic 
changes or necrosis in existing lesions), treatment may continue until the next scheduled 
assessment.  If at the next scheduled assessment, progression is confirmed, the date of 
progression should be the earlier date when progression was suspected. 
REFERENCE 
Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid 
tumors: revised RECIST guideline (version 1.1). Eur J Cancer 2009;45:22847. 
 


 
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Appendix 6  
European Organisation for the Research and Treatment of 
Cancer Quality-of-Life Questionnaire (EORTC QLQ-C30) 
This document must not be reproduced.  The Sponsor will provide a copy of the 
document upon request. 
 
 
 


Appendix 6: European Organisation for Research and Treatment of Cancer Quality-of-Life 
Questionnaire (EORTC QLQ-C30) 
  
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141/Protocol GO42661, Version 6 
 
 


 
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Appendix 7  
European Organisation for Research and Treatment of Cancer 
Quality-of-Life Questionnaire for Cholangiocarcinoma and 
Cancer of the Gallbladder (EORTC QLQ-BIL21) 
This document must not be reproduced.  The Sponsor will provide a copy of the 
document upon request. 
 
 


 
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Appendix 8  
European Organisation for Research and Treatment of Cancer 
Item Library 77 (EORTC IL77) 
This document must not be reproduced.  The Sponsor will provide a copy of the 
document upon request. 
 
 


 
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Appendix 9  
Patient Global Impression of Change and Its Importance (PGI-CI) 
This document must not be reproduced.  The Sponsor will provide a copy of the 
document upon request. 
 


 
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Appendix 10  
Patient Global Impression of Severity (PGI-S) 
This document must not be reproduced.  The Sponsor will provide a copy of the 
document upon request. 
 


 
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Appendix 11  
Patient-Reported Outcome Common Terminology Criteria for 
Adverse Events (PRO-CTCAE) 
 


 
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Appendix 12  
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 myocarditis  
 Autoimmune myelitis  
 Autoimmune oophoritis 
 Autoimmune orchitis 
 Autoimmune 
thrombocytopenic purpura 
 Behçet disease 
 Bullous pemphigoid 
 Chronic fatigue syndrome 
 Chronic inflammatory 
demyelinating polyneuropathy 
 Churg-Strauss syndrome 
 Crohn disease 
 Dermatomyositis 
 Diabetes mellitus type 1 
 Dysautonomia 
 Epidermolysis bullosa 
acquisita 
 Gestational pemphigoid 
 Giant cell arteritis 
 Goodpasture syndrome 
 Granulomatosis with 
polyangiitis 
 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 
 


 
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Appendix 13  
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: 
 
Monitoring devices:  ECG monitor, blood pressure monitor, oxygen saturation 
monitor, and thermometer 
 
Oxygen 
 
Epinephrine for subcutaneous, intramuscular, IV, and/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 14  
Overall Guidelines for Management of Patients Who Experience 
Adverse Events 
DOSE MODIFICATIONS 
There will be no dose modifications for atezolizumab.  No dose modifications are 
permitted for bevacizumab/placebo aside from weight-based dose changes as outlined 
in the protocol. 
Recommendations on dose modifications for cisplatin and gemcitabine (CisGem) are 
provided in the Safety Plan (Section 5.1.5). 
TREATMENT INTERRUPTION 
Atezolizumab treatment may be temporarily suspended in patients experiencing toxicity 
considered to be related to study treatment.  If corticosteroids are initiated for treatment 
of the toxicity, they must be tapered over  1 month to the equivalent of  10 mg/day oral 
prednisone before atezolizumab can be resumed.  If atezolizumab is withheld for 
 12 weeks after event onset, the patient will be discontinued from atezolizumab.  
However, atezolizumab may be withheld for  12 weeks to allow for patients to taper off 
corticosteroids prior to resuming treatment.  Atezolizumab can be resumed after being 
withheld for  12 weeks if the patient is likely to derive clinical benefit.  The decision to 
re-challenge patients with atezolizumab should be based on the investigator's 
benefitrisk assessment and documented by the investigator.  The Medical Monitor is 
available to advise as needed.  Atezolizumab treatment may be suspended for reasons 
other than toxicity (e.g., surgical procedures).  The acceptable length of treatment 
interruption 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. 
Bevacizumab/placebo treatment may be temporarily suspended in patients experiencing 
toxicity considered to be related to study treatment.  If the event resolves to Grade  1, 
bevacizumab/placebo may be restarted at the same dose level.  If bevacizumab/placebo 
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/placebo.  
Bevacizumab/placebo can be resumed after being withheld for  42 days if the patient is 
likely to derive clinical benefit. 
Gemcitabine and cisplatin treatment may be temporarily suspended in patients who 
experience toxicity considered to be related to study treatment.  If gemcitabine or 
cisplatin have been withheld for  42 days because of toxicity, the patient should be 
discontinued from gemcitabine or cisplatin. 


Appendix 14: Overall Guidelines for Management of Patients Who Experience 
Adverse Events 
  
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150/Protocol GO42661, Version 6 
Atezolizumab, bevacizumab/placebo, gemcitabine, or cisplatin treatment may be 
suspended for reasons other than toxicity (e.g., surgical procedures).  The investigator 
will determine the acceptable length of treatment interruption.  If atezolizumab, 
bevacizumab/placebo, gemcitabine, or cisplatin are transiently withheld or permanently 
discontinued, one or all of the other drugs can be continued as long as the patients are 
experiencing clinical benefit in the opinion of the investigator.  However, 
bevacizumab/placebo should not be continued as a single agent.  Recommendations on 
CisGem dose interruptions are provided in the Safety Plan (Section 5.1.5). 
MANAGEMENT GUIDELINES 
Guidelines for management of patients who experience specific adverse events are 
provided in Table 1.  See both Table 1 and Table 2 for adverse events that occur during 
the chemotherapy combination phase.  See Table 2 for adverse events that occur during 
the cancer immunotherapy (CIT)/placebo phase. 
Specific adverse events associated with gemcitabine or cisplatin are provided below.  
For adverse events that are not listed herein, see guidelines in the applicable local 
prescribing information (if available) or Summary of Product Characteristics.  For cases 
in which management guidelines are not covered in the protocol or prescribing 
information, patients should be managed as deemed clinically appropriate by the 
investigator. 


Appendix 14: Overall Guidelines for Management of Patients Who Experience 
Adverse Events 
  
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Table 1 
Guidelines for Management of Patients Who Experience Specific 
Adverse Events with Atezolizumab plus Bevacizumab/Placebo 
with or without Cisplatin and Gemcitabine 
Event 
Action to Be Taken 
IRRs, anaphylaxis, and 
hypersensitivity reactions 
 Guidelines for management of IRRs for atezolizumab are 
provided in Appendix 15. 
 Guidelines for management of IRRs for bevacizumab/placebo 
are provided below. 
 For anaphylaxis precautions, see Appendix 13. 
 For hypersensitivity reactions and allergic reactions, 
permanently discontinue the causative agent. 
IRR to bevacizumab/placebo, 
Grade 1  
 Systemic intervention is not indicated.  Continue 
bevacizumab/placebo. 
IRR to bevacizumab/placebo, 
Grade 2  
 Reduce infusion rate to  50% or interrupt infusion at the 
discretion of the investigator per medical judgment. 
 If the infusion is interrupted, it may be resumed at  50% of the 
rate prior to the reaction after the patient's symptoms have 
adequately resolved and increased in 50% increments up to 
the full rate if well tolerated.  Infusions may be restarted at the 
full rate during the next cycle. 
IRR to bevacizumab/placebo, 
Grade 3 or 4 
 Stop infusion and permanently discontinue 
bevacizumab/placebo. 
 Administer aggressive symptomatic treatment (e.g., oral or IV 
antihistamine, antipyretic, glucocorticoids, epinephrine, 
bronchodilators, oxygen) if clinically indicated. 


Appendix 14: Overall Guidelines for Management of Patients Who Experience 
Adverse Events 
  
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Table 1 
Guidelines for Management of Patients Who Experience Specific 
Adverse Events with Atezolizumab plus Bevacizumab/Placebo 
with or without Cisplatin and Gemcitabine (cont.) 
Event 
Action to Be Taken 
Gastrointestinal toxicity 
GI perforation, any grade 
 
Withhold atezolizumab, gemcitabine, or cisplatin. 
 
Permanently discontinue bevacizumab/placebo. 
 
Initiate treatment per institutional guidelines. 
 
If event improves, consider resuming atezolizumab. 
gemcitabine, or cisplatin If not, permanently discontinue 
atezolizumab, gemcitabine, or cisplatin. a 
Bowel obstruction, Grade 2 
 
Atezolizumab, gemcitabine, or cisplatin. may be continued 
at the discretion of the investigator. 
 
Withhold bevacizumab/placebo for partial obstruction 
requiring medical intervention. 
 
Bevacizumab/placebo may be restarted upon complete 
resolution of event. 
Bowel obstruction, Grade 3 
or 4 
 
Atezolizumab, gemcitabine, or cisplatin may be continued 
at the discretion of the investigator. 
 
Withhold bevacizumab/placebo until complete resolution. 
 
If surgery is necessary, patient may restart 
bevacizumab/placebo after full recovery from surgery and 
at the investigator's discretion. 
Posterior reversible encephalopathy syndrome 
Posterior reversible 
encephalopathy syndrome, 
any grade confirmed by 
magnetic resonance 
imaging 
 
Withhold atezolizumab and cisplatin.  Permanently 
discontinue bevacizumab/placebo and gemcitabine. 
 
If event improves, consider resuming atezolizumab and 
cisplatin.  If not, permanently discontinue atezolizumab 
and cisplatin. a 
a Resumption of treatment may be considered if the investigator believes the patient is likely to 
derive clinical benefit. 
 


Appendix 14: Overall Guidelines for Management of Patients Who Experience 
Adverse Events 
  
Atezolizumab and Bevacizumab—F. Hoffmann-La Roche Ltd 
153/Protocol GO42661, Version 6 
Table 1 
Guidelines for Management of Patients Who Experience Specific 
Adverse Events with Atezolizumab plus Bevacizumab/Placebo 
with or without Cisplatin and Gemcitabine (cont.) 
Hypertension a 
General guidance  
 Treat with antihypertensive medication as needed. 
Hypertension, Grade 1 
 Continue atezolizumab, bevacizumab/placebo, gemcitabine, or 
cisplatin. 
 Consider increased BP monitoring. 
Hypertension, 
Grade 2  
 Continue atezolizumab, gemcitabine, or cisplatin. 
 If asymptomatic, begin or modify baseline anti-hypertensive 
therapy and continue bevacizumab/placebo. 
 If symptomatic, start or adjust anti-hypertensive therapy. 
Hypertension, Grade 3 
 Continue atezolizumab, gemcitabine, or cisplatin. 
 Modify existing anti-hypertensive therapy (more than one drug or 
more intensive therapy than previously indicated). 
 Withhold bevacizumab/placebo until symptoms resolve and BP 
 160/90 mmHg. 
Hypertension, Grade 4 
 Atezolizumab, gemcitabine, or cisplatin may be continued at the 
discretion of the investigator. 
 Permanently discontinue bevacizumab/placebo. 
Hemorrhage 
Hemorrhage, Grade 3 or 
4 (excluding cerebral 
hemorrhage) 
 Continue atezolizumab. gemcitabine, or cisplatin. 
 Permanently discontinue bevacizumab/placebo. 
CNS hemorrhage, any 
grade 
 Atezolizumab, gemcitabine, or cisplatin may be continued at the 
discretion of the investigator. 
 Permanently discontinue bevacizumab/placebo. 
Grade  2 hemoptysis 
( 2.5 mL of bright red 
blood per episode) 
 Continue atezolizumab, gemcitabine, or cisplatin. 
 Permanently discontinue bevacizumab/placebo. 
Bleeding in patients on 
full-dose anticoagulant 
therapy 
 Continue atezolizumab, gemcitabine, or cisplatin. 
 Permanently discontinue bevacizumab/placebo. 
a Vascular disorders (including hypertension and hypotension) are possible adverse events of 
atezolizumab, considering the mechanism of action. 
 


Appendix 14: Overall Guidelines for Management of Patients Who Experience 
Adverse Events 
  
Atezolizumab and Bevacizumab—F. Hoffmann-La Roche Ltd 
154/Protocol GO42661, Version 6 
Table 1 
Guidelines for Management of Patients Who Experience Specific 
Adverse Events with Atezolizumab plus Bevacizumab/Placebo 
with or without Cisplatin and Gemcitabine (cont.) 
Event 
Action to Be Taken 
Thromboembolic events 
Venous thromboembolic event, 
Grade 3 
 Atezolizumab, gemcitabine, or cisplatin may be continued at 
the discretion of the investigator. 
 Withhold bevacizumab/placebo treatment.  If the planned 
duration of full-dose anticoagulation is  2 weeks, 
bevacizumab/placebo should be withheld until the full-dose 
anticoagulation period is over.  The use of direct oral 
anticoagulants is not recommended. 
 If the planned duration of full-dose anticoagulation is 
 2 weeks, bevacizumab/placebo may be resumed during 
full-dose anticoagulation if all of the criteria below are met: 
– The patient must not have pathological conditions that 
carry high risk of bleeding (e.g., tumor involving major 
vessels or other conditions). 
– The patient must not have had hemorrhagic events 
Grade  2 while in the study. 
– The patient must be on stable dose of heparin, 
low-molecular-weight heparin, or have an in-range INR 
(usually 23) on a stable dose of warfarin prior to 
restarting bevacizumab/placebo. 
 If thromboemboli worsen/recur upon resumption of study 
therapy, discontinue bevacizumab/placebo. 
Venous thromboembolic event, 
Grade 4 
 Atezolizumab, gemcitabine, or cisplatin may be continued at 
the discretion of the investigator. 
 Permanently discontinue bevacizumab/placebo. 
Arterial thromboembolic event, 
any grade 
 Atezolizumab, gemcitabine, or cisplatin may be continued at 
the discretion of the investigator. 
 Permanently discontinue bevacizumab/placebo. 


Appendix 14: Overall Guidelines for Management of Patients Who Experience 
Adverse Events 
  
Atezolizumab and Bevacizumab—F. Hoffmann-La Roche Ltd 
155/Protocol GO42661, Version 6 
Table 1 
Guidelines for Management of Patients Who Experience Specific 
Adverse Events with Atezolizumab plus Bevacizumab/Placebo 
with or without Cisplatin and Gemcitabine (cont.) 
Event 
Action to Be Taken 
Proteinuria 
Proteinuria, Grade 1 
(1  by dipstick; urinary protein 
 1.0 g/24 hours) 
 Continue atezolizumab, bevacizumab/placebo, gemcitabine, 
and cisplatin. 
Proteinuria, Grade 2  
(2  and 3  by dipstick; urinary 
protein 1.03.4 g/24 hours) 
 Continue atezolizumab, gemcitabine, or cisplatin. 
 For 2   dipstick:  Continue bevacizumab/placebo and collect 
24-hour urine protein prior to subsequent 
bevacizumab/placebo administration. 
 For 3  dipstick:  Obtain 24-hour urine prior to administering 
bevacizumab/placebo. 
 Withhold bevacizumab/placebo for urinary protein 
 2 g/24 hours. 
 If bevacizumab is withheld and urine protein improves to 
 2 g/24 hours  42 days after event onset, resume 
bevacizumab/placebo.  If not, permanently discontinue 
bevacizumab/placebo. 
Proteinuria, Grade 3  
(4  by dipstick; urinary protein 
 3.5 g/24 hours) with no 
diagnosis of nephrotic 
syndrome 
 Atezolizumab, gemcitabine, or cisplatin may be continued at 
the discretion of the investigator. 
 Withhold bevacizumab/placebo. 
 If urine protein improves to  2 g/24 hours  42 days after 
event onset, resume bevacizumab/placebo.  If not, 
permanently discontinue bevacizumab/placebo. 
Nephrotic syndrome, 
Grade 3 or 4 
 Atezolizumab, gemcitabine, or cisplatin may be continued at 
the discretion of the investigator. 
 Permanently discontinue bevacizumab/placebo. 
Fistula 
Tracheoesophageal fistula 
and fistula formation involving 
an internal organ, any grade 
 Withhold atezolizumab, gemcitabine, or cisplatin. 
 Permanently discontinue bevacizumab/placebo. 
 If event improves, consider resuming atezolizumab, 
gemcitabine, or cisplatin.  If not, permanently discontinue 
atezolizumab. a 
Fistula formation not involving 
an internal organ, Grade 4 
 Withhold atezolizumab, gemcitabine, or cisplatin. 
 Permanently discontinue bevacizumab/placebo. 
 If event improves, consider resuming atezolizumab, 
gemcitabine, or cisplatin.  If not, permanently discontinue 
atezolizumab, gemcitabine, or cisplatin. a 
a Resumption of treatment may be considered if the investigator believes the patient is likely to 
derive clinical benefit. 


Appendix 14: Overall Guidelines for Management of Patients Who Experience 
Adverse Events 
  
Atezolizumab and Bevacizumab—F. Hoffmann-La Roche Ltd 
156/Protocol GO42661, Version 6 
Table 1 
Guidelines for Management of Patients Who Experience Specific 
Adverse Events with Atezolizumab plus Bevacizumab/Placebo 
with or without Cisplatin and Gemcitabine (cont.)  
Event 
Action to Be Taken 
Wound dehiscence 
Wound dehiscence, any grade 
requiring medical or surgical 
therapy 
 Atezolizumab, gemcitabine, or cisplatin may be continued 
at the discretion of the investigator. 
 Permanently discontinue bevacizumab/placebo. 
Congestive heart failure 
Congestive heart failure,  
Grade 3 or 4 
 Atezolizumab may be continued at the discretion of the 
investigator. 
 Permanently discontinue bevacizumab/placebo, 
gemcitabine, or cisplatin. 
Diarrhea 
Diarrhea, Grade 1 or 2  
 Follow guidelines for atezolizumab in Appendix 15. 
 Continue bevacizumab/placebo, gemcitabine and 
cisplatin. 
Diarrhea, Grade 3 or 4 
 Follow guidelines for atezolizumab in Appendix 15. 
 Consider withholding bevacizumab/placebo.  If event 
improves, resume bevacizumab/placebo.  If not, 
permanently discontinue bevacizumab/placebo. 
 If event resolves to Grade 1 or better within 42 days, b 
resume gemcitabine and cisplatin with dose reduced by 
one level. c, d  If not, permanently discontinue gemcitabine 
and cisplatin. 
Pulmonary toxicity 
Pulmonary toxicity, 
Grade 1 or 2  
 Follow guidelines for atezolizumab in Appendix 15. 
 Continue gemcitabine and cisplatin. 
Pulmonary toxicity, 
Grade 3 or 4 
 Follow guidelines for atezolizumab in Appendix 15. 
 Permanently discontinue gemcitabine.  Withhold 
bevacizumab/placebo and cisplatin. 
 If event improves, resume bevacizumab/placebo and 
cisplatin at current dose.  If not, permanently discontinue 
bevacizumab/placebo and cisplatin. 
a Resumption of treatment may be considered if the investigator believes the patient is likely 
to derive clinical benefit. 
b If the investigator believes the patient is likely to derive clinical benefit, can be resumed 
after being withheld for  42 days. 
c Recommendations on dose modifications for gemcitabine and cisplatin are provided in the 
Safety Plan (Section 5.1.5). 
d Cisplatin may be resumed at current dose if the investigator believes the patient is likely to 
derive clinical benefit. 
 


Appendix 14: Overall Guidelines for Management of Patients Who Experience 
Adverse Events 
  
Atezolizumab and Bevacizumab—F. Hoffmann-La Roche Ltd 
157/Protocol GO42661, Version 6 
Table 1 
Guidelines for Management of Patients Who Experience Specific 
Adverse Events with Atezolizumab plus Bevacizumab/Placebo 
with or without Cisplatin and Gemcitabine (cont.) 
Dermatologic events 
Dermatologic event, Grade 1 
or 2 
 Follow guidelines for atezolizumab in Appendix 15 
Appendix 15. 
 Continue bevacizumab/placebo, gemcitabine, or cisplatin. 
Dermatologic event, Grade 3 
 Follow guidelines for atezolizumab in Appendix 15. 
 ·Withhold bevacizumab/placebo, gemcitabine, or cisplatin. 
 If event resolves to Grade 1 or better, resume 
{bevacizumab/placebo, gemcitabine, or cisplatin 
 Permanently discontinue bevacizumab/placebo, 
gemcitabine, or cisplatin if withheld for  42 days. 
Dermatologic event, Grade 4 
 Follow guidelines for atezolizumab in Appendix 15. 
 Permanently discontinue bevacizumab/placebo, 
gemcitabine, or cisplatin. 
Neurologic toxicity 
Neurologic toxicity, 
Grade 1 or 2  
 Follow guidelines for atezolizumab in Appendix 15. 
 Continue bevacizumab/placebo, gemcitabine and 
cisplatin. 
Neurologic toxicity, 
Grade 3 or 4 
 Follow guidelines for atezolizumab in Appendix 15. 
 Consider withholding bevacizumab/placebo.  If event 
improves, resume bevacizumab/placebo.  If not, 
permanently discontinue bevacizumab/placebo. 
 Withhold gemcitabine and cisplatin. 
 If event resolves to Grade 1 or better within 42 days, b 
resume gemcitabine and cisplatin with dose reduced by 
one level. c, d  If not, permanently discontinue gemcitabine 
and cisplatin. 
a Resumption of treatment may be considered if the investigator believes the patient is likely 
to derive clinical benefit. 
b If the investigator believes the patient is likely to derive clinical benefit, can be resumed after 
being withheld for  42 days. 
c Recommendations on dose modifications for gemcitabine and cisplatin are provided in the 
Safety Plan (Section 5.1.5). 
d Cisplatin may be resumed at current dose if the investigator believes the patient is likely to 
derive clinical benefit. 


 
Atezolizumab and Bevacizumab—F. Hoffmann-La Roche Ltd 
158/Protocol GO42661, Version 6 
Table 1 
Guidelines for Management of Patients Who Experience Specific 
Adverse Events with Atezolizumab plus Bevacizumab/Placebo 
with or without Cisplatin and Gemcitabine (cont.) 
Hepatic toxicity 
Hepatic toxicity, Grade 1 or 2  
 Follow guidelines for atezolizumab in Appendix 15. 
 Continue bevacizumab/placebo, gemcitabine and 
cisplatin. 
Hepatic toxicity, Grade 3 
 Follow guidelines for atezolizumab in Appendix 15. 
 Permanently discontinue gemcitabine. 
 Consider withholding bevacizumab/placebo.  If event 
improves, resume bevacizumab/placebo.  If not, 
permanently discontinue bevacizumab/placebo. 
  Withhold cisplatin. 
 If event resolves to Grade 1 or better within 42 days, a 
resume cisplatin with dose reduced by one level. c, d  
If not, permanently discontinue cisplatin. 
Hepatic toxicity, Grade 4 
 Follow guidelines for atezolizumab in Appendix 15. 
 Consider withholding bevacizumab/placebo.  If event 
improves, resume bevacizumab/placebo.  If not, 
permanently discontinue bevacizumab/placebo. 
 Permanently discontinue gemcitabine and cisplatin. 
a Resumption of treatment may be considered if the investigator believes the patient is likely 
to derive clinical benefit. 
b If the investigator believes the patient is likely to derive clinical benefit, can be resumed after 
being withheld for  42 days. 
c Recommendations on dose modifications for gemcitabine and cisplatin are provided in the 
Safety Plan (Section 5.1.5). 
d Cisplatin may be resumed at current dose if the investigator believes the patient is likely to 
derive clinical benefit. 
 
 


Appendix 14: Overall Guidelines for Management of Patients Who Experience 
Adverse Events 
  
Atezolizumab and Bevacizumab—F. Hoffmann-La Roche Ltd 
159/Protocol GO42661, Version 6 
Table 1 
Guidelines for Management of Patients Who Experience Specific 
Adverse Events with Atezolizumab plus Bevacizumab/Placebo 
with or without Cisplatin and Gemcitabine (cont.) 
Bevacizumab-related toxicities not described above 
Grade 1 or 2 
 Continue atezolizumab, bevacizumab/placebo, gemcitabine, 
and cisplatin. 
Grade 3 
 Continue atezolizumab, gemcitabine, and cisplatin.  Withhold 
bevacizumab/placebo. 
 If event resolves to Grade 1 or better  42 days after event 
onset, resume bevacizumab/placebo.  If not, permanently 
discontinue bevacizumab/placebo. a 
Grade 4 
 Withhold atezolizumab, bevacizumab/placebo, gemcitabine, 
and cisplatin. 
 If event improves, consider resuming atezolizumab, 
gemcitabine, and cisplatin.  If not, permanently discontinue 
atezolizumab, gemcitabine, and cisplatin. a 
 If event resolves to Grade 1 or better  42 days after event 
onset, resume bevacizumab/placebo.  If not, permanently 
discontinue bevacizumab/placebo. a 
Atezolizumab-related toxicities not described above 
Grade 1 or 2 
 Follow guidelines for atezolizumab in Appendix 15. 
 Continue bevacizumab/placebo, gemcitabine, and cisplatin. 
Grade 3 or 4 
 Follow guidelines for atezolizumab in Appendix 15. 
 Withhold bevacizumab/placebo, gemcitabine, and cisplatin. 
 If event resolves to Grade 1 or better   42 days after event 
onset, resume bevacizumab/placebo, gemcitabine, and 
cisplatin.  If not, permanently discontinue 
bevacizumab/placebo, gemcitabine, and cisplatin. a 
a Resumption of treatment may be considered if the investigator believes the patient is likely 
to derive clinical benefit. 
b If the investigator believes the patient is likely to derive clinical benefit, can be resumed after 
being withheld for  42 days. 
c Recommendations on dose modifications for gemcitabine and cisplatin are provided in the 
Safety Plan (Section 5.1.5). 
d Cisplatin may be resumed at current dose if the investigator believes the patient is likely to 
derive clinical benefit. 
 
 


Appendix 14: Overall Guidelines for Management of Patients Who Experience 
Adverse Events 
  
Atezolizumab and Bevacizumab—F. Hoffmann-La Roche Ltd 
160/Protocol GO42661, Version 6 
Table 2 
Guidelines for Management of Patients Who Experience Specific 
Adverse Events with Cisplatin and Gemcitabine 
Hematologic toxicity on Day 1: ANC  109/L (1500/L) and/or platelet count  100109/L 
(100,000/L) 
Nadir a ANC  0.5  109/L 
(500/L), absence of febrile 
neutropenia, and nadir platelet 
count  50  109/L (50,000/L) 
 Continue atezolizumab and bevacizumab/placebo.  
Withhold gemcitabine and cisplatin. 
 If ANC is  1.5  109/L (1500/L) and platelet count is 
 100  109/L (100,000/L) within 42 days, b resume 
gemcitabine and cisplatin at current dose. c  If not, 
permanently discontinue gemcitabine and cisplatin. 
Nadir a ANC  0.5  109/L 
(500/L) and nadir a platelet 
count  50  109/L (50,000/L) 
or 
Febrile neutropenia 
or 
Nadir a platelet count 
 50  109/L (50,000/L) without 
bleeding 
 Withhold atezolizumab, bevacizumab/placebo, 
gemcitabine, and cisplatin. 
 If event improves, resume atezolizumab and 
bevacizumab/placebo.  If not, permanently discontinue 
atezolizumab and bevacizumab/placebo. 
 If ANC is  1.5  109/L (1500/L) and platelet count is 
 100  109/L (100,000/L) within 42 days, b resume 
gemcitabine and cisplatin dose reduced by one level. c, d 
If not, permanently discontinue gemcitabine and cisplatin. 
Nadir a platelet count 
 50  109/L (50,000/L) with 
bleeding 
Any occurrence 
 Withhold atezolizumab and bevacizumab/placebo. 
 If event improves, resume atezolizumab and 
bevacizumab/placebo.  If not, permanently discontinue 
atezolizumab and bevacizumab/placebo. 
First occurrence 
 Withhold gemcitabine and cisplatin. 
 If ANC is  1.5  109/L (1500/L) and platelet count is 
 100  109/L (100,000/L) within 42 days, b resume 
gemcitabine  and cisplatin with dose reduced by 2 levels. c  
If not, permanently discontinue gemcitabine and cisplatin. 
Second occurrence 
 Permanently discontinue gemcitabine and cisplatin. 
a Resumption of treatment may be considered if the investigator believes the patient is likely 
to derive clinical benefit. 
b If the investigator believes the patient is likely to derive clinical benefit, can be resumed after 
being withheld for  42 days. 
c Recommendations on dose modifications for gemcitabine and cisplatin are provided in the 
Safety Plan (Section 5.1.5). 
d Cisplatin may be resumed at current dose if the investigator believes the patient is likely to 
derive clinical benefit. 
 
 


Appendix 14: Overall Guidelines for Management of Patients Who Experience 
Adverse Events 
  
Atezolizumab and Bevacizumab—F. Hoffmann-La Roche Ltd 
161/Protocol GO42661, Version 6 
Table 2 
Guidelines for Management of Patients Who Experience Specific 
Adverse Events with Cisplatin and Gemcitabine (cont.) 
Hematologic toxicity on Day 8 
ANC  1.0  109/L (1000/L), 
absence of febrile neutropenia, 
and platelet count 100  109/L 
(100,000/L) 
 Continue gemcitabine and cisplatin at current dose. 
ANC 0.50.99  109/L 
(500999/L) 
 
or 
 
Platelet count 5099  109/L 
(50,00090,000/L) 
 Continue gemcitabine and cisplatin with dose reduced by 
one level. c, d  
ANC  0.5  109/L (500/L) 
or 
Platelet count  50  109/L 
(50,000/L) 
 Withhold gemcitabine and cisplatin. 
 Treatment may be resumed on Day 1 of the next cycle if 
ANC is  1.5  109/L (1500/L) and platelet count is 
 100  109/L (100,000/L). 
Nephrotoxicity 
CrCl  60 mL/min at time of 
scheduled treatment 
 Continue atezolizumab, bevacizumab/placebo, 
gemcitabine, and cisplatin. 
CrCl  60 mL/min at time of 
scheduled treatment 
 Withhold cisplatin. Atezolizumab, bevacizumab/placebo 
and gemcitabine may be continued at the discretion of the 
investigator. 
If event improves to CrCl  60 mL/min within 42 days, b 
cisplatin may be resumed with dose reduced by one level c 
at the discretion of the investigator.  If not, permanently 
discontinue cisplatin. 
a Resumption of treatment may be considered if the investigator believes the patient is likely 
to derive clinical benefit. 
b If the investigator believes the patient is likely to derive clinical benefit, can be resumed after 
being withheld for  42 days. 
c Recommendations on dose modifications for gemcitabine and cisplatin are provided in the 
Safety Plan (Section 5.1.5). 
d Cisplatin may be resumed at current dose if the investigator believes the patient is likely to 
derive clinical benefit. 
 
 


Appendix 14: Overall Guidelines for Management of Patients Who Experience 
Adverse Events 
  
Atezolizumab and Bevacizumab—F. Hoffmann-La Roche Ltd 
162/Protocol GO42661, Version 6 
Table 2 
Guidelines for Management of Patients Who Experience Specific 
Adverse Events with Cisplatin and Gemcitabine (cont.) 
Mucositis 
Mucositis, Grade 1 or 2  
 Continue atezolizumab, bevacizumab/placebo, 
gemcitabine, and cisplatin. 
Mucositis, Grade 3 or 4  
 Continue atezolizumab and bevacizumab/placebo.  
Withhold gemcitabine and cisplatin. 
 If event resolves to Grade 1 or better within 42 days, b 
resume gemcitabine and cisplatin with dose reduced by 
one level. c, d  If not, permanently discontinue gemcitabine 
and cisplatin. 
Hemolytic-uremic syndrome 
Hemolytic-uremic syndrome, 
any grade 
 Permanently discontinue gemcitabine.  Withhold 
atezolizumab, bevacizumab/placebo, and cisplatin. 
 If event improves, resume atezolizumab 
bevacizumab/placebo and cisplatin at current dose.  
If not, permanently discontinue atezolizumab, 
bevacizumab/placebo and cisplatin. 
Capillary leak syndrome 
Capillary leak syndrome, 
any grade 
 Permanently discontinue gemcitabine.  Withhold 
atezolizumab, bevacizumab/placebo and cisplatin. 
 If event improves, resume atezolizumab, 
bevacizumab/placebo and cisplatin at current dose.  
If not, permanently discontinue atezolizumab, 
bevacizumab/placebo and cisplatin. 
Ototoxicity 
 
 If ototoxicity is suspected, audiometry will be performed to 
assess hearing. 
For loss of greater than 
25 decibels in two consecutive 
hearing frequencies 
 Continue atezolizumab, bevacizumab/placebo and 
gemcitabine. 
 Withhold cisplatin for 1 week, and audiometry assessment 
will be repeated.  If hearing loss is resolved, then the 
patient will be re-treated with a cisplatin dose that is one 
level lower than the prior cycle. d  Patients will not undergo 
routine audiology monitoring for this study.  If not, 
permanently discontinue cisplatin. 
a Resumption of treatment may be considered if the investigator believes the patient is likely 
to derive clinical benefit. 
b If the investigator believes the patient is likely to derive clinical benefit, can be resumed after 
being withheld for  42 days. 
c Recommendations on dose modifications for gemcitabine and cisplatin are provided in the 
Safety Plan (Section 5.1.5). 
d Cisplatin may be resumed at current dose if the investigator believes the patient is likely to 
derive clinical benefit. 


Appendix 14: Overall Guidelines for Management of Patients Who Experience 
Adverse Events 
  
Atezolizumab and Bevacizumab—F. Hoffmann-La Roche Ltd 
163/Protocol GO42661, Version 6 
Table 2 
Guidelines for Management of Patients Who Experience Specific 
Adverse Events with Cisplatin and Gemcitabine (cont.) 
Chemotherapy-related toxicities not described above 
Grade 1 or 2 
 Continue atezolizumab, bevacizumab/placebo, gemcitabine, 
and cisplatin. 
Grade  3 
 Continue atezolizumab and bevacizumab/placebo.  Withhold 
gemcitabine and cisplatin. 
 If event resolves to Grade 1 or better within 42 days, b 
resume gemcitabine and cisplatin with dose reduced by one 
level. c, d  If not, permanently discontinue gemcitabine and 
cisplatin. 
Grade 4 
 Withhold atezolizumab, bevacizumab/placebo, gemcitabine, 
and cisplatin. 
 If event improves, resume atezolizumab and 
bevacizumab/placebo.  If not, permanently discontinue 
atezolizumab and bevacizumab. 
 If event resolves to Grade 1 or better within 42 days, a 
resume gemcitabine and cisplatin with dose reduced by one 
level. c, d  If not, permanently discontinue gemcitabine and 
cisplatin. 
a Resumption of treatment may be considered if the investigator believes the patient is likely to 
derive clinical benefit. 
b If the investigator believes the patient is likely to derive clinical benefit, can be resumed after 
being withheld for  42 days. 
c Recommendations on dose modifications for gemcitabine and cisplatin are provided in the 
Safety Plan (Section 5.1.5). 
d Cisplatin may be resumed at current dose if the investigator believes the patient is likely to 
derive clinical benefit. 
 
 


 
Atezolizumab and Bevacizumab—F. Hoffmann-La Roche Ltd 
164/Protocol GO42661, Version 6 
Appendix 15  
Risks Associated with Atezolizumab and Guidelines for 
Management of Adverse Events Associated with Atezolizumab 
Toxicities associated or possibly associated with atezolizumab treatment should be 
managed according to standard medical practice.  Additional tests, such as autoimmune 
serology or biopsies, should be used to evaluate for a possible immunogenic etiology. 
Although most immune-mediated adverse events observed with immunomodulatory 
agents have been mild and self-limiting, such events should be recognized early and 
treated promptly to avoid potential major complications.  Discontinuation of atezolizumab 
may not have an immediate therapeutic effect, and in severe cases, immune-mediated 
toxicities may require acute management with topical corticosteroids, systemic 
corticosteroids, or other immunosuppressive agents. 
The following are general recommendations for management of any other adverse events 
that may occur and are not specifically listed in the following subsections.  
 
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. 
 
In general, atezolizumab therapy should be continued with close monitoring for 
Grade 1 toxicities, with the exception of some neurologic toxicities. 
 
Consider holding 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.   
 
Hold atezolizumab for Grade 3 toxicities and initiate treatment with high-dose 
corticosteroids (1
2 mg/kg/day 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 
hormone-replacement therapy. 
 
The investigator should consider the benefitrisk balance a given patient may be 
experiencing 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 the investigator’s assessment of the benefits and risks 


Appendix 15: Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab 
  
Atezolizumab and Bevacizumab—F. Hoffmann-La Roche Ltd 
165/Protocol GO42661, Version 6 
and documented by the investigator.  The Medical Monitor is available to advise as 
needed. 
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.  Coronavirus disease 2019 (COVID-19) evaluation should be performed 
per institutional guidelines where relevant.  Management guidelines for pulmonary 
events are provided in Table 1. 
Table 1 
Management Guidelines for Pulmonary Events, Including 
Pneumonitis 
Event 
Management 
Pulmonary event, 
Grade 1  
 Continue atezolizumab and monitor closely. 
 Re-evaluate on serial imaging. 
 Consider patient referral to pulmonary specialist. 
 For Grade 1 pneumonitis, consider withholding atezolizumab 
Pulmonary event, 
Grade 2 
 Withhold atezolizumab for up to 12 weeks after event onset. a 
 Refer patient to pulmonary and infectious disease specialists and 
consider bronchoscopy or BAL 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 the  
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 the 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. 


Appendix 15: Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab 
  
Atezolizumab and Bevacizumab—F. Hoffmann-La Roche Ltd 
166/Protocol GO42661, Version 6 
 If event does not improve within 48 hours after initiating corticosteroids, 
consider adding an immunosuppressive agent. 
 If event resolves to Grade 1 or better, taper corticosteroids over 
 1 month. 
BAL  bronchoscopic alveolar lavage; IV  Intravenous 
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. 
d In case of pneumonitis, atezolizumab should not be resumed after permanent 
discontinuation. 








Appendix 15: Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab 
  
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Table 3 
Management Guidelines for Gastrointestinal Events (Diarrhea or 
Colitis) 
Event 
Management 
Diarrhea or 
colitis, Grade 1 
 Continue atezolizumab. 
 Initiate symptomatic treatment. 
 Endoscopy is recommended if symptoms persist for  7 days. 
 Monitor closely. 
Diarrhea or 
colitis, Grade 2 
 Withhold atezolizumab for up to 12 weeks after event onset. a 
 Initiate symptomatic treatment. 
 If strong clinical suspicion for immune-mediated colitis, start empiric 
IV steroids 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 the 
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 


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Table 3 
Management Guidelines for Gastrointestinal Events (Diarrhea or 
Colitis) (cont.) 
 
Event 
Management 
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. 
GI  gastrointestinal. 
a Atezolizumab may be withheld for a longer period of time (i.e.,  12 weeks after event onset) 
to allow for corticosteroids (if initiated) to be reduced to the equivalent of  10 mg/day oral 
prednisone.  The acceptable length of the extended period of time must be based on 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. 
 
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.  The patient should be referred to an 
endocrinologist if an endocrinopathy is suspected.  Thyroid-stimulating hormone 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. 


Appendix 15: Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab 
  
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Table 4 
Management Guidelines for Endocrine Events 
Event 
Management 
Grade 1 hypothyroidism 
 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. 
Grade 3 or 4 
hypothyroidism 
 Withhold atezolizumab. 
 Initiate treatment with thyroid replacement hormone. 
 Monitor TSH closely. 
 Refer to an 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 
Grade 1 hyperthyroidism 
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. 
Grade 2 
hyperthyroidism 
 Consider withholding atezolizumab. 
 Initiate treatment with anti-thyroid drug such as methimazole 
or carbimazole as needed. 
 Consider patient referral to endocrinologist. 
 Resume atezolizumab when symptoms are controlled and 
thyroid function is improving. 
Grade 3 or 4 
hyperthyroidism 
 Withhold atezolizumab. 
 Initiate treatment with anti-thyroid drugs such as methimazole or 
carbimazole as needed. 
 Refer to an endocrinologist. 
 Resume atezolizumab when symptoms are controlled and 
thyroid function is improving. 


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Atezolizumab and Bevacizumab—F. Hoffmann-La Roche Ltd 
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 Permanently discontinue atezolizumab and contact the 
Medical Monitor for life-threatening immune-mediated 
hyperthyroidism. c 
 
 


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Adverse Events Associated with Atezolizumab 
  
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Table 4 
Management Guidelines for Endocrine Events (cont.) 
Event 
Management 
Symptomatic adrenal 
insufficiency, Grade 24  
 Withhold atezolizumab for up to 12 weeks after event onset. a 
 Refer patient to endocrinologist. 
 Perform appropriate imaging. 
 Initiate treatment with corticosteroids equivalent to 
12 mg/kg/day IV methylprednisolone and convert to 
12 mg/kg/day oral prednisone or equivalent upon 
improvement. 
 If event resolves to Grade 1 or better and patient is stable on 
replacement therapy, resume atezolizumab. b 
 If event does not resolve to Grade 1 or better or patient is not 
stable on replacement therapy while withholding 
atezolizumab, permanently discontinue atezolizumab and 
contact the 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. 


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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. 
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. 
 


Appendix 15: Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab 
  
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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. 
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. 
 


Appendix 15: Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab 
  
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IMMUNE-MEDIATED CARDIAC EVENTS 
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., B-
type natriuretic peptide) or cardiac imaging abnormalities, dyspnea, chest pain, 
palpitations, fatigue, decreased exercise tolerance, or syncope.  Myocarditis may also be 
a clinical manifestation of myositis or associated with pericarditis (see section on 
pericardial disorders below) and should be managed accordingly.  Immune-mediated 
myocarditis needs to be distinguished from myocarditis resulting from infection 
(commonly viral, e.g., in a patient who reports a recent history of gastrointestinal illness), 
ischemic events, underlying arrhythmias, exacerbation of preexisting cardiac conditions, 
or progression of malignancy. 
All patients with possible myocarditis should be urgently evaluated by performing cardiac 
enzyme assessment, an ECG, a chest X-ray, an echocardiogram, and a cardiac MRI as 
appropriate per institutional guidelines.  A cardiologist should be consulted.  
An endomyocardial biopsy may be considered to enable a definitive diagnosis and 
appropriate treatment, if clinically indicated. 
Patients with signs and symptoms of myocarditis, in the absence of an identified 
alternate etiology, should be treated according to the guidelines in Table 6. 


Appendix 15: Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab 
  
Atezolizumab and Bevacizumab—F. Hoffmann-La Roche Ltd 
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IMMUNE-MEDIATED PERICARDIAL DISORDERS 
Immune-mediated pericarditis should be suspected in any patient presenting with chest 
pain and may be associated with immune-mediated myocarditis (see section on 
myocarditis above). 
Immune-mediated pericardial effusion and cardiac tamponade should be suspected in 
any patient presenting with chest pain associated with dyspnea or hemodynamic 
instability.  
Patients should be evaluated for other causes of pericardial disorders such as infection 
(commonly viral), cancer related (metastatic disease or chest radiotherapy), cardiac 
injury related (post myocardial infarction or iatrogenic), and autoimmune disorders, 
and should be managed accordingly. 
All patients with suspected pericardial disorders should be urgently evaluated by 
performing an ECG, chest X-ray, transthoracic echocardiogram, and cardiac MRI as 
appropriate per institutional guidelines.  A cardiologist should be consulted.  
Pericardiocentesis should be considered for diagnostic or therapeutic purposes, if 
clinically indicated. 
Patients with signs and symptoms of pericarditis, pericardial effusion, or cardiac 
tamponade, in the absence of an identified alternate etiology, should be treated 
according to the guidelines in Table 6.  Withhold treatment with atezolizumab for 
Grade 1 pericarditis and conduct a detailed cardiac evaluation to determine the etiology 
and manage accordingly. 


Appendix 15: Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab 
  
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Table 6 
Management Guidelines for Immune-Mediated Cardiac Events 
Event 
Management 
Immune-mediated 
myocarditis,  
Grades 24 
 
Immune mediated 
pericardial disorders, 
Grades 24 
 Permanently discontinue atezolizumab and contact the  
Medical Monitor. a 
 Refer patient to cardiologist. 
 Initiate treatment as per institutional guidelines and consider 
antiarrhythmic drugs, temporary pacemaker, ECMO, VAD, or 
pericardiocentesis as appropriate. 
 Initiate treatment with corticosteroids equivalent to 12 mg/kg/day 
IV methylprednisolone and convert to 12 mg/kg/day oral 
prednisone or equivalent upon improvement. 
 If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent. 
 If event resolves to Grade 1 or better, taper corticosteroids over 
 1 month. 
ECMO  extracorporeal membrane oxygenation; VAD  ventricular assist device. 
 
 
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, 
antipyretic 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. 
Infusion-related reactions 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. 
Cytokine release syndrome 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).  Cytokine release syndrome 
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. 


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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 the 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 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’s judgment.  If a diagnosis of SARS-CoV-2 infection is 
confirmed, the disease should be managed as per local or institutional guidelines. 


Appendix 15: Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab 
  
Atezolizumab and Bevacizumab—F. Hoffmann-La Roche Ltd 
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Table 7 
Management Guidelines for Infusion-Related Reactions and 
Cytokine Release Syndrome 
Event 
Management 
Grade 1 a 
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, antipyretic medications, and/or analgesics, and 
monitor closely for IRRs and/or CRS. 
Grade 2 a 
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 as described in this appendix. 
 Consider IV corticosteroids (e.g., methylprednisolone 2 mg/kg/day or 
dexamethasone 10 mg every 6 hours). 
 Consider anti-cytokine therapy.  
 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. 


Appendix 15: Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab 
  
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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 MAS as described in this 
appendix. 
 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. f 
 Administer symptomatic treatment. c 
 Admit patient to ICU and initiate hemodynamic monitoring, mechanical 
ventilation, and/or IV fluids and vasopressors as needed.  Monitor 
other organ function closely.  Manage constitutional symptoms and 
organ toxicities as per institutional practice. 
 Rule out other inflammatory conditions that can mimic CRS 
(e.g., sepsis).  If no improvement within 24 hours, initiate workup and 
assess for signs and symptoms of HLH or MAS as described in this 
appendix. 
 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. 


Appendix 15: Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab 
  
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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.  National Cancer Institute CTCAE v5.0 should be used when reporting severity of 
IRRs, CRS, or organ toxicities associated with CRS on the Adverse Event eCRF.  Organ 
toxicities associated with CRS should not influence overall CRS grading. 
b Fever is defined as temperature  38C not attributable to any other cause.  In patients who 
develop CRS and then receive anti-pyretic, anti-cytokine, or corticosteroid therapy, fever is 
no longer required when subsequently determining event severity (grade).  In this case, the 
grade is driven by the presence of hypotension and/or hypoxia. 
c Symptomatic treatment may include oral or IV antihistamines, anti 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 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 See 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  
Event 
Management 
Amylase and/or lipase 
elevation, Grade 2 
Amylase and/or lipase  1.52.0  ULN: 
 Continue atezolizumab. 
 Monitor amylase and lipase weekly. 
 For prolonged elevation (e.g.,  3 weeks), consider treatment 
with corticosteroids equivalent to 10 mg/day oral prednisone. 
Asymptomatic with amylase and/or lipase  2.05.0  ULN: 
 Treat as a Grade 3 event. 
Amylase and/or lipase 
elevation, Grade 3 or 4 
 Withhold atezolizumab for up to 12 weeks after event onset. a 
 Refer patient to GI specialist. 
 Monitor amylase and lipase every other day. 
 If no improvement, consider treatment with corticosteroids 
equivalent to 12 mg/kg/day oral prednisone. 
 If event resolves to Grade 1 or better, resume atezolizumab. b 
 If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and 
contact the Medical Monitor. c 
 For recurrent events, permanently discontinue atezolizumab 
and contact the Medical Monitor. c 
GI  gastrointestinal. 
a Atezolizumab may be withheld for a longer period of time (i.e.,  12 weeks after event onset) 
to allow for corticosteroids (if initiated) to be reduced to the equivalent of  10 mg/day oral 
prednisone.  The acceptable length of the extended period of time must be based on 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 8 
Management Guidelines for Pancreatic Events, Including 
Pancreatitis (cont.) 
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. 
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. 
 


Appendix 15: Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab 
  
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DERMATOLOGIC EVENTS 
The majority of cases of rash reported with the use of atezolizumab were mild in severity 
and self-limited, with or without pruritus.  Although uncommon, cases of severe 
cutaneous adverse reactions such as Stevens-Johnson syndrome and toxic epidermal 
necrolysis have been reported with atezolizumab.  A dermatologist should evaluate 
persistent and/or severe rash or pruritus.  A biopsy should be considered unless 
contraindicated.  Management guidelines for dermatologic events are provided in 
Table 9. 
Table 9 
Management Guidelines for Dermatologic Events 
Event 
Management 
Dermatologic 
event, Grade 1  
 Continue atezolizumab. 
 Consider treatment with topical corticosteroids and/or other symptomatic 
therapy (e.g., antihistamines). 
Dermatologic 
event, Grade 2  
 Continue atezolizumab. 
 Consider patient referral to dermatologist for evaluation and, if indicated, 
biopsy. 
 Initiate treatment with topical corticosteroids. 
 Consider treatment with higher-potency topical corticosteroids if event 
does not improve. 
 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 the 
Medical Monitor. c 


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Table 9 
Management Guidelines for Dermatologic Events (cont.)  
Event 
Management 
Dermatologic 
event, Grade 4 
 Permanently discontinue atezolizumab and contact the 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. 
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. 
 
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 etiologies.  Management guidelines for neurologic disorders are provided in 
Table 10, with specific guidelines for myelitis provided in Table 1. 
 


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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: 
– 
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. 
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 oral 
or IV prednisone. 
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 1 
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 a neurologist.  
Immune-mediated myelitis, 
Grade 2 
 
Permanently discontinue atezolizumab and contact the 
Medical Monitor.  
 
Investigate etiology and refer patient to a neurologist. 
 
Rule out infection. 
 
Initiate treatment with corticosteroids equivalent to 
12 mg/kg/day oral prednisone. 
Immune-mediated myelitis, 
Grade 3 or 4 
 
Permanently discontinue atezolizumab and contact the 
Medical Monitor. 
 
Refer patient to a neurologist. 
 
Initiate treatment as per institutional guidelines. 
 
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 1112 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. 


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Event 
Management 
 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. 
 
 
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 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 . 
Table 1213 Management Guidelines for Renal Events 
Event 
Management 
Renal event, 
Grade 1 
 Continue atezolizumab. 
 Monitor kidney function, including creatinine and urine protein, closely 
until values resolve to within normal limits or to baseline values. 
Renal event, 
Grade 2 
 Withhold atezolizumab for up to 12 weeks after event onset. a 
 Refer patient to renal specialist. 
 Initiate treatment with corticosteroids equivalent to 12 mg/kg/day oral 
prednisone. 
 If event resolves to Grade 1 or better, resume atezolizumab. b 
 If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab 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. 


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Event 
Management 
 If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent. 
 If event resolves to Grade 1 or better, taper corticosteroids over 
 1 month. 
a Atezolizumab may be withheld for a longer period of time (i.e.,  12 weeks after event onset) 
to allow for corticosteroids (if initiated) to be reduced to 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. 
 
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 increase), and 
imaging (electromyography/MRI) features, and is confirmed with a muscle biopsy.  
Patients with possible myositis should be referred to a rheumatologist or neurologist.  
Patients with possible myositis should be monitored for signs of myocarditis 
Patients with signs and symptoms of myositis, in the absence of an identified alternate 
etiology, should be treated according to the guidelines in Table . 
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 the 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. 


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Event 
Management 
 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 
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 14 Management Guidelines for Immune-Mediated Myositis (cont.) 
Event 
Management 
Immune-mediated 
myositis, Grade 3 
 Withhold atezolizumab for up to 12 weeks after event onset a 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. 
 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 
 For recurrent events, treat as a Grade 4 event.  Permanently 
discontinue atezolizumab and contact the Medical Monitor. c 
Immune-mediated 
myositis, Grade 4 
 Permanently discontinue atezolizumab and contact the Medical 
Monitor. c 
 Refer patient to rheumatologist or neurologist. 
 Initiate treatment as per institutional guidelines. 
 Respiratory support may be required in more severe cases. 
 Initiate treatment with corticosteroids equivalent to 12 mg/kg/day IV 
methylprednisolone, or higher-dose bolus if patient is severely 
compromised (e.g., cardiac or respiratory symptoms, dysphagia, or 
weakness that severely limits mobility); convert to 12 mg/kg/day oral 
prednisone or equivalent upon improvement. 
 If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent. 
 If event resolves to Grade 1 or better, taper corticosteroids over 
 1 month. 
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 


Appendix 15: Risks Associated with Atezolizumab and Guidelines for Management of 
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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. 
 
HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS AND MACROPHAGE 
ACTIVATION SYNDROME 
Immune-mediated reactions may involve any organ system and may lead to 
hemophagocytic lymphohistiocytosis (HLH) and macrophage activation syndrome 
(MAS). 
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 5 of the 
following 8 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 
 
Patients with suspected MAS should be diagnosed according to published criteria for 
systemic juvenile idiopathic arthritis by Ravelli et al. 2016.  A febrile patient should be 
classified as having MAS if the following criteria are met: 
 
Ferritin  684 mg/L (684 ng/mL) 
 
At least two of the following: 
– 
Platelet count  181  109/L (181,000/L) 
– 
AST  48 U/L 


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– 
Triglycerides  1.761 mmol/L (156 mg/dL) 
– 
Fibrinogen  3.6 g/L (360 mg/dL) 
 
Patients with suspected HLH or MAS should be treated according to the guidelines in 
Table . 
Table 1315 Management Guidelines for Suspected Hemophagocytic 
Lymphohistiocytosis or Macrophage Activation Syndrome 
Event 
Management 
Suspected HLH 
or MAS 
 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; MAS  macrophage activation syndrome. 
 
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 Program 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: 


Appendix 15: Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab 
  
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196/Protocol GO42661, Version 6 
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Signature Page for Protocol - GO42661 - TECENTRIQ - v6 - Global/Core - Published
System identifier: RIM-CLIN-466913
Approval Task
Company Signatory
03-Feb-2023 17:20:55 GMT+0000