A Phase Ib/II, Open-Label, Multicenter, Randomized Umbrella Study Evaluating the Efficacy and Safety of Multiple Immunotherapy-Based Treatment Combinations in Patients With Metastatic Pancreatic Ductal Adenocarcinoma (Morpheus-Pancreatic Cancer)
Phase: PHASE1
Conditions: Pancreatic Adenocarcinoma
Sponsor: Hoffmann-La Roche

 
Official Title: 
A Phase Ib/II, Open-Label, Multicenter, Randomized Umbrella Study 
Evaluating the Efficacy and Safety of Multiple Immunotherapy-Based 
Treatment Combinations in Patients with Metastatic Pancreatic Ductal 
Adenocarcinoma (Morpheus–Pancreatic Cancer) 
NCT Number: 
NCT03193190 
Document Date: 
Protocol Amendment Version 16: 04-Oct-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any unpublished data, is the property of F. Hoffmann-La Roche Ltd (or under its control) and therefore 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. 
Pancreatic Immunotherapy Combinations—F. Hoffmann-La Roche Ltd 
Protocol WO39608, Version 16 
PROTOCOL 
TITLE: 
A PHASE Ib/II, OPEN-LABEL, MULTICENTER, 
RANDOMIZED UMBRELLA STUDY EVALUATING 
THE EFFICACY AND SAFETY OF MULTIPLE 
IMMUNOTHERAPY-BASED TREATMENT 
COMBINATIONS IN PATIENTS WITH METASTATIC 
PANCREATIC DUCTAL ADENOCARCINOMA 
(MORPHEUS–PANCREATIC CANCER) 
PROTOCOL NUMBER: 
WO39608 
VERSION NUMBER: 
16
TEST COMPOUNDS: 
Atezolizumab (RO5541267), Bevacizumab 
(RO4876646), Tiragolumab (RO7092284), 
Tocilizumab (RO4877533) 
STUDY PHASE: 
Phase Ib/II 
REGULATORY AGENCY 
IDENTIFIER NUMBERS: 
IND Number:  132,850 
EudraCT Number:  2016-004126-42 
EU CT Number:  to be determined 
Clinical Investigation Identification Number (CIV ID): 
Not applicable 
NCT Number:  NCT03193190 
SPONSOR’S NAME AND 
LEGAL REGISTERED 
ADDRESS: 
F. Hoffmann-La Roche Ltd
Grenzacherstrasse 124
4070 Basel, Switzerland
APPROVAL: 
See electronic signature and date stamp on the final 
page of this document. 

Pancreatic Immunotherapy Combinations—F. Hoffmann-La Roche Ltd 
2/Protocol WO39608, Version 16  
PROTOCOL HISTORY 
Protocol 
Associated Country-Specific Protocol 
Version 
Date Final 
Country 
Version 
Date Final 
16 
See electronic date 
stamp on final 
page of this 
document. 
 
 
 
15 
14 March 2023 
 
 
 
13 
7 December 2022 
Japan 
14 
25 January 2023 
11 
12 March 2022 
Japan 
12 
12 March 2022 
9 
21 July 2020 
Japan 
10 
25 August 2020 
8 
9 April 2020 
 
 
 
6 
22 November 2019 
ex-United States 
7 
5 December 2019 
4 
11 May 2018 
Germany 
5 
22 October 2019 
1 
4 February 2017 
Spain 
3 
28 February 2018 
Germany 
2 
5 October 2017 
 

Pancreatic Immunotherapy Combinations—F. Hoffmann-La Roche Ltd 
3/Protocol WO39608, Version 16  
PROTOCOL AMENDMENT, VERSION 16: 
RATIONALE 
Protocol WO39608, Version 16 has been updated to remove the atezolizumab plus 
chemotherapy (nab-paclitaxel and gemcitabine) plus AB928 arm, as the treatment arm 
has met the criteria for closure.  In addition, the protocol has been aligned with the 
Atezolizumab Investigator's Brochure, Version 20.  Substantive changes to the protocol, 
along with a rationale for each change, are summarized below. 
 
A section describing duration of participation has been added to align with Clinical 
Trials Regulation (CTR) requirements (Section 3.3).   
 
The study length has been increased to 79 years due to expanded study arm 
enrollment (Section 3.3)   
 
The section ‘Exclusion Criteria for AB928-Containing Arm during Stage 1’ (formerly 
Section 4.1.2.4) has been removed due to closure of the atezolizumab plus 
chemotherapy (nab-paclitaxel and gemcitabine) plus AB928 study arm.  Information 
regarding the Emergency Medical Call Center has been added for completeness 
(Section 5.4.1).   
 
It has been made explicit that expedited safety reports are notified to EudraVigilance 
(Section 5.7).   
 
The adverse event management guidelines have been updated to align with the 
Atezolizumab Investigator's Brochure, Version 20 (Appendix 2). 
– 
The management guidelines for Grade 1 pulmonary events have been updated 
to include consideration of resuming treatment.   
– 
Guidance for the management of immune-mediated cardiac events in high-risk 
patients has been included.  
– 
Use of transthoracic echocardiogram has been added to the guidance for 
evaluation of immune-mediated myocarditis.  
– 
The dose and duration of initial corticosteroid treatment for the management of 
Grade 24 immune-mediated myocarditis or pericardial disorders has been 
updated.   
– 
The potential association of myasthenia with myositis has been clarified, and 
further guidance for the management of neurologic disorders has been added.  
– 
Management guidelines for immune-mediated myositis have been updated.   
 
The atezolizumab plus chemotherapy (nab-paclitaxel and gemcitabine) plus AB928 
arm has been removed due to meeting the criteria for closure.  The content of 
Appendix 12 [previously entitled "Study Details Specific to Atezo  Chemo  AB928 
Arm (Cohort 1)"] has been removed.  Appendix 12 will serve as a placeholder for a 
future arm to avoid having to renumber subsequent appendices. 
 

Pancreatic Immunotherapy Combinations—F. Hoffmann-La Roche Ltd 
4/Protocol WO39608, Version 16  
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. 

 
Pancreatic Immunotherapy Combinations—F. Hoffmann-La Roche Ltd 
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TABLE OF CONTENTS 
PROTOCOL AMENDMENT ACCEPTANCE FORM .......................................... 11 
PROTOCOL SYNOPSIS .................................................................................... 12 
1. 
BACKGROUND ............................................................................ 19 
1.1 
Treatment for Pancreatic Cancer ............................................. 19 
1.2 
First-Line Treatment for Pancreatic Cancer ............................. 19 
1.3 
Second-Line Treatment for Pancreatic Cancer ........................ 20 
1.4 
Study Rationale ....................................................................... 21 
1.5 
Covid-19 Benefit–Risk Assessment ......................................... 22 
2. 
OBJECTIVES AND ENDPOINTS ................................................. 24 
3. 
STUDY DESIGN ........................................................................... 29 
3.1 
Description of the Study ........................................................... 29 
3.1.1 
Overview of Study Design........................................................ 29 
3.1.2 
Stage 1 .................................................................................... 32 
3.1.3 
Safety Evaluation Phase .......................................................... 37 
3.1.4 
Second-Line Treatment for Cohort 1 Control Arm ................... 37 
3.1.5 
Stage 2 Treatment for Cohort 2 ............................................... 37 
3.1.6 
Assessments and Monitoring ................................................... 38 
3.1.7 
Internal Monitoring Committee ................................................. 39 
3.1.8 
Scientific Oversight Committee ................................................ 39 
3.2 
End of Study and Length of Study ........................................... 40 
3.3 
Duration of Participation .................................................... 40 
3.4 
Rationale for Study Design ...................................................... 40 
3.4.1 
Rationale for Patient Population .............................................. 40 
3.4.2 
Rationale for Immunotherapy-Based Treatment beyond 
Initial Radiographic Progression .............................................. 40 
.................................... 41 
4. 
MATERIALS AND METHODS ...................................................... 42 
4.1 
Patients .................................................................................... 42 
4.1.1 
Inclusion Criteria ...................................................................... 42 
4.1.1.1 
Inclusion Criteria for Stage 1.................................................... 42 

 
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4.1.1.2 
Inclusion Criteria for Stage 1 and Stage 2 ............................... 43 
4.1.1.3 
Inclusion Criteria for Stage 2.................................................... 44 
4.1.2 
Exclusion Criteria ..................................................................... 44 
4.1.2.1 
Exclusion Criteria for Stage 1 .................................................. 44 
4.1.2.2 
Exclusion Criteria for Stage 1 and Stage 2 .............................. 45 
4.1.2.3 
Exclusion Criteria for Bevacizumab-Containing Arm during 
Stage 1 .................................................................................... 48 
4.1.2.4 
Exclusion Criteria for Tiragolumab-Containing Arm during 
Stage 1 .................................................................................... 50 
4.1.2.5 
Exclusion Criteria for Tocilizumab-Containing Arm during 
Stage 1 .................................................................................... 50 
4.2 
Method of Treatment Assignment ............................................ 51 
4.3 
Study Treatment ...................................................................... 52 
4.3.1 
Investigational Medicinal Product Accountability ..................... 52 
4.3.2 
Post-Trial Access to Study Treatment ..................................... 52 
4.4 
Concomitant Therapy and Prohibited Food ............................. 52 
4.5 
Study Assessments ................................................................. 52 
4.5.1 
Informed Consent Forms and Screening ................................. 53 
4.5.2 
Medical History, Molecular Profile, Concomitant 
Medication, and Demographic Data ......................................... 53 
4.5.3 
Physical Examinations ............................................................. 53 
4.5.4 
Vital Signs ................................................................................ 54 
4.5.5 
Tumor and Response Evaluations ........................................... 54 
4.5.6 
Chest X-Ray ............................................................................ 55 
4.5.7 
Laboratory, Biomarker, and Other Biological Samples ............ 55 
4.5.8 
Electrocardiograms .................................................................. 59 
...... 59 
......................................................... 60 
4.5.11 
Optional Samples for Research Biosample Repository ........... 61 
4.5.11.1 
Overview of the Research Biosample Repository .................... 61 
4.5.11.2 
Approval by the Institutional Review Board or Ethics 
Committee ............................................................................... 62 
4.5.11.3 
Sample Collection .................................................................... 62 
4.5.11.4 
Confidentiality .......................................................................... 62 

 
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4.5.11.5 
Consent to Participate in the Research Biosample 
Repository................................................................................ 63 
4.5.11.6 
Withdrawal from the Research Biosample Repository ............. 63 
4.5.11.7 
Monitoring and Oversight ......................................................... 64 
4.6 
Treatment, Patient, Study, and Site Discontinuation ................ 64 
4.6.1 
Study Treatment Discontinuation ............................................. 64 
4.6.2 
Patient Discontinuation from Study .......................................... 65 
4.6.3 
Study Discontinuation .............................................................. 65 
4.6.4 
Site Discontinuation ................................................................. 66 
5. 
ASSESSMENT OF SAFETY ......................................................... 66 
5.1 
Safety Plan .............................................................................. 66 
5.2 
Safety Parameters and Definitions .......................................... 66 
5.2.1 
Adverse Events ........................................................................ 66 
5.2.2 
Serious Adverse Events (Immediately Reportable to the 
Sponsor) .................................................................................. 67 
5.2.3 
Adverse Events of Special Interest (Immediately 
Reportable to the Sponsor) ...................................................... 68 
5.3 
Methods and Timing for Capturing and Assessing 
Safety Parameters ................................................................... 68 
5.3.1 
Adverse Event Reporting Period .............................................. 68 
5.3.2 
Eliciting Adverse Event Information ......................................... 68 
5.3.3 
Assessment of Severity of Adverse Events ............................. 69 
5.3.4 
Assessment of Causality of Adverse Events............................ 70 
5.3.5 
Procedures for Recording Adverse Events .............................. 71 
............. 71 
5.3.5.2 
Diagnosis versus Signs and Symptoms ................................... 72 
5.3.5.3 
Adverse Events That Are Secondary to Other Events ............. 72 
5.3.5.4 
Persistent or Recurrent Adverse Events .................................. 73 
5.3.5.5 
Abnormal Laboratory Values ................................................... 73 
5.3.5.6 
Abnormal Vital Sign Values ..................................................... 74 
5.3.5.7 
Abnormal Liver Function Tests ................................................ 74 
5.3.5.8 
Deaths ..................................................................................... 75 
5.3.5.9 
Preexisting Medical Conditions ................................................ 75 

 
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5.3.5.10 
Lack of Efficacy or Worsening of PDAC .................................. 75 
5.3.5.11 
Hospitalization or Prolonged Hospitalization ............................ 76 
5.3.5.12 
Reporting Requirements for Cases of Overdose, 
Medication Error, Drug Abuse, or Drug Misuse ....................... 76 
5.4 
Immediate Reporting Requirements from Investigator to 
Sponsor ................................................................................... 78 
5.4.1 
Emergency Medical Contacts .................................................. 79 
5.4.2 
Reporting Requirements for Serious Adverse Events and 
Adverse Events of Special Interest .......................................... 79 
5.4.2.1 
Events That Occur prior to Study Treatment Initiation ............. 79 
5.4.2.2 
Events That Occur after Study Treatment Initiation ................. 80 
5.4.3 
Reporting Requirements for Pregnancies ................................ 80 
5.5 
Follow-Up of Patients after Adverse Events............................. 80 
5.5.1 
Investigator Follow-Up ............................................................. 80 
5.5.2 
Sponsor Follow-Up .................................................................. 80 
5.6 
Adverse Events That Occur after the Adverse Event 
Reporting Period ...................................................................... 81 
5.7 
Expedited Reporting to Health Authorities, Investigators, 
Institutional Review Boards, and Ethics Committees ............... 81 
6. 
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN ......... 82 
6.1 
Determination of Sample Size ................................................. 82 
6.2 
Summaries of Conduct of Study .............................................. 82 
6.3 
Summaries of Demographic and Baseline Characteristics ...... 83 
6.4 
Efficacy Analyses ..................................................................... 83 
6.4.1 
Primary Efficacy Endpoint ........................................................ 83 
6.4.2 
Secondary Efficacy Endpoints ................................................. 83 
................................................ 84 
6.5 
Safety Analyses ....................................................................... 84 
6.6 
Pharmacokinetic Analyses ....................................................... 85 
6.7 
Immunogenicity Analyses ........................................................ 85 
................................................................ 86 
..................................................................... 86 
7. 
DATA COLLECTION AND MANAGEMENT ................................. 86 
7.1 
Data Quality Assurance ........................................................... 86 

 
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7.2 
Electronic Case Report Forms ................................................. 87 
7.3 
Source Data Documentation .................................................... 87 
7.4 
Use of Computerized Systems ................................................ 87 
7.5 
Retention of Records ............................................................... 88 
8. 
ETHICAL CONSIDERATIONS ...................................................... 88 
8.1 
Compliance with Laws and Regulations .................................. 88 
8.2 
Informed Consent .................................................................... 88 
8.3 
Institutional Review Board or Ethics Committee ...................... 90 
8.4 
Confidentiality .......................................................................... 90 
8.5 
Financial Disclosure ................................................................. 91 
9. 
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION ....................................................................... 91 
9.1 
Study Documentation .............................................................. 91 
9.2 
Protocol Deviations .................................................................. 91 
9.3 
Site Inspections ....................................................................... 91 
9.4 
Administrative Structure ........................................................... 91 
9.5 
Publication of Data and Protection of Trade Secrets ............... 92 
9.6 
Protocol Amendments ............................................................. 93 
10. 
REFERENCES.............................................................................. 94 
 
LIST OF TABLES 
 
 
 
Table 1 
Target and Proposed Mechanism-of-Action Classification for 
Experimental Investigational Medicinal Products ........................ 22 
Table 2 
Objectives and Corresponding Endpoints for Stage 1 ................ 24 
Table 3 
Objectives and Corresponding Endpoints for Stage 2 ................ 27 
Table 4 
Stage 1 Treatment Regimens ..................................................... 33 
Table 5 
Treatment Arms with Completed Enrollment and Patient 
Follow-Up .................................................................................... 36 
Table 6 
Stage 2 Treatment Regimens for Cohort 2 ................................. 38 

 
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LIST OF FIGURES 
Figure 1 
Study Schema ............................................................................. 30 
Figure 2 
Detailed Study Design:  Cohort 1 ................................................ 34 
Figure 3 
Detailed Study Design:  Cohort 2 ................................................ 35 
 
 
LIST OF APPENDICES 
Appendix 1 
Response Evaluation Criteria in Solid Tumors, 
Version 1.1 (RECIST v1.1).......................................................... 97 
Appendix 2 
Management of Atezolizumab-Specific Adverse Events ........... 106 
Appendix 3 
ECOG Performance Status Scale ............................................. 141 
Appendix 4 
Preexisting Autoimmune Diseases and Immune Deficiencies .. 142 
Appendix 5 
Anaphylaxis Precautions ........................................................... 143 
Appendix 6 
Schedules of Activities for Screening ........................................ 144 
Appendix 7 
Study Details Specific to Control Arm (Cohorts 1 and 2) .......... 153 
Appendix 8 
Placeholder for Future Arm ....................................................... 166 
Appendix 9 
Placeholder for Future Arm ....................................................... 167 
Appendix 10 
Placeholder for Future Arm ....................................................... 168 
Appendix 11 
Placeholder for Future Arm ....................................................... 169 
Appendix 12 
Placeholder for Future Arm ............................................... 170 
Appendix 13 
Placeholder for Future Arm ....................................................... 171 
Appendix 14 
Study Details Specific to Atezo  Chemo  Tira Arm 
(Cohort 1) .................................................................................. 172 
Appendix 15 
Study Details Specific to Atezo  Chemo  Bev Arm 
(Cohort 1) .................................................................................. 227 
Appendix 16 
Study Details Specific to Atezo  Chemo  TCZ Arm 
(Cohort 1) .................................................................................. 294 
Appendix 17 
Investigational Medicinal Product Designations 
(for Use in European Economic Area) ...................................... 355 
 

 
Pancreatic Immunotherapy Combinations—F. Hoffmann-La Roche Ltd 
11/Protocol WO39608, Version 16 
PROTOCOL AMENDMENT ACCEPTANCE FORM 
TITLE: 
A PHASE Ib/II, OPEN-LABEL, MULTICENTER, 
RANDOMIZED UMBRELLA STUDY EVALUATING 
THE EFFICACY AND SAFETY OF MULTIPLE 
IMMUNOTHERAPY-BASED TREATMENT 
COMBINATIONS IN PATIENTS WITH METASTATIC 
PANCREATIC DUCTAL ADENOCARCINOMA 
(MORPHEUSPANCREATIC CANCER) 
PROTOCOL NUMBER: 
WO39608 
VERSION NUMBER: 
16 
TEST COMPOUNDS: 
Atezolizumab (RO5541267), Bevacizumab 
(RO4876646),Tiragolumab (RO7092284), Tocilizumab 
(RO4877533) 
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 as 
instructed by Covance. 
 

 
Pancreatic Immunotherapy Combinations—F. Hoffmann-La Roche Ltd 
12/Protocol WO39608, Version 16
 
 
PROTOCOL SYNOPSIS 
PROTOCOL TITLE: 
A PHASE Ib/II, OPEN-LABEL, MULTICENTER, RANDOMIZED 
UMBRELLA STUDY EVALUATING THE EFFICACY AND 
SAFETY OF MULTIPLE IMMUNOTHERAPY-BASED 
TREATMENT COMBINATIONS IN PATIENTS WITH 
METASTATIC PANCREATIC DUCTAL ADENOCARCINOMA 
(MORPHEUSPANCREATIC CANCER) 
REGULATORY AGENCY 
IDENTIFIER NUMBERS: 
IND Number:  132,850 
EudraCT Number:  2016-004126-42 
EU CT Number: to be determined 
Clinical Investigation Identification Number (CIV ID):  Not 
applicable 
NCT Number:  NCT03193190 
STUDY RATIONALE 
The purpose of this study is to evaluate the efficacy, safety, and pharmacokinetics of 
immunotherapy-based treatment combinations in patients with metastatic pancreatic ductal 
adenocarcinoma (PDAC).  Current treatment options for patients with metastatic PDAC are 
primarily limited to gemcitabine-based or fluoropyrimidine-based chemotherapies which are 
associated with significant toxicities that negatively affect quality of life.  For patients whose 
disease has progressed during chemotherapy, there are no approved treatment options.  
Therefore, there is a high unmet need for improved medical intervention for patients with 
metastatic PDAC. 
 

 
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OBJECTIVES AND ENDPOINTS  
Table 1 
Objectives and Corresponding Endpoints for Stage 1 
Primary Efficacy Objective 
Corresponding Endpoint 
 To evaluate the efficacy of 
immunotherapy-based treatment 
combinations during Stage 1 
 Objective response, defined as a complete 
response or partial response on two consecutive 
occasions  4 weeks apart during Stage 1, as 
determined by the investigator according to 
RECIST v1.1 
Secondary Efficacy Objective 
Corresponding Endpoints 
 To evaluate the efficacy of 
immunotherapy-based treatment 
combinations during Stage 1 
 PFS after randomization, defined as the time from 
randomization to the first occurrence of disease 
progression or death from any cause (whichever 
occurs first) in Stage 1, as determined by the 
investigator according to RECIST v1.1 
 OS after randomization, defined as the time from 
randomization to death from any cause 
 OS at specific timepoints (e.g., 6 months) 
 DOR, defined as the time from the first occurrence 
of a documented objective response to disease 
progression or death from any cause (whichever 
occurs first) in Stage 1, as determined by the 
investigator according to RECIST v1.1 
 Disease control, defined as stable disease 
for  12 weeks or a complete or partial response, as 
determined by the investigator according to 
RECIST v1.1 
Safety Objective 
Corresponding Endpoints 
 To evaluate the safety of 
immunotherapy-based treatment 
combinations during Stage 1 
 Incidence, nature, and severity of adverse events 
and laboratory abnormalities, with severity 
determined according to National Cancer Institute 
Common Terminology Criteria for Adverse Events, 
Version 4.0 
 Change from baseline in vital signs and ECG 
parameters 
 Change from baseline in targeted clinical 
laboratory test results 
ADA  anti-drug antibody; DOR  duration of response; OS  overall survival; 
PFS  progression-free survival; PK  pharmacokinetic; RECIST  Response Evaluation Criteria 
in Solid Tumors. 
Note:  Overall response at a single timepoint will be assessed by the investigator using 
RECIST v1.1. 
  
 
 

 
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Table 2 
Objectives and Corresponding Endpoints for Stage 2 
Safety Objective 
Corresponding Endpoints 
 To evaluate the safety of 
immunotherapy-based treatment 
combinations during Stage 2 
 Incidence, nature, and severity of adverse events 
and laboratory abnormalities, with severity 
determined according to National Cancer Institute 
Common Terminology Criteria for Adverse Events, 
Version 4.0 
 Change from baseline in vital signs and ECG 
parameters 
 Change from baseline in targeted clinical 
laboratory test results 
ADA  anti-drug antibody; DOR  duration of response; PFS  progression-free survival; 
PK  pharmacokinetic; RECIST  Response Evaluation Criteria in Solid Tumors. 
Note:  Overall response at a single timepoint will be assessed by the investigator using 
RECIST v1.1. 
  
OVERALL DESIGN AND STUDY POPULATION 
This is a Phase Ib/II, open-label, multicenter, randomized umbrella study in patients with 
metastatic PDAC.  The study is designed with the flexibility to open new treatment arms as new 
treatments become available, close existing treatment arms that demonstrate minimal clinical 
activity or unacceptable toxicity, or modify the patient population (e.g., with regard to prior anti-
cancer treatment or biomarker status).  Two cohorts will be enrolled in parallel in this study:  
Cohort 1 will consist of patients who have received no prior systemic therapy for metastatic 
PDAC, and Cohort 2 will consist of patients who have received one line of prior systemic therapy 
for PDAC.  Currently, there are no arms open for enrollment in Cohort 2.  In each cohort, eligible 
patients will initially be randomly assigned to one of several treatment arms (Stage 1).  Patients 
in Cohort 2 who experience disease progression, loss of clinical benefit, or unacceptable toxicity 
during Stage 1 may be eligible to receive treatment with a different treatment combination 
(Stage 2) 
Several key aspects of the study design and study population are summarized below. 
Table 3 
Study Design and Study Population 
Phase: 
Phase Ib/II 
Population Type: 
Adult patients 
Control Method: Standard of care 
Active comparator 
Population Diagnosis 
or Condition: 
Metastatic pancreatic 
ductal 
adenocarcinoma 
Interventional 
Model: 
Parallel 
Population Age: 
 18 years 
Test 
Compounds: 
Atezolizumab (RO5541267), 
Bevacizumab (RO4876646), 
Tiragolumab (RO7092284), 
Tocilizumab (RO4877533) 
Site Distribution: 
Multi-site and 
multi‑region 
Active 
Comparator: 
Gemcitabine, 
Nab-paclitaxel, 
5-Fluororuracil, Leucovorin, 
Oxaliplatin 
Study Intervention 
Assignment Method: 
Randomization 
Number of Arms: 7 
Number of 
Participants to Be 
Enrolled: 
Approximately 
290470 
  

 
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STUDY TREATMENT 
Table 4 
Stage 1 Study Treatments for Cohort 1 
Stage 1 Study Treatments for Cohort 1 
Treatment Group 
Administration Method and Schedule 
Standard treatment 
(chemotherapy) 
(28-day cycles) 
 Nab-paclitaxel 125 mg/m2 IV on Days 1, 8, and 15 of each cycle  
 Gemcitabine 1000 mg/m2 IV on Days 1, 8, and 15 of each cycle 
Atezolizumab plus 
chemotherapy plus 
bevacizumab 
(CIT combination) 
(28-day cycles) 
 Atezolizumab: 840 mg IV infusion over 3060 minutes on Days 1 
and 15 of each cycle 
 Bevacizumab: 10 mg/kg IV infusion over 3090 minutes on 
Days 1 and 15 of each cycle 
 Nab-paclitaxel 125 mg/m2 IV on Days 1, 8, and 15 of each cycle  
 Gemcitabine 1000 mg/m2 IV on Days 1, 8, and 15 of each cycle 
Atezolizumab plus 
chemotherapy plus tiragolumab 
(CIT combination) 
(28-day cycles) 
 Atezolizumab:  840 mg IV infusion over 3060 minutes on Days 1 
and 15 of each cycle 
 Tiragolumab:  420 mg IV infusion over
minutes on Days 1 
and 15 of each cycle 
 Nab-paclitaxel 125 mg/m2 IV on Days 1, 8, and 15 of each cycle  
 Gemcitabine 1000 mg/m2 IV on Days 1, 8, and 15 of each cycle 
Atezolizumab plus 
chemotherapy plus tocilizumab 
(CIT combination) 
(28-day cycles) 
 Tocilizumab:  8 mg/kg IV infusion over 60 minutes on Day 1 of 
each cycle 
 Atezolizumab:  1680 mg IV infusion over 3060 minutes on Day 1 
of each cycle 
 Nab-paclitaxel 125 mg/m2 IV on Days 1, 8, and 15 of each cycle  
 Gemcitabine 1000 mg/m2 IV on Days 1, 8, and 15 of each cycle 
CIT  cancer immunotherapy. 
  
Table 5 
Stage 1 Study Treatments for Cohort 2 
Stage 1 Study Treatments for Cohort 2 
Treatment Group 
Administration Method and Schedule 
Standard treatment 
(chemotherapy) 
(28-day cycles) 
 Nab-paclitaxel 125 mg/m2 IV on Days 1, 8, and 15 of each cycle 
 Gemcitabine 1000 mg/m2 IV on Days 1, 8, and 15 of each cycle 
or 
 Oxaliplatin 85 mg/m2 IV over 2 hours ( 5 minutes) on Days 1 and 15 of 
each cycle 
 Leucovorin 400 mg/m2 IV over 2 hours ( 15 minutes) on Days 1 and 
15 of each cycle 
 5-Fluorouracil 400 mg/m2 IV push on Days 1 and 15 of each cycle 
 5-Fluorouracil 2400 mg/m2 IV continuous infusion over 46 ( 2) hours on 
Days 1 and 2 and on Days 15 and 16 of each cycle 
There are currently no treatments for Cohort 2 Stage 1. 
nab-paclitaxel  nanoparticle albuminbound paclitaxel. 
  
There will be no dose modifications for atezolizumab, bevacizumab, or tiragolumab in this study. 

 
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For management of drug-related toxicities, the dose of nab-paclitaxel may be reduced by 
25 mg/m2 (one dose level) up to two times, the dose of gemcitabine may be reduced by 
200 mg/m2 (one dose level) up to two times, and tocilizumab may be reduced up to one time, as 
outlined in Table 6. 
 
Table 6 
Recommended Dose Reductions for Nab-Paclitaxel, Gemcitabine and 
Tocilizumab 
 
Initial Dose 
First Dose Reduction 
Second Dose Reduction 
Nab-paclitaxel 
125 mg/m2 
100 mg/m2 
75 mg/m2 
Gemcitabine 
1000 mg/m2 
800 mg/m2 
600 mg/m2 
Tocilizumab 
8 mg/kg 
4 mg/kg 
NA 
NA  not applicable; nab-paclitaxel  nanoparticle albuminbound paclitaxel. 
  
DURATION OF PARTICIPATION 
Treatment will continue until disease progression per Response Evaluation Criteria in Solid 
Tumors, Version 1.1. (RECIST v1.1).  The total duration of study, from screening of the first 
patient to the end of the study, is expected to be approximately 7  9 years if expansion is 
ungated. 
COMMITTEES 
Independent Committees: Not applicable 
Other Committees: 
Internal Monitoring Committee and Scientific Oversight Committee 
 
 
 

 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Definition 
5-FU 
5-fluorouracil 
ADA 
anti-drug antibody, also known as anti-therapeutic 
antibody 
ASCO 
American Society of Clinical Oncology 
Atezo 
atezolizumab 
BCRP 
breast cancer resistance protein 
Bev 
bevacizumab 
Chemo 
chemotherapy (nab-paclitaxel and gemcitabine) 
CIT 
cancer immunotherapy 
COVID-19 
coronavirus disease 2019 
CRS 
cytokine release syndrome 
CT 
computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
DOR 
duration of response 
EC 
Ethics Committee 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic Case Report Form 
EDC 
electronic data capture 
ESMO 
European Society for Medical Oncology 
FFPE 
formalin-fixed, paraffin-embedded 
FOLFIRINOX 
leucovorin, 5-fluorouracil, irinotecan, and oxaliplatin 
FOLFOX 
5-fluorouracil, leucovorin, and oxaliplatin 
GI 
gastrointestinal 
HIPAA 
Health Insurance Portability and Accountability Act 
ICH 
International Council for Harmonisation 
IFN 
interferon 
IL 
interleukin 
IMC 
Internal Monitoring Committee 
IND 
Investigational New Drug (Application) 

 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS (CONT.) 
Abbreviation 
Definition 
IRB 
Institutional Review Board 
IRR 
infusion-related reaction 
IxRS 
interactive voice or web-based response system 
LPLV 
last patient, last visit 
MRI 
magnetic resonance imaging 
nab-paclitaxel 
nanoparticle albuminbound paclitaxel 
NCCN 
National Cancer Comprehensive Network 
NCI 
National Cancer Institute 
NCI CTCAE v4.0 
National Cancer Institute Common Terminology 
Criteria for Adverse Events, Version 4.0 
NGS 
next-generation sequencing 
ORR 
objective response rate 
OS 
overall survival (rate) 
PBMC 
peripheral blood mononuclear cell 
PCR 
polymerase chain reaction 
PDAC 
pancreatic ductal adenocarcinoma 
PFS 
progression-free survival 
P-gp 
P-glycoprotein 
PK 
pharmacokinetic 
PPD 
purified protein derivative 
RBR 
Research Biosample Repository 
RECIST 
Response Evaluation Criteria in Solid Tumors 
SARS-CoV-2 
severe acute respiratory syndrome coronavirus 2 
SITC 
Society for Immunotherapy of Cancer 
SOC 
Scientific Oversight Committee 
T3 
triiodothyronine 
T4 
thyroxine 
TB 
tuberculosis 
Tira 
tiragolumab 
TCZ 
tocilizumab 
UGT 
UDP-glucuronosyltransferase 
ULN 
upper limit of normal 
VCA 
viral capsid antigen 

 
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1. 
BACKGROUND 
1.1 
TREATMENT FOR PANCREATIC CANCER 
Pancreatic cancer is known for its aggressiveness, and the high incidence and mortality 
rates have remained unchanged for the last 20 years.  It is the fourth leading cause of 
cancer-related mortality in the United States as well as in the European Union, with 
increasing world-wide mortality rates that align with the projection of being the second 
leading cause of cancer death in the United States by 2030 (Malvezzi et al. 2014; 
American Cancer Society 2016).  Presently, surgical resection offers the only therapeutic 
means of cure.  However, only 15%20% of patients have resectable disease and 80% 
present with advanced disease at initial diagnosis.  Even patients who receive curative 
surgery will have disease relapses, resulting in 5-year survival rates of 25%30% and 
10% in patients with node-negative and node-positive disease at 
pancreaticoduodenectomy, respectively (Trede et al. 1990; Geer and Brennan 1993; 
Tsao et al. 1994; Yeo et al. 1995).  Patients who have locally advanced and 
unresectable disease often receive radiochemotherapy, resulting in a median overall 
survival (OS) of 913 months, but rarely offering long-term survival (Czito et al. 2000).  
Patients with metastatic disease at initial diagnosis have the worst prognosis, with a 
median OS of 8.511.1 months with first-line treatment with FOLFIRINOX (leucovorin, 5-
fluorouracil [5-FU], irinotecan, and oxaliplatin) or with nanoparticle albuminbound 
paclitaxel (nab-paclitaxel) plus gemcitabine (Conroy et al. 2011; Von Hoff et al. 2013), 
with a 5-year OS for metastatic cancer of 2% (Malvezzi et al. 2014; American Cancer 
Society 2016).  Therefore, there is a high unmet need for improved medical intervention. 
1.2 
FIRST-LINE TREATMENT FOR PANCREATIC CANCER 
Two treatment regimens, FOLFIRINOX and combination treatment with nab-paclitaxel 
plus gemcitabine, have been established as standard of care for the first-line treatment 
of patients with metastatic pancreatic ductal adenocarcinoma (PDAC) on the basis of 
two randomized studies comparing combination treatment with gemcitabine alone.  
The ACCORD-11 study demonstrated statistically significantly improved efficacy 
(p  0.001) for FOLFIRINOX compared with gemcitabine with respect to OS (median OS, 
11.1 vs. 6.8 months), objective response rate (ORR) (31.6% vs. 9.4%), and 
progression-free survival (PFS) (median PFS, 6.4 vs. 3.3 months) (Conroy et al. 2011).  
The MPACT study demonstrated statistically significantly improved efficacy (p  0.001) 
for nab-paclitaxel plus gemcitabine compared with gemcitabine with respect to OS 
(median OS, 8.5 vs. 6.7 months), ORR (23% vs. 7%), and PFS (median PFS, 
5.5 vs. 3.7 months) (Von Hoff et al. 2013). 

 
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Given its high toxicity profile, FOLFIRINOX is recommended for patients with a more 
favorable comorbidity profile, as described in guidelines from the European Society for 
Medical Oncology (ESMO) (Ducreux et al. 2015), the American Society of Clinical 
Oncology (ASCO) (Sohal et al. 2016), and the National Cancer Comprehensive Network 
(NCCN 2017).  Nab-paclitaxel plus gemcitabine is recommended for patients with a less 
favorable comorbidity profile. 
Despite the improvements in OS associated with FOLFIRINOX and nab-paclitaxel plus 
gemcitabine, the 5-year survival rate for advanced pancreatic disease remains poor 
(Sohal et al. 2016), emphasizing the great need for treatment regimens with improved 
survival outcomes.  Participation in a clinical trial is listed as a preferred option 
(NCCN 2017). 
1.3 
SECOND-LINE TREATMENT FOR PANCREATIC CANCER 
Second-line treatment for pancreatic cancer depends on the type of first-line therapy and 
the local standard of care, as described in the ESMO, ASCO, and NCCN guidelines 
(Ducreux et al. 2015; Sohal et al. 2016; NCCN 2017).  When patients receive 
FOLFIRINOX as first-line therapy, gemcitabine-based therapy is often used as 
second-line therapy (Portal et al. 2015).  Nab-paclitaxel plus gemcitabine demonstrated 
a median PFS and median OS of 5.1 months and 8.8 months, respectively, and a 
17.5% ORR in the second-line setting (Portal et al. 2015; NCCN 2017).  In contrast, 
when nab-paclitaxel plus gemcitabine is utilized for first-line therapy, 5-FUcontaining 
regimens, including FOLFOX (5-FU, leucovorin, and oxaliplatin) (Chiorean et al. 2016) 
and nanoliposomal irinotecan plus 5-FU plus leucovorin, are recommended by ESMO 
and NCCN guidelines (Ducreux et al. 2015; NCCN 2017).  In two studies of FOLFOX as 
second-line treatment in patients with pancreatic cancer (FIRGEM and CONKO-003 
studies), no objective responses were observed.  Median PFS and median OS were 
1.7 months and 4.3 months, respectively, in the FIRGEM study (Zaanan et al. 2014) and 
2.9 months and 5.9 months, respectively, in the CONKO-003 study (Oettle et al. 2014).  
In the NAPOLI-1 Phase III study in patients with metastatic pancreatic cancer who 
progressed after a gemcitabine-based regimen, treatment with nanoliposomal irinotecan 
plus 5-FU and leucovorin versus treatment with 5-FU and leucovorin alone resulted in 
statistically significant improvement in median OS (6.1 months vs. 4.2 months; p  0.012) 
and median PFS (3.1 months vs. 1.5 months; p  0.0001).  Nanoliposomal irinotecan 
monotherapy did not demonstrate a statistically significant improvement in efficacy 
(Wang-Gillam et al. 2016).  Participation in a clinical trial is recommended as the 
preferred option for second-line therapy (NCCN 2017). 

 
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1.4 
STUDY RATIONALE 
This study will enroll two populations of patients with metastatic PDAC:  patients who 
have received no prior systemic treatment for metastatic PDAC (Cohort 1) and patients 
who have received one line of prior systemic therapy for PDAC (Cohort 2).  Given the 
relatively poor prognosis and limited treatment options for these patients, these 
populations are considered appropriate for trials of novel therapeutic candidates. 
Recent therapeutic advances for patients with metastatic pancreatic cancer have 
prolonged OS, but the prognosis still remains poor, with a median OS of approximately 
8.511 months in the first-line setting (Conroy et al. 2011; Von Hoff et al. 2013).  
Patients who receive second-line treatment for their disease have an even worse 
prognosis, with a median OS of approximately 6 months (Oettle et al. 2014; 
Zaanan et al. 2014; Wang-Gillam et al. 2016).  Approved therapies are associated with 
significant toxicities (e.g., neuropathy, febrile neutropenia, and myelosuppression) that 
negatively affect quality of life.  Currently, no treatment options are available for 
patients whose disease has progressed during or after gemcitabine-based and 
fluoropyrimidine-based therapies. 
Cancer immunotherapy (CIT) has demonstrated clear clinical efficacy, with significant 
survival benefits observed across multiple advanced malignancies.  Currently, the 
prevailing CIT approach is to circumvent immune evasion mechanisms and reinvigorate 
anti-tumor responses by targeting T-cell inhibitory factors such as PD-L1/PD-1.  While 
these targets have resulted in remarkable clinical therapeutic success for various cancer 
indications, ongoing research indicates that a series of stepwise events is necessary for 
the generation of a continuous anti-tumor immune response (Chen and Mellman 2013).  
Each event is critical for an effective response, and each is also susceptible to several 
tumor immune-evasion mechanisms.  Thus, the need to identify and circumvent the 
various factors that account for the absence of an effective anti-cancer immune 
response will be critical for propagating cancer immunity and advancing the field of CIT, 
most likely through combined targeted therapy regimens. 
This Phase Ib/II umbrella study is designed to accelerate the development of CIT 
combinations by identifying early signals and establishing proof-of-concept clinical data 
in patients with PDAC.  The study is designed with the flexibility to open new treatment 
arms as new treatment combinations become available and close existing treatment 
arms that demonstrate minimal clinical activity or unacceptable toxicity.  Enrollment of 
multiple experimental arms within a single study, rather than one or two experimental 
arms within multiple studies, will result in an overall reduction in the number of patients 
receiving control arm treatment.  More importantly, this study will assess the importance 
of simultaneously targeting multiple mechanisms of immune escape through immune cell 
priming and activation, tumor infiltration, and/or recognition of tumor cells for elimination. 
To improve the confidence of clinical signal detection in the experimental arms, this 
study will include a control arm in which patients will receive one of two standard 

 
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chemotherapy regimens.  Moreover, patients who experience disease progression with 
the initial treatment regimen (Stage 1) may be eligible to continue treatment with a 
different treatment regimen (Stage 2), which may advance the scientific understanding of 
immune escape mechanisms in patients who fail to respond to, or experience disease 
progression during, treatment with a CIT or chemotherapy regimen. 
The target and proposed mechanism-of-action classification for each experimental 
investigational medicinal product (IMP) is summarized in Table 1.  The control and 
experimental treatment regimens are described in Section 3.1.1 (see Table 4 and 
Table 6).  Background information and a rationale for each treatment combination, 
including a benefitrisk assessment for experimental agents, are provided in the 
respective appendix for that treatment arm, as outlined in Appendices 7, 12, 1416. 
Table 1 
Target and Proposed Mechanism-of-Action Classification for 
Experimental Investigational Medicinal Products 
Experimental 
IMP 
Target 
Proposed Mechanism-of-Action Classification 
Atezolizumab 
PD-L1 
Checkpoint inhibitor 
Bevacizumab 
VEGF 
Angiogenesis inhibitor, recruitment of T cells to the 
tumor microenvironment a 
Tiragolumab 
TIGIT 
TIGIT antagonist, improves activation and 
effectiveness of T-cell and NK-cell tumor-killing 
activity b 
Tocilizumab 
IL-6R 
IL-6R inhibitor; decreases tumor-associated 
macrophages, T-regulatory cells, and 
myeloid-derived suppressor cells c 
IL-6R  interleukin-6 receptor; IMP  investigational medicinal product; NK  natural 
killer; TIGIT  T-cell immunoreceptor with Ig and ITIM domains; VEGF  vascular 
endothelial growth factor. 
a Wallin et al. 2016. 
b Stanietsky et al. 2009; Yu et al. 2009; Johnston et al. 2014. 
c Rose-John et al. 2006; Scheller et al. 2011; Fisher et al. 2014. 
 
1.5 
COVID-19 BENEFIT–RISK ASSESSMENT 
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. 
A possible consequence of immune checkpoint inhibition may be the modulation of the 
host immune response to acute infection, which may result in immunopathology or 

 
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dysregulated immune system defenses (Wykes and Lewin 2018).  In nonclinical models, 
PD-1/PD-L1 blockade appears to be associated with serious exacerbation of 
inflammation in the setting of acute (as opposed to chronic) viral infection with 
lymphocytic choriomeningitis virus (Clone 13) (Frebel et al. 2012).  However, there are 
insufficient and inconsistent clinical data to assess if outcome from SARS-CoV-2 
infection is altered by CIT. 
Severe SARS-CoV-2 infection appears to be associated with a cytokine release 
syndrome (CRS) involving the inflammatory cytokines interleukin (IL)-6, IL-10, IL-2, and 
interferon (IFN)- (Merad and Martin 2020).  While it is not known, there may be a 
potential for an increased risk of an enhanced inflammatory response if a patient 
develops acute SARS-CoV-2 infection while receiving immune checkpoint inhibitor 
therapies (e.g., atezolizumab).  At this time, there is insufficient evidence for causal 
association between immune checkpoint inhibitor therapies 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 immune checkpoint inhibitor therapies 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. 
There are limited data concerning the possible interactions between CIT 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 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 CIT (SITC 2020).  For patients 
enrolling in this study and receiving CIT, a decision to administer the vaccine to a patient 
should be made on an individual basis by the investigator in consultation with the 
patient. 
In alignment with clinical practice procedures, factors to consider when making the 
individualized decision for patients receiving CIT 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. 

 
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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). 
2. 
OBJECTIVES AND ENDPOINTS 
This study will evaluate the efficacy, safety, and pharmacokinetics of 
immunotherapy-based treatment combinations in patients with metastatic PDAC.  
Specific objectives and corresponding endpoints for the study are outlined below for 
Stage 1 (see Table 2) and Stage 2 (see Table 3). 
Table 2 
Objectives and Corresponding Endpoints for Stage 1 
Primary Efficacy Objective 
Corresponding Endpoint 
 To evaluate the efficacy of 
immunotherapy-based treatment 
combinations during Stage 1 
 Objective response, defined as a complete response or 
partial response on two consecutive occasions  4 weeks 
apart during Stage 1, as determined by the investigator 
according to RECIST v1.1 
Secondary Efficacy Objective 
Corresponding Endpoints 
 To evaluate the efficacy of 
immunotherapy-based treatment 
combinations during Stage 1 
 PFS after randomization, defined as the time from 
randomization to the first occurrence of disease 
progression or death from any cause (whichever occurs 
first) in Stage 1, as determined by the investigator 
according to RECIST v1.1 
 OS after randomization, defined as the time from 
randomization to death from any cause 
 OS at specific timepoints (e.g., 6 months) 
 DOR, defined as the time from the first occurrence of a 
documented objective response to disease progression 
or death from any cause (whichever occurs first) in 
Stage 1, as determined by the investigator according to 
RECIST v1.1 
 Disease control, defined as stable disease for  12 weeks 
or a complete or partial response, as determined by the 
investigator according to RECIST v1.1 
ADA  anti-drug antibody; DOR  duration of response; OS  overall survival; 
PFS  progression-free survival; PK  pharmacokinetic; RECIST  Response Evaluation Criteria in 
Solid Tumors. 
Note:  Overall response at a single timepoint will be assessed by the investigator using 
RECIST v1.1 (see Appendix 1). 

 
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Table 2 
Objectives and Corresponding Endpoints for Stage 1 (cont.) 
Safety Objective 
Corresponding Endpoints 
 To evaluate the safety of 
immunotherapy-based treatment 
combinations during Stage 1 
 Incidence, nature, and severity of adverse events and 
laboratory abnormalities, with severity determined 
according to National Cancer Institute Common 
Terminology Criteria for Adverse Events, Version 4.0 
 Change from baseline in vital signs and ECG 
parameters 
 Change from baseline in targeted clinical laboratory test 
results 
ADA  anti-drug antibody; DOR  duration of response; OS  overall survival; 
PFS  progression-free survival; PK  pharmacokinetic; RECIST  Response Evaluation Criteria in 
Solid Tumors. 
Note:  Overall response at a single timepoint will be assessed by the investigator using 
RECIST v1.1 (see Appendix 1). 

 
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Table 2 
Objectives and Corresponding Endpoints for Stage 1 (cont.) 
ADA  anti-drug antibody; DOR  duration of response; OS  overall survival; 
PFS  progression-free survival; PK  pharmacokinetic; RECIST  Response Evaluation Criteria in 
Solid Tumors. 
Note:  Overall response at a single timepoint will be assessed by the investigator using 
RECIST v1.1 (see Appendix 1). 
  

 
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Table 3 
Objectives and Corresponding Endpoints for Stage 2 
Safety Objective 
Corresponding Endpoints 
 To evaluate the safety of 
immunotherapy-based treatment 
combinations during Stage 2 
 Incidence, nature, and severity of adverse events 
and laboratory abnormalities, with severity 
determined according to National Cancer Institute 
Common Terminology Criteria for Adverse Events, 
Version 4.0 
 Change from baseline in vital signs and ECG 
parameters 
 Change from baseline in targeted clinical laboratory 
test results 
ADA  anti-drug antibody;
 
PK  pharmacokinetic; 
. 
Note:  Overall response at a single timepoint will be assessed by the investigator using 
RECIST v1.1 (see Appendix 1). 
 

 
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Table 3 
Objectives and Corresponding Endpoints for Stage 2 (cont.) 
ADA  anti-drug antibody; DOR  duration of response; PFS  progression-free survival; 
PK  pharmacokinetic; RECIST  Response Evaluation Criteria in Solid Tumors. 
Note:  Overall response at a single timepoint will be assessed by the investigator using 
RECIST v1.1 (see Appendix 1). 
 

 
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3. 
STUDY DESIGN 
3.1 
DESCRIPTION OF THE STUDY 
3.1.1 
Overview of Study Design 
This is a Phase Ib/II, open-label, multicenter, randomized umbrella study in patients with 
metastatic PDAC.  The study is designed with the flexibility to open new treatment arms 
as new treatments become available, close existing treatment arms that demonstrate 
minimal clinical activity or unacceptable toxicity, or modify the patient population 
(e.g., with regard to prior anti-cancer treatment or biomarker status).  Two cohorts will 
be enrolled in parallel in this study:  Cohort 1 will consist of patients who have received 
no prior systemic therapy for metastatic PDAC, and Cohort 2 will consist of patients who 
have received one line of prior systemic therapy for PDAC (see Figure 1).  Currently, 
there are no arms open for enrollment in Cohort 2.  In each cohort, eligible patients will 
initially be randomly assigned to one of several treatment arms (Stage 1; see 
Section 3.1.2).  Patients in Cohort 2 who experience disease progression, loss of clinical 
benefit, or unacceptable toxicity during Stage 1 may be eligible to receive treatment with 
a different treatment combination (Stage 2; see Section 3.1.5). 

 
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Figure 1 Study Schema 
 
CIT  cancer immunotherapy; PDAC  pancreatic ductal adenocarcinoma; R  randomization; RECIST  Response Evaluation Criteria in Solid Tumors. 
a If deemed clinically feasible by the investigator, patients enrolled in an experimental arm during the expansion phase will undergo an 
on-treatment biopsy 4 weeks after initiation of Stage 1 treatment (or 6 weeks after initiation of Stage 1 treatment for patients in the 
Atezo  Chemo  TCZ arm), unless on-treatment tissue samples have already been collected and determined to be evaluable from a minimum of 
15 patients treated with the same CIT combination. 
b Refer to Table 4 for a summary of available Stage 1 treatment regimens in Cohorts 1 and 2. 

 
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c If deemed clinically feasible by the investigator, a biopsy will be performed for patients who discontinue Stage 1 because of unacceptable 
toxicity, disease progression per RECIST v1.1, or loss of clinical benefit as determined by the investigator (see details on tissue sample 
collection in Section 4.5.7). 
d Refer to Table 6 for a summary of available Stage 2 treatment regimens. 

 
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3.1.2 
Stage 1 
During Stage 1, patients in Cohort 1 will be randomly assigned to a control arm 
(chemotherapy) or an experimental arm consisting of atezolizumab and chemotherapy in 
combination with bevacizumab (Atezo  Chemo  Bev), tiragolumab 
(Atezo  Chemo  Tira), or tocilizumab (Atezo  Chemo  TCZ), and patients in Cohort 2 
will be randomly assigned to a control arm (chemotherapy) or an experimental arm, as 
outlined in Table 4 (see also Figure 2 and Figure 3).  Details on the treatment regimens 
for Stage 1 are provided in Appendices 7, 12, 1416, as specified in Table 4.  Table 5 
lists Stage 1 treatment arms for which enrollment and patient follow-up have been 
completed. 
Approximately 290470 patients will be enrolled during Stage 1.  Enrollment within the 
experimental arms will take place in two phases:  a preliminary phase followed by an 
expansion phase.  For most arms, approximately 15 patients will be enrolled during the 
preliminary phase.  However, approximately 30 patients will be enrolled in the 
Atezo  Chemo  TCZ arm during the preliminary phase to ensure a sufficient number of 
patients with high C-reactive protein to facilitate the evaluation of benefit and risk in this 
subpopulation.  If clinical activity is observed in an experimental arm during the 
preliminary phase, approximately 25 additional patients may be enrolled in that arm 
during the expansion phase.  The Sponsor may decide to delay or suspend enrollment 
within a given treatment arm.  In some arms, randomization will be suspended to allow 
for a safety evaluation in a minimum of 6 patients (see Section 3.1.3 for details).  
Experimental arms with minimal clinical activity or unacceptable toxicity will not undergo 
expansion.  Additional patients may be enrolled to ensure balance among treatment 
arms with respect to demographic and baseline characteristics, including potential 
predictive biomarkers, to enable further subgroup analyses.  New experimental arms 
may be added during the course of the study by amending the protocol. 
Patients in Stage 1 will be randomly assigned to treatment arms, and the randomization 
ratio will depend on the number of experimental arms that are open for enrollment 
(e.g., if an arm is added or enrollment in an arm is suspended pending analysis of 
results from the preliminary phase),
 
  Randomization will take into 
account arm-specific exclusion criteria.  Patients will be ineligible for a specific arm if 
they meet any of the exclusion criteria outlined for that arm (see Section 4.1.2).  Details 
on treatment assignment and randomization are provided in Section 4.2. 

 
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Table 4 
Stage 1 Treatment Regimens 
Cohort 
Arm Name 
Treatment a 
Number of Patients b 
Appendix 
Preliminary 
Phase 
Expansion 
Phase c 
1 
Control 
Nab-paclitaxel and 
gemcitabine  
Variable b 
Appendix 7 
 
Atezo  Chemo  Bev 
Atezolizumab, 
nab-paclitaxel, 
gemcitabine, and 
bevacizumab 
15 
25 
Appendix 15 
 
Atezo  Chemo  Tira 
Atezolizumab, 
nab-paclitaxel, 
gemcitabine, and 
tiragolumab 
20 d 
25 
Appendix 14  
 
Atezo  Chemo  TCZ 
Atezolizumab, 
nab-paclitaxel, 
gemcitabine, and 
tocilizumab  
30 d ,e 
25 
Appendix 16  
2 
Control 
One of the following 
treatment regimens, as 
determined on the basis of 
the patient's first-line 
treatment regimen: 
 Nab-paclitaxel and 
gemcitabine 
 mFOLFOX6  
Variable b 
Appendix 7  
Atezo  atezolizumab; Bev  bevacizumab; Chemo  chemotherapy (nab-paclitaxel and gemcitabine); 
mFOLFOX6  5-fluorouracil, leucovorin, and oxaliplatin; nab-paclitaxel  nanoparticle albuminbound 
paclitaxel; TCZ  tocilizumab; Tira  tiragolumab. 
a The Sponsor may decide to delay or suspend enrollment within a given treatment arm.  Thus, all listed 
experimental arms may not be open for enrollment at the same time. 
b The randomization ratio will depend on the number of experimental arms that are open for enrollment 
(e.g., if an arm is added or enrollment in an arm is suspended pending analysis of results from the 
preliminary phase), 
 
 (see Section 4.2 for details). 
c If clinical activity is observed in an experimental arm during the preliminary phase, approximately 
25 additional patients may be enrolled in that arm during the expansion phase.  Experimental arms with 
minimal clinical activity or unacceptable toxicity will not undergo expansion. 
d Randomization will be suspended in the Atezo  Chemo  Tira, and Atezo  Chemo  TCZ arms to allow for 
a safety evaluation in a minimum of 6 patients (see Section 3.1.3 for details). 
e Approximately 30 patients will be enrolled in the Atezo  Chemo  TCZ arm during the preliminary phase to 
ensure a sufficient number of patients with high C-reactive protein levels to facilitate the evaluation of 
benefit and risk in this subpopulation. 

 
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Figure 2 Detailed Study Design:  Cohort 1 
 
 
 
Atezo  atezolizumab; Bev  bevacizumab; Chemo  chemotherapy (nab-paclitaxel and gemcitabine); nab-paclitaxel  nanoparticle albuminbound 
paclitaxel; PDAC  pancreatic ductal adenocarcinoma; R  randomization; TCZ  tocilizumab; Tira  tiragolumab. 

 
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Figure 3 Detailed Study Design:  Cohort 2 
 
 
mFOLFOX6  5-fluorouracil, leucovorin, and oxaliplatin; nab-paclitaxel  nanoparticle albuminbound paclitaxel; PDAC  pancreatic ductal 
adenocarcinoma; R  randomization; RECIST  Response Evaluation Criteria in Solid Tumors. 
a Patients in Cohort 2 who experience disease progression per RECIST v1.1, loss of clinical benefit as determined by the investigator (details 
provided below), or unacceptable toxicity during Stage 1 may be eligible to receive a different treatment combination during Stage 2, provided 
they meet the eligibility criteria.  Details are provided in the respective appendix for each treatment arm (see Appendices 7, 12, 1416). 
 

 
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Table 5 
Treatment Arms with Completed Enrollment and Patient Follow-Up 
Stage 
Cohort 
Arm Name 
Treatment 
Number of Patients Enrolled 
Protocol Versions 
Describing Arm 
Preliminary Phase 
Expansion Phase 
1 
1 
Atezo  Chemo  Seli 
Atezolizumab, 
nab-paclitaxel, gemcitabine, 
and selicrelumab 
9 
0 
49 
1 
1 
Atezo + Chemo + 
AB928 
Atezolizumab, 
nab-paclitaxel, 
gemcitabine, and AB928 
15 
0 
8-15 
1 
2 
Atezo  BL-8040 
Atezolizumab and BL-8040 
16 
0 
15 
1 
2 
Atezo  Cobi 
Atezolizumab and 
cobimetinib 
15 
0 
19 
1 
2 
Atezo  PEGPH20 
Atezolizumab and PEGPH20 
40 
26 
19 
1 
2 
Atezo  RO6874281 
Q2W 
Atezolizumab and 
RO6874281 Q2W 
15 
0 
49 
1 
2 
Atezo  RO6874281 
Q3W 
Atezolizumab and 
RO6874281 Q3W 
16 
0 
49 
2 
2 
Atezo  Cobi 
Atezolizumab and 
cobimetinib 
14 
N/A 
19 
2 
2 
Atezo  RO6874281 
Q2W 
Atezolizumab and 
RO6874281 Q2W 
1 
N/A 
49 
2 
2 
Atezo  RO6874281 
Q3W 
Atezolizumab and 
RO6874281 Q3W 
6 
N/A 
49 
Atezo  atezolizumab; Chemo  chemotherapy (nab-paclitaxel and gemcitabine); Cobi  cobimetinib; N/A  not applicable; 
nab-paclitaxel  nanoparticle albuminbound paclitaxel; Q2W  every 2 weeks; Q3W  every 3 weeks; Seli  selicrelumab. 
 
 

 
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Patients in the control arms will continue to receive treatment until unacceptable toxicity 
or disease progression per Response Evaluation Criteria in Solid Tumors, Version 1.1 
(RECIST v1.1).  Patients in the experimental arms will continue to receive treatment until 
unacceptable toxicity or loss of clinical benefit as determined by the investigator after an 
integrated assessment of radiographic and biochemical data, local biopsy results 
(if available), and clinical status (e.g., symptomatic deterioration such as pain secondary 
to disease).  Because of the possibility of an initial increase in tumor burden caused by 
immune cell infiltration in the setting of a T-cell response (termed pseudoprogression) 
with atezolizumab and other CITs, radiographic progression per RECIST v1.1 may not 
be indicative of true disease progression.  In the absence of unacceptable toxicity, 
patients who meet criteria for disease progression per RECIST v1.1 while receiving 
treatment with a CIT combination will be permitted to continue 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 
 
3.1.3 
Safety Evaluation Phase 
To account for potential overlapping toxicities in the Atezo Chemo  Tira, and 
Atezo  Chemo  TCZ arms, enrollment within each arm will be suspended after 
approximately 6 patients have been enrolled to allow for a safety evaluation.  The safety 
evaluation will be based on safety data from a minimum of 6 patients who have received 
at least one dose of treatment (i.e., one dose of each agent for a given combination) and 
completed safety follow-up assessments during at least one full treatment cycle.  If the 
combination is determined to be sufficiently safe, enrollment will be resumed in that arm. 
3.1.4 
Second-Line Treatment for Cohort 1 Control Arm 
Patients in the Cohort 1 control arm who experience disease progression per 
RECIST v1.1 will be given the option of enrolling in Cohort 2 (if open for enrollment), 
provided they meet eligibility criteria (see Section 4.1). 
3.1.5 
Stage 2 Treatment for Cohort 2 
Patients in the Cohort 2 control arm who experience disease progression per 
RECIST v1.1 and patients in a Cohort 2 experimental arm who experience loss of 
clinical benefit as determined by the investigator (as described above) during Stage 1 
will be given the option of receiving a different treatment combination during Stage 2, as 
outlined in Table 6, provided they meet eligibility criteria (see Section 4.1) and Stage 2 

 
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arms are open for enrollment.  Patients who experience unacceptable toxicity during 
Stage 1 may be eligible to receive treatment during Stage 2.  Patients in Cohort 2 who 
are eligible for more than one Stage 2 treatment arm will be assigned to a treatment arm 
by the Sponsor.  Stage 2 treatment must begin within 3 months after the patient has 
experienced disease progression per RECIST v1.1, loss of clinical benefit, or 
unacceptable toxicity in Stage 1 and will continue until unacceptable toxicity or loss of 
clinical benefit as determined by the investigator.  However, it is recommended that 
patients begin Stage 2 treatment as soon as possible. 
Table 6 
Stage 2 Treatment Regimens for Cohort 2 
Arm Name 
Treatment 
Appendix 
No Stage 2 treatment currently available 
 
 
Enrollment in a treatment arm may be stopped during Stage 2 on the basis of 
 
 from these arms during Stage 1 
.  The Sponsor 
may also decide to discontinue enrollment in Stage 2 treatment arms on the basis of a 
review of all available safety data, preliminary efficacy data, and supportive information 
, as appropriate. 
3.1.6 
Assessments and Monitoring 
All patients will be closely monitored for adverse events throughout the study, and 
adverse events will be graded according to the National Cancer Institute Common 
Terminology Criteria for Adverse Events, Version 4.0 (NCI CTCAE v4.0). 
 
 
 
Patients will undergo tumor assessments every 6 weeks (from Day 1 of Cycle 1) during 
the first 48 weeks and then every 6 or 12 weeks thereafter (see Section 4.5.5 and 
Appendices 7, 12, 1416 for details).  Response will be assessed by the investigator 
using RECIST v1.1 (see Appendix 1).  If clinical activity is demonstrated in an 
experimental arm, the Sponsor may request that tumor assessment scans for that arm 
and the corresponding control arm be submitted for evaluation by an Independent 
Review Facility. 
Baseline tumor tissue samples will be collected from all patients, preferably by means of 
a biopsy performed at study entry.  If a biopsy is not deemed feasible by the investigator, 
archival tumor tissue may be submitted, provided the tissue was obtained within 
3 months prior to enrollment and the patient has not received any anti-cancer therapy 
since the time of the biopsy.  If deemed clinically feasible by the investigator, tumor 
tissue will also be collected for patients who discontinue Stage 1 because of 
unacceptable toxicity, disease progression per RECIST v1.1, or loss of clinical benefit as 
determined by the investigator.  For patients enrolled in an experimental arm during the 

 
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expansion phase, an on-treatment tumor tissue sample will be collected 6 weeks after 
initiation of Stage 1 treatment for patients in the Atezo  Chemo  TCZ arm or 4 weeks 
after initiation of Stage 1 treatment in other experimental arms (if deemed clinically 
feasible by the investigator), unless on-treatment tissue samples have already been 
collected and determined to be evaluable from a minimum of 15 patients treated with the 
same CIT combination.  These samples will be utilized for 
 
 and details on tissue sample 
collection in Section 4.5.7). 
To characterize the pharmacokinetic (PK) properties and/or immunogenicity of 
atezolizumab and the other therapeutic agents, blood samples will be taken at various 
timepoints before and during study treatment administration. 
On the basis of a review of real-time safety data and available PK data, treatment 
regimens may be modified by the Sponsor as deemed appropriate. 
A schedule of activities is provided for each treatment arm in Appendices 7, 12, 1416. 
3.1.7 
Internal Monitoring Committee 
An Internal Monitoring Committee (IMC) will monitor patient safety throughout the study.  
The IMC will include representatives from Clinical Science, Safety Science, and 
Biostatistics.  In addition to the ongoing assessment of the incidence, nature, and 
severity of adverse events, serious adverse events, deaths, and laboratory abnormalities 
performed by the investigator and the Medical Monitor, the IMC will review all necessary 
cumulative data at regular intervals during the study.  At the time of each review, the 
IMC will make appropriate recommendations (e.g., the study should continue as 
planned, enrollment in a specific arm should be discontinued, a treatment regimen 
should be modified, the protocol should be amended, enrollment should be held pending 
further safety evaluations).  Decisions will be made in consideration of the totality of the 
available data.  Ad-hoc meetings may be called in addition to scheduled meetings, as 
necessary, to provide recommendations on management of any new safety issues.  
Specific operational details such as the committee's composition, frequency and timing 
of meetings, and members' roles and responsibilities will be detailed in an IMC Charter. 
3.1.8 
Scientific Oversight Committee 
A Scientific Oversight Committee (SOC) will act as a consultative body to the Sponsor, 
providing external expert opinions on the safety data collected during the study.  
This committee will consist of an external group of at least three oncology experts in CIT 
who will advise the Sponsor on the interpretation of study data.  For this purpose, the 
SOC will evaluate aggregate safety data on a periodic basis, 
 
 from the time of the first meeting of the SOC.  Members will follow a charter 
that outlines their roles and responsibilities.  Data being evaluated by the SOC will 
include demographic, adverse event, serious adverse event, and relevant laboratory 

 
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data.  The SOC may review efficacy data if safety concerns necessitate benefitrisk 
assessments.  The Sponsor will retain all decision-making authority for this study. 
3.2 
END OF STUDY AND LENGTH OF STUDY 
The end of this study is defined as the date when the last patient completes the last visit 
(LPLV), including survival follow-up visits conducted by telephone or in the clinic.   
3.3 
DURATION OF PARTICIPATION 
Treatment will continue until disease progression per Response Evaluation 
Criteria in Solid Tumors, Version 1.1. (RECIST v1.1).  The total duration of 
study, from screening of the first patient to the end of the study, is expected to 
be approximately 7 years or 9 years if expansion is ungated.    
3.4 
RATIONALE FOR STUDY DESIGN 
3.4.1 
Rationale for Patient Population 
Pancreatic cancer is a disease of high unmet medical need with an overall 5-year 
survival rate of  5%.  Chemotherapy remains the standard-of-care treatment for 
metastatic disease, as described in Section 1.  Despite recent improvements in 
treatment, the prognosis for patients with metastatic PDAC remains poor, with a median 
OS of approximately 8.511.1 months (Conroy et al. 2011; Von Hoff et al. 2013).  
Patients who receive second-line treatment for their disease have an even more limited 
prognosis, with a median OS of approximately 4.36.1 months (Oettle et al. 2014; 
Zaanan et al. 2014, Wang-Gillam et al. 2016).  Approved therapies are associated with 
significant toxicities (e.g., neuropathy, febrile neutropenia, myelosuppression, and 
alopecia) that negatively affect quality of life.  Therefore, there is a continuing need for 
more efficacious, better-tolerated treatments for patients with metastatic PDAC. 
3.4.2 
Rationale for Immunotherapy-Based Treatment beyond Initial 
Radiographic Progression 
In studies of immunotherapeutic agents, complete response, partial response, and 
stable disease have each been shown to occur after radiographic evidence of an 
apparent increase in tumor burden.  This initial increase in tumor burden caused by 
immune cell infiltration in the setting of a T-cell response has been termed 
pseudoprogression (Hales et al. 2010).  In Study PCD4989g, evidence of tumor growth 
followed by a response was observed in several tumor types.  In addition, in some 
responding patients with radiographic evidence of progression, biopsies of new lesions 
or areas of new growth in existing lesions revealed immune cells and no viable cancer 
cells.  Because of the potential for a response after pseudoprogression, this study will 
allow patients randomly allocated to immunotherapy-based treatment arms to continue 
combination treatment after apparent radiographic progression per RECIST v1.1, 
provided the benefitrisk ratio is judged to be favorable by the investigator (see criteria in 
Section 3.1.2).  Patients should be discontinued for unacceptable toxicity or loss of 
clinical benefit as determined by the investigator after an integrated assessment of 

 
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radiographic and biochemical data, local biopsy results (if available), and clinical status 
(see Section 3.1.2 for details). 

 
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4. 
MATERIALS AND METHODS  
4.1 
PATIENTS 
4.1.1 
Inclusion Criteria 
Patients must meet all of the criteria outlined in Sections 4.1.1.1 and 4.1.1.2 to qualify 
for Stage 1.  Patients must meet all of the criteria outlined in Sections 4.1.1.2 and 4.1.1.3 
to qualify for Stage 2. 
4.1.1.1 
Inclusion Criteria for Stage 1 
Patients must meet all of the following criteria to qualify for Stage 1: 
 
Age  18 years at the time of signing Informed Consent Form 
 
ECOG Performance Status of 0 or 1 (see Appendix 3) 
 
Histologically or cytologically confirmed metastatic PDAC 
The definitive diagnosis of metastatic PDAC is made by evaluating the 
histopathologic data within the context of clinical and radiographic data. 
Patients with endocrine or acinar pancreatic carcinoma are not eligible for 
the study. 
 
For patients in Cohort 1:  no prior systemic treatment for PDAC 
 
For patients in Cohort 2:  disease progression during administration of either 
5FU or gemcitabine-based first-line chemotherapy in the metastatic or locally 
advanced setting and, for patients treated in the locally advanced setting, 
occurrence of metastasis within 6 months after initiation of chemotherapy 
Prior chemotherapy administered as a radiation sensitizer will not be 
considered first-line chemotherapy.  Patients who had disease progression 
during or within 6 months after administration of capecitabine plus gemcitabine 
are not eligible for the study. 
 
Life expectancy  3 months, as determined by the investigator 
 
Availability of a representative tumor specimen that is suitable for determination of 
PD-L1 and/or additional biomarker status via central testing 
Baseline tumor tissue samples will be collected from all patients, preferably by 
means of a biopsy performed at study entry.  If a biopsy is not deemed feasible 
by the investigator, archival tumor tissue may be submitted, provided the tissue 
was obtained from a biopsy performed within 3 months prior to enrollment and 
the patient has not received any anti-cancer therapy since the time of the 
biopsy. 
A formalin-fixed, paraffin-embedded (FFPE) tumor specimen in a paraffin block 
(preferred) or 1016 slides (16 slides preferred) containing unstained, freshly 
cut, serial sections must be submitted along with an associated pathology 
report.  Refer to Section 4.5.7 for additional information on tumor specimens 
collected at screening. 
 

 
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4.1.1.2 
Inclusion Criteria for Stage 1 and Stage 2 
Patients must meet all of the following criteria to qualify for Stage 1 and to qualify for 
Stage 2: 
 
Signed Informed Consent Form 
 
Ability to comply with the study protocol, in the investigator’s judgment 
 
Measurable disease (at least one target lesion) according to RECIST v1.1 
Previously irradiated lesions can be considered as measurable disease only if 
progressive disease has been unequivocally documented at that site since 
radiation. 
 
Adequate hematologic and end-organ function, defined by the following laboratory 
test results, obtained within 14 days prior to initiation of study treatment: 
 
For patients receiving therapeutic anticoagulation:  stable anticoagulant regimen 
 
For women of childbearing potential:  agreement to remain abstinent (refrain from 
heterosexual intercourse) or use contraceptive measures, and agreement to 
refrain from donating eggs, as outlined for each specific treatment arm in 
Appendices 7, 12, 1416 
 
For men:  agreement to remain abstinent (refrain from heterosexual intercourse) or 
use contraceptive measures, and agreement to refrain from donating sperm, as 
outlined for each specific treatment arm in Appendices 7, 12, 1416 

 
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4.1.1.3 
Inclusion Criteria for Stage 2 
Patients must meet all of the following criteria to qualify for Stage 2: 
 
ECOG Performance Status of 0, 1, or 2 (see Appendix 3) 
 
Patients randomly allocated to the control arm during Stage 1:  ability to initiate 
Stage 2 treatment within 3 months after experiencing unacceptable toxicity or 
disease progression per RECIST v1.1 while receiving control treatment 
 
Patients randomly allocated to an experimental arm during Stage 1:  ability to initiate 
Stage 2 treatment within 3 months after experiencing unacceptable toxicity not 
related to atezolizumab or loss of clinical benefit as determined by the investigator 
(see Section 3.1.2 for details) while receiving Stage 1 treatment 
 
Availability of a tumor specimen from a biopsy performed upon discontinuation of 
Stage 1 because of unacceptable toxicity, disease progression per RECIST v1.1, or 
loss of clinical benefit as determined by the investigator 
 
4.1.2 
Exclusion Criteria 
Patients will be excluded from enrollment in specific arms during Stage 1 or enrollment 
during Stage 2 if they meet any of the criteria outlined in subsequent sections, as 
specified by treatment arm below: 
Stage 
Cohort 
Treatment Arm 
Applicable Exclusion Criteria 
1 
1 
Control 
Sections 4.1.2.1 and 4.1.2.2 
Atezo  Chemo  Bev 
Sections 4.1.2.1, 4.1.2.2, and 4.1.2.3 
Atezo  Chemo  Tira 
Sections 4.1.2.1, 4.1.2.2, and 4.1.2.5 
Atezo  Chemo  TCZ 
Sections 4.1.2.1, 4.1.2.2, and 4.1.2.6 
Atezo  atezolizumab; Bev  bevacizumab; Chemo  chemotherapy (nab-paclitaxel and 
gemcitabine); TCZ  tocilizumab; Tira  tiragolumab. 
 
4.1.2.1 
Exclusion Criteria for Stage 1 
Patients who meet any of the following criteria will be excluded from Stage 1: 
 
Prior treatment with T-cell co-stimulating or immune checkpoint blockade therapies 
(including antiCTLA-4, antiPD-1, and antiPD-L1 therapeutic antibodies) 
 
Treatment with investigational therapy within 28 days prior to initiation of study 
treatment 
 
Systemic treatment for PDAC within 2 weeks or 5 half-lives of the drug (whichever is 
longer) prior to initiation of study treatment 
 
Adverse events from prior anti-cancer therapy that have not resolved to Grade  1 or 
better, with the exception of alopecia of any grade and Grade  2 peripheral 
neuropathy 
 
For patients in Cohort 2:  known dihydropyrimidine dehydrogenase deficiency 
 
Eligible only for the control arm 
 

 
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4.1.2.2 
Exclusion Criteria for Stage 1 and Stage 2 
Patients who meet any of the following criteria will be excluded from Stage 1 and from 
Stage 2: 
 
Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent 
drainage procedures (i.e., more than one time per month) 
 
Uncontrolled tumor-related pain 
 
Symptomatic, untreated, or actively progressing CNS metastases 
Patients with a history of treated CNS lesions are eligible, provided that all of 
the following criteria are met: 
 
Uncontrolled hypercalcemia 
, or 
corrected serum calcium  ULN) or symptomatic hypercalcemia requiring continued 
use of bisphosphonate therapy  
Patients who are receiving bisphosphonate therapy for other reasons 
(e.g., bone metastasis or osteoporosis) and who do not have a history of 
clinically significant hypercalcemia are eligible for the study. 

 
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 
History of leptomeningeal disease 
 
– 
– 
– 
 
 
Positive HIV test at screening or at any time prior to screening 
 
 
 
Known clinically significant liver disease, including alcoholic hepatitis, cirrhosis, fatty 
liver disease, and inherited liver disease 

 
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 
Active tuberculosis (TB) 
 
Severe infection within 4 weeks prior to initiation of study treatment, including, but 
not limited to, hospitalization for complications of infection, bacteremia, or severe 
pneumonia, or any active infection that, in the opinion of the investigator, could 
impact patient safety 
 
Treatment with therapeutic oral or IV antibiotics within 2 weeks prior to initiation of 
study treatment 
Patients receiving prophylactic antibiotics (e.g., to prevent a urinary tract 
infection or chronic obstructive pulmonary disease exacerbation) are eligible for 
the study. 
 
Significant cardiovascular disease (such as New York Heart Association Class II or 
greater cardiac disease, myocardial infarction, or cerebrovascular accident) within 
12 months prior to initiation of study treatment, or unstable arrhythmia or unstable 
angina within 3 months prior to initiation of study treatment 
 
Grade  3 hemorrhage or bleeding event within 28 days prior to initiation of study 
treatment 
 
Prior allogeneic stem cell or solid organ transplantation 
 
Major surgical procedure other than for diagnosis within 4 weeks prior to initiation of 
study treatment, or anticipation of need for a major surgical procedure during the 
course of the study 
Placement of a central venous access catheter (e.g., port or similar) is not 
considered a major surgical procedure and is therefore permitted. 
 
History of malignancy other than pancreatic carcinoma within 2 years prior to 
screening, with the exception of those 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 
 
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 
Women of childbearing potential must have a negative serum pregnancy test 
result within 14 days prior to initiation of study treatment. 
 
Treatment with a live, attenuated vaccine within 4 weeks prior to initiation of study 
treatment, or anticipation of need for such a vaccine during treatment with 
atezolizumab or within 5 months after the last dose of atezolizumab 
 
History of severe allergic anaphylactic reactions to chimeric or humanized 
antibodies or fusion proteins 
 
Known hypersensitivity to Chinese hamster ovary cell products or recombinant 
human antibodies 

 
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 
Known allergy or hypersensitivity to any of the study drugs or any of their excipients 
 
Treatment with systemic immunostimulatory agents (including, but not limited to, 
IFN and IL-2) within 4 weeks or 5 half-lives of the drug (whichever is longer) prior to 
initiation of study treatment 
 
Treatment with systemic immunosuppressive medication (including, but not limited 
to, corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide, and 
anti-tumor necrosis factor  agents) within 2 weeks prior to initiation of study 
treatment, or anticipation of need for systemic immunosuppressive medication 
during the course of the study, with the following exceptions: 
 
Patients entering Stage 2:  immunotherapy-related adverse events that have not 
resolved to Grade 1 or better or to baseline at the time of consent with the following 
exception:  patients with ongoing endocrine events that are adequately managed 
with supplemental therapy are eligible 
 
4.1.2.3 
Exclusion Criteria for Bevacizumab-Containing Arm during 
Stage 1 
Patients who meet any of the following criteria will be excluded from the 
bevacizumab-containing arms during Stage 1: 
 
Inadequately controlled hypertension, defined as systolic blood pressure 
 150 mmHg and/or diastolic blood pressure  100 mmHg (average of at least 
three readings at two 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 initiation of study treatment 
 
History of hemoptysis ( 2.5 mL of bright red blood per episode) within 1 month 
prior to initiation of study treatment 
 
Evidence of bleeding diathesis or significant coagulopathy (in the absence of 
therapeutic anticoagulation) 
 
Current or recent ( 10 days prior to initiation of study treatment) use of aspirin 
( 325 mg/day) or clopidogrel ( 75 mg/day) 

 
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Use of full-dose oral or parenteral anticoagulants for therapeutic purpose is 
permitted as long as the INR and/or aPTT is within therapeutic limits (according 
to institution standards) within 7 days prior to initiation of study treatment and 
the patient has been on a stable dose of anticoagulants for  2 weeks prior to 
initiation of study treatment.  Prophylactic use of anticoagulants is allowed. 
 
Core biopsy or other minor surgical procedure, excluding placement of a vascular 
access device, within 3 days prior to initiation of study treatment 
 
History of abdominal or tracheoesophageal fistula, gastrointestinal (GI) perforation, 
or intra-abdominal abscess within 6 months prior to initiation of study treatment 
 
History of intestinal obstruction and/or clinical signs or symptoms of GI obstruction, 
including subocclusive or occlusive syndrome related to the underlying disease, 
within 6 months prior to initiation of study treatment or requirement for routine 
parenteral hydration, parenteral nutrition, or tube feeding within 6 months prior to 
initiation of study treatment  
Patients with signs or symptoms of subocclusive or occlusive syndrome or with 
intestinal obstruction at the time of initial diagnosis may be enrolled if they had 
received definitive (surgical) treatment for symptom resolution. 
 
Evidence of abdominal free air that is not explained by paracentesis or recent 
surgical procedure 
 
Serious, non-healing or dehiscing wound, active ulcer, or untreated bone fracture 
 
Grade  2 proteinuria, as demonstrated by  2 protein on dipstick urinalysis and 
 1.0 g of protein in a 24-hour urine collection 
All patients with  2 protein on dipstick urinalysis at screening must undergo a 
24-hour urine collection for protein.  Patients with  2 protein on dipstick 
urinalysis are eligible for the study. 
 
Metastatic disease that involves major airways or blood vessels, or centrally located 
mediastinal tumor masses ( 30 mm from the carina) of large volume 
 
History of intra-abdominal inflammatory process within 6 months prior to initiation 
of study treatment, including, but not limited to, peptic ulcer disease, diverticulitis, 
or colitis 
 
Radiotherapy within 28 days or abdominal/pelvic radiotherapy within 60 days prior to 
initiation of study treatment 
 
Major surgical procedure, open biopsy, or significant traumatic injury within 28 days 
prior to initiation of study treatment; or abdominal surgery, abdominal interventions 
or significant abdominal traumatic injury within 60 days prior to initiation of study 
treatment; or anticipation of need for major surgical procedure during the course of 
the study or non-recovery from side effects of any such procedure 
 

 
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4.1.2.4 
Exclusion Criteria for Tiragolumab-Containing Arm during 
Stage 1 
Patients who meet any of the following criteria will be excluded from the 
tiragolumab-containing arm during Stage 1: 
 
Prior treatment with an anti-TIGIT agent 
 
 
4.1.2.5 
Exclusion Criteria for Tocilizumab-Containing Arm during 
Stage 1 
Patients who meet any of the following criteria will be excluded from the 
tocilizumab-containing arm during Stage 1: 
 
Preexisting CNS demyelinating or seizure disorders 
 
History of diverticulitis, chronic ulcerative lower GI disease (e.g., Crohn’s disease, 
ulcerative colitis), or other symptomatic lower GI conditions that might predispose a 
patient to GI perforation 
 
Current liver disease unrelated to the underlying cancer diagnosis, as determined by 
the investigator 
 
Active current infection or history of recurrent bacterial, viral, fungal (excluding 
fungal infections of the nail bed), mycobacterial, or other infection, including, but not 
limited to, atypical mycobacterial disease, 
 
In the setting of a pandemic or epidemic, screening for active infections should 
be considered according to local or institutional guidelines or those of 
applicable professional societies (e.g., ASCO or ESMO). 
 
Active TB as documented by a positive purified protein derivative (PPD) skin test or 
TB blood test and confirmed by a positive chest X-ray within 3 months prior to 
initiation of study treatment 
Patients with a positive PPD skin test or TB blood test followed by a negative 
chest X-ray may be eligible for the study. 
 
Untreated, latent TB 
 
History of, or currently active, primary or secondary immunodeficiency 
 
 
 

 
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4.2 
METHOD OF TREATMENT ASSIGNMENT 
This is a randomized, open-label study.  After initial 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 Stage 1 treatment assignment from the interactive voice or 
web-based response system (IxRS).  Patients who enroll in Stage 2 will be assigned to 
treatment through use of the IxRS and will retain the same patient identification number 
that was assigned in Stage 1. 
For Stage 1, this study will employ a permuted-block randomization method with 
dynamically changing randomization ratios to account for fluctuation in the number of 
treatment arms that are open for enrollment over the course of the study.  At study 
initiation, patients will be randomly assigned with an approximately equal ratio 
 
to one of four treatment arms (three experimental arms plus control arm) (initial 
randomization scheme) until approximately 15 patients have been enrolled within each 
arm.  Thereafter, the randomization ratio will depend on the number of experimental 
arms that are open for enrollment (e.g., if an arm is added or enrollment in an arm is 
suspended pending analysis of results from the preliminary phase), 
 
 
 
 
 
 
 
Patients will be ineligible for a specific arm if they meet any of the exclusion criteria 
outlined for that arm (see Section 4.1.2). 
 
 
 
 
Patients in Cohort 2 may be eligible for treatment in Stage 2.  Patients who are 
eligible for more than one Stage 2 treatment arm will be assigned a treatment arm by 
the Sponsor. 
Patients who do not receive at least one dose of each drug for their assigned 
treatment regimen will not be included in the efficacy analyses.  Additional patients 
may be randomized in Stage 1 to reach the target number of treated patients planned 
for analysis. 

 
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4.3 
STUDY TREATMENT  
Details on the therapeutic agents for each treatment arm are provided in the respective 
appendix for that treatment arm, as outlined in Appendices 7, 12, 1416. 
4.3.1 
Investigational Medicinal Product Accountability 
The IMPs for this study are atezolizumab, 5-FU, leucovorin, oxaliplatin, nab-paclitaxel, 
gemcitabine, bevacizumab, tiragolumab, and tocilizumab.  Appendix 17 identifies all 
investigational medicinal products for this study.  All IMPs required for completion of this 
study will be provided by the Sponsor where required by local practices.  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. 
IMPs either will be disposed of at the study site according to the study site’s institutional 
standard operating procedure or will be returned to the Sponsor (if supplied by the 
Sponsor) with the appropriate documentation.  The site’s method of destroying 
Sponsor-supplied IMPs must be agreed to by the Sponsor.  The site must obtain written 
authorization from the Sponsor before any Sponsor-supplied IMP is destroyed, and IMP 
destruction must be documented on the appropriate form. 
Accurate records of all IMPs received at, dispensed from, returned to, and disposed of by 
the study site should be recorded on a drug inventory log. 
4.3.2 
Post-Trial Access to Study Treatment 
Currently, the Sponsor does not have any plans to provide study treatments or 
interventions to patients who have completed the study.  The Sponsor may evaluate 
whether to continue providing study treatments in accordance with the Roche Global 
Policy on Continued Access to Investigational Medicinal Product, available at the 
following website: 
http://www.roche.com/policy_continued_access_to_investigational_medicines.pdf 
4.4 
CONCOMITANT THERAPY AND PROHIBITED FOOD 
Details on concomitant therapy, prohibited food, and additional restrictions for each 
treatment arm are provided in the respective appendix for that treatment arm, as outlined 
in Appendices 7, 12, 1416. 
4.5 
STUDY ASSESSMENTS  
A schedule of activities to be performed during the study is provided for each treatment 
arm in Appendices 7, 12, 1416.  All activities must be performed and documented for 
each patient.  Patients will be closely monitored for safety and tolerability throughout the 
study.  Patients should be assessed 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 
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. 
Written informed consent must also be obtained before performing screening 
evaluations for Stage 2. 
Screening evaluations are to be performed within 28 days prior to initiation of study 
treatment (Day 1) in Stage 1 or Stage 2.  All screening evaluations must be completed 
and reviewed to confirm that patients meet all eligibility criteria before enrollment. 
Patients who fail their first screening for study eligibility (Stage 1 or Stage 2) may qualify 
for two re-screening opportunities (for a total of three screenings per patient) at the 
investigator’s discretion.  Patients must re-sign the consent form prior to re-screening.  
Results of standard-of-care tests or examinations performed prior to obtaining informed 
consent and within 28 days prior to Day 1 (within 14 days prior to Day 1 for laboratory 
tests) may be used; such tests do not need to be repeated for screening or re-screening. 
4.5.2 
Medical History, Molecular Profile, 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.  
The patient's molecular profile for pancreatic cancer, if available, will be recorded at 
screening and whenever updated information becomes available during the study.  
In addition, all medications (e.g., prescription drugs, over-the-counter drugs, vaccines, 
herbal or homeopathic remedies, nutritional supplements) used by the patient within a 
specified time prior to initiation of study treatment will be recorded (as outlined for each 
arm in Appendices 7, 12, 1416).  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 electronic Case Report Form (eCRF). 

 
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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, and systolic and 
diastolic blood pressure while the patient is in a seated position, pulse oximetry, and 
temperature. 
Vital signs should be measured within 60 minutes prior to administration of each study 
treatment and, if clinically indicated, during or after treatment administration.  In addition, 
vital signs should be measured at other specified timepoints as outlined for each arm in 
the schedules of activities in Appendices 7, 12, 1416. 
4.5.5 
Tumor and Response Evaluations 
Patients will undergo tumor assessments at baseline, every 6 weeks ( 1 week) for the 
first 48 weeks following initiation of combination treatment, and every 12 weeks 
( 2 weeks) thereafter, regardless of dose delays, until radiographic disease progression 
according to RECIST v1.1, except in the case of patients who continue treatment after 
radiographic disease progression; such patients will undergo tumor assessments every 
6 weeks ( 1 week) until loss of clinical benefit as determined by the investigator 
(see Section 3.1.2 for details).  Thus, tumor assessments are to continue according to 
schedule in patients who discontinue treatment for reasons other than disease 
progression or loss of clinical benefit, even if they start new, nonprotocol-specified 
anti-cancer therapy.  At the investigator’s discretion, tumor assessments may be 
repeated at any time if progressive disease is suspected. 
Baseline tumor assessments for Stage 2 must be performed within 28 days prior to 
initiation of Stage 2 treatment (i.e., Day 1 of Cycle 1).  Tumor assessments performed 
prior to or at the time of unacceptable toxicity, disease progression per RECIST v1.1, or 
loss of clinical benefit during Stage 1 may serve as baseline assessments for Stage 2, 
provided the tumor assessments are performed within 28 days prior to initiation of 
Stage 2 treatment. 
All measurable and/or evaluable lesions should be assessed and documented at 
screening (in both Stage 1 and Stage 2).  Tumor assessments performed as standard of 
care prior to obtaining informed consent and within 28 days prior to initiation of study 
treatment do not have to be repeated at screening. 
Screening assessments must include CT scans (with IV contrast; with or without oral 
contrast) or magnetic resonance imaging (MRI) scans (with IV contrast) 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 (i.e., in patients with contrast 

 
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allergy or impaired renal clearance), a non-contrast CT scan of the chest may be 
performed and MRI scans (with IV contrast, if feasible) of the abdomen and pelvis 
should be performed.  A CT scan with contrast or MRI scan with contrast of the head, 
bone scans, and CT scans of the neck should 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/CT 
scanner, the CT acquisition must be consistent with the standards for a full-contrast 
diagnostic CT scan. 
All measurable and/or evaluable lesions identified at baseline should be re-assessed at 
subsequent tumor evaluations according to the schedule described above.  The same 
radiographic procedures used to assess disease sites at screening should be used 
for subsequent tumor assessments (e.g., the same contrast protocol for CT scans).  
To facilitate evaluation of post-progression tumor changes while treatment is ongoing, 
tumor assessments must be continued after disease progression per RECIST v1.1 for 
patients who receive treatment beyond progression.  This includes continued 
measurement of target lesions, evaluation of non-target lesions (including monitoring for 
further worsening of any non-target lesions that have shown unequivocal progression), 
and evaluation of any newly identified lesions (including measurements, if lesions are 
measurable) at all subsequent assessments. 
Overall response at a single timepoint will be assessed by the investigator using 
RECIST v1.1 (see Appendix 1).  Assessments should be performed by the same 
evaluator, if possible, to ensure internal consistency across visits.  Available results must 
be reviewed by the investigator prior to treatment administration. 
4.5.6 
Chest X-Ray 
A chest X-ray will be performed at screening for patients in Cohort 1, for patients 
who have a positive tuberculin PPD skin test or TB blood test, provided a 
tocilizumab-containing arm is open for enrollment. 
4.5.7 
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:  WBC count, RBC count, hemoglobin, hematocrit, platelet count, and 
differential count (neutrophils, eosinophils, basophils, monocytes, lymphocytes, 
other cells) 

 
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 
Chemistry panel (serum or plasma):  CPK (performed for specified arms only; 
details provided in schedules of activities), bicarbonate or carbon dioxide 
(if considered standard of care for the region), sodium, potassium, magnesium, 
chloride, glucose, BUN or urea, creatinine, total protein, albumin, phosphorus, 
calcium, total bilirubin, ALP, ALT, and AST 
 
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) 
 
Ferritin and -glutamyl transferase (performed for specified arms only; details 
provided in schedules of activities) 
 
Tuberculin PPD skin test or TB blood test (performed at screening, provided a 
tocilizumab-containing arm is open for enrollment; see  Appendix 6) 
 
C-reactive protein 
 
LDH 
 
CA19-9 
 
Pregnancy test 
All women of childbearing potential will have a serum pregnancy test at Stage 1 
screening.  Urine or serum pregnancy tests will be performed at specified 
subsequent visits.  If a urine pregnancy test is positive, it must be confirmed by 
a serum pregnancy test. 
A woman is considered to be of childbearing potential if she is postmenarcheal, 
has not reached a postmenopausal state ( 12 continuous months of 
amenorrhea with no identified cause other than menopause), and has not 
undergone surgical sterilization (removal of ovaries and/or uterus). 

 
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 
Urinalysis (pH, specific gravity, glucose, protein, ketones, and blood) 
Dipstick urinalysis is permitted.  However, patients in Cohort 1 with  2 protein 
on dipstick urinalysis at screening must undergo a 24-hour urine collection for 
protein if a bevacizumab-containing arm is open for enrollment. 
 
The following samples will be sent to one or several central laboratories or to the 
Sponsor or a designee for analysis: 
 
Serum sample for analysis of autoantibodies:  antinuclear antibody, 
antidouble-stranded DNA, circulating anti-neutrophil cytoplasmic antibody, and 
perinuclear anti-neutrophil cytoplasmic antibody 
 
Plasma or serum samples for PK analysis through use of validated assays 
(see Appendices 7, 12, 1416) 
 
Plasma or serum samples for immunogenicity analysis through use of validated 
assays (see Appendices 7, 12, 1416) 
 
 
Tumor tissue sample collected at baseline for determination of PD-L1 expression 
and for 
 

 
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 
Patients enrolled in an experimental arm during the expansion phase:  tumor tissue 
sample collected 4 weeks ( 7 days) after initiation of Stage 1 treatment or 6 weeks 
( 7 days) after initiation of Stage 1 treatment for patients in the 
Atezo  Chemo  TCZ arm (if deemed clinically feasible by the investigator) for 
  
 
Tumor tissue sample collected during Stage 1, at the time of unacceptable toxicity, 
disease progression per RECIST v1.1, or loss of clinical benefit as determined by 
the investigator (see Section 3.1.2 for details), if deemed clinically feasible by the 
investigator, for 
 
For sampling procedures, storage conditions, and shipment instructions, see the 
laboratory manual. 
Unless the patient gives specific consent for his or her leftover samples to be stored for 
 (see Section 4.5.11), biological samples will be destroyed 
when the final Clinical Study Report has been completed, with the following exceptions: 
 
Serum and plasma samples collected for PK analysis or immunogenicity analysis 
may be needed for additional immunogenicity characterization and PK and 
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. 

 
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 
 
will be destroyed no later than 5 years after the final Clinical Study Report has been 
completed, with the exception of the samples that undergo
 which will be 
stored until they are no longer needed or until they are exhausted.  However, the 
storage period for the
samples will be in accordance with the Institutional 
Review Board or Ethics Committee (IRB/EC) approved Informed Consent Form and 
applicable laws (e.g., health authority requirements). 
 
When a patient withdraws from the study, samples collected prior to the date of 
withdrawal may still be analyzed, unless the patient specifically requests that the 
samples be destroyed or local laws require destruction of the samples.  However, if 
samples have been tested prior to withdrawal, results from those tests will remain as 
part of the overall research data. 
Data arising from sample analysis will be subject to the confidentiality standards 
described in Section 8.4. 
Given the complexity and 
, 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. 
4.5.8 
Electrocardiograms 
An ECG is required at screening and when clinically indicated.  ECGs for each patient 
should be obtained from the same machine wherever possible.  Lead placement should 
be as consistent as possible.  It is recommended that patients be resting in a supine 
position for at least 10 minutes prior to ECG recording. 
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. 

 
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4.5.11 
Optional Samples for Research Biosample Repository 
4.5.11.1 
Overview of the Research Biosample Repository 
The Research Biosample Repository (RBR) is a centrally administered group of facilities 
used for the long-term storage of human biologic specimens, including body fluids, solid 
tissues, and derivatives thereof (e.g., DNA, RNA, proteins, peptides).  The collection, 
storage, and analysis of RBR specimens will facilitate the rational design of new 
pharmaceutical agents and the development of biomarker assays, which may allow for 
individualized drug therapy for patients in the future. 
Specimens for the RBR will be collected from patients who give specific consent to 
participate in this optional research.  RBR specimens will be used to achieve the 
following objectives: 
 
To study the association of biomarkers with efficacy, adverse events, or disease 
progression 
 
To increase knowledge and understanding of disease biology 
 
To study drug response, including drug effects and the processes of drug absorption 
and disposition 
 
To develop 
 assays and establish the performance characteristics of these 
assays 
 

 
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4.5.11.2 
Approval by the Institutional Review Board or Ethics 
Committee 
Collection and submission of biological samples to the RBR is contingent upon the 
review and approval of the exploratory research and the RBR portion of the Informed 
Consent Form by each site's IRB/EC and, if applicable, an appropriate regulatory body.  
If a site has not been granted approval for RBR sampling, this section of the protocol 
(Section 4.5.11) will not be applicable at that site. 
4.5.11.3 
Sample Collection 
The following samples will be stored in the RBR and used for research purposes, 
including, but not limited to, research on biomarkers related to CIT or diseases: 
 
Blood samples collected on Day 1 of Cycle 1 during Stage 1 and Stage 2 
 
Leftover blood, serum, plasma, PBMC, and tumor tissue samples (with the 
exception of leftover tissue from archival FFPE blocks, which will be returned to 
sites) and any derivatives thereof (e.g., DNA, RNA, proteins, peptides) collected 
during Stage 1 or Stage 2 of the study, including leftover tissue samples from 
additional tumor biopsies or medically indicated procedures (e.g., bronchoscopy, 
esophagogastroduodenoscopy, colonoscopy) performed at the investigator's 
discretion 
 
The above samples may be sent to one or more laboratories for analysis of germline or 
somatic mutations via 
 
Genomics is increasingly informing researchers’ understanding of disease pathobiology.  
 provides a comprehensive characterization of the genome and, along with clinical 
data collected in this study, may increase the opportunity for developing new therapeutic 
approaches.  Data will be analyzed in the context of this study but will also be explored 
in aggregate with data from other studies.  The availability of a larger dataset will assist 
in identification of important pathways, guiding the development of new targeted agents. 
For sampling procedures, storage conditions, and shipment instructions, see the 
laboratory manual. 
RBR specimens are to be stored until they are no longer needed or until they are 
exhausted.  However, the RBR storage period will be in accordance with the 
IRB/EC-approved Informed Consent Form and applicable laws (e.g., health authority 
requirements). 
4.5.11.4 
Confidentiality 
Specimens and associated data will be labeled with a unique patient identification 
number. 
Patient medical information associated with RBR specimens is confidential and may be 
disclosed to third parties only as permitted by the Informed Consent Form (or separate 

 
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authorization for use and disclosure of personal health information) signed by the 
patient, unless permitted or required by law. 
Given the complexity and exploratory nature of the analyses of RBR specimens, 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. 
Data generated from RBR specimens must be available for inspection upon request by 
representatives of national and local health authorities, and Sponsor monitors, 
representatives, and collaborators, as appropriate. 
Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of the RBR data will become and remain the exclusive and unburdened property 
of the Sponsor, except where agreed otherwise. 
4.5.11.5 
Consent to Participate in the Research Biosample Repository 
The Informed Consent Form will contain a separate section that addresses participation 
in the RBR.  The investigator or authorized designee will explain to each patient the 
objectives, methods, and potential hazards of participation in the RBR.  Patients will be 
told that they are free to refuse to participate and may withdraw their specimens at any 
time and for any reason during the storage period.  A separate, specific signature will be 
required to document a patient's agreement to provide optional RBR specimens.  
Patients who decline to participate will not provide a separate signature. 
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 RBR Research 
Sample Informed Consent eCRF. 
In the event of an RBR participant's death or loss of competence, the participant's 
specimens and data will continue to be used as part of the RBR research. 
4.5.11.6 
Withdrawal from the Research Biosample Repository 
Patients who give consent to provide RBR specimens have the right to withdraw their 
specimens from the RBR at any time for any reason.  After withdrawal of consent, any 
remaining samples will be destroyed or will no longer be linked to the patient.  However, 
if RBR specimens have been tested prior to withdrawal of consent, results from those 
tests will remain as part of the overall research data.  If a patient wishes to withdraw 
consent to the testing of his or her specimens, the investigator must inform the Medical 
Monitor in writing of the patient's wishes through use of the appropriate RBR Subject 
Withdrawal Form and, if the trial is ongoing, must enter the date of withdrawal on the 
RBR Research Sample Withdrawal of Informed Consent eCRF.  If a patient wishes to 
withdraw consent to the testing of his or her RBR samples after closure of the site, the 

 
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investigator must inform the Sponsor by emailing the study number and patient number 
to the following email address: 
global.rcr-withdrawal@roche.com 
A patient's withdrawal from Study WO39608 does not, by itself, constitute withdrawal of 
specimens from the RBR.  Likewise, a patient's withdrawal from the RBR does not 
constitute withdrawal from Study WO39608. 
4.5.11.7 
Monitoring and Oversight 
RBR specimens will be tracked in a manner consistent with Good Clinical Practice by a 
quality-controlled, auditable, and appropriately validated laboratory information 
management system, to ensure compliance with data confidentiality as well as 
adherence to authorized use of specimens as specified in this protocol and in the 
Informed Consent Form.  Sponsor monitors and auditors will have direct access to 
appropriate parts of records relating to patient participation in the RBR for the purposes 
of verifying the data provided to the Sponsor.  The site will permit monitoring, audits, 
IRB/EC review, and health authority inspections by providing direct access to source 
data and documents related to the RBR samples. 
4.6 
TREATMENT, PATIENT, STUDY, AND SITE DISCONTINUATION 
4.6.1 
Study Treatment Discontinuation 
Patients must permanently discontinue study treatment 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 determines it is in the best interest of the patient 
 
Use of another non-protocol anti-cancer therapy 
 
Pregnancy 
 
Experimental arms:  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 3.1.2 for details) 
 
Control arm:  radiographic disease progression per RECIST v1.1 
 
The primary reason for study treatment discontinuation should be documented on the 
appropriate eCRF. 
Patients will return to the clinic for a treatment discontinuation visit  30 days after the 
last dose of study treatment.  The visit at which response assessment shows 

 
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progressive disease or loss of clinical benefit 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 provided for each arm in 
Appendices 7, 12, 1416. 
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).  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 only.  For an 
experimental arm in which all patients discontinued treatment and passed the safety 
follow-up window, as well as approximately 80% of patients discontinued the study, the 
Sponsor may conclude the arm (the remaining approximately 20% of patients will be 
discontinued from the study). 
4.6.2 
Patient Discontinuation from Study 
Patients have the right to voluntarily withdraw from the study at any time for any reason.  
In addition, the investigator has the right to withdraw a patient from the study at any time.  
Reasons for withdrawal from the study may include, but are not limited to, the following: 
 
Withdrawal of consent 
 
Study termination or site closure 
 
Patient non-compliance, defined as failure to comply with protocol requirements as 
determined by the investigator or Sponsor 
 
Every effort should be made to obtain information on patients who withdraw from the 
study.  The primary reason for withdrawal from the study should be documented on the 
appropriate eCRF.  Patients who withdraw from the study will not be replaced. 
4.6.3 
Study Discontinuation 
The Sponsor has the right to terminate this study at any time.  Reasons for terminating 
the study may include, but are not limited to, the following: 
 
The incidence or severity of adverse events in this or other studies indicates a 
potential health hazard to patients. 
 
Patient enrollment is unsatisfactory. 
 
The Sponsor will notify the investigator if the Sponsor decides to discontinue the study. 

 
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4.6.4 
Site Discontinuation 
The Sponsor has the right to close a site at any time.  Reasons for closing a site may 
include, but are not limited to, the following: 
 
Excessively slow recruitment 
 
Poor protocol adherence 
 
Inaccurate or incomplete data recording 
 
Non-compliance with the International Council for Harmonisation (ICH) guideline for 
Good Clinical Practice 
 
No study activity (i.e., all patients have completed the study and all obligations have 
been fulfilled) 
 
5. 
ASSESSMENT OF SAFETY  
5.1 
SAFETY PLAN 
A safety plan for each treatment arm, including a summary of risks and management 
guidelines for patients who experience specific adverse events, is provided in the 
respective appendix for that treatment arm, as outlined in Appendices 7, 12, 1416. 
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., ASCO or ESMO). 
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 5.3.5.12. 
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 

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

 
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5.2.3 
Adverse Events of Special Interest (Immediately Reportable to 
the Sponsor) 
Adverse events of special interest are required to be reported by the investigator to 
the Sponsor immediately (i.e., no more than 24 hours after learning of the event; 
see Section 5.4.2 for reporting instructions).  Adverse events of special interest for each 
treatment arm are listed in the respective appendix for that treatment arm, as outlined in 
Appendices 7, 12, 1416. 
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 5.3.5.12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). 
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?"  
 

 
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5.3.3 
Assessment of Severity of Adverse Events 
The adverse event severity grading scale for the NCI CTCAE (v4.0) will be used for 
assessing adverse event severity.  Table 7 will be used for assessing severity for 
adverse events that are not specifically listed in the NCI CTCAE. 
Table 7 
Adverse Event Severity Grading Scale for Events Not Specifically 
Listed in NCI CTCAE 
Grade 
Severity 
1 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
or intervention not indicated 
2 
Moderate; minimal, local, or non-invasive intervention indicated; or limiting 
age-appropriate instrumental activities of daily living a 
3 
Severe or medically significant, but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; or 
limiting self-care activities of daily living b, c 
4 
Life-threatening consequences or urgent intervention indicated d 
5 
Death related to adverse event d 
NCI CTCAE  National Cancer Institute Common Terminology Criteria for Adverse Events. 
Note:  Based on the most recent version of NCI CTCAE (v4.0), which can be found at:  
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm 
a Instrumental activities of daily living refer to preparing meals, shopping for groceries or 
clothes, using the telephone, managing money, etc. 
b Examples of self-care activities of daily living include bathing, dressing and undressing, 
feeding oneself, using the toilet, and taking medications, as performed by patients who are 
not bedridden. 
c If an event is assessed as a "significant medical event," it must be reported as a serious 
adverse event (see Section 5.4.2 for reporting instructions), per the definition of serious 
adverse event in Section 5.2.2. 
d Grade 4 and 5 events must be reported as serious adverse events (see Section 5.4.2 for 
reporting instructions), per the definition of serious adverse event in Section 5.2.2. 
 

 
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5.3.4 
Assessment of Causality of Adverse Events 
Investigators should use their knowledge of the patient, the circumstances surrounding 
the event, and an evaluation of any potential alternative causes to determine whether an 
adverse event is considered to be related to study treatment, indicating "yes" or "no" 
accordingly.  The following guidance should be taken into consideration (see also 
Table 9): 
 
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 

 
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 
Presence of nontreatment-related factors that are known to be associated with the 
occurrence of the event 
 
Table 9 
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 one adverse event term should be recorded in the event field on the Adverse 
Event eCRF. 
5.3.5.1 
Infusion-Related or Injection Reactions and 
There may be significant overlap in signs and symptoms of infusion-related reactions 
(IRRs) and
  While IRRs occur during or within 24 hours after treatment 
administration, time to onset of
may vary.  Differential diagnosis should be applied, 
particularly for
(occurring more than 24 hours after treatment 
administration), to rule out other etiologies such as delayed hypersensitivity reactions, 
sepsis or infections,
 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 or injection should be captured 
on the Adverse Event eCRF as a diagnosis (e.g., "infusion-related reaction," "injection-
site reaction," or "
").  Avoid ambiguous terms such as 
"systemic reaction." 

 
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" on the Adverse Event eCRF.  Associated signs and symptoms should be 
recorded on the dedicated Infusion-Related or Injection Reaction eCRF or 
 
.  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 Adverse Event eCRF, with associated signs and symptoms also recorded 
separately on the dedicated Infusion-Related or Injection Reaction eCRF or 
 
 
In recognition of the challenges in clinically distinguishing between IRRs and 
, 
consolidated guidelines for medical management of IRRs and 
 are provided in 
Appendix 2. 
5.3.5.2 
Diagnosis versus Signs and Symptoms 
For adverse events other than IRRs (see Section 5.3.5.1), 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. 

 
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5.3.5.4 
Persistent or Recurrent Adverse Events 
A persistent adverse event is one that extends continuously, without resolution, between 
patient evaluation timepoints.  Such events should only be recorded once on the 
Adverse Event eCRF.  The initial severity (intensity or grade) of the event will be 
recorded at the time the event is first reported.  If a persistent adverse event becomes 
more severe, the most extreme severity should also be recorded on the Adverse Event 
eCRF.  If the event becomes serious, it should be reported to the Sponsor immediately 
(i.e., no more than 24 hours after learning that the event became serious; see 
Section 5.4.2 for reporting instructions).  The Adverse Event eCRF should be updated 
by changing the event from "non-serious" to "serious," providing the date that the event 
became serious, and completing all data fields related to serious adverse events. 
A recurrent adverse event is one that resolves between patient evaluation timepoints 
and subsequently recurs.  Each recurrence of an adverse event should be recorded as a 
separate event on the Adverse Event eCRF. 
5.3.5.5 
Abnormal Laboratory Values 
Not every laboratory abnormality qualifies as an adverse event.  A laboratory test result 
must be reported as an adverse event if it meets any of the following criteria: 
 
Is accompanied by clinical symptoms 
 
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." 

 
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Observations of the same clinically significant laboratory abnormality from visit to visit 
should only be recorded once on the Adverse Event eCRF (see Section 5.3.5.4 for 
details on recording persistent adverse events). 
5.3.5.6 
Abnormal Vital Sign Values 
Not every vital sign abnormality qualifies as an adverse event.  A vital sign result must 
be reported as an adverse event if it meets any of the following criteria: 
 
Is accompanied by clinical symptoms 
 
Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation) 
 
Results in a medical intervention or a change in concomitant therapy 
 
Is clinically significant in the investigator’s judgment  
 
It is the investigator’s responsibility to review all vital sign findings.  Medical and scientific 
judgment should be exercised in deciding whether an isolated vital sign abnormality 
should be classified as an adverse event. 
If a clinically significant vital sign abnormality is a sign of a disease or syndrome 
(e.g., high blood pressure), only the diagnosis (i.e., hypertension) should be recorded on 
the Adverse Event eCRF. 
Observations of the same clinically significant vital sign abnormality from visit to visit 
should only be recorded once on the Adverse Event eCRF (see Section 5.3.5.4 for 
details on recording persistent adverse events). 
5.3.5.7 
Abnormal Liver Function Tests 
The finding of an elevated ALT or AST ( 3  baseline value) in combination with either 
an elevated total bilirubin ( 2  ULN) or clinical jaundice in the absence of cholestasis or 
other causes of hyperbilirubinemia is considered to be an indicator of severe liver injury 
(as defined by Hy's Law).  Therefore, investigators must report as an adverse event the 
occurrence of either of the following: 
 
Treatment-emergent ALT or AST  3  baseline value in combination with total 
bilirubin  2  ULN (of which  35% is direct bilirubin) 
 
Treatment-emergent ALT or AST  3  baseline value in combination with clinical 
jaundice 
 
The most appropriate diagnosis or (if a diagnosis cannot be established) the abnormal 
laboratory values should be recorded on the Adverse Event eCRF (see Section 5.3.5.2) 
and reported to the Sponsor immediately (i.e., no more than 24 hours after learning of 
the event), either as a serious adverse event or an adverse event of special interest 
(see Section 5.4.2). 

 
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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 PDAC should be recorded on the Death 
Attributed to Progressive Disease eCRF.  All other deaths that occur during the 
adverse event reporting period, regardless of relationship to study treatment, must be 
recorded on the Adverse Event eCRF and immediately reported to the Sponsor 
(see Section 5.4.2). 
Death should be considered an outcome and not a distinct event.  The event or condition 
that caused or contributed to the fatal outcome should be recorded as the single medical 
concept on the Adverse Event eCRF.  Generally, only one such event should be 
reported.  If the cause of death is unknown and cannot be ascertained at the time of 
reporting, "unexplained death" should be recorded on the Adverse Event eCRF.  If the 
cause of death later becomes available (e.g., after autopsy), "unexplained death" should 
be replaced by the established cause of death.  The term "sudden death" should not be 
used unless combined with the presumed cause of death (e.g., "sudden cardiac death"). 
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 PDAC 
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. 

 
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5.3.5.11 
Hospitalization or Prolonged Hospitalization 
Any adverse event that results in hospitalization (i.e., inpatient admission to a hospital) 
or prolonged hospitalization should be documented and reported as a serious adverse 
event (per the definition of serious adverse event in Section 5.2.2), except as 
outlined below. 
An event that leads to hospitalization under the following circumstances should not be 
reported as an adverse event or a serious adverse event: 
 
Hospitalization for respite care 
 
Planned hospitalization required by the protocol (e.g., for study treatment 
administration or performance of an efficacy measurement for the study) 
 
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 
Reporting Requirements for Cases of Overdose, Medication 
Error, Drug Abuse, or Drug Misuse 
Overdose (accidental or intentional), medication error, drug abuse, and drug misuse 
(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 
 
Intentional overdose:  intentional administration of a drug in a quantity that is higher 
than the assigned dose 

 
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 
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. 
 
Drug abuse:  intentional excessive use of a drug that may lead to addiction or 
dependence, physical harm, and/or psychological harm 
 
Drug misuse:  intentional deviation in the administration of a drug that does not 
qualify as drug abuse 
In cases where drug is to be self-administered by the patient, drug misuse 
could involve the drug being administered to someone other than the patient. 
 
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, 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, bevacizumab, tiragolumab, and tocilizumab, 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. 
 
Intentional overdose:  Enter the adverse event term.  Check the "Intentional 
overdose" box.  If drug abuse is suspected, check the "Drug abuse" box.  If drug 
abuse is not suspected, check the "Drug misuse" box. 
 
Medication error that does not qualify as an overdose:  Enter the adverse event 
term.  Check the "Medication error" box. 
 
Medication error that qualifies as an overdose:  Enter the adverse event term.  
Check the "Accidental overdose" and "Medication error" boxes. 
 
Drug abuse that does not qualify as an overdose:  Enter the adverse event term.  
Check the "Drug abuse" box. 
 
Drug abuse that qualifies as an overdose:  Enter the adverse event term.  Check the 
"Intentional overdose" and "Drug abuse" boxes. 
 
Drug misuse that does not qualify as an overdose:  Enter the adverse event term.  
Check the "Drug misuse" box. 
 
Drug misuse that qualifies as an overdose:  Enter the adverse event term.  Check 
the "Intentional overdose" and "Drug misuse" boxes. 
 
In addition, all special situations associated with atezolizumab, bevacizumab, 
tiragolumab, and tocilizumab, regardless of whether they result in an adverse event, 
should be recorded on the Adverse Event eCRF and reported to the Sponsor 

 
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immediately (i.e., no more than 24 hours after learning of the event).  Special situations 
should be recorded as described below: 
 
Accidental overdose:  Enter the drug name and "accidental overdose" as the event 
term.  Check the "Accidental overdose" and "Medication error" boxes. 
 
Intentional overdose:  Enter the drug name and "intentional overdose" as the event 
term.  Check the "Intentional overdose" box.  If drug abuse is suspected, check the 
"Drug abuse" box.  If drug abuse is not suspected, check the "Drug misuse" box. 
 
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. 
 
Drug abuse that does not qualify as an overdose:  Enter the drug name and "drug 
abuse" as the event term.  Check the "Drug abuse" box. 
 
Drug abuse that qualifies as an overdose:  Enter the drug name and "intentional 
overdose" as the event term.  Check the "Intentional overdose" and "Drug abuse" 
boxes. 
 
Drug misuse that does not qualify as an overdose:  Enter the drug name and "drug 
misuse" as the event term.  Check the "Drug misuse" box. 
 
Drug misuse that qualifies as an overdose:  Enter the drug name and "intentional 
overdose" as the event term.  Check the "Intentional overdose" and "Drug misuse" 
boxes. 
 
Drug administered to someone other than the patient:  Enter the drug name and 
"patient supplied drug to third party" as the event term.  Check the "Drug misuse" 
box. 
 
As an example, an accidental overdose that resulted in a headache would require two 
entries on the Adverse Event eCRF, one entry to report the accidental overdose and one 
entry to report the headache.  The "Accidental overdose" and "Medication error" boxes 
would need to be checked for both entries. 
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) 
 
The investigator must report new significant follow-up information for these events 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 
Emergency Medical Contacts 
 
To ensure the safety of study patients, access to the Medical Monitors is available 
24 hours per day, 7 days per week.  Details will be provided separately.  
An Emergency Medical Call Center will also be available 24 hours per day, 
7 days per week. 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, i ncluding toll-
free numbers for the Emergency Medical Call Center, will be distributed to 
investigators.  
5.4.2 
Reporting Requirements for Serious Adverse Events and 
Adverse Events of Special Interest 
5.4.2.1 
Events That Occur prior to Study Treatment Initiation 
After informed consent has been obtained but prior to initiation of study treatment, only 
serious adverse events caused by a protocol-mandated intervention should be reported.  
The paper Clinical Trial Serious Adverse Event/Special Situations Form provided to 
investigators should be completed and submitted to the Sponsor or its designee 
immediately (i.e., no more than 24 hours after learning of the event), either by faxing or 
by scanning and emailing the form using the fax number or email address provided to 
investigators. 

 
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5.4.2.2 
Events That Occur after Study Treatment Initiation 
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 Serious 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 last dose 
of study treatment are provided in Section 5.6. 
5.4.3 
Reporting Requirements for Pregnancies 
Reporting requirements for pregnancies are described for each treatment arm in the 
respective appendix for that treatment arm, as outlined in Appendices 7, 12, 1416. 
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, electronic mail, and/or a 
monitoring visit to obtain additional case details and outcome information (e.g., from 

 
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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 adverse event reporting period
, 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 Serious 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.   
The Sponsor has a legal responsibility to notify regulatory authorities about the 
safety of a study treatment under clinical investigation.  The Sponsor will 
comply with regulatory requirements for expedited safety reporting to 
regulatory authorities (which includes the use of applicable systems, such as 
EudraVigilance), IRBs, ECs, and investigators.   
To determine reporting requirements for single adverse event cases, the Sponsor will 
assess the expectedness of these events using the following reference documents: 
 
Atezolizumab Investigator's Brochure 
 
E.U. Summary of Product Characteristics for nab-paclitaxel 
 
Ireland Summary of Product Characteristics for 5-FU, leucovorin, oxaliplatin, and 
gemcitabine 
 
Bevacizumab Investigator's Brochure 
 
Tiragolumab Investigator's Brochure 
 
Tocilizumab Investigator's Brochure 
 

 
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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 final study analysis will be based on patient data collected through study 
discontinuation.  If not otherwise specified, efficacy analyses will be based on the 
efficacy-evaluable population, defined as all patients who receive at least one dose of 
each drug for their assigned treatment regimen, and safety analyses will be based on 
the safety-evaluable population, defined as all patients who receive any amount of study 
treatment. 
In both cohorts, the analysis results will be summarized by the treatment regimen that 
patients actually received, as well as by stage (Stage 1 or Stage 2).  Data will be 
described and summarized as warranted by sample size.  Continuous variables will be 
summarized through use of means, standard deviations, medians, and ranges.  
Categorical variables will be summarized through use of counts and percentages.  
Listings will be used in place of tables in the event of small sample sizes. 
New baseline values will be established for the Stage 2 efficacy and safety analyses.  
For evaluation of tumor response, new baseline tumor assessments will be established 
as described in Section 4.5.5.  For other endpoints (e.g., change from baseline in vital 
signs or laboratory test results), the last non-missing value prior to the patient's first dose 
during Stage 2 will serve as the new baseline. 
6.1 
DETERMINATION OF SAMPLE SIZE 
This study is not designed to make explicit power and type I error considerations for a 
hypothesis test.  Instead, this study is designed to obtain preliminary efficacy, safety, 
and PK data on immunotherapy-based treatment combinations when administered to 
patients with metastatic PDAC.  Cohort 1 will consist of patients who have received no 
prior systemic therapy for metastatic PDAC, and Cohort 2 will consist of patients who 
have received one line of prior systemic therapy for PDAC. 
Approximately 290470 patients will be randomly allocated to the control and 
experimental arms during the study:  approximately 110250 patients in Cohort 1 and 
approximately 180220 patients in Cohort 2. 
6.2 
SUMMARIES OF CONDUCT OF STUDY 
Enrollment will be summarized by region, country, and investigator by treatment arm 
within the two stages.  Patient disposition will be summarized by treatment arm within 

 
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each stage.  Major protocol deviations, including major deviations with regard to the 
inclusion and exclusion criteria, will be summarized by treatment arm within each stage. 
For the safety-evaluable population, study drug administration data will be tabulated or 
listed by treatment arm within each stage, and any dose modifications will be flagged.  
Means and standard deviations will be used to summarize the total dose and dose 
intensity for each study drug.  Reasons for discontinuation of study drugs will also be 
tabulated. 
6.3 
SUMMARIES OF DEMOGRAPHIC AND BASELINE 
CHARACTERISTICS 
Demographic and baseline characteristics (including age, sex, race/ethnicity, weight, 
malignancy duration, metastatic disease site, and baseline ECOG Performance Status) 
will be summarized overall and by treatment arm within each stage. 
6.4 
EFFICACY ANALYSES 
6.4.1 
Primary Efficacy Endpoint 
The primary efficacy endpoint is objective response during Stage 1, as defined in 
Section 2 (see Table 2).  Patients with missing or no response assessments will be 
classified as non-responders. 
ORR, the proportion of patients with a complete or partial response, will be calculated 
for each arm, along with 95% confidence intervals (ClopperPearson method).  
The difference in ORR between the experimental arms and the control arm will also be 
calculated, along with 95% confidence intervals, using the Wald method with continuity 
correction. 
6.4.2 
Secondary Efficacy Endpoints 
The secondary efficacy endpoints are PFS, OS, OS at specific timepoints 
(e.g., 6 months), duration of response (DOR), and disease control during Stage 1, as 
defined in Section 2 (see Table 2).  PFS, DOR, and disease control are determined by 
the investigator according to RECIST v1.1. 
DOR will be derived for efficacy-evaluable patients with a complete or partial response. 
For patients who do not have documented disease progression or death in a study 
stage, PFS and DOR will be censored at the day of the last tumor assessment. 
Patients who are still alive at the time of OS analysis will be censored at the last date 
they were known to be alive. 
The Kaplan-Meier method will be used to estimate the median for PFS, OS, and DOR, 
with 95% confidence intervals constructed through use of the Brookmeyer and Crowley 
method.  OS rate at specific timepoints will also be estimated using the Kaplan-Meier 

 
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method, with 95% confidence intervals calculated on the basis of Greenwood’s estimate 
for the variance. 
Disease control rate, the proportion of patients with stable disease for  12 weeks, a 
partial response, or a complete response, will be calculated for each treatment arm, with 
95% confidence intervals estimated through use of Clopper-Pearson’s exact method. 
6.5 
SAFETY ANALYSES 
Verbatim adverse event terms will be mapped to Medical Dictionary for Regulatory 
Activities thesaurus terms, and adverse event severity will be graded according to 
NCI CTCAE v4.0, 
 
 
Safety will be assessed through summaries of adverse events, changes in laboratory 
test results, changes in vital signs and ECGs, and exposure to study drugs.  Exposure to 
combination treatment and length of safety follow-up will be summarized by treatment 
arm within each stage. 
Treatment-emergent adverse events occurring after initiation of treatment will be 
summarized.  For each patient, the maximum reported severity of each adverse event 
will be used in the summaries by severity grade.  All treatment-emergent adverse 
events, serious adverse events, adverse events leading to withdrawal of study 
treatment, Grade  3 adverse events, deaths, and causes of death will be listed and 
summarized by mapped term, appropriate thesaurus level, and NCI CTCAE severity 
grade. 
Relevant laboratory, vital sign (pulse rate, respiratory rate, blood pressure, 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 

 
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used to summarize the baseline and maximum post-baseline severity grade.  Changes 
in vital signs and ECGs will be summarized. 
6.6 
PHARMACOKINETIC ANALYSES 
Sparse samples will be collected for potential PK analyses of atezolizumab (patients 
who receive at least one dose of atezolizumab) and specified drugs given in combination 
with atezolizumab (patients who receive at least one dose of the drug).  Serum or 
plasma concentrations of the various study drugs may 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 by 
cycle and day when appropriate and as data allow.  Individual and median serum or 
plasma concentrations of the various study drugs may be plotted by treatment arm and 
cycle and day.  PK data for combination drugs may be compared with available historical 
data from internal and published previous studies.  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. 
6.7 
IMMUNOGENICITY ANALYSES 
Immunogenicity may be assessed for atezolizumab and other study treatments as 
appropriate (refer to arm-specific appendices for details).  The immunogenicity analyses 
will include all patients with at least one anti-drug antibody (ADA) assessment.  Patients 
will be grouped according to treatment received or, if no treatment is received prior to 
study discontinuation, according to treatment assigned. 
For atezolizumab, the numbers and proportions of ADA-positive patients and 
ADA-negative patients at baseline (baseline prevalence) and after baseline 
(post-baseline incidence) will be summarized by treatment group.  When determining 
post-baseline incidence, patients are considered to be ADA positive if they are ADA 
negative or are 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 post-baseline samples is at least 
 unit 
greater than the titer of the baseline sample (treatment-enhanced ADA response).  
Patients are considered to be ADA negative if they are ADA negative or are missing data 
at baseline and all post-baseline samples are negative, or if they are ADA positive at 
baseline but do not have any post-baseline samples with a titer that is at least 
 
unit greater than the titer of the baseline sample (treatment unaffected). 
For other study treatments for which ADAs are tested, ADA positivity will be determined 
according to standard methods established for previous studies of these drugs. 
The relationship between ADA status and safety, efficacy, PK, and 
 endpoints 
may be analyzed and reported via descriptive statistics. 

 
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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 will be sent 
directly to the Sponsor, using the Sponsor’s standard procedures to handle and process 
the electronic transfer of these data. 
eCRFs and correction documentation will be maintained in the EDC system’s audit trail.  
System backups for data stored by the Sponsor and records retention for the study data 
will be consistent with the Sponsor’s standard procedures. 

 
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7.2 
ELECTRONIC CASE REPORT FORMS  
eCRFs are to be completed through use of a Sponsor-designated EDC system.  
Sites will receive training and have access to a manual for appropriate eCRF 
completion.  eCRFs will be submitted electronically to the Sponsor and should be 
handled in accordance with instructions from the Sponsor. 
All eCRFs should be completed by designated, trained site staff.  eCRFs should be 
reviewed and electronically signed and dated by the investigator or a designee. 
At the end of the study, the investigator will receive patient data for his or her site in a 
readable format on a compact disc that must be kept with the study records.  
Acknowledgement of receipt of the compact disc is required. 
7.3 
SOURCE DATA DOCUMENTATION 
Study monitors will perform ongoing source data verification and review to confirm that 
critical protocol data (i.e., source data) entered into the eCRFs by authorized site 
personnel are accurate, complete, and verifiable from source documents. 
Source documents (paper or electronic) are those in which patient data are recorded 
and documented for the first time.  They include, but are not limited to, hospital records, 
clinical and office charts, laboratory notes, memoranda, patient-reported outcomes, 
evaluation checklists, pharmacy dispensing records, recorded data from automated 
instruments, copies of transcriptions that are certified after verification as being accurate 
and complete, microfiche, photographic negatives, microfilm or magnetic media, X-rays, 
patient files, and records kept at pharmacies, laboratories, and medico-technical 
departments involved in a clinical trial. 
Before study initiation, the types of source documents that are to be generated will be 
clearly defined in the Trial Monitoring Plan.  This includes any protocol data to be 
entered directly into the eCRFs (i.e., no prior written or electronic record of the data) and 
considered source data. 
Source documents that are required to verify the validity and completeness of data 
entered into the eCRFs must not be obliterated or destroyed and must be retained per 
the policy for retention of records described in Section 7.5. 
To facilitate source data verification and review, the investigators and institutions must 
provide the Sponsor direct access to applicable source documents and reports for 
trial-related monitoring, Sponsor audits, and IRB/EC review.  The study site must also 
allow inspection by applicable health authorities. 
7.4 
USE OF COMPUTERIZED SYSTEMS 
When clinical observations are entered directly into a study site’s computerized medical 
record system (i.e., in lieu of original hardcopy records), the electronic record can serve 

 
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as the source document if the system has been validated in accordance with health 
authority requirements pertaining to computerized systems used in clinical research.  
An acceptable computerized data collection system allows preservation of the original 
entry of data.  If original data are modified, the system should maintain a viewable audit 
trail that shows the original data as well as the reason for the change, name of the 
person making the change, and date of the change. 
7.5 
RETENTION OF RECORDS 
Records and documents pertaining to the conduct of this study and the distribution of 
IMPs, including eCRFs, Informed Consent Forms, laboratory test results, and medication 
inventory records, must be retained by the Principal Investigator for at least 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 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 U.S. Food and Drug 
Administration 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 Forms (and ancillary sample Informed Consent 
Forms such as a Mobile Nursing Informed Consent Form, if applicable) will be provided 
to each site.  If applicable, they will be provided in a certified translation into 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 

 
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forms proposed by the site (collectively, the "Consent Forms") before IRB/EC 
submission.  The final IRB/ECapproved Consent Forms must be provided to the 
Sponsor for health authority submission purposes according to local requirements. 
If applicable, the Informed Consent Form will contain separate sections for any optional 
procedures.  The investigator or authorized designee will explain to each patient the 
objectives, methods, and potential risks associated with each optional procedure.  
Patients will be told that they are free to refuse to participate and may withdraw their 
consent at any time for any reason.  A separate, specific signature will be required to 
document a patient's agreement to participate in optional procedures.  Patients who 
decline to participate will not provide a separate signature. 
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. 
Patients must be re-consented to the most current version of the Consent Forms (or to a 
significant new information/findings addendum in accordance with applicable laws and 
IRB/EC policy) during their participation in the study.  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. 

 
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8.3 
INSTITUTIONAL REVIEW BOARD OR ETHICS COMMITTEE 
This protocol, the Informed Consent Forms, any information to be given to the patient, 
and relevant supporting information must be submitted to the IRB/EC by the Principal 
Investigator and reviewed and approved by the IRB/EC before the study is initiated.  
In addition, any patient recruitment materials must be approved by the IRB/EC. 
The Principal Investigator is responsible for providing written summaries of the status of 
the study to the IRB/EC annually or more frequently in accordance with the 
requirements, policies, and procedures established by the IRB/EC.  Investigators are 
also responsible for promptly informing the IRB/EC of any protocol amendments (see 
Section 9.6). 
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 
, 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 Roche policy on study data publication 
(see Section 9.5). 

 
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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. 
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 (i.e., LPLV). 
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 
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. 
9.4 
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.  
Screening and enrollment will occur through an IxRS. 

 
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Central facilities will be used for certain study assessments throughout the study 
(e.g., specified laboratory tests, biomarker analyses, and PK analyses), as specified in 
Section 4.5.7.  Accredited local laboratories will be used for routine monitoring; local 
laboratory ranges will be collected. 
An IMC will be employed to monitor and evaluate patient safety throughout the study.  
An SOC will provide external expert opinions on the safety data collected during 
the study. 
9.5 
PUBLICATION 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, both at scientific 
congresses and in peer-reviewed journals.  The Sponsor will comply with all 
requirements for publication of study results.  In addition, 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 
provided upon request.  For more information, refer to 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 
country, the Sponsor aims to publish results from analyses of additional endpoints and 
exploratory data that are clinically meaningful and statistically sound. 
The investigator must agree to submit all manuscripts or abstracts to the Sponsor prior 
to submission for publication or presentation.  This allows the Sponsor to protect 
proprietary information and to provide comments based on information from other 
studies that may not yet be available to the investigator. 
In accordance with standard editorial and ethical practice, the Sponsor will generally 
support publication of multicenter trials only in their entirety and not as individual center 
data.  In this case, a coordinating investigator will be designated by mutual agreement. 
Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements.  Any formal publication 
of the study in which contribution of Sponsor personnel exceeded that of conventional 
monitoring will be considered as a joint publication by the investigator and the 
appropriate Sponsor personnel. 

 
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Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of data from this study will become and remain the exclusive and unburdened 
property of the Sponsor, except where agreed otherwise. 
9.6 
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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American Cancer Society. Cancer Facts & Figures 2016 [resource on the Internet]. 
2016 [cited 28 February 2018]. Available from: 
http://www.cancer.org/research/cancerfactsstatistics/cancerfactsfigures2016/. 
Chen DS, Mellman I. Oncology meets immunology: the cancer-immunity cycle. Immunity 
2013;39:110. 
Chiorean EG, Von Hoff DD, Tabermero J, et al. Second-line therapy after nab-paclitaxel 
plus gemcitabine or after gemcitabine for patients with metastatic pancreatic 
cancer. Br J Cancer 2016;115:18894. 
Conroy T, Desseigne F, Ychou M, et al. FOLFIRINOX versus gemcitabine for metastatic 
pancreatic cancer. N Engl J Med 2011;364:181725. 
Czito BG, Willett CG, Clark JW, et al. Current perspectives on locally advanced 
pancreatic cancer. Oncology 2000;14:153545. 
Ducreux M, Cuhna AS, Caramella C, et al. Cancer of the pancreas: ESMO clinical 
practice guidelines. Ann Oncol 2015;26(Suppl 5):v5668. 
Fisher DT, Appenheimer MM, Evans SS, et al. The two faces of IL-6 in the tumor 
microenvironment. Semin Immunol 2014;26:3847. 
Frebel H, Nindl V, Schuepbach RA, et al. Programmed death 1 protects from fatal 
circulatory failure during systemic virus infection of mice. J Exp Med 
2012;209:248599. 
Geer RJ, Brennan MF. Prognostic indicators for survival after resection of pancreatic 
adenocarcinoma. Am J Surg 1993;165:6872; discussion 723. 
Hales RK, Banchereau J, Ribas A, et al. Assessing oncologic benefit in clinical trials of 
immunotherapy agents. Ann Oncol 2010;21:194451. 
Johnston RJ, Comps-Agrar L, Hackney J, et al. The immunoreceptor TIGIT regulates 
antitumor and antiviral CD8(+) T cell effector function. Cancer Cell 
2014;26:92337. 
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. 
Malvezzi M, Bertuccio P, Levi F, et al. European cancer mortality predictions for the year 
2014. Ann Oncol 2014;25:16506. 
Merad M, Martin JC. Pathological inflammation in patients with COVID-19: a key role for 
monocytes and macrophages. Nat Rev Immunol 2020;20:35562. 

 
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[NCCN] National Comprehensive Cancer Network. NCCN clinical practice guidelines in 
oncology (NCCN guidelines); pancreatic adenocarcinoma; version 3.2017 
[resource on the Internet]. September 2017 [cited: 28 February 2018]. Available 
from: https://www.nccn.org/professionals/physician_gls/default.aspx. 
[NCCN] National Comprehensive Cancer Network. Recommendations of the NCCN 
COVID-19 Vaccination Advisory Committee [resource on the Internet]. 2021 
[cited: 28 May 2021]. Available from:  
https://www.nccn.org/docs/default-source/covid-19/2021_covid-
19_vaccination_guidance_v2-0.pdf?sfvrsn=b483da2b_2. 
Oettle H, Riess H, Stieler M, et al. Second-line oxaliplatin, folinic acid, and fluorouracil 
versus folinic acid and fluorouracil alone for gemcitabine-refractory pancreatic 
cancer: outcomes from the CONKO-003 trial. J Clin Oncol 2014;32:24239. 
Portal A, Pernot S, Tougeron D, et al. Nab-paclitaxel plus gemcitabine for metastatic 
pancreatic adenocarcinoma after FOLFIRINOX failure: an AGEO prospective 
multicenter cohort. Br J Cancer 2015;113:98995. 
Rose-John S, Scheller J, Elson G, et al. Interleukin-6 biology is coordinated by 
membrane-bound and soluble receptors. J Leukoc Biol 2006;80:22736. 
Scheller J, Chalaris A, Schmidt-Arras D, et al.. The pro- and anti-inflammatory properties 
of the cytokine interleukin-6.  Biochim Biophys Acta 2011;1813:87888. 
[SITC] Society for Immunotherapy of Cancer. Society for Immunotherapy of Cancer 
statement on SARS-CoV-2 vaccination and cancer immunotherapy [resource on 
the Internet]. Press release: 23 December 2020 [cited: 28 May 2021]. Available 
from: 
https://www.sitcancer.org/aboutsitc/press-releases/2020/sitc-statement-sars-cov-2-
vaccination-cancer-immunotherapy. 
Sohal DP, Mangu PB, Khorana AA, et al. Metastatic pancreatic cancer: American 
Society of Clinical Oncology clinical practice guideline. J Clin Oncol 
2016;34:278496. 
Stanietsky N, Simic H, Arapovic J, et al. The interaction of TIGIT with PVR and PRVL2 
inhibits human NK cell cytotoxicity. Proc Natl Acad Sci USA 2009;106:1785863. 
Trede M, Schwall G, Saeger HD. Survival after pancreatoduodenectomy. 118 
consecutive resections without an operative mortality. Ann Surg 1990;211:44758. 
Tsao JI, Rossi RL, Lowell JA. Pylorus-preserving pancreatoduodenectomy. Is it an 
adequate cancer operation? Arch Surg 1994;129:40512. 
Von Hoff DD, Ervin T, Arena FP, et al. Increased survival in pancreatic cancer with 
nab-paclitaxel plus gemcitabine. N Engl J Med 2013;369:1691703. 

 
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Wang-Gillam A, Li C-P, Bodoky G, et al. Nanoliposomal irinotecan with fluorouracil and 
folinic acid in metastatic pancreatic cancer after previous gemcitabine-based 
therapy (NAPOLI-1): a global, randomised, open-label, phase 3 trial. Lancet 
2016;387:54557. 
Wallin JJ, Bendell JC, Funke R, et al. Atezolizumab in combination with bevacizumab 
enhances antigen-specific T-cell migration in metastatic renal cell carcinoma. Nat 
Commun 2016;7:12624. 
Wykes MN, Lewin SR. Immune checkpoint blockade in infectious diseases. Nat Rev 
Immunol 2018;18:91104. 
Yeo CJ, Cameron JL, Lillemoe KD, et al. Pancreaticoduodenectomy for cancer of the 
head of the pancreas. 201 patients. Ann Surg 1995;221:72131; discussion 
7313. 
Yu X, Harden K, Gonzalez LC, et al. The surface protein TIGIT suppresses T cell 
activation by promoting the generation of mature immunoregulatory dendritic cells. 
Nat Immunol 2009;10:4857. 
Zaanan A, Trouiloud I, Markoutsaki T, et al. FOLFOX as second-line chemotherapy in 
patients with pretreated metastatic pancreatic cancer from the FIRGEM study. 
BMC Cancer 2014;14:441. 
 

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

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DEFINITION OF NON-MEASURABLE LESIONS 
Non-measurable tumor lesions encompass small lesions (longest diameter  10 mm or 
pathological lymph nodes with short axis  10 mm but  15 mm) as well as truly 
non-measurable lesions.  Lesions considered truly non-measurable include 
leptomeningeal disease, ascites, pleural or pericardial effusion, inflammatory breast 
disease, lymphangitic involvement of skin or lung, peritoneal spread, and abdominal 
mass/abdominal organomegaly identified by physical examination that is not measurable 
by reproducible imaging techniques. 
SPECIAL CONSIDERATIONS REGARDING LESION MEASURABILITY 
Bone lesions, cystic lesions, and lesions previously treated with local therapy require 
particular comment, as outlined below. 
Bone Lesions: 
 
Technetium-99m bone scans, sodium fluoride positron emission tomography scans, 
and plain films are not considered adequate imaging techniques for measuring bone 
lesions.  However, these techniques can be used to confirm the presence or 
disappearance of bone lesions. 
 
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) because 
they are, by definition, simple cysts. 
 
Cystic lesions thought to represent cystic metastases can be considered 
measurable lesions if they meet the definition of measurability described above.  
However, if non-cystic lesions are present in the same patient, these are preferred 
for selection as target lesions. 
 
Lesions with Prior Local Treatment: 
 
Tumor lesions situated in a previously irradiated area or in an area subjected to 
other loco-regional therapy are usually not considered measurable unless there has 
been demonstrated progression in the lesion. 
 

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METHODS FOR ASSESSING LESIONS 
All measurements should be recorded in metric notation, using calipers if clinically 
assessed.  All baseline evaluations should be performed as close as possible to the 
treatment start and 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, because CT is more sensitive than X-ray, particularly in identifying new 
lesions.  However, lesions on chest X-ray may be considered measurable if they are 
clearly defined and surrounded by aerated lung. 
CT AND MRI SCANS 
CT is the best currently available and reproducible method to measure lesions selected 
for response assessment.  In this guideline, the definition of measurability of lesions on 
CT scan is based on the assumption that CT slice thickness is  5 mm.  When CT scans 
have slice thickness of  5 mm, the minimum size for a measurable lesion should be 
twice the slice thickness.  MRI is also acceptable. 
If prior to enrollment it is known that a patient is unable to undergo CT scans with IV 
contrast because of allergy or renal insufficiency, the decision as to whether a 
non-contrast CT or MRI (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 prior studies, if possible.  Each case should be discussed with the 
radiologist to determine if substitution of these other approaches is possible and, if not, 
the patient should be considered not evaluable from that point forward.  Care must be 
taken in measurement of target lesions and interpretation of non-target disease or new 

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lesions on a different modality, because the same lesion may appear to have a different 
size using a new modality. 
ENDOSCOPY, LAPAROSCOPY, ULTRASOUND, TUMOR MARKERS, 
CYTOLOGY, HISTOLOGY 
Endoscopy, laparoscopy, ultrasound, tumor markers, cytology, and histology cannot be 
utilized for objective tumor evaluation. 
ASSESSMENT OF TUMOR BURDEN 
To assess objective response or future progression, it is necessary to estimate the 
overall tumor burden at baseline and use this as a comparator for subsequent 
measurements. 
IDENTIFICATION OF TARGET AND NON-TARGET LESIONS 
When more than one measurable lesion is present at baseline, all lesions up to a 
maximum of five lesions total (and a maximum of two lesions per organ) representative 
of all involved organs should be identified as target lesions and will be recorded and 
measured at baseline.  This means that, for instances in which patients have only one 
or two organ sites involved, a maximum of two lesions (one site) and four lesions 
(two sites), respectively, will be recorded.  Other lesions (albeit measurable) in those 
organs will be considered non-target lesions. 
Target lesions should be selected on the basis of their size (lesions with the longest 
diameter) and 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 because 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 

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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 complete response criteria are met, because a normal lymph node is defined as having 
a short axis of  10 mm. 
Measuring Lesions That Become Too Small to Measure 
During the study, all target lesions (lymph node and nonlymph node) recorded at 
baseline should have their actual measurements recorded at each subsequent 
evaluation, even when very small (e.g., 2 mm).  However, sometimes lesions or lymph 
nodes that are recorded as target lesions at baseline become so faint on CT scan that 
the radiologist may not feel comfortable assigning an exact measurement and may 
report them as being too small to measure.  When this occurs, it is important that a value 
be recorded on the CRF, as follows: 
 
If it is the opinion of the radiologist that the lesion has likely disappeared, the 
measurement should be recorded as 0 mm. 
 
If the lesion is believed to be present and is faintly seen but too small to measure, a 
default value of 5 mm should be assigned and "too small to measure" should be 
ticked.  (Note:  It is less likely that this rule will be used for lymph nodes because 
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 (CR):  Disappearance of all target lesions 
Any pathological lymph nodes must have reduction in short axis to  10 mm. 
 
Partial response (PR):  At least a 30% decrease in the sum of diameters of all target 
lesions, taking as reference the baseline sum of diameters, in the absence of CR 
 
Progressive disease (PD):  At least a 20% increase in the sum of diameters of target 
lesions, taking as reference the smallest sum of diameters at prior timepoints 
(including baseline)  
In addition to the relative increase of 20%, the sum of diameters must also 
demonstrate an absolute increase of  5 mm. 
 
Stable disease (SD):  Neither sufficient shrinkage to qualify for CR or PR nor 
sufficient increase to qualify for PD 
 

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CRITERIA FOR NON-TARGET LESIONS 
Definitions of the criteria used to determine the tumor response for the group of 
non-target lesions are provided below.  While some non-target lesions may actually be 
measurable, they need not be measured and instead should be assessed only 
qualitatively at the timepoints specified in the schedules of activities. 
 
CR:  Disappearance of all non-target lesions and (if applicable) normalization of 
tumor marker level 
All lymph nodes must be non-pathological in size ( 10 mm short axis). 
 
Non-CR/Non-PD:  Persistence of one or more non-target lesions and/or 
(if applicable) maintenance of tumor marker level above the normal limits 
 
PD:  Unequivocal progression of existing non-target lesions 
 
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. 

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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 A1-1 provides a summary of the overall response status calculation at each 
response assessment timepoint for patients who have measurable disease at baseline. 
Table A1-1 Criteria for Overall Response at a Single Timepoint:  Patients 
with Target Lesions (with or without Non-Target Lesions) 
Target Lesions 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
CR 
No 
CR 
CR 
Non-CR/non-PD 
No 
PR 
CR 
Not all evaluated 
No 
PR 
PR 
Non-PD or not all 
evaluated 
No 
PR 
SD 
Non-PD or not all 
evaluated 
No 
SD 
Not all evaluated 
Non-PD 
No 
NE 
PD 
Any 
Yes or no 
PD 
Any 
PD 
Yes or no 
PD 
Any 
Any 
Yes 
PD 
CR  complete response; NE  not evaluable; PD  progressive disease; PR  partial 
response; SD  stable disease. 
 
MISSING ASSESSMENTS AND NOT-EVALUABLE DESIGNATION 
When no imaging/measurement is done at all at a particular timepoint, the patient is not 
evaluable at that timepoint.  If measurements are made on only a subset of target 
lesions at a timepoint, usually the case is also considered not evaluable at that 
timepoint, unless a convincing argument can be made that the contribution of the 
individual missing lesions would not change the assigned timepoint response.  This 
would be most likely to happen in the case of PD.  For example, if a patient had a 
baseline sum of 50 mm with three measured lesions and during the study only two 
lesions were assessed, but those gave a sum of 80 mm, the patient will have achieved 
PD status, regardless of the contribution of the missing lesion. 

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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 
having "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 A1-1. 
For equivocal findings of progression (e.g., very small and uncertain new lesions; cystic 
changes or necrosis in existing lesions), treatment may continue until the next scheduled 
assessment.  If at the next scheduled assessment, progression is confirmed, the date of 
progression should be the earlier date when progression was suspected. 
REFERENCES 
Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid 
tumors: revised RECIST guideline (version 1.1). Eur J Cancer 2009;45:22847. 
 

 
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Appendix 2  
Management of Atezolizumab-Specific Adverse Events 
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 subsequent 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. 
 
 
 
 
 

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 
 
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 also have computed 
tomography (CT) scans of the chest performed at every tumor assessment. 
All pulmonary events should be thoroughly evaluated for other commonly reported 
etiologies such as pneumonia or other infection, lymphangitic carcinomatosis, pulmonary 
embolism, heart failure, chronic obstructive pulmonary disease, or pulmonary 
hypertension.  COVID-19 evaluation should be performed per institutional 
guidelines where relevant.  Management guidelines for pulmonary events are provided 
in Table A2-1. 

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Table A2-1 Management Guidelines for Pulmonary Events, Including 
Pneumonitis 
Event 
Management 

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Table A2-1 Management Guidelines for Pulmonary Events, Including 
Pneumonitis (cont.) 
a 
b 
c 
d 
 
HEPATIC EVENTS 
Eligible patients must have adequate liver function, as manifested by measurements of 
total bilirubin and hepatic transaminases, and liver function will be monitored throughout 
study treatment.  Management guidelines for hepatic events are provided in Table A2-2. 
Patients with right upper-quadrant abdominal pain and/or unexplained nausea or 
vomiting should have liver function tests (LFTs) performed immediately and reviewed 
before administration of the next dose of study drug. 
For patients with elevated LFTs, concurrent medication, viral hepatitis, and toxic or 
neoplastic etiologies should be considered and addressed, as appropriate. 

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Table A2-2 Management Guidelines for Hepatic Events 
Event 
Management 
a
b
c

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Table A2‑2 Management Guidelines for Hepatic Events (cont.) 
 
 
Event 
Management 
a 
b 
c 
 
GASTROINTESTINAL EVENTS 
Management guidelines for diarrhea or colitis are provided in Table A2-3. 
All events of diarrhea or colitis should be thoroughly evaluated for other more common 
etiologies.  For events of significant duration or magnitude or associated with signs of 
systemic inflammation or acute-phase reactants (e.g., increased C-reactive protein, 
platelet count, or bandemia):  Perform sigmoidoscopy (or colonoscopy, if appropriate) 
with colonic biopsy, with three to five specimens for standard paraffin block to check for 
inflammation and lymphocytic infiltrates to confirm colitis diagnosis. 

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Table A2-3 Management Guidelines for Gastrointestinal Events 
(Diarrhea or Colitis) 
Event 
Management 
a
b
c

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Table A2-3 Management Guidelines for Gastrointestinal Events 
(Diarrhea or Colitis) (cont.) 
Event 
Management 
a 
b 
c 
  
ENDOCRINE EVENTS 
Management guidelines for endocrine events are provided in Table A2-4. 
Patients with unexplained symptoms such as headache, fatigue, myalgias, impotence, 
constipation, or mental status changes should be investigated for the presence of 
thyroid, pituitary, or adrenal endocrinopathies.  The patient should be referred to an 
endocrinologist if an endocrinopathy is suspected.  Thyroid-stimulating hormone (TSH) 
and free triiodothyronine and thyroxine levels should be measured to determine whether 
thyroid abnormalities are present.  Pituitary hormone levels and function tests 
(e.g., TSH, growth hormone, luteinizing hormone, follicle-stimulating hormone, 
testosterone, prolactin, adrenocorticotropic hormone [ACTH] levels, and ACTH 
stimulation test) and magnetic resonance imaging (MRI) of the brain (with detailed 

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pituitary sections) may help to differentiate primary pituitary insufficiency from primary 
adrenal insufficiency. 
Table A2-4 Management Guidelines for Endocrine Events 
Event 
Management 

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Table A2-4 Management Guidelines for Endocrine Events (cont.) 
a 
b 
c 

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Table A2-4 Management Guidelines for Endocrine Events (cont.) 
Event 
Management 
a 
b 
c 

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Table A2-4 Management Guidelines for Endocrine Events (cont.) 
Event 
Management 
a 
b 
c 
 

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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 A2-5. 
Table A2-5 Management Guidelines for Ocular Events 
Event 
Management 
a 
b 
c 
 

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IMMUNE-MEDIATED CARDIAC EVENTS 
In high-risk patients (including those with abnormal baseline cardiac troponin 
levels, when available), transthoracic echocardiogram (TTE) monitoring should 
be considered, as clinically indicated, and based on local clinical practice.   
Management guidelines for cardiac events are provided in Table A2-6. 
IMMUNE-MEDIATED MYOCARDITIS 
Immune-mediated myocarditis should be suspected in any patient presenting with signs 
or symptoms suggestive of myocarditis, including, but not limited to, laboratory 
(e.g., troponin, B‑type natriuretic peptide) or cardiac imaging abnormalities, dyspnea, 
chest pain, palpitations, fatigue, decreased exercise tolerance, or syncope.  Myocarditis 
may also be a clinical manifestation of myositis or associated with pericarditis (see 
section on immune-mediated pericardial disorders below) and should be managed 
accordingly.  Immune-mediated myocarditis needs to be distinguished from myocarditis 
resulting from infection (commonly viral, e.g., in a patient who reports a recent history of 
gastrointestinal illness), ischemic events, underlying arrhythmias, exacerbation of 
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, a TTE for evaluation of left 
ventricular ejection fraction and global longitudinal strain, and a cardiac MRI 
as appropriate per institutional guidelines.  A cardiologist should be consulted.  
An endomyocardial biopsy may be considered to enable a definitive diagnosis and 
appropriate treatment, if clinically indicated. 
Patients with signs and symptoms of myocarditis, in the absence of an identified 
alternate etiology, should be treated according to the guidelines in Table A2-6. 

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IMMUNE-MEDIATED PERICARDIAL DISORDERS 
Immune-mediated pericarditis should be suspected in any patient presenting with chest 
pain and may be associated with immune-mediated myocarditis (see section on 
immune-mediated myocarditis above). 
Immune-mediated pericardial effusion and cardiac tamponade should be suspected in 
any patient presenting with chest pain associated with dyspnea or hemodynamic 
instability. 
Patients should be evaluated for other causes of pericardial disorders such as infection 
(commonly viral), cancer (e.g., metastatic disease), cancer treatment (e.g., chest 
radiotherapy), cardiac injury (e.g., injury due to myocardial infarction or 
iatrogenesis), and autoimmune disorders, and should be managed accordingly. 
All patients with suspected pericardial disorders should be urgently evaluated by 
performing an ECG, chest X-ray, TTE, and cardiac MRI as appropriate per institutional 
guidelines.  A cardiologist should be consulted.  Pericardiocentesis should be 
considered for diagnostic or therapeutic purposes, if clinically indicated. 
Patients with signs and symptoms of pericarditis, pericardial effusion, or cardiac 
tamponade, in the absence of an identified alternate etiology, should be treated 
according to the guidelines in Table A2-6.  Withhold treatment with atezolizumab for 
Grade 1 pericarditis and conduct a detailed cardiac evaluation to determine the etiology 
and manage accordingly. 

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Table A2-6 Management Guidelines for Immune-Mediated Cardiac Events 
Event 
Management 
 
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. 
IRRs are known to occur with the administration of monoclonal antibodies and have 
been reported with atezolizumab.  These reactions, which are thought to be due to 
release of cytokines and/or other chemical mediators, occur within 24 hours of 
atezolizumab administration and are generally mild to moderate in severity. 
CRS is defined as a supraphysiologic response following administration of any immune 
therapy that results in activation or engagement of endogenous or infused T cells and/or 
other immune effector cells.  Symptoms can be progressive, always include fever at the 
onset, and may include hypotension, capillary leak (hypoxia), and end-organ dysfunction 

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(Lee et al. 2019).  CRS has been well documented with chimeric antigen receptor T-cell 
therapies and bispecific T-cell engager antibody therapies but has also been reported 
with immunotherapies that target PD-1 or PD-L1 (Rotz et al. 2017; Adashek and 
Feldman 2019), including atezolizumab. 
There may be significant overlap in signs and symptoms of IRRs and CRS, and in 
recognition of the challenges in clinically distinguishing between the two, consolidated 
guidelines for the medical management of IRRs and CRS are provided in Table A2-7. 
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection appears to be 
associated with a CRS involving the inflammatory cytokines interleukin (IL)-6, IL-10, IL-2, 
and interferon- (Merad and Martin 2020).  If a patient develops suspected CRS during 
the study, a differential diagnosis should include SARS-CoV-2 infection, which should be 
confirmed or refuted through assessment of exposure history, appropriate laboratory 
testing, and clinical or radiologic evaluations per investigator’s judgment.  If a diagnosis 
of SARS-CoV-2 infection is confirmed, the disease should be managed as per local or 
institutional guidelines. 

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Table A2-7 Management Guidelines for Infusion-Related Reactions and 
Cytokine Release Syndrome 
Event 
Management 

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Table A2-7 Management Guidelines for Infusion-Related Reactions and 
Cytokine Release Syndrome (cont.)  
Event 
Management 

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Table A2-7 Management Guidelines for Infusion-Related Reactions and 
Cytokine Release Syndrome (cont.)  
 
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 A2-8. 

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Table A2-8 Management Guidelines for Pancreatic Events, Including 
Pancreatitis  
Event 
Management 
a
b
c

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Table A2-8 Management Guidelines for Pancreatic Events, Including 
Pancreatitis (cont.) 
Event 
Management 
a 
b 
c 
 

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DERMATOLOGIC EVENTS 
The majority of cases of rash reported with the use of atezolizumab were mild in severity 
and self-limiting, with or without pruritus.  Although uncommon, cases of severe 
cutaneous adverse reactions such as Stevens-Johnson syndrome and toxic epidermal 
necrolysis have been reported with atezolizumab.  A dermatologist should evaluate 
persistent and/or severe rash or pruritus.  A biopsy should be considered unless 
contraindicated.  Management guidelines for dermatologic events are provided in 
Table A2-9. 
Table A2-9 Management Guidelines for Dermatologic Events 
Event 
Management 
a 
b 
c 
 

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Table A2-9 Management Guidelines for Dermatologic Events (cont.) 
Event 
Management 
a
b
c
 

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NEUROLOGIC DISORDERS 
Patients may present with signs and symptoms of sensory and/or motor neuropathy.  
Diagnostic workup is essential for an accurate characterization to differentiate between 
alternative etiologies.  Myasthenia may be associated with myositis (see section on 
immune-mediated myositis) and patients should be managed accordingly.   
Management guidelines for neurologic disorders are provided in Table A2-10, with 
specific guidelines for myelitis provided in Table A2-11. 
Table A2-10 Management Guidelines for Neurologic Disorders 
Event 
Management 

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a 
b 
c 
 
 

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Table A2-11 Management Guidelines for Immune-Mediated Myelitis 
Event 
Management 

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IMMUNE-MEDIATED MENINGOENCEPHALITIS 
Immune-mediated meningoencephalitis should be suspected in any patient presenting 
with signs or symptoms suggestive of meningitis or encephalitis, including, but not 
limited to, headache, neck pain, confusion, seizure, motor or sensory dysfunction, and 
altered or depressed level of consciousness.  Encephalopathy from metabolic or 
electrolyte imbalances needs to be distinguished from potential meningoencephalitis 
resulting from infection (bacterial, viral, or fungal) or progression of malignancy, or 
secondary to a paraneoplastic process. 
All patients being considered for meningoencephalitis should be urgently evaluated with 
a CT scan and/or MRI scan of the brain to evaluate for metastasis, inflammation, or 
edema.  If deemed safe by the treating physician, a lumbar puncture should be 
performed, and a neurologist should be consulted. 
Patients with signs and symptoms of meningoencephalitis, in the absence of 
an identified alternate etiology, should be treated according to the guidelines in 
Table A2-12. 
Table A2-12 Management Guidelines for Immune-Mediated 
Meningoencephalitis 
Event 
Management 
 
RENAL EVENTS 
Eligible patients must have adequate renal function, and renal function, including serum 
creatinine, should be monitored throughout study treatment.  Patients with abnormal 
renal function should be evaluated and treated for other more common etiologies 
(including prerenal and postrenal causes, and concomitant medications such as 

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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 A2-13. 
Table A2-13 Management Guidelines for Renal Events  
Event 
Management 
a 
b 
c 
 
 

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IMMUNE-MEDIATED MYOSITIS 
Myositis or inflammatory myopathies are a group of disorders sharing the common 
feature of inflammatory muscle injury; dermatomyositis and polymyositis are among the 
most common disorders.  Initial diagnosis is based on clinical (muscle weakness, muscle 
pain, skin rash in dermatomyositis), biochemical (serum creatine kinase/creatine 
phosphokinase increase), and imaging (electromyography/MRI) features, and is 
confirmed with a muscle biopsy.  Patients may initially present with low grade 
nondescript symptoms including mild pain and weakness; thus, there should be 
a low threshold for suspicion of myositis.  Patients with possible myositis should be 
referred to a rheumatologist or neurologist.  Patients with possible myositis should be 
monitored for signs of myocarditis (see section on immune-mediated myocarditis) 
and myasthenia gravis (bulbar symptoms such as dysphagia, dysphoria, and 
dyspnea; see section on neurologic disorders). 
Patients with signs and symptoms of myositis, in the absence of an identified alternate 
etiology, should be treated according to the guidelines in Table A2-14. 

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Table A2-14 Management Guidelines for Immune-Mediated Myositis 
Event 
Management 
a 
b 
c 

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Table A2‑14 Management Guidelines for Immune-Mediated Myositis (cont.) 
Event 
Management 

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Table A2‑14 Management Guidelines for Immune-Mediated Myositis (cont.) 
a 
b 
c 
 
HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS  
Immune-mediated reactions may involve any organ system and may lead to 
hemophagocytic lymphohistiocytosis (HLH). 
Clinical and laboratory features of severe CRS overlap with HLH, and HLH should be 
considered when CRS presentation is atypical or prolonged. 
Patients with suspected HLH should be diagnosed according to published criteria by 
McClain and Eckstein (2014).  A patient should be classified as having HLH if five of the 
following eight criteria are met: 
 
Fever  38.5°C 
 
Splenomegaly 
 
Peripheral blood cytopenia consisting of at least two of the following: 
– 
Hemoglobin  90 g/L (9 g/dL) ( 100 g/L [10 g/dL] for infants  4 weeks old) 
– 
Platelet count  100  109/L (100,000/L) 
– 
ANC  1.0  109/L (1000/L) 
 
Fasting triglycerides  2.992 mmol/L (265 mg/dL) and/or fibrinogen  1.5 g/L 
(150 mg/dL) 
 
Hemophagocytosis in bone marrow, spleen, lymph node, or liver 
 
Low or absent natural killer cell activity 
 
Ferritin  500 mg/L (500 ng/mL) 
 
Soluble IL-2 receptor (soluble CD25) elevated  2 standard deviations above 
age-adjusted laboratory-specific norms 
  

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Patients with suspected HLH should be treated according to the guidelines in Table A2-
15. 
Table A2-15 Management Guidelines for Suspected Hemophagocytic 
Lymphohistiocytosis  
Event 
Management 
 

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REFERENCES 
Adashek ML, Feldman M. Cytokine release syndrome resulting from antiprogrammed 
death-1 antibody: raising awareness among community oncologist. J Oncol 
Practice 2019;15:5024. 
La Rosée P. Treatment of hemophagocytic lymphohistiocytosis in adults. Hematology 
Am Soc Hematol Educ Protram 2015;1:1906. 
La Rosée P, Horne A, Hines M, et al. Recommendations for the management of 
hemophagocytic lymphohistiocytosis in adults. Blood 2019;133:246577. 
Lee DW, Santomasso BD, Locke FL, et al. ASTCT consensus grading for cytokine 
release syndrome and neurologic toxicity associated with immune effector cells. 
Biol Blood Marrow Transplant 2019;25:62538. 
McClain KL, Eckstein O. Clinical features and diagnosis of hemophagocytic 
lymphohistiocytosis. Up to Date [resource on the Internet]. 2014 [updated 
29 October 2018; cited: 17 May 2019]. Available from: 
https://www.uptodate.com/contents/clinical-features-and-diagnosis-of-
hemophagocytic-lymphohistiocytosis. 
Merad M, Martin JC. Pathological inflammation in patients with COVID-19: a key role for 
monocytes and macrophages. Nat Rev Immunol 2020;20:35562. 
Riegler LL, Jones GP, Lee DW. Current approaches in the grading and management of 
cytokine release syndrome after chimeric antigen receptor T-cell therapy. Ther Clin 
Risk Manag 2019;15:32335. 
Rotz SJ, Leino D, Szabo S, et al. Severe cytokine release syndrome in a patient 
receiving PD-1-directed therapy. Pediatr Blood Cancer 2017;64:e26642. 
Schram AM, Berliner N. How I treat hemophagocytic lymphohistiocytosis in the adult 
patient. Blood 2015;125:290814. 
 

 
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Appendix 3  
ECOG Performance Status Scale 
Grade 
Description 
0 
Fully active; able to carry on all pre-disease performance without 
restriction. 
1 
Restricted in physically strenuous activity but ambulatory and able to carry 
out work of a light or sedentary nature (e.g., light housework or office 
work). 
2 
Ambulatory and capable of all self-care but unable to carry out any work 
activities.  Up and about  50% of waking hours. 
3 
Capable of only limited self-care; confined to a bed or chair  50% of 
waking hours. 
4 
Completely disabled.  Cannot carry on any self-care.  Totally confined to 
bed or chair. 
5 
Dead. 
ECOG  Eastern Cooperative Oncology Group. 
 
 

 
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Appendix 4  
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 

 
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Appendix 5  
Anaphylaxis Precautions 
EQUIPMENT NEEDED 
 
Oxygen 
 
Epinephrine for SC, IV, and/or endotracheal use in accordance with standard 
practice 
 
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. 
Maintain an adequate airway. 
3. 
Administer antihistamines, epinephrine, or other medications as required by patient 
status and directed by the physician in charge. 
4. 
Continue to observe the patient and document observations. 
 
 

 
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Appendix 6  
Schedules of Activities for Screening 
Table A6-1  
Schedule of Activities for Stage 1 Screening:  Cohort 1 
Assessment/Procedure 
Stage 1 Screening a 
(Day –28 to –1) 
Informed consent 
x b 
Demographic data 
x 
Medical history and baseline conditions 
x 
Molecular profile of pancreatic cancer (if available) 
x 
Vital signs c 
x 
Weight 
x 
Height 
x 
Complete physical examination d 
x 
ECOG Performance Status 
x 
ECG e 
x 
TB test 
x f 
Chest X-ray 
x g 
Hematology h 
x i 
Chemistry j 
x i 
Coagulation (INR, aPTT) 
x i 
TSH, free T3 (or total T3 k), free T4 
x i 
C-reactive protein 
x i 
LDH 
x i 
Pregnancy test m 
x i 
Urinalysis n 
x i 
Serum autoantibody sample o 
x i 
Tumor biopsy p 
x 
Baseline tumor assessments q 
x 
Concomitant medications r 
x 
Adverse events s 
x 
CT  computed tomography; EBNA  Epstein-Barr nuclear antigen;
 
ECOG  Eastern Cooperative Oncology Group; eCRF  electronic Case Report Form; 
; MRI  magnetic resonance imaging; PCR  polymerase chain 
reaction; RECIST v1.1  Response Evaluation Criteria in Solid Tumors, Version 1.1; 
T3  triiodothyronine; T4  thyroxine; TB  tuberculosis; TSH  thyroid-stimulating hormone; 
VCA  viral capsid antigen. 

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Table A6-1 Schedule of Activities for Stage 1 Screening:  Cohort 1 (cont.) 
a Patients who fail their first screening for study eligibility may qualify for two re-screening 
opportunities (for a total of three screenings per patient) at the investigator’s discretion.  
Patients must re-sign the consent form prior to re-screening.  Results of standard-of-care 
tests or examinations performed prior to obtaining informed consent and within 28 days prior 
to Day 1 (within 14 days prior to Day 1 for laboratory tests) may be used; such tests do not 
need to be repeated for screening or re-screening. 
b Informed consent must be documented before any study-specific screening procedure is 
performed and may be obtained more than 28 days before initiation of study treatment. 
c Vital signs include respiratory rate, pulse rate, and systolic and diastolic blood pressure while 
the patient is in a seated position, pulse oximetry, and temperature.  Record abnormalities 
observed at baseline on the General Medical History and Baseline Conditions eCRF. 
d Complete physical examination includes evaluation of the head, eyes, ears, nose, and 
throat, and the cardiovascular, dermatologic, musculoskeletal, respiratory, gastrointestinal, 
genitourinary, and neurologic systems.  Record abnormalities observed at baseline on the 
General Medical History and Baseline Conditions eCRF. 
e It is recommended that patients be resting in a supine position for at least 10 minutes prior to 
ECG recording. 
f  TB test will be performed only if a tocilizumab-containing arm is open for enrollment.  
Patients will undergo a tuberculin purified protein derivative (PPD) skin test or a TB blood 
test within 28 days prior to initiation of study treatment. 
g A chest X-ray will be performed at screening for patients who have a positive tuberculin PPD 
skin test or TB blood test, provided a tocilizumab-containing arm is open for enrollment. 
h Hematology includes WBC count, RBC count, hemoglobin, hematocrit, platelet count, 
differential count (neutrophils, eosinophils, basophils, monocytes, lymphocytes, other cells). 
i Screening laboratory test results must be obtained within 14 days prior to initiation of study 
treatment. 
j Chemistry panel (serum or plasma) includes bicarbonate or total carbon dioxide 
(if considered standard of care for the region), sodium, potassium, magnesium, chloride, 
glucose, BUN or urea, creatinine, total protein, albumin, phosphorus, calcium, total bilirubin, 
ALP, ALT, and AST. 
k Total T3 may be performed for sites where free T3 is not performed. 
l 
m All women of childbearing potential will have a serum pregnancy test at screening. 
n Urinalysis includes pH, specific gravity, glucose, protein, ketones, and blood; dipstick 
permitted.  Patients with  2 protein on dipstick urinalysis at screening must undergo a 
24-hour urine collection for protein, but only if a bevacizumab-containing arm is open for 
enrollment. 
o Autoantibody analysis includes anti-nuclear antibody, antidouble-stranded DNA, circulating 
anti-neutrophil cytoplasmic antibody, and perinuclear anti-neutrophil cytoplasmic antibody. 

Appendix 6:  Schedules of Activities for Screening 
  
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146/Protocol WO39608, Version 16
 
 
Table A6-1 Schedule of Activities for Stage 1 Screening:  Cohort 1 (cont.) 
p Baseline tumor tissue samples will be collected from all patients, preferably by means of a 
biopsy performed at study entry.  If a biopsy is not deemed feasible by the investigator, 
archival tumor tissue may be submitted, provided that the tissue was obtained from a 
biopsy performed within 3 months prior to enrollment and that the patient has not received 
any anti-cancer therapy since the time of the biopsy.  Refer to Section 4.5.7 for tissue 
sample requirements. 
q All measurable and/or evaluable lesions should be assessed and documented at screening. 
Tumor assessments performed as standard of care prior to obtaining informed consent and 
within 28 days prior to initiation of study treatment do not have to be repeated at screening.  
Screening assessments must include CT scans (with IV contrast; with or without oral 
contrast) or MRI scans (with IV contrast) 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 (i.e., in patients with contrast allergy or impaired renal clearance), a 
non-contrast CT scan of the chest may be performed and MRI scans (with IV contrast, if 
feasible) of the abdomen and pelvis should be performed.  A CT scan with contrast or MRI 
scan with contrast of the head, bone scans, and CT scans of the neck should 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.  Refer to Section 4.5.5 for further 
details on tumor assessments. 
r Includes any medication (e.g., prescription drugs, over-the-counter drugs, vaccines, herbal 
or homeopathic remedies, nutritional supplements) used by a patient within 10 days prior to 
initiation of study treatment. 
s After informed consent has been obtained but prior to initiation of study treatment, only 
serious adverse events caused by a protocol-mandated intervention should be reported.  
The 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. 
 

Appendix 6:  Schedules of Activities for Screening 
  
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147/Protocol WO39608, Version 16
 
 
Table A6-2 Schedule of Activities for Stage 1 Screening:  Cohort 2 
Assessment/Procedure 
Stage 1 Screening a 
(Day –28 to –1) 
Informed consent 
x b 
Demographic data 
x 
Medical history and baseline conditions 
x 
Molecular profile of pancreatic cancer (if available) 
x 
Vital signs c 
x 
Weight 
x 
Height 
x 
Complete physical examination d 
x 
ECOG Performance Status 
x 
ECG e 
x 
Hematology f 
x g 
Chemistry h 
x g 
Coagulation (INR, aPTT) 
x g 
TSH, free T3 (or total T3 i), free T4 
x g 
C-reactive protein 
x g 
LDH 
x g 
Pregnancy test k 
x g 
Urinalysis l 
x g 
Serum autoantibody sample m 
x g 
Tumor biopsy n 
x 
Baseline tumor assessments o 
x o 
Concomitant medications p 
x 
Adverse events q 
x 

Appendix 6:  Schedules of Activities for Screening 
  
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Table A6-2 Schedule of Activities for Stage 1 Screening:  Cohort 2 (cont.) 
CT  computed tomography; ECOG  Eastern Cooperative Oncology Group; eCRF  electronic 
Case Report Form;
; 
; MRI  magnetic resonance imaging; 
RECIST v1.1  Response Evaluation Criteria in Solid Tumors, Version 1.1; 
T3  triiodothyronine; T4  thyroxine; TSH  thyroid-stimulating hormone. 
a Patients who fail their first screening for study eligibility may qualify for two re-screening 
opportunities (for a total of three screenings per patient) at the investigator’s discretion.  
Patients must re-sign the consent form prior to re-screening.  Results of standard-of-care 
tests or examinations performed prior to obtaining informed consent and within 28 days 
prior to Day 1 (within 14 days prior to Day 1 for laboratory tests) may be used; such tests do 
not need to be repeated for screening or re-screening. 
b Informed consent must be documented before any study-specific screening procedure is 
performed and may be obtained more than 28 days before initiation of study treatment. 
c Vital signs include respiratory rate, pulse rate, and systolic and diastolic blood pressure 
while the patient is in a seated position, pulse oximetry, and temperature.  Record 
abnormalities observed at baseline on the General Medical History and Baseline Conditions 
eCRF.  
d Complete physical examination includes evaluation of the head, eyes, ears, nose, and 
throat, and the cardiovascular, dermatologic, musculoskeletal, respiratory, gastrointestinal, 
genitourinary, and neurologic systems.  Record abnormalities observed at baseline on the 
General Medical History and Baseline Conditions eCRF. 
e It is recommended that patients be resting in a supine position for at least 10 minutes prior 
to ECG recording. 
f Hematology includes WBC count, RBC count, hemoglobin, hematocrit, platelet count, 
differential count (neutrophils, eosinophils, basophils, monocytes, lymphocytes, other cells). 
g Screening laboratory test results must be obtained within 14 days prior to initiation of study 
treatment. 
h Chemistry panel (serum or plasma) includes bicarbonate or total carbon dioxide 
(if considered standard of care for the region), sodium, potassium, magnesium, chloride, 
glucose, BUN or urea, creatinine, total protein, albumin, phosphorus, calcium, total bilirubin, 
ALP, ALT, and AST. 
i Total T3 may be performed for sites where free T3 is not performed. 
j 
k All women of childbearing potential will have a serum pregnancy test at screening. 
l Urinalysis includes pH, specific gravity, glucose, protein, ketones, and blood; dipstick 
permitted. 
m Autoantibody analysis includes anti-nuclear antibody, antidouble-stranded DNA, 
circulating anti-neutrophil cytoplasmic antibody, and perinuclear anti-neutrophil cytoplasmic 
antibody. 
 

Appendix 6:  Schedules of Activities for Screening 
  
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149/Protocol WO39608, Version 16
 
 
Table A6-2 Schedule of Activities for Stage 1 Screening:  Cohort 2 (cont.) 
n Baseline tumor tissue samples will be collected from all patients, preferably by means of a 
biopsy performed at study entry.  If a biopsy is not deemed feasible by the investigator, 
archival tumor tissue may be submitted, provided that the tissue was obtained from a 
biopsy performed within 3 months prior to enrollment and that the patient has not received 
any anti-cancer therapy since the time of the biopsy.  Refer to Section 4.5.7 for tissue 
sample requirements. 
o All measurable and/or evaluable lesions should be assessed and documented at screening. 
Tumor assessments performed as standard of care prior to obtaining informed consent and 
within 28 days prior to initiation of study treatment do not have to be repeated at screening.  
Screening assessments must include CT scans (with IV contrast; with or without oral 
contrast) or MRI scans (with IV contrast) 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 (i.e., in patients with contrast allergy or impaired renal clearance), a 
non-contrast CT scan of the chest may be performed and MRI scans (with IV contrast, if 
feasible) of the abdomen and pelvis should be performed.  A CT scan with contrast or MRI 
scan with contrast of the head, bone scans, and CT scans of the neck should 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.  Refer to Section 4.5.5 for further 
details on tumor assessments. 
p Includes any medication (e.g., prescription drugs, over-the-counter drugs, vaccines, herbal 
or homeopathic remedies, nutritional supplements) used by a patient within 10 days prior to 
initiation of study treatment. 
q After informed consent has been obtained but prior to initiation of study treatment, only 
serious adverse events caused by a protocol-mandated intervention should be reported.  
The 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. 
 

Appendix 6:  Schedules of Activities for Screening 
  
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150/Protocol WO39608, Version 16
 
 
Table A6-3  
Schedule of Activities for Stage 2 Screening:  Cohort 2 
Assessment/Procedure 
Stage 2 Screening a 
Informed consent 
x b 
Molecular profile of pancreatic cancer (if available) 
x 
Vital signs c 
x 
Weight 
x 
Complete physical examination d 
x 
ECOG Performance Status 
x 
ECG e 
x 
Hematology f 
x g 
Chemistry h 
x g 
Coagulation (INR, aPTT) 
x g 
TSH, free T3 (or total T3 i), free T4 
x g 
C-reactive protein 
x g 
LDH 
x g 
Pregnancy test k 
x g 
Urinalysis l 
x g 
Tumor response assessments m 
x m, n 
Concomitant medications o 
x 
Adverse events p 
x 
CT  computed tomography; ECOG  Eastern Cooperative Oncology Group; 
eCRF  electronic Case Report Form;
 
; 
MRI  magnetic resonance imaging; RECIST v1.1  Response Evaluation Criteria in Solid 
Tumors, Version 1.1; T3  triiodothyronine; T4  thyroxine; TSH  thyroid-stimulating 
hormone. 
a The visit at which response assessment shows progressive disease may be used as the 
Stage 2 screening visit.  Patients who fail their first screening for study eligibility may 
qualify for two re-screening opportunities (for a total of three screenings per patient) at 
the investigator’s discretion.  Patients must re-sign the consent form prior to 
re-screening. 
b Written informed consent must be obtained before performing screening evaluations for 
Stage 2 except as noted in footnote "n" below. 
c Vital signs include respiratory rate, pulse rate, and systolic and diastolic blood pressure 
while the patient is in a seated position, pulse oximetry, and temperature.  Record 
abnormalities observed at baseline on the General Medical History and Baseline 
Conditions eCRF. 
 

Appendix 6:  Schedules of Activities for Screening 
  
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Table A6-3 Schedule of Activities for Stage 2 Screening:  Cohort 2 (cont.) 
d Complete physical examination includes evaluation of the head, eyes, ears, nose, and 
throat, and the cardiovascular, dermatologic, musculoskeletal, respiratory, gastrointestinal, 
genitourinary, and neurologic systems.  Record abnormalities observed at baseline on the 
General Medical History and Baseline Conditions eCRF. 
e It is recommended that patients be resting in a supine position for at least 10 minutes prior 
to ECG recording. 
f Hematology includes WBC count, RBC count, hemoglobin, hematocrit, platelet count, 
differential count (neutrophils, eosinophils, basophils, monocytes, lymphocytes, other cells). 
g Screening laboratory test results must be obtained within 14 days prior to initiation of study 
treatment. 
h Chemistry panel (serum or plasma) includes bicarbonate or total carbon dioxide (if 
considered standard of care for the region), sodium, potassium, magnesium, chloride, 
glucose, BUN or urea, creatinine, total protein, albumin, phosphorus, calcium, total bilirubin, 
ALP, ALT, and AST. 
i Total T3 may be performed for sites where free T3 is not performed. 
j 
k All women of childbearing potential will have a urine or serum pregnancy test at screening. 
l Urinalysis includes pH, specific gravity, glucose, protein, ketones, and blood; dipstick 
permitted. 
m All measurable and/or evaluable lesions should be assessed and documented at screening. 
Tumor assessments performed as standard of care prior to obtaining informed consent and 
within 28 days prior to initiation of study treatment do not have to be repeated at screening.  
Screening assessments must include CT scans (with IV contrast; with or without oral 
contrast) or MRI scans (with IV contrast) 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 (i.e., in patients with contrast allergy or impaired renal clearance), a non-
contrast CT scan of the chest may be performed and MRI scans (with IV contrast, if 
feasible) of the abdomen and pelvis should be performed.  A CT scan with contrast or MRI 
scan with contrast of the head, bone scans, and CT scans of the neck should 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.  Refer to Section 4.5.5 for further 
details on tumor assessments. 
n Baseline tumor assessments for Stage 2 must be performed within 28 days prior to initiation 
of Stage 2 treatment (i.e., Day 1 of Cycle 1).  Tumor assessments performed prior to or at 
the time of loss of clinical benefit or unacceptable toxicity during Stage 1 may serve as 
baseline assessments for Stage 2, provided the tumor assessments are performed within 
28 days prior to initiation of Stage 2 treatment. 
 

Appendix 6:  Schedules of Activities for Screening 
  
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152/Protocol WO39608, Version 16
 
 
Table A6-3 Schedule of Activities for Stage 2 Screening:  Cohort 2 (cont.) 
o Includes any medication (e.g., prescription drugs, over-the-counter drugs, vaccines, herbal 
or homeopathic remedies, nutritional supplements) used by a patient within 10 days prior to 
initiation of study treatment. 
p After informed consent has been obtained but prior to initiation of study treatment, only 
serious adverse events caused by a protocol-mandated intervention should be reported.  
The 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. 
 

 
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Appendix 7  
Study Details Specific to Control Arm (Cohorts 1 and 2) 
TABLE OF CONTENTS 
A7–1 
Materials and Methods Specific to Control Arm ..................... 154 
A7–1.1 
Treatment in Control Arm ...................................................... 154 
A7–1.1.1 
Formulation, Packaging, and Handling .................................. 154 
A7–1.1.2 
Dosage, Administration, and Compliance .............................. 154 
A7–1.1.3 
Second-Line Treatment for Cohort 1 Control Arm ................. 155 
A7–1.1.4 
Stage 2 Treatment for Cohort 2 Control Arm ......................... 156 
A7–1.2 
Concomitant Therapy, Prohibited Food, and Other 
Restrictions for Control Arm ................................................... 156 
A7–1.3 
Contraception Requirements for Control Arm ........................ 157 
A7–2 
Assessment of Safety for Control Arm ................................... 158 
A7–2.1 
Safety Plan for Control Arm ................................................... 158 
A7–2.1.1 
Risks Associated with Control Agents ................................... 158 
A7–2.1.2 
Management of Patients Who Experience Specific 
Adverse Events in the Control Arm ........................................ 158 
A7–2.2 
Adverse Events of Special Interest for Control Arm 
(Immediately Reportable to the Sponsor) .............................. 158 
A7–2.3 
Reporting Requirements for Pregnancies in Control Arm ...... 159 
A7–2.3.1 
Pregnancies in Female Patients ............................................ 159 
A7–2.3.2 
Pregnancies in Female Partners of Male Patients ................. 159 
A7–2.3.3 
Abortions................................................................................ 160 
A7–2.3.4 
Congenital Anomalies/Birth Defects ...................................... 160 
A7–3 
Schedule of Activities for Control Arm ................................... 161 
 

Appendix 7:  Study Details Specific to Control Arm (Cohorts 1 and 2) 
  
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A7–1 
MATERIALS AND METHODS SPECIFIC TO CONTROL ARM 
A7–1.1 
TREATMENT IN CONTROL ARM 
A7–1.1.1 
Formulation, Packaging, and Handling 
For information on the formulation, packaging, and handling of the control agents, refer 
to the local prescribing information for each agent. 
A7–1.1.2 
Dosage, Administration, and Compliance 
In Cohort 1, patients in the control arm will receive nanoparticle albuminbound 
paclitaxel (nab-paclitaxel) and gemcitabine.  In Cohort 2, patients in the control arm will 
receive treatment with one of two treatment regimens (see Table A7-1), as determined 
on the basis of the patient's first-line treatment regimen.  Patients who progressed on a 
prior fluoropyrimidine-based regimen will receive nab-paclitaxel and gemcitabine.  
Patients who progressed on a prior gemcitabine-based regimen will receive mFOLFOX6 
(5-fluorouracil [5-FU], leucovorin, and oxaliplatin).  Patients will receive treatment until 
unacceptable toxicity or disease progression per Response Evaluation Criteria in Solid 
Tumors, Version 1.1 (RECIST v1.1).  It is recommended that 
 
  Treatment will be administered according to 
institutional standards 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 5. 

Appendix 7:  Study Details Specific to Control Arm (Cohorts 1 and 2) 
  
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Table A7-1 Treatment Regimens for Control Arm 
Cohort 
Treatment 
Regimen 
Cycle 
Length 
Dose, Route, and Regimen  
(drugs listed in order of administration) 
1 
Nab-paclitaxel and 
gemcitabine 
28 days 
 Nab-paclitaxel 125 mg/m2 IV over 30 ( 5) minutes on 
Days 1, 8, and 15 of each cycle 
 Gemcitabine 1000 mg/m2 IV over 30 ( 5) minutes on 
Days 1, 8, and 15 of each cycle 
2 
Nab-paclitaxel and 
gemcitabine a  
28 days 
 Nab-paclitaxel 125 mg/m2 IV over 30 ( 5) minutes on 
Days 1, 8, and 15 of each cycle 
 Gemcitabine 1000 mg/m2 IV over 30 ( 5) minutes 
on Days 1, 8, and 15 of each cycle 
mFOLFOX6 b 
28 days 
 Oxaliplatin 85 mg/m2 IV over 2 hours ( 5 minutes) on 
Days 1 and 15 of each cycle 
 Leucovorin 400 mg/m2 IV over 2 hours ( 15 minutes) 
on Days 1 and 15 of each cycle 
 5-Fluorouracil 400 mg/m2 IV push on Days 1 and 15 
of each cycle 
 5-Fluorouracil 2400 mg/m2 IV continuous infusion 
over 46 ( 2) hours on Days 1 and 2 and on Days 15 
and 16 of each cycle 
mFOLFOX6  5-fluorouracil, leucovorin, and oxaliplatin; nab-paclitaxel  nanoparticle albuminbound 
paclitaxel. 
a Patients who progressed on a prior fluoropyrimidine-based regimen will receive nab-paclitaxel 
and gemcitabine. 
b Patients who progressed on a prior gemcitabine-based regimen will receive mFOLFOX6. 
 
Treatment may be interrupted for reasons other than toxicity (e.g., surgical procedures).  
The acceptable length of treatment interruption must be based on an assessment of 
benefitrisk by the investigator and in alignment with the protocol requirements for the 
duration of treatment and documented by the investigator.  The Medical Monitor is 
available to advise as needed. 
Medication errors should be noted on the Study Drug Administration electronic Case 
Report Form (eCRF).  Adverse events associated with a medication error should be 
recorded on the Adverse Event eCRF. 
A7–1.1.3 
Second-Line Treatment for Cohort 1 Control Arm 
Patients in the Cohort 1 control arm who experience disease progression per 
RECIST v1.1 will be given the option of enrolling in Cohort 2, provided they meet 
eligibility criteria (see Section 4.1) and the cohort is open for enrollment. 

Appendix 7:  Study Details Specific to Control Arm (Cohorts 1 and 2) 
  
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A7–1.1.4 
Stage 2 Treatment for Cohort 2 Control Arm 
Patients in the Cohort 2 control arm who experience disease progression per 
RECIST v1.1 will be given the option of receiving a different treatment combination 
during Stage 2, as outlined in Table A7-2, provided they meet eligibility criteria 
(see Section 4.1) and the arm is open for enrollment.  Patients who experience 
unacceptable toxicity may also be eligible to receive treatment during Stage 2, provided 
they meet eligibility criteria and the arm is open for enrollment.  The Medical Monitor is 
available to advise as needed.  
 
 However, it is 
recommended that patients begin Stage 2 treatment as soon as possible.  Tumor 
assessments performed prior to or at the time of disease progression or unacceptable 
toxicity during Stage 1 may serve as baseline assessments for Stage 2, provided the 
tumor assessments are performed within 28 days prior to initiation of Stage 2 treatment 
(i.e., Day 1 of Cycle 1).  Stage 2 treatment will continue until unacceptable toxicity or 
loss of clinical benefit as determined by the investigator. 
Table A7-2 
Stage 2 Treatment Regimens Available for the Control Arm 
of Cohort 2 
Study Treatment  
Appendix 
No Stage 2 treatment currently available 
 
A7–1.2 
CONCOMITANT THERAPY, PROHIBITED FOOD, AND OTHER 
RESTRICTIONS FOR CONTROL ARM 
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 study treatment 
from 10 days prior to initiation of study treatment to the treatment discontinuation visit.  
All such medications should be reported to the investigator and recorded on the 
Concomitant Medications eCRF. 
For information on permitted, prohibited, or cautionary therapy, prohibited foods, and 
other restrictions (as applicable) for the control agents, refer to the local prescribing 
information for each agent. 

Appendix 7:  Study Details Specific to Control Arm (Cohorts 1 and 2) 
  
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A7–1.3 
CONTRACEPTION REQUIREMENTS FOR CONTROL ARM 
Contraception requirements for women and men in the control arm are outlined below: 
 
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 during the treatment period and for 6 months after the last 
dose of study treatment.  Women must refrain from donating eggs during this 
same period. 
A woman is considered to be of childbearing potential if she is postmenarcheal, 
has not reached a postmenopausal state ( 12 continuous months of 
amenorrhea with no identified cause other than menopause), and has not 
undergone surgical sterilization (removal of ovaries and/or uterus). 
Examples of contraceptive methods with a failure rate of  1% per year include 
bilateral tubal ligation, male sterilization, hormonal contraceptives that inhibit 
ovulation, hormone-releasing intrauterine devices, and copper intrauterine 
devices. 
The reliability of sexual abstinence should be evaluated in relation to the 
duration of the clinical trial and the preferred and usual lifestyle of the patient.  
Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation 
methods) and withdrawal are not acceptable methods of contraception. 
 
 
For men:  agreement to remain abstinent (refrain from heterosexual intercourse) or 
use contraceptive measures, and agreement to refrain from donating sperm, as 
defined below: 
With female partners of childbearing potential, men must remain abstinent or 
use a condom plus an additional contraceptive method that together result in a 
failure rate of  1% per year during the treatment period and for 6 months after 
the last dose of study treatment.  Men must refrain from donating sperm during 
this same period. 
With pregnant female partners, men must remain abstinent or use a condom 
during the treatment period and for 6 months after the last dose of study 
treatment to avoid exposing the embryo. 
The reliability of sexual abstinence should be evaluated in relation to the 
duration of the clinical trial and the preferred and usual lifestyle of the patient.  
Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation 
methods) and withdrawal are not acceptable methods of contraception. 
Male patients receiving mFOLFOX6 should be advised regarding the 
conservation of sperm prior to treatment because of the possibility of 
irreversible infertility resulting from therapy with 5-FU and oxaliplatin.   
 

Appendix 7:  Study Details Specific to Control Arm (Cohorts 1 and 2) 
  
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A7–2 
ASSESSMENT OF SAFETY FOR CONTROL ARM 
A7–2.1 
SAFETY PLAN FOR CONTROL ARM 
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 control agents 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.  Adverse events will 
be reported as described in Sections 5.25.6. 
A7–2.1.1 
Risks Associated with Control Agents 
Risks associated with each control agent can be found in the local prescribing 
information for that agent.  Patients receiving mFOLFOX6 should be advised to avoid 
prolonged exposure to sunlight because of the risk of photosensitivity with 5-FU. 
Neutropenia and lymphopenia associated with chemotherapy may increase the risk for 
developing an infection; however, this is not specific to the risk of infection with severe 
acute respiratory syndrome coronavirus 2 (SARS-CoV-2).  For the evaluation of the 
impact of the coronavirus disease 2019 (COVID-19) pandemic and COVID-19 
vaccination on the benefitrisk assessment, please refer to Section 1.5. 
A7–2.1.2 
Management of Patients Who Experience Specific Adverse 
Events in the Control Arm 
Guidelines for management of patients who experience specific adverse events 
(including dose modifications and treatment interruptions) can be found for each control 
agent in the local prescribing information for that agent. 
A7–2.2 
ADVERSE EVENTS OF SPECIAL INTEREST FOR CONTROL 
ARM (IMMEDIATELY REPORTABLE TO THE SPONSOR) 
Adverse events of special interest are required to be reported by the investigator to the 
Sponsor immediately (i.e., no more than 24 hours after learning of the event; see 
Section 5.4.2 for reporting instructions).  Adverse events of special interest for the 
control arm are as follows: 
 
Cases of potential drug-induced liver injury that include an elevated ALT or AST in 
combination with either elevated bilirubin or clinical jaundice, as defined by Hy's Law 
(see Section 5.3.5.7) 

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 
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. 
 
A7–2.3 
REPORTING REQUIREMENTS FOR PREGNANCIES IN 
CONTROL ARM 
A7–2.3.1 
Pregnancies in Female Patients 
Female patients of childbearing potential will be instructed to immediately inform the 
investigator if they become pregnant during the study or within 6 months after the last 
dose of study treatment.  A 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. 
A7–2.3.2 
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 last dose of study treatment.  A 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.  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 when updated information on the course and 

Appendix 7:  Study Details Specific to Control Arm (Cohorts 1 and 2) 
  
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outcome of the pregnancy 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 investigator and/or obstetrician. 
A7–2.3.3 
Abortions 
Any 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). 
A7–2.3.4 
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). 

Appendix 7:  Study Details Specific to Control Arm (Cohorts 1 and 2) 
  
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A7–3 
SCHEDULE OF ACTIVITIES FOR CONTROL ARM 
Table A7-3 Schedule of Activities for Control Arm (Cohorts 1 and 2) 
 
Stage 1 
Screening  
(see 
Appendix 6) 
Treatment Cycles (28-day cycles) a 
Stage 2 Scrn. 
(see 
Appendix 6) d 
or Treat. 
Discon. e 
Follow-Up e 
Cycle 1 b 
Cycles  2 
Day –28 
to –1 
Day 1 
 
Day 8 c 
(3 days) 
Day 15 
( 3 days) 
Day 1 
( 3 days) 
Day 8 c 
( 3 days) 
Day 15 
( 3 days) 
Every 
3 Months 
Molecular profile of pancreatic cancer 
(if available) 
See 
Appendix 6 
Whenever updated information becomes available  
 
Vital signs f 
x 
x c 
x 
x 
x c 
x 
x 
 
Weight 
x g 
x c, g 
x g 
x g 
x c, g 
x g 
x 
 
Complete physical examination h 
 
 
 
 
 
 
x 
 
Limited physical examination i 
x g 
x c, g 
x g 
x g 
x c, g 
x g 
 
 
ECOG Performance Status 
x g 
 
 
x g 
 
 
x 
 
ECG j 
Perform as clinically indicated g 
 
 
Hematology k 
x l, m 
x c, l 
x l 
x l 
x c, l 
x l 
x l 
 
Chemistry n 
x l, m 
x c, l 
x l 
x l 
x c, l 
x l 
x l 
 
CA19-9 
x l 
 
 
x l 
 
 
x 
 
Pregnancy test o 
x l, m 
 
 
x l 
 
 
x 
x o 
Urinalysis p 
Perform as clinically indicated 
 
 

Appendix 7:  Study Details Specific to Control Arm (Cohorts 1 and 2) 
  
Table A7‑3 Schedule of Activities for Control Arm (Cohorts 1 and 2) (cont.) 
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Stage 1 
Screening  
(see 
Appendix 6) 
Treatment Cycles (28-day cycles) a 
Stage 2 Scrn.  
(see 
Appendix 6) d 
or Treat. 
Discon. e 
Follow-Up e 
Cycle 1 b 
Cycles  2 
Day –28 
to –1 
Day 1 
 
Day 8 c 
(3 days) 
Day 15 
( 3 days) 
Day 1 
( 3 days) 
Day 8 c 
( 3 days) 
Day 15 
( 3 days) 
Every 
3 Months 
See 
Appendix 6 
Tumor response assessments 
x v, w, x 
Concomitant medications y 
x 
x c 
x 
x 
x c 
x 
x 
 
Adverse events z 
x 
x c 
x 
x 
x c 
x 
x z 
x z 
Nab-paclitaxel and gemcitabine 
administration aa, bb 
x 
x 
x 
x 
x 
x 
 
 
mFOLFOX6 administration bb, cc 
x 
 
x 
x 
 
x 
 
 
Survival follow-up and anti-cancer 
treatment 
 
 
 
 
 
 
 
x dd 

Appendix 7:  Study Details Specific to Control Arm (Cohorts 1 and 2) 
  
Table A7‑3 Schedule of Activities for Control Arm (Cohorts 1 and 2) (cont.) 
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CT  computed tomography; Discon.  discontinuation; ECOG  Eastern Cooperative Oncology Group; eCRF  electronic Case Report Form; 
mFOLFOX6  5-fluorouracil, leucovorin, and oxaliplatin;  nab-paclitaxel  nanoparticle albuminbound paclitaxel; PBMC  peripheral blood 
mononuclear cell; RBR  Research Biosample Repository; RECIST v1.1  Response Evaluation Criteria in Solid Tumors, Version 1.1; 
Scrn.  screening; Treat.  treatment. 
Note:  On treatment days, all assessments should be performed prior to dosing, unless otherwise specified. 
a 
If a visit is precluded because of a holiday, vacation, or other circumstance, it can occur outside of the specified window. 
b 
It is recommended that treatment be initiated no later than 7 days after randomization. 
c 
The Day 8 visit applies only to patients who receive nab-paclitaxel and gemcitabine. 
d 
In Cohort 2, patients who experience disease progression per RECIST v1.1 and (if Medical Monitor is in agreement) patients who experience 
unacceptable toxicity will be given the option of receiving a different treatment combination during Stage 2 (provided Stage 2 is open for 
enrollment; see Section A71.1.4 for details) and will undergo screening assessments to determine eligibility (see Appendix 6).  Stage 2 
treatment must begin within 3 months after the patient has experienced disease progression or unacceptable toxicity.  However, it is 
recommended that patients begin Stage 2 treatment as soon as possible.  Study details specific to the Stage 2 treatment regimens are 
provided in the applicable appendix.  Written informed consent must be obtained before performing screening evaluations for Stage 2, except 
as noted in footnote "x" below. 
e 
Patients in Cohort 1 will return to the clinic for a treatment discontinuation visit not more than 30 days after the last dose of study treatment.  
Patients in Cohort 2 will return to the clinic for a Stage 2 screening or treatment discontinuation visit not more than 30 days after the last dose 
of study treatment.  The visit at which disease progression is confirmed may be used as the Stage 2 screening or treatment discontinuation 
visit.  Treatment discontinuation assessments must be performed for all patients, regardless of whether they enter Stage 2.  Patients in 
Cohort 1, and patients in Cohort 2 who do not enter Stage 2, will undergo follow-up assessments after completing the treatment 
discontinuation visit. 
f 
Vital signs include respiratory rate, pulse rate, and systolic and diastolic blood pressure while the patient is in a seated position, pulse oximetry, 
and temperature.  Record new or worsened clinically significant abnormalities on the Adverse Event eCRF.  Vital signs should be measured 
within 60 minutes prior to study treatment and, if clinically indicated, during or after treatment administration. 
g 
Assessment may be performed within 24 hours prior to dosing during the treatment period. 
h 
Complete physical examination includes evaluation of the head, eyes, ears, nose, and throat, and the cardiovascular, dermatologic, 
musculoskeletal, respiratory, gastrointestinal, genitourinary, and neurologic systems.  Record new or worsened clinically significant 
abnormalities on the Adverse Event eCRF. 
 

Appendix 7:  Study Details Specific to Control Arm (Cohorts 1 and 2) 
  
Table A7‑3 Schedule of Activities for Control Arm (Cohorts 1 and 2) (cont.) 
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i 
Perform a limited, symptom-directed examination at specified timepoints and as clinically indicated at other timepoints.  Record new or 
worsened clinically significant abnormalities on the Adverse Event eCRF. 
j 
It is recommended that patients be resting in a supine position for at least 10 minutes prior to ECG recording. 
k 
Hematology includes WBC count, RBC count, hemoglobin, hematocrit, platelet count, and differential count (neutrophils, eosinophils, 
basophils, monocytes, lymphocytes, other cells). 
l 
Laboratory tests must be performed within 96 hours prior to dosing during the treatment period. 
m 
If screening laboratory assessments were performed within 96 hours prior to Day 1 of Cycle 1, they do not have to be repeated. 
n 
Chemistry panel (serum or plasma) includes bicarbonate or carbon dioxide (if considered standard of care for the region), sodium, potassium, 
magnesium, chloride, glucose, BUN or urea, creatinine, total protein, albumin, phosphorus, calcium, total bilirubin, ALP, ALT, and AST. 
o 
All women of childbearing potential will have urine or serum pregnancy tests performed at specified visits during treatment and at 3 months 
and 6 months after the last dose of study treatment.  If a urine pregnancy test is positive, it must be confirmed by a serum pregnancy test. 
p 
Urinalysis includes pH, specific gravity, glucose, protein, ketones, and blood; dipstick permitted. 
q 
r 
s 
Not applicable for a site that has not been granted approval for RBR sampling.  Performed only for patients at participating sites who have 
provided written informed consent to participate. 
t 
u 
v 
Patients will undergo tumor assessments at baseline, every 6 weeks ( 1 week) for the first 48 weeks following treatment initiation, and every 
12 weeks ( 2 weeks) thereafter, regardless of dose delays, until radiographic disease progression according to RECIST v1.1.  Thus, tumor 
assessments are to continue according to schedule in patients who discontinue treatment for reasons other than disease progression, even if 
they start new nonprotocol-specified anti-cancer therapy. 
 

Appendix 7:  Study Details Specific to Control Arm (Cohorts 1 and 2) 
  
Table A7‑3 Schedule of Activities for Control Arm (Cohorts 1 and 2) (cont.) 
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w 
All measurable and/or evaluable lesions identified at baseline should be re-assessed at subsequent tumor evaluations according to the tumor 
assessment schedule described above (see footnote “v”).  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).  Refer to Section 4.5.5 for further details on 
tumor assessments. 
x 
For patients who undergo screening for Stage 2:  Baseline tumor assessments for Stage 2 must be performed within 28 days prior to initiation 
of Stage 2 treatment (i.e., Day 1 of Cycle 1).  Tumor assessments performed prior to or at the time of disease progression per RECIST v1.1 or 
unacceptable toxicity during Stage 1 may serve as baseline assessments for Stage 2, provided the tumor assessments are performed within 
28 days prior to initiation of Stage 2 treatment. 
y 
Includes 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 study treatment from 10 days prior to initiation of study treatment until the treatment 
discontinuation visit. 
z 
  After this 
period, all deaths, regardless of cause, should be reported.  In addition, the Sponsor should be notified if the investigator becomes aware of 
any serious adverse event that is believed to be related to prior exposure to study treatment (see Section 5.6).  The investigator should follow 
each adverse event until the event has resolved to baseline grade or better, the event is assessed as stable by the investigator, 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. 
aa 
Patients in Cohort 1, and patients in Cohort 2 who progressed on prior fluoropyrimidine-based therapy, will receive nab-paclitaxel and 
gemcitabine as outlined in Table A7-1 of Appendix 7. 
bb 
Treatment will continue until unacceptable toxicity or disease progression per RECIST v1.1. 
cc 
Patients in Cohort 2 who progressed on prior gemcitabine-based therapy will receive mFOLFOX6 as outlined in Table A7-1 of Appendix 7. 
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 only. 

 
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Appendix 8  
Placeholder for Future Arm 
The atezolizumab plus PEGPH20 arm has been removed, as the treatment arm has met 
the criteria for closure per Section 4.6.1.  The content of Appendix 8 [previously entitled 
"Study Details Specific to Atezo  PEGPH20 Arm (Cohort 2)]" has been deleted.  
Appendix 8 will serve as a placeholder for a future arm to avoid having to renumber 
subsequent appendices. 

 
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Appendix 9  
Placeholder for Future Arm 
The content of Appendix 9 Schedules of Activities for Screening has been moved to 
Appendix 6.  The previous content of Appendix 6 [previously entitled "Study Details 
Specific to Control Arm (Cohorts 1 and 2)]" has moved to Appendix 7.  Appendix 9 will 
serve as a placeholder for a future arm to avoid having to renumber subsequent 
appendices. 
 

 
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Appendix 10  
Placeholder for Future Arm 
The content of Appendix 10 Management of Atezolizumab-Specific Adverse Events has 
been moved to Appendix 2.  The previous content of Appendix 2 [previously entitled 
"Modified RECIST v1.1 for Immune-Based Therapeutics (iRECIST)]" has been removed.  
Appendix 10 will serve as a placeholder for a future arm to avoid having to renumber 
subsequent appendices. 

  
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Appendix 11  
Placeholder for Future Arm 
The atezolizumab plus RO6874281 Q2W and the atezolizumab plus RO6874281 Q3W 
arms have been removed, as the treatment arms have met the criteria for closure per 
Section 4.6.1.  The content of Appendix 11 [previously entitled "Study Details Specific to 
Atezo  RO6874281 Q2W and Atezo  RO6874281 Q3W Arms (Cohort 2)"] has been 
deleted.  Appendix 11 will serve as a placeholder for a future arm to avoid having to 
renumber subsequent appendices. 
 

  
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Appendix 12   
Placeholder for Future Arm 
The atezolizumab plus chemotherapy (nab-paclitaxel and gemcitabine) plus 
AB928 arm has been removed, as the treatment arm has met the criteria for 
closure per Section 4.6.1.  The content of Appendix 12 [previously entitled 
"Study Details Specific to Atezo   Chemo   AB928 Arm (Cohort 1)"] has been 
deleted.  Appendix 12 will serve as a placeholder for a future arm to avoid 
having to renumber subsequent appendices. 

  
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Appendix 13  
Placeholder for Future Arm 
The atezolizumab plus chemotherapy (nab-paclitaxel and gemcitabine) plus 
selicrelumab arm has been removed, as the treatment arm has met the criteria for 
closure per Section 4.6.1.  The content of Appendix 13 [previously entitled "Study Details 
Specific to Atezo  Chemo  Seli Arm (Cohort 1)"] has been deleted.  Appendix 13 will 
serve as a placeholder for a future arm to avoid having to renumber subsequent 
appendices. 
 

 
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Appendix 14  
Study Details Specific to Atezo  Chemo  Tira Arm (Cohort 1) 
TABLE OF CONTENTS 
A14–1 
Background on Atezo  Chemo  Tira Arm ........................... 175 
A14–1.1 
Background on Atezolizumab ................................................ 175 
A14–1.2 
Background on Nab‑Paclitaxel and Gemcitabine in 
Pancreatic Cancer ................................................................. 175 
A14–1.3 
Background on Tiragolumab .................................................. 176 
A14–2 
Rationale for Atezo  Chemo  Tira Arm ................................. 176 
A14–2.1 
The PD-L1 Pathway ............................................................... 176 
A14–2.2 
The TIGIT Pathway ................................................................ 177 
A14–2.3 
Combination Treatment with Chemotherapy and an 
AntiPD‑L1/PD‑1 Agent ......................................................... 178 
A14–2.4 
Combined Inhibition of the PD-L1/PD-1 and TIGIT 
Pathways ............................................................................... 178 
A14–2.5 
Combination Treatment with Chemotherapy, an AntiPD-
L1/PD-1 Agent, and an Anti-TIGIT Agent .............................. 179 
A14–2.6 
Clinical Studies of Tiragolumab ............................................. 179 
A14–2.6.1 
Clinical Study of Tiragolumab as a Single Agent or in 
Combination with Atezolizumab ............................................. 179 
A14–2.6.2 
Clinical Study of Tiragolumab in Combination with 
Atezolizumab in Patients with PD-L1Positive NSCLC ......... 180 
A14–2.7 
Clinical Study of Atezolizumab in Combination with 
Nab‑Paclitaxel and Gemcitabine ............................................ 181 
A14–2.8 
Benefit–Risk Assessment ...................................................... 181 
A14–3 
Rationale for Dose and Schedule for Atezo  Chemo  Tira 
Arm ........................................................................................ 182 
A14–3.1 
Rationale for Atezolizumab Dose and Schedule .................... 182 
A14–3.2 
Rationale for tiragolumab Dose and Schedule....................... 182 
A14–4 
Materials and Methods Specific to Atezo  Chemo  Tira 
Arm ........................................................................................ 183 
A14–4.1 
Treatment in Atezo  Chemo  Tira Arm ................................. 183 
A14–4.1.1 
Formulation, Packaging, and Handling .................................. 183 
A14–4.1.1.1 Atezolizumab ......................................................................... 183 
A14–4.1.1.2 Tiragolumab ........................................................................... 183 
A14–4.1.1.3 Nab-Paclitaxel ........................................................................ 183 

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A14–4.1.1.4 Gemcitabine ........................................................................... 183 
A14–4.1.2 
Dosage, Administration, and Compliance .............................. 183 
A14–4.1.2.1 Atezolizumab ......................................................................... 184 
A14–4.1.2.2 Tiragolumab ........................................................................... 185 
A14–4.1.2.3 Nab-Paclitaxel and Gemcitabine ............................................ 187 
A14–4.2 
Concomitant Therapy for Atezo  Chemo  Tira Arm .............. 187 
A14–4.2.1 
Permitted Therapy for Atezo  Chemo  Tira Arm ................... 187 
A14–4.2.2 
Cautionary Therapy for Atezo  Chemo  Tira Arm ................. 189 
A14–4.2.2.1 Corticosteroids, Immunosuppressive Medications, and 
Tumor Necrosis Factor‑ Inhibitors ....................................... 189 
A14–4.2.2.2 Medications Given with Precaution due to Effects Related 
to Cytochrome P450 Enzymes .............................................. 189 
A14–4.2.2.3 Herbal Therapies ................................................................... 190 
A14–4.2.3 
Prohibited Therapy for Atezo  Chemo  Tira Arm .................. 190 
A14–4.3 
contraception Requirements for Atezo  Chemo  Tira Arm .... 190 
A14–5 
Assessment of Safety for Atezo  Chemo  Tira Arm .............. 192 
A14–5.1 
Safety Plan for Atezo  Chemo  Tira Arm .............................. 192 
A14–5.1.1 
Risks Associated with Atezolizumab ...................................... 192 
A14–5.1.2 
Risks Associated with Nab-Paclitaxel .................................... 192 
A14–5.1.3 
Risks Associated with Gemcitabine ....................................... 193 
A14–5.1.4 
Risks Associated with Tiragolumab ....................................... 193 
 ................................................... 193 
A14–5.1.4.2 Immune-Related Reactions ................................................... 193 
A14–5.1.4.3 Immune-Mediated Adverse Events ........................................ 194 
A14–5.1.4.4 Lymphopenia ......................................................................... 194 
 .............................................................. 195 
A14–5.1.5 
Risks Associated with Combination Use of Atezolizumab, 
Nab‑Paclitaxel, Gemcitabine, and Tiragolumab ..................... 195 
A14–5.1.6 
Management of Patients Who Experience Specific 
Adverse Events in Atezo  Chemo  Tira Arm ......................... 195 
A14–5.1.6.1 Dose Modifications ................................................................ 195 
A14–5.1.6.2 Treatment Interruption for Toxicities ...................................... 196 
A14–5.1.6.3 Management Guidelines for Adverse Events ......................... 197 

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A14–5.2 
Adverse Events of Special Interest for 
Atezo  Chemo  Tira Arm (Immediately Reportable 
to the Sponsor) ...................................................................... 212 
A14–5.3 
Reporting Requirements for Pregnancies in 
Atezo  Chemo  Tira Arm ...................................................... 213 
A14–5.3.1 
Pregnancies in Female Patients ............................................ 213 
A14–5.3.2 
Pregnancies in Female Partners of Male Patients ................. 214 
A14–5.3.3 
Abortions................................................................................ 214 
A14–5.3.4 
Congenital Anomalies/Birth Defects ...................................... 214 
A14–6 
Schedules of Activities and Sample Collection for 
Atezo  Chemo  Tira Arm ...................................................... 215 
 

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A14–1 
BACKGROUND ON ATEZO  CHEMO  TIRA ARM 
A14–1.1 
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 
and quality of tumor-specific T-cell responses, resulting in improved anti-tumor activity 
(Fehrenbacher et al. 2016; Rosenberg et al. 2016).  Atezolizumab has minimal binding 
to Fc receptors, thus eliminating detectable Fc-effector function and associated 
antibody-mediated clearance of activated effector T cells. 
Atezolizumab shows anti-tumor activity in both nonclinical models and cancer patients 
and is being investigated as a potential therapy in a wide variety of malignancies.  
Atezolizumab is being studied as a single agent in the advanced cancer and adjuvant 
therapy settings, as well as in combination with chemotherapy, targeted therapy, and 
cancer immunotherapy. 
Atezolizumab has been generally well tolerated.  Adverse events with potentially 
immune-mediated causes consistent with an immunotherapeutic agent, including rash, 
influenza-like illness, endocrinopathies, hepatitis or transaminitis, pneumonitis, colitis, 
and myasthenia gravis, have been observed (see Atezolizumab Investigator's Brochure 
for detailed safety results).  To date, these events have been manageable with 
treatment. 
Atezolizumab is approved for the treatment of urothelial carcinoma, nonsmall cell lung 
cancer, small-cell lung cancer, triple-negative breast cancer, hepatocellular carcinoma, 
melanoma, and alveolar soft part sarcoma. 
Refer to the Atezolizumab Investigator's Brochure for details on nonclinical and 
clinical studies. 
A14–1.2 
BACKGROUND ON NAB‑PACLITAXEL AND GEMCITABINE IN 
PANCREATIC CANCER  
Nanoparticle albuminbound paclitaxel (nab-paclitaxel) is a microtubule inhibitor that is 
approved in combination with gemcitabine for the first-line treatment of patients with 
metastatic adenocarcinoma of the pancreas.  Gemcitabine is a nucleoside metabolic 
inhibitor that is approved for the treatment of locally advanced or metastatic 
adenocarcinoma of the pancreas. 
The combination of nab-paclitaxel and gemcitabine has been established as the 
standard-of-care chemotherapy regimen for metastatic pancreatic cancer and is 

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classified as Category 1 (intervention is appropriate based upon high-level evidence) by 
the National Comprehensive Cancer Network for this indication (Von Hoff et al. 2013; 
NCCN 2017). 
A14–1.3 
BACKGROUND ON TIRAGOLUMAB   
Tiragolumab is a fully human IgG1/kappa monoclonal antibody that binds TIGIT and 
prevents its interaction with CD155 (also known as poliovirus receptor [PVR]).  
Therapeutic blockade of TIGIT by tiragolumab represents an attractive strategy for 
cancer therapy and is expected to enhance the magnitude and quality of tumor-specific 
T-cell responses, which may result in improved meaningful anti-tumor activity when 
tiragolumab is used in combination with other cancer immunotherapies and administered 
with chemotherapy.  The available nonclinical and clinical data provide a strong rationale 
for evaluating the potential clinical benefit of tiragolumab in cancer patients. 
Please refer to the Tiragolumab Investigator’s Brochure for additional details on the 
nonclinical and clinical studies for tiragolumab. 
A14–2 
RATIONALE FOR ATEZO  CHEMO  TIRA ARM 
A14–2.1 
THE PD-L1 PATHWAY 
Encouraging clinical data emerging in the field of tumor immunotherapy have 
demonstrated that therapies focused on enhancing T-cell responses against cancer can 
result in a significant survival benefit in patients with advanced malignancies 
(Hodi et al. 2010; Kantoff et al. 2010; Chen et al. 2012). 
The PD-L1 pathway serves as an immune checkpoint to temporarily dampen immune 
responses in states of chronic antigen stimulation, such as chronic infection or cancer.  
PD-L1 is an extracellular protein that downregulates immune responses through binding 
to its two receptors, PD-1 and B7-1.  PD-1 is an inhibitory receptor expressed on T cells 
following T-cell activation, and expression is sustained in states of chronic stimulation 
(Blank et al. 2005; Keir et al. 2008).  B7-1 is a molecule expressed on antigen-
presenting cells and activated T cells.  Binding of PD-L1 to PD-1 and B7-1 inhibits T-cell 
proliferation and activation, cytokine production, and cytolytic activity, leading to the 
functional inactivation or exhaustion of T cells (Butte et al. 2007; Yang et al. 2011).  
Overexpression of PD-L1 on tumor cells has been reported to impede anti-tumor 
immunity, resulting in immune evasion (Blank and Mackensen 2007).  Therefore, 
interruption of the PD-L1 pathway represents an attractive strategy for restoring tumor-
specific T-cell immunity. 
Targeting the PD-L1 pathway with atezolizumab has demonstrated activity in patients 
with advanced malignancies who have failed standard-of-care therapies.  Objective 
responses have been observed across a broad range of malignancies, including 

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nonsmall cell lung cancer, urothelial carcinoma, renal cell carcinoma, melanoma, 
colorectal cancer, head and neck cancer, gastric cancer, breast cancer, and sarcoma 
(see Atezolizumab Investigator's Brochure for detailed efficacy results). 
It has been shown that in pancreatic cancer tissues, both PD-L1 and PD-L2 are 
expressed and that tumor PD-L1, but not PD-L2, expression significantly correlates with 
postoperative prognosis.  Moreover, PD-L1 expression is inversely correlated with 
tumor-infiltrating lymphocytes, particularly CD8 T cells (Nomi et al. 2007).  However, no 
clinically significant response to single-agent checkpoint inhibitors has been observed in 
patients with pancreatic cancer (Royal et al. 2010; Brahmer et al. 2012). 
A14–2.2 
THE TIGIT PATHWAY 
TIGIT is an immune inhibitory receptor that is a member of the immunoglobulin 
superfamily.  TIGIT is expressed on the surface of activated T-cell and natural killer 
(NK)cell subsets and interacts with high affinity with CD155 (also known as PVR) 
(Yu et al. 2009).  Genetic ablation of TIGIT in T cells in mice results in exacerbated 
T-cell responses in nonclinical models of autoimmune and viral infections, demonstrating 
the role of TIGIT in inhibiting T-cell responses (Joller et al. 2011; Johnston et al. 2014).  
TIGIT expression is elevated in the tumor microenvironment in many human tumors, is 
concordantly expressed with other immune checkpoint receptors such as PD-1 on the 
surface of T cells and is associated with impaired T-cell function and anti-tumor immunity 
(Johnston et al. 2014; Manieri et al. 2017).  Activation of TIGIT on T cells and NK cells 
limits cellular proliferation, effector cytokine production, and killing of target tumor cells 
(Stanietsky et al. 2009; Yu et al. 2009; Johnston et al. 2014; Wang et al. 2015; Manieri et 
al. 2017). 
TIGIT is expressed in a wide variety of human tumors, including most solid tumors, 
such as NSCLC, breast cancer  and melanoma, and hematologic tumors, such as 
multiple myeloma and non-Hodgkin lymphoma, and fluorescence-activated cell sorting 
analysis of T cells isolated from fresh tumor samples revealed that TIGIT and PD-1 are 
also co-expressed on tumor-infiltrating T cells (Johnston et al. 2014; Yadav et al. 2016; 
Yang 2016; Guillerey at al. 2018).  TIGIT expression was 30%80% and 50%80% on 
tumor-infiltrating CD4 and CD8 T cells, respectively (Johnston et al. 2014). 
The TIGIT ligand PVR is broadly expressed in solid tumors, including human pancreatic 
cancer tissues.  PVR is mainly expressed in the plasma membrane and cytoplasm of 
cancer cells and with limited expression in non-cancer tissues, including islet cells.  
There exists a significant inverse correlation between PVR expression in pancreatic 
cancer and the presence of tumor-infiltrating CD4 and CD8 T cells.  Also, high PVR 
expression correlates with poor prognosis in patients with pancreatic cancer 

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(Nishiwada et al. 2015).  Thus, PVR may play a critical role through both immunologic 
and non-immunologic mechanisms in pancreatic cancer. 
It has been demonstrated that pancreatic tumors with high cytolytic activity exhibit 
increased expression of multiple immune checkpoint genes, including TIGIT 
(Balli et al. 2017). 
Therefore, TIGIT is a potential target for therapeutic intervention, aimed at restoring the 
immune response against the tumor.  Agents that inhibit TIGIT’s interaction with PVR 
may inhibit an important source of tumor-associated immune suppression and therefore 
may enhance the activity of other immune-based therapies.  Nonclinical studies that 
blocked antibodies in genetically deficient mice have revealed a key role for TIGIT in 
regulating T-cell responses in cancer.  Together, these data support the hypothesis that 
anti-TIGIT may reactivate anti-tumor immunity and provide clinical benefits to patients 
with cancer. 
A14–2.3 
COMBINATION TREATMENT WITH CHEMOTHERAPY AND AN 
ANTIPD‑L1/PD‑1 AGENT 
In nonclinical immune-competent mouse tumor models, treatment with multiple classes 
of chemotherapeutic agents resulted in activation or increase of tumor-infiltrating CD8 
T cells and the combination of anti-PD-L1 with several chemotherapeutic agents showed 
increased efficacy compared with single-agent treatment (Belvin et al. 2016). 
Indeed, the addition of antiPD-L1/PD-1 to standard chemotherapy demonstrated 
encouraging anti-tumor activity and acceptable safety in early Phase I and II studies 
(Giaccone et al. 2015; Langer et al. 2016; Rizvi et al. 2016).  In multiple, large, 
randomized, Phase III trials in patients with different advanced solid tumors, the addition 
of antiPD-L1/PD-1 to standard chemotherapy led to significantly longer overall survival 
and progression-free survival (PFS) than chemotherapy alone (Gandhi et al. 2018; 
Horn et al. 2018; Paz-Ares et al. 2018; Schmid et al. 2018).  As a result of these trials, 
antiPD-L1/PD-1 in combination with chemotherapies have been approved by health 
authorities for patients with advanced cancer. 
A14–2.4 
COMBINED INHIBITION OF THE PD-L1/PD-1 AND TIGIT 
PATHWAYS 
Durable clinical benefit is limited to a minority of patients treated with single-agent 
PD-L1/PD-1 inhibitors.  Therapies targeting the mechanisms of resistance to 
antiPD-L1/PD-1 therapies are needed to improve outcomes in patients with solid-tumor 
cancers.  Resistance to PD-L1/PD-1 blockade may result in the expression of multiple 
co-inhibitory receptors on the surface of effector T cells.  Nonclinical tumor models have 
shown that TIGIT selectively suppresses the effector function of chronically stimulated 
CD8 T cells, and that inhibiting both TIGIT and PD-L1/PD-1 results in superior efficacy 

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compared with single-agent treatments (Johnston et al. 2014).  Hence, targeting TIGIT 
and PD-L1 with tiragolumab and atezolizumab, respectively, may enhance the efficacy 
of PD-L1/PD-1 blockade across different cancer types (see Section A14–2.6 for a 
description of clinical studies of tiragolumab combined with atezolizumab). 
A14–2.5 
COMBINATION TREATMENT WITH CHEMOTHERAPY, AN 
ANTIPD-L1/PD-1 AGENT, AND AN ANTI-TIGIT AGENT 
It is well established that patients with many solid tumor types benefit when 
chemotherapy is added to an antiPD-L1/PD-1 agent.  Phase I clinical data show 
enhanced clinical efficacy when atezolizumab (antiPD-L1 agent) and tiragolumab 
(anti-TIGIT agent) are combined (see Section A14–2.6).  Thus, it is hypothesized that 
adding dual checkpoint inhibition to chemotherapy may result in enhanced and more 
durable responses than either therapy modality alone.  An exploratory study in gastric 
cancer has shown that after treatment with platinum chemotherapy, patients with a 
higher percentage of CD8TIGIT T cells had increased rates of cancer relapse and 
shorter disease-free survival (Tang et al. 2019).  In another study in esophageal cancer, 
the levels of CD155, the ligand for TIGIT, were increased after chemotherapy 
(Yoshida et al. 2019).  As the TIGIT pathway is associated with immune dysfunction, 
these findings suggest that TIGIT blockade to restore T-cell function could potentially 
improve outcomes for patients undergoing chemotherapy.  In support of this hypothesis, 
in vitro studies showed that TIGIT blockade countered the suppression of T-cell 
proliferation and activation following chemotherapy (Tang et al. 2019).  Evaluating the 
safety of atezolizumab and tiragolumab with chemotherapy in patients with metastatic 
pancreatic ductal adenocarcinoma (PDAC) in this study will contribute to the clinical 
understanding of adding antiPD-L1 and anti-TIGIT agents to chemotherapy. 
A14–2.6 
CLINICAL STUDIES OF TIRAGOLUMAB 
Tiragolumab is currently under investigation in two ongoing clinical studies in patients 
with solid tumors (Studies GO30103 and GO40290). 
A14–2.6.1 
Clinical Study of Tiragolumab as a Single Agent or in 
Combination with Atezolizumab 
Study GO30103 is a first-in-human, Phase I, open-label, dose-escalation and 
dose-expansion study of tiragolumab as a single agent and in combination with 
atezolizumab in patients with locally advanced, recurrent, or metastatic incurable tumors, 
including urothelial cancer, renal cell cancer, NSCLC, head and neck squamous cell 
carcinoma, esophageal cancer, colorectal cancer (CRC), gastric cancer, 
cholangiocarcinoma, and triple-negative breast cancer. 

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No maximum tolerated dose (MTD), dose-limiting toxicities (DLTs), or clear dose-related 
trends in the incidence or severity of adverse events have been determined for 
tiragolumab as a single agent or in combination with atezolizumab.  
 
 
 
 
 
Overall, tiragolumab as a single agent or in combination with atezolizumab has been 
well tolerated, adverse events have been manageable, and the safety profile is observed 
to be consistent across different solid tumor indications. 
A14–2.6.2 
Clinical Study of Tiragolumab in Combination with 
Atezolizumab in Patients with PD-L1Positive NSCLC 
Study GO40290 is a Phase II, randomized, blinded, placebo-controlled study of 
tiragolumab plus atezolizumab compared with placebo plus atezolizumab in patients with 
previously untreated locally advanced unresectable or metastatic PD-L1positive 
(defined as tumor proportion score [TPS]  1%) NSCLC. 
As of the data cutoff date of 30 June 2019, a total of 135 patients with a PD-L1 
TPS  1% received tiragolumab plus atezolizumab (n  67) or placebo plus atezolizumab 
(n  68).  In the intent-to-treat (ITT) population, the confirmed objective response rate 
(ORR) was higher in the tiragolumab plus atezolizumab arm (31.3%) than the placebo 
plus atezolizumab arm (16.2%).  In the subgroup of patients with TPS  50%, the 
confirmed ORR was higher in the tiragolumab plus atezolizumab arm (n  29; 55.2% 
[95% CI: 35.4%, 75.0%]) than the placebo plus atezolizumab arm (n  29; 17.2% 
[95% CI: 1.8%, 32.7%]).  Of note, responders in the tiragolumab plus atezolizumab arm 
included patients with both squamous and non-squamous histology. 
In the ITT population, investigator-assessed progression-free survival (PFS) was 
improved in the tiragolumab plus atezolizumab arm over the placebo plus 
atezolizumab arm (stratified hazard ratio [HR]  0.57 [95% CI: 0.37, 0.90]; median PFS, 
5.4 vs. 3.6 months, respectively).  In the subgroup of patients with TPS  50%, 
investigator-assessed PFS was improved in the tiragolumab plus atezolizumab arm over 

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the placebo plus atezolizumab arm (unstratified HR  0.33 [95% CI: 0.15, 0.72]; median 
PFS, not estimable vs. 3.9 months, respectively). 
To date, most adverse events have been Grade 1 or Grade 2.  Serious adverse events, 
Grade 35 adverse events, adverse events leading to discontinuation, and adverse 
events leading to death have been balanced between the two treatment arms.  Serious 
and high-grade treatment-related adverse events have also been balanced between the 
two treatment arms.  Immune-mediated adverse events have been balanced between 
the two treatment arms, with the exception of a higher frequency of infusion-related 
reaction and rash reported in the atezolizumab plus tiragolumab arm. 
 
 
 
Overall, tiragolumab in combination with atezolizumab has been well tolerated, adverse 
events have been manageable, and the safety profile seems to be consistent as 
reported across different solid tumor indications. 
Refer to the Tiragolumab Investigator’s Brochure for additional details on all ongoing and 
planned clinical studies. 
A14–2.7 
CLINICAL STUDY OF ATEZOLIZUMAB IN COMBINATION WITH 
NAB‑PACLITAXEL AND GEMCITABINE 
An ongoing Phase I study (GO30140) includes an arm that is evaluating atezolizumab in 
combination with nab-paclitaxel and gemcitabine in treatment-naive patients with 
metastatic pancreatic cancer. 
Adverse events observed to date are consistent with the known risks of atezolizumab, 
nab-paclitaxel, and gemcitabine.  Atezolizumab in combination with cytotoxic 
chemotherapy has not been associated with additive severe (Grade  3) toxicities, 
indicating that atezolizumab can be safely combined with standard chemotherapy.  
As of the data cutoff date of 24 October 2017, the confirmed objective response rate 
was 41.7%, the median progression-free survival was 7 months, and the median 
overall survival was 10.6 months for 24 efficacy-evaluable patients with metastatic 
pancreatic cancer. 
A14–2.8 
BENEFIT–RISK ASSESSMENT 
Metastatic PDAC is an incurable disease with a high unmet need for improved medical 
intervention.  Taking into account the potentially synergistic mechanisms of action of 

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tiragolumab and atezolizumab, as well as the preliminary efficacy and manageable 
safety profiles of the above-described combinations, treatment with atezolizumab, 
chemotherapy (nab-paclitaxel and gemcitabine), and tiragolumab (Atezo  Chemo  Tira) 
appears to have therapeutic potential in solid tumors such as PDAC. 
Because of the potential for overlapping toxicities, a minimum of 6 patients in the 
Atezo Chemo  Tira arm must complete a safety evaluation before additional patients 
can be enrolled in that arm.  Refer to Section 3.1.3 for details. 
COVID-19 Benefit‒Risk Assessment 
In the setting of the coronavirus disease 2019 (COVID-19) pandemic, patients with 
comorbidities, including those patients with pancreatic cancer, are a more vulnerable 
population.  In some retrospective analyses, infection with severe acute respiratory 
syndrome coronavirus 2 (SARS-CoV-2) has been associated with higher mortality in 
patients with cancer.  It is unclear whether or how cancer therapies such as 
chemotherapy, targeted therapy, or immunotherapy impact the incidence or severity of 
COVID-19.  At this time, there is insufficient evidence for a causal association between 
atezolizumab or tiragolumab and an increased risk of COVID-19.  Neutropenia and 
lymphopenia associated with chemotherapy may increase the risk for developing an 
infection in patients receiving atezolizumab in combination with chemotherapy; however, 
this is not specific to the risk of infection with SARS-CoV-2 (see Section A145.1). 
For the evaluation of the impact of the COVID-19 pandemic and COVID-19 vaccination 
on the benefitrisk assessment, please refer to Section 1.5. 
A14–3 
RATIONALE FOR DOSE AND SCHEDULE FOR 
ATEZO  CHEMO  TIRA ARM 
A14–3.1 
RATIONALE FOR ATEZOLIZUMAB DOSE AND SCHEDULE 
Atezolizumab will be administered at a fixed dose of 840 mg every 2 weeks (Q2W) 
(840 mg on Days 1 and 15 of each 28-day cycle), which is an approved dosage for 
atezolizumab. 

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A14–4 
MATERIALS AND METHODS SPECIFIC TO 
ATEZO  CHEMO  TIRA ARM 
A14–4.1 
TREATMENT IN ATEZO  CHEMO  TIRA ARM 
A14–4.1.1 
Formulation, Packaging, and Handling 
A14–4.1.1.1 Atezolizumab 
The atezolizumab drug product will be supplied by the Sponsor as a 
 
  The vial contains approximately 
 of 
atezolizumab solution. 
For information on the formulation and handling of atezolizumab, see the pharmacy 
manual and the Atezolizumab Investigator's Brochure. 
A14–4.1.1.2 Tiragolumab 
The tiragolumab drug product will be supplied in 
  The vial 
contains 
 of tiragolumab.  The approximate concentration of tiragolumab antibody 
in each vial is 
. 
For information on the formulation and handling of tiragolumab, see the pharmacy 
manual and the Tiragolumab Investigator's Brochure. 
A14–4.1.1.3 Nab-Paclitaxel 
For information on the formulation, packaging, and handling of nab-paclitaxel, refer to 
the local prescribing information. 
A14–4.1.1.4 Gemcitabine 
For information on the formulation, packaging, and handling of gemcitabine, refer to the 
local prescribing information. 
A14–4.1.2 
Dosage, Administration, and Compliance 
Patients in the Atezo  Chemo  Tira arm will receive treatment as outlined in  
Table A14-1 until unacceptable toxicity or loss of clinical benefit as determined by the 
investigator after an integrated assessment of radiographic and biochemical data, local 
biopsy results (if available), and clinical status (e.g., symptomatic deterioration such as 

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pain secondary to disease) (see Section 3.1.2 for details). 
 
 
Table A14-1 
Treatment Regimen for Atezo  Chemo  Tira Arm 
Cycle Length 
Dose, Route, and Regimen 
(drugs listed in order of administration) 
28 days 
 Atezolizumab 840 mg IV on Days 1 and 15 of each cycle 
 Tiragolumab 420 mg IV on Days 1 and 15 of each cycle a 
 Nab-paclitaxel 125 mg/m2 IV on Days 1, 8, and 15 of each cycle b 
 Gemcitabine 1000 mg/m2 IV on Days 1, 8, and 15 of each cycle 
Atezo  Chemo Tira  atezolizumab plus chemotherapy (nab-paclitaxel and gemcitabine) 
plus tiragolumab; IRR  infusion-related reaction; nab-paclitaxel  nanoparticle 
albuminbound paclitaxel. 
a On Day 1 of Cycle 1, tiragolumab will be administered 
 minutes after completion of 
the atezolizumab infusion.  The interval between subsequent infusions will be 
minutes if the previous atezolizumab infusion was given
and 
tolerated without an IRR or
minutes if the patient experienced an IRR with the 
previous atezolizumab infusion. 
b On Day 1 of Cycle 1, nab-paclitaxel will be administered 60 minutes after completion of 
the tiragolumab infusion.  The interval between subsequent infusions will be 30 minutes 
if the previous tiragolumab infusion was tolerated without an IRR or 60 minutes if the 
patient experienced an IRR with the previous tiragolumab infusion. 
 
Refer to the pharmacy manual for detailed instructions on drug preparation, storage, and 
administration. 
Medication errors 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.  
No safety data related to overdosing of atezolizumab or tiragolumab are available.  
For information on overdosing of nab-paclitaxel or gemcitabine, refer to the local 
prescribing information for each agent. 
A14–4.1.2.1 Atezolizumab 
Atezolizumab will be administered by IV infusion at a fixed dose of 840 mg on Days 1 
and 15 of each 28-day cycle. 
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 5.  
Atezolizumab infusions will be administered per the instructions outlined in Table A14-2. 

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Table A14-2 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, pulse oximetry, and 
temperature) should be recorded within 
60 minutes prior to the infusion. 
 
Atezolizumab should be infused over 
60 ( 15) minutes. 
 
If clinically indicated, vital signs should be 
recorded every 15 ( 5) minutes during the 
infusion and 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 recorded 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 recorded during the infusion and 
at 30 ( 10) minutes after the infusion. 
 
Guidelines for medical management of infusion-related reactions (IRRs) for 
atezolizumab are provided in Appendix 2.   
No dose modification for atezolizumab is allowed.  Guidelines for treatment interruption 
or discontinuation because of toxicities are provided in Section A145.1.6.  
Atezolizumab treatment may be interrupted for reasons other than toxicity (e.g., surgical 
procedures).  The acceptable length of treatment interruption must be based on an 
assessment of benefitrisk by the investigator and in alignment with the protocol 
requirements for the duration of treatment and documented by the investigator.  
The Medical Monitor is available to advise as needed. 
A14–4.1.2.2 Tiragolumab  
Tiragolumab will be administered by IV infusion at a fixed dose of 420 mg on Days 1 
and 15 of each 28-day cycle.  On Day 1 of Cycle 1, tiragolumab will be administered 
minutes after completion of the atezolizumab infusion.  The interval between 
subsequent infusions will be 
minutes if the previous atezolizumab infusion was 
tolerated without an IRR or 
minutes if the patient experienced an IRR with the 
previous atezolizumab infusion. 

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Administration of tiragolumab 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 5.  
Atezolizumab infusions will be administered per the instructions outlined in Table A14-3. 
Table A14-3 Administration of First and Subsequent Tiragolumab 
Infusions 
First Infusion 
Subsequent Infusions 
 
Guidelines for medical management of IRRs for atezolizumab are provided in 
Appendix 2.   
No dose modification for tiragolumab is allowed.  Guidelines for treatment interruption or 
discontinuation because of toxicities are provided in Section A145.1.6.  Tiragolumab 
treatment may be interrupted for reasons other than toxicity (e.g., surgical procedures).  
The acceptable length of treatment interruption must be based on an assessment of 
benefitrisk by the investigator and in alignment with the protocol requirements for the 

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duration of treatment and documented by the investigator.  The Medical Monitor is 
available to advise as needed. 
A14–4.1.2.3 Nab-Paclitaxel and Gemcitabine 
On Days 1, 8, and 15, patients will receive nab-paclitaxel 125 mg/m2, administered by IV 
infusion over 30 ( 5) minutes, followed by gemcitabine 1000 mg/m2, administered by IV 
infusion over 30 ( 5) minutes.  On Day 1 of Cycle 1, nab-paclitaxel will be administered 
60 minutes after completion of the tiragolumab infusion to allow for observation after 
tiragolumab administration.  The interval between subsequent infusions will be 
30 minutes if the previous tiragolumab infusion was tolerated without an IRR or 
60 minutes if the patient experienced an IRR with the previous tiragolumab infusion. 
Nab-paclitaxel and gemcitabine will be administered according to institutional standards 
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 5.   
Guidelines for nab-paclitaxel and gemcitabine dose modification and treatment 
interruption or discontinuation because of toxicities are provided in Section A145.1.6.  
Nab-paclitaxel and gemcitabine treatment may be interrupted for reasons other than 
toxicity (e.g., surgical procedures).  The acceptable length of treatment interruption must 
be based on an assessment of benefitrisk by the investigator and in alignment with the 
protocol requirements for the duration of treatment and documented by the 
investigator.  The Medical Monitor is available to advise as needed. 
A14–4.2 
CONCOMITANT THERAPY FOR ATEZO  CHEMO  TIRA ARM 
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 study treatment from 
10 days prior to initiation of study treatment to the treatment discontinuation visit.  
All such medications should be reported to the investigator and recorded on the 
Concomitant Medications eCRF. 
A14–4.2.1 
Permitted Therapy for Atezo  Chemo  Tira Arm 
Patients are permitted to use the following therapies during the study: 
 

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 
Oral contraceptives 
 
Hormone-replacement therapy 
 
Prophylactic or therapeutic anticoagulation therapy (such as warfarin at a stable 
dose or low-molecular-weight heparin) 
 
Vaccinations (such as influenza, COVID-19) 
Live, attenuated vaccines are not permitted (see Section A144.2.3). 
 
Megestrol acetate administered as an appetite stimulant after initiation of study 
treatment 
 
Mineralocorticoids (e.g., fludrocortisone) 
 
Inhaled corticosteroids administered for chronic obstructive pulmonary disease 
or asthma 
 
Low-dose corticosteroids administered for orthostatic hypotension or adrenocortical 
insufficiency 
 
Hormonal therapy with gonadotropinreleasing hormone agonists or antagonists for 
prostate cancer 
 
Palliative radiotherapy (e.g., treatment of known bony metastases or symptomatic 
relief of pain) as outlined below: 
Palliative radiotherapy is permitted, provided it does not interfere with the 
assessment of tumor target lesions (e.g., the lesion to be irradiated must not be 
the only site of measurable disease).  Treatment with nab-paclitaxel and 
gemcitabine should be withheld during palliative radiotherapy.  Treatment with 
atezolizumab and tiragolumab may be continued during palliative radiotherapy. 
 
Radiotherapy to the brain as outlined below: 
Patients whose extracranial tumor burden is stable or responding to study 
treatment and who are subsequently found to have three or fewer brain 
metastases may receive radiotherapy to the brain (either stereotactic 
radiosurgery or whole-brain radiation therapy) provided that all of the following 
criteria are met: 
– 
The patient has no evidence of progression or 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. 

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– 
Anti-convulsant therapy, if required, is administered at a stable dose. 
 
Premedication with antihistamines, antipyretics, and/or analgesics may be administered 
for the second and subsequent atezolizumab and tiragolumab infusions only, at the 
discretion of the investigator. 
In general, investigators should manage a patient’s care with supportive therapies 
as clinically indicated, per local standard practice.  Patients who experience 
infusion-associated symptoms may be treated symptomatically with acetaminophen, 
ibuprofen, diphenhydramine, and/or H2-receptor antagonists (e.g., famotidine, 
cimetidine), or equivalent medications per local standard practice.  Serious 
infusion-associated events manifested by dyspnea, hypotension, wheezing, 
bronchospasm, tachycardia, reduced oxygen saturation, or respiratory distress should 
be managed with supportive therapies as clinically indicated (e.g., supplemental oxygen 
and 2-adrenergic agonists; see Appendix 5).   
A14–4.2.2 
Cautionary Therapy for Atezo  Chemo  Tira Arm 
A14–4.2.2.1 Corticosteroids, Immunosuppressive Medications, and Tumor 
Necrosis Factor‑ Inhibitors 
Systemic corticosteroids, immunosuppressive medications, and tumor necrosis factor- 
(TNF-) inhibitors may attenuate potential beneficial immunologic effects of treatment 
with atezolizumab and/or tiragolumab.  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 and/or tiragolumab therapy (refer to Appendix 2 for 
details).  
A14–4.2.2.2 Medications Given with Precaution due to Effects Related to 
Cytochrome P450 Enzymes 
The metabolism of nab-paclitaxel is catalyzed by CYP2C8 and CYP3A4.  Caution should 
be exercised when nab-paclitaxel is concomitantly administered with known CYP2C8 or 
CYP3A4 inhibitors (e.g., atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, 
nefazodone, nelfinavir, ritonavir, saquinavir, and telithromycin) or inducers (e.g., rifampin 
and carbamazepine). 
The above lists of cautionary medications are not necessarily comprehensive.  
The investigator should consult the prescribing information when determining whether a 

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concomitant medication can be safety administered with study treatment.  In addition, 
the Medical Monitor is available to advise if questions arise regarding medications not 
listed above. 
A14–4.2.2.3 Herbal Therapies 
Concomitant use of herbal therapies is not recommended because their 
pharmacokinetics, safety profiles, and potential drug-drug interactions are generally 
unknown.  However, herbal therapies not intended for the treatment of cancer 
(see Section A144.2.3) may be used during the study at the discretion of the 
investigator. 
A14–4.2.3 
Prohibited Therapy for Atezo  Chemo  Tira Arm 
Use of the following concomitant therapies is prohibited as described below: 
 
 
 
 
 
A14–4.3 
CONTRACEPTION REQUIREMENTS FOR 
ATEZO  CHEMO  TIRA ARM 
Contraception requirements for women and men in the Atezo  Chemo  Tira arm are 
outlined below: 
 
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: 

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Women must remain abstinent or use contraceptive methods with a failure rate 
of  1% per year during the treatment period and for 5 months after the last 
dose of atezolizumab or tiragolumab, and 6 months after the last dose of 
nab-paclitaxel or gemcitabine.  Women must refrain from donating eggs during 
this same period. 
A woman is considered to be of childbearing potential if she is postmenarcheal, 
has not reached a postmenopausal state ( 12 continuous months of 
amenorrhea with no identified cause other than menopause), and has not 
undergone surgical sterilization (removal of ovaries and/or uterus). 
Examples of contraceptive methods with a failure rate of  1% per year include 
bilateral tubal ligation, male sterilization, hormonal contraceptives that inhibit 
ovulation, hormone-releasing intrauterine devices, and copper intrauterine 
devices. 
The reliability of sexual abstinence should be evaluated in relation to the 
duration of the clinical trial and the preferred and usual lifestyle of the patient.  
Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation 
methods) and withdrawal are not acceptable methods of contraception. 
 
For men:  agreement to remain abstinent (refrain from heterosexual intercourse) or 
use contraceptive methods, and agreement to refrain from donating sperm, as 
defined below: 
With female partners of childbearing potential, men who are receiving 
chemotherapy must remain abstinent or use a condom plus an additional 
contraceptive method that together result in a failure rate of  1% per year 
during the treatment period and for 6 months after the last dose of 
nab-paclitaxel or gemcitabine and men who are not receiving chemotherapy 
must remain abstinent or use a condom during the treatment period and for 
90 days after the last dose of tiragolumab.  Men must refrain from donating 
sperm during this same period. 
With pregnant female partners, men must remain abstinent or use a condom 
during the treatment period and for 90 days after the last dose of tiragolumab 
and 6 months after the last dose of nab-paclitaxel or gemcitabine to avoid 
exposing the embryo. 
The reliability of sexual abstinence should be evaluated in relation to the 
duration of the clinical trial and the preferred and usual lifestyle of the patient.  
Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation 
methods) and withdrawal are not acceptable methods of contraception. 
 

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A14–5 
ASSESSMENT OF SAFETY FOR ATEZO  CHEMO  TIRA ARM 
A14–5.1 
SAFETY PLAN FOR ATEZO  CHEMO  TIRA ARM 
The safety plan for patients in this study is based on clinical experience with 
atezolizumab, nab-paclitaxel, gemcitabine, and tiragolumab in completed and 
ongoing studies.  The anticipated important safety risks are outlined below 
(see Sections A145.1.1, A145.1.2, A145.1.3, A145.1.4, and A145.1.5).  Guidelines 
for management of patients who experience specific adverse events are provided in 
Section A145.1.6. 
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 study treatment 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.  Adverse events will 
be reported as described in Sections 5.25.6. 
A14–5.1.1 
Risks Associated with Atezolizumab 
Atezolizumab has been associated with risks such as the following:  IRRs and 
immune-mediated hepatitis, pneumonitis, colitis, pancreatitis, diabetes mellitus, 
hypothyroidism, hyperthyroidism, adrenal insufficiency, hypophysitis, Guillain-Barré 
syndrome, myasthenic syndrome or myasthenia gravis, facial paresis, myelitis, 
meningoencephalitis, myocarditis, pericardial disorders, nephritis, myositis, and severe 
cutaneous adverse reactions.  In addition, immune-mediated reactions may involve any 
organ system and may lead to HLH.  Refer to Appendix 2 of the protocol and Section 6 
of the Atezolizumab Investigator's Brochure for a detailed description of anticipated 
safety risks for atezolizumab. 
A14–5.1.2 
Risks Associated with Nab-Paclitaxel  
The following are the most common adverse events observed with nab-paclitaxel in 
patients with PDAC:  neutropenia, fatigue, peripheral neuropathy, nausea, alopecia, 
peripheral edema, diarrhea, pyrexia, vomiting, decreased appetite, rash, and 
dehydration.  The following adverse events have also been observed:  
myelosuppression (primarily neutropenia, anemia, thrombocytopenia), cranial nerve 
palsies, hypersensitivity reactions, pneumonitis, myalgia, arthralgia, cardiotoxicity 
(myocardial disorders, cardiac failure, angina, tachycardia, ventricular arrhythmia), 
cystoid macular edema, Stevens-Johnson syndrome/toxic epidermal necrolysis, sepsis, 
infusion-site reactions/extravasation, hepatic toxicity (drug-induced liver injury), acute 
renal failure, scleroderma, and drug-induced lupus erythematous. 
For more details regarding the safety profile for nab-paclitaxel, refer to the nab-paclitaxel 
prescribing information. 

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A14–5.1.3 
Risks Associated with Gemcitabine  
The most common adverse events observed with gemcitabine are nausea/vomiting, 
anemia, hepatic transaminitis, neutropenia, increased ALP, proteinuria, fever, hematuria, 
rash, thrombocytopenia, dyspnea, and peripheral edema.  The following adverse events 
have also been observed:  renal failure, hemolytic-uremic syndrome, interstitial 
pneumonitis, myocardial infarction, arrhythmia, and heart failure. 
For more details regarding the safety profile for gemcitabine, refer to the gemcitabine 
prescribing information. 
A14–5.1.4 
Risks Associated with Tiragolumab 
A14–5.1.4.2  
Infusion-Related Reactions 
Because tiragolumab is a therapeutic monoclonal antibody and targets immune cells, 
IRRs associated with hypersensitivity reactions and/or target-mediated cytokine release 
may occur.  Clinical signs and symptoms of such reactions may include rigors, chills, 
wheezing, pruritus, flushing, rash, hypotension, hypoxemia, and fever.  
 
 

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Refer to Section A144.1.2.2 for detailed guidance on administration of tiragolumab in 
this study.  Refer to Appendix 5 for guidance on anaphylaxis precautions and 
Appendix 2 for guidance on the management of IRRs. 
A14–5.1.4.3 Immune-Mediated Adverse Events 
Nonclinical models have suggested a role of TIGIT signaling interruption in 
autoimmunity.  In a knockout model (TIGIT/), loss of TIGIT signaling resulted in 
hyperproliferative T-cell responses and exacerbation of experimental autoimmune 
encephalitis (EAE).  TIGIT/ and wild-type B6 mice were immunized with suboptimal 
doses of myelin oligodendrocyte glycoprotein peptide to induce EAE.  In contrast to 
the wild-type B6 mice, the majority of the TIGIT/ mice developed severe EAE 
(Joller et al. 2011). 
Patients with a history of autoimmune disease will be excluded from this study.  
In addition, patients with a history of severe immune-mediated adverse events 
associated with prior immunotherapy or adverse events that did not resolve to baseline 
after discontinuation of prior immunotherapy will be excluded from this study.  Refer to 
Section 4.1.2 for details. 
In this study, specified immune-mediated adverse events will be considered adverse 
events of special interest and will be captured accordingly (see Section A145.2 for the 
list of adverse events of special interest and Section 5.4.2 for reporting instructions). 
A14–5.1.4.4 Lymphopenia 
The IgG1 backbone of tiragolumab with the intact Fc-effector function may lead to 
ADCC-mediated reduction in lymphocyte count. 
 
  Transient 
lymphocyte count decreases without clinical sequelae have been observed in patients 
treated with tiragolumab, alone or in combination with atezolizumab, in the Phase I study 
in solid tumors (Study GO30103).  Patients with a lymphocyte count  0.5  109/L 

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(500/L) will be excluded from the study (see Section 4.1.2).  Complete blood counts will 
be monitored throughout the study (see Section A14–6). 
 
 
A14–5.1.5 
Risks Associated with Combination Use of Atezolizumab, 
Nab‑Paclitaxel, Gemcitabine, and Tiragolumab 
The following adverse events are potential overlapping toxicities associated with 
combination use of atezolizumab, nab-paclitaxel, gemcitabine, and tiragolumab:  
immune-mediated toxicities, including HLH, and others (described in Appendix 2), 
gastrointestinal toxicities, hematologic toxicity, dermatologic toxicities, and hepatic 
toxicity. 
A14–5.1.6 
Management of Patients Who Experience Specific Adverse 
Events in Atezo  Chemo  Tira Arm 
On Day 1 of each cycle, patients are required to have an ANC of  1.5  109/L (1500/L) 
and a platelet count of  100  109/L (100,000/L) to receive treatment with nab-paclitaxel 
and gemcitabine.  Guidelines for management of hematologic toxicities and other 
toxicities (including guidelines for dose modification and treatment interruption or 
discontinuation) are provided in Table A14-5. 
A14–5.1.6.1 Dose Modifications 
 
For management of drug-related toxicities, the dose of nab-paclitaxel may be reduced by 
25 mg/m2 (one dose level) up to two times and the dose of gemcitabine may be reduced 
by 200 mg/m2 (one dose level) up to two times, as outlined in Table A14-4. 

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Table A14-4 Recommended Dose Reductions for Nab-Paclitaxel and 
Gemcitabine 
 
Initial Dose 
First Dose Reduction 
Second Dose Reduction 
Nab-paclitaxel 
125 mg/m2 
100 mg/m2 
75 mg/m2 
Gemcitabine 
1000 mg/m2 
800 mg/m2 
600 mg/m2 
nab-paclitaxel  nanoparticle albuminbound paclitaxel. 
 
If further dose reduction is indicated for nab-paclitaxel and/or gemcitabine after two dose 
reductions, that drug (or both drugs, if applicable) should be discontinued, but the patient 
may continue other study treatments at the investigator's discretion.  After dose 
reduction, the dose may be escalated during subsequent administrations at the 
investigator's discretion. 
A14–5.1.6.2 Treatment Interruption for Toxicities 
Atezolizumab and/or tiragolumab may be temporarily suspended in patients 
experiencing toxicity considered to be related to study treatment.  
 
Nab-paclitaxel and/or gemcitabine treatment may be temporarily suspended in patients 
experiencing toxicity considered to be related to study treatment (see Table A14-5).  
If nab-paclitaxel or gemcitabine have been withheld for  56 days because of toxicity, the 
patient should be discontinued from both chemotherapy agents.  However, 
nab-paclitaxel or gemcitabine can be resumed after being withheld for  56 days if the 

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patient is likely to derive clinical benefit.  The decision to re-challenge patients with 
nab-paclitaxel and/or gemcitabine should be based on investigator's assessment of 
benefitrisk and documented by the investigator.  The Medical Monitor is available to 
advise as needed. 
 
 
 
Refer to Section A144.1.2 for information on dose interruptions for reasons other 
than toxicity. 
A14–5.1.6.3 Management Guidelines for Adverse Events 
Guidelines for management of patients who experience specific adverse events are 
provided in Table A14-5.  These guidelines are intended to inform rather than supersede 
an investigator's clinical judgment and assessment of the benefitrisk balance when 
managing individual cases. 
The investigator may use discretion in adhering to the guidelines for nab-paclitaxel and 
gemcitabine described below, taking into account the severity of the event and benefit 
versus risk for the patient, with the goal of maximizing patient compliance and access to 
supportive care.  Additionally, the prescribing information, as well as local hospital or 
clinical practice, must be followed. 

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Table A14-5 Guidelines for Management of Patients Who Experience 
Specific Adverse Events in Atezo  Chemo  Tira Arm 
Event 
Action to Be Taken 
IRRs, CRS, anaphylaxis, and hypersensitivity reactions 
General guidance 
 Guidelines for management of IRRs and CRS for 
atezolizumab and tiragolumab are provided in Appendix 2. 
 Guidelines for management of IRRs for nab-paclitaxel and 
gemcitabine are provided below. 
 For anaphylaxis precautions, see Appendix 5. 
 For severe hypersensitivity reactions, permanently 
discontinue the causative agent. 
IRR to chemotherapy, Grade 1  
 Reduce infusion rate to half the rate being given at the time of 
event onset. 
 After the event has resolved, the investigator should wait for 
30 minutes while delivering the infusion at the reduced rate. 
 If the infusion is tolerated at the reduced rate for 30 minutes 
after symptoms have resolved, the infusion rate may be 
increased to the original rate. 
IRR to chemotherapy, Grade 2 
 Interrupt infusion. 
 Administer aggressive symptomatic treatment (e.g., oral or IV 
antihistamine, antipyretic, glucocorticoids, epinephrine, 
bronchodilators, oxygen). 
 After symptoms have resolved to baseline, resume infusion at 
half the rate being given at the time of event onset. 
 For subsequent infusions, administer oral premedication with 
antihistamine and antipyretic and monitor closely for IRRs. 
Atezo  Chemo  Tira  atezolizumab plus chemotherapy (nab-paclitaxel and gemcitabine) plus 
tiragolumab; CRS  cytokine release syndrome; IRR  infusion-related reaction; 
nab-paclitaxel  nanoparticle albuminbound paclitaxel; TSH  thyroid-stimulating hormone. 
a Resumption of treatment may be considered if the investigator believes the patient is likely to 
derive clinical benefit.  The decision to re-challenge patients should be based on investigator's 
assessment of benefitrisk and documented by the investigator (or an appropriate delegate).  
The Medical Monitor is available to advise as needed. 
b The dose of nab-paclitaxel may be reduced by 25 mg/m2 (one dose level) up to two times and 
the dose of gemcitabine may be reduced by 200 mg/m2 (one dose level) up to two times 
(see Section A145.1.6.1 for details). 

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Table A14‑5 Guidelines for Management of Patients Who Experience 
Specific Adverse Events in Atezo  Chemo  Tira Arm (cont.) 
Event 
Action to Be Taken 
IRRs, CRS, anaphylaxis, and hypersensitivity reactions (cont.) 
IRR to chemotherapy, 
Grade 3 or 4 
 Stop infusion. 
 Administer aggressive symptomatic treatment (e.g., oral or IV 
antihistamine, antipyretic, glucocorticoids, epinephrine, 
bronchodilators, oxygen). 
 Permanently discontinue treatment and contact Medical Monitor. a 
Hemophagocytic 
lymphohistiocytosis  
 Follow guidelines for atezolizumab in Appendix 2. 
 Withhold all treatment and contact Medical Monitor. 
Gastrointestinal toxicity 
Diarrhea or colitis, Grade 1 
 Follow guidelines for atezolizumab and tiragolumab in 
Appendix 2. 
 Continue nab-paclitaxel and gemcitabine. 
Diarrhea or colitis, Grade 2 
 Follow guidelines for atezolizumab and tiragolumab in 
Appendix 2. 
 Continue nab-paclitaxel and gemcitabine. 
Diarrhea or colitis, Grade 3 
 Follow guidelines for atezolizumab and tiragolumab in 
Appendix 2. 
 Withhold nab-paclitaxel and gemcitabine. 
 If event resolves to Grade 1 or better  56 days after event onset, 
resume nab-paclitaxel and gemcitabine with dose reduced by one 
level. b  If not, permanently discontinue nab-paclitaxel and 
gemcitabine. a 
Diarrhea or colitis, Grade 4 
 Follow guidelines for atezolizumab and tiragolumab in 
Appendix 2. 
 Permanently discontinue nab-paclitaxel and gemcitabine. a 
Atezo  Chemo  Tira  atezolizumab plus chemotherapy (nab-paclitaxel and gemcitabine) plus 
tiragolumab; CRS  cytokine release syndrome; IRR  infusion-related reaction; 
nab-paclitaxel  nanoparticle albuminbound paclitaxel; TSH  thyroid-stimulating hormone. 
a Resumption of treatment may be considered if the investigator believes the patient is likely to 
derive clinical benefit.  The decision to re-challenge patients should be based on investigator's 
assessment of benefitrisk and documented by the investigator (or an appropriate delegate).  
The Medical Monitor is available to advise as needed. 
b The dose of nab-paclitaxel may be reduced by 25 mg/m2 (one dose level) up to two times and 
the dose of gemcitabine may be reduced by 200 mg/m2 (one dose level) up to two times 
(see Section A145.1.6.1 for details). 

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Table A14‑5 Guidelines for Management of Patients Who Experience 
Specific Adverse Events in Atezo  Chemo  Tira Arm (cont.) 
Event 
Action to Be Taken 
Gastrointestinal toxicity (cont.) 
Mucositis, Grade 1 or 2 
 Continue atezolizumab, tiragolumab, nab-paclitaxel, and 
gemcitabine. 
Mucositis, Grade 3 
 Continue atezolizumab and tiragolumab.  Withhold nab-paclitaxel 
and gemcitabine. 
 If event resolves to Grade 1 or better  56 days after event onset, 
resume nab-paclitaxel and gemcitabine with dose reduced by one 
level. b  If not, permanently discontinue nab-paclitaxel and 
gemcitabine. a 
Mucositis, Grade 4 
 Permanently discontinue atezolizumab, tiragolumab, 
nab-paclitaxel, and gemcitabine. a 
Febrile neutropenia 
Grade 3 or 4 
 Withhold atezolizumab, tiragolumab, nab-paclitaxel, and 
gemcitabine. 
 If fever resolves and ANC improves to  1.5  109/L (1500/L) 
 56 days after event onset, resume nab-paclitaxel and 
gemcitabine with dose reduced by one level. b  If not, permanently 
discontinue nab-paclitaxel and gemcitabine. a 
 If fever resolves and ANC improves to  1.5  109/L (1500/L) 
 12 weeks after event onset, resume atezolizumab and 
tiragolumab.  If not, permanently discontinue atezolizumab and 
tiragolumab. a 
Atezo  Chemo  Tira  atezolizumab plus chemotherapy (nab-paclitaxel and gemcitabine) plus 
tiragolumab; CRS  cytokine release syndrome; IRR  infusion-related reaction; 
nab-paclitaxel  nanoparticle albuminbound paclitaxel; TSH  thyroid-stimulating hormone. 
a Resumption of treatment may be considered if the investigator believes the patient is likely to 
derive clinical benefit.  The decision to re-challenge patients should be based on investigator's 
assessment of benefitrisk and documented by the investigator (or an appropriate delegate).  
The Medical Monitor is available to advise as needed. 
b The dose of nab-paclitaxel may be reduced by 25 mg/m2 (one dose level) up to two times and 
the dose of gemcitabine may be reduced by 200 mg/m2 (one dose level) up to two times 
(see Section A145.1.6.1 for details). 

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Table A14‑5 Guidelines for Management of Patients Who Experience 
Specific Adverse Events in Atezo  Chemo  Tira Arm (cont.) 
Event 
Action to Be Taken 
Hematologic toxicity at Day 1 (excluding febrile neutropenia) 
ANC  1.5  109/L (1500/L) 
and 
Platelet count  100  109/L 
(100,000/L) 
 Continue atezolizumab, tiragolumab, nab-paclitaxel, and 
gemcitabine. 
ANC  1.5  109/L (1500/L) 
and/or 
Platelet count  100  109/L 
(100,000/L) 
 Continue atezolizumab and tiragolumab.  Withhold 
nab-paclitaxel and gemcitabine. 
 Permanently discontinue nab-paclitaxel or gemcitabine if 
withheld  56 days after event onset. a  
Hematologic toxicity at Day 8 (excluding febrile neutropenia) 
ANC  1.0  109/L (1000/L) 
and 
Platelet count  75  109/L 
(75,000/L) 
 Continue nab-paclitaxel and gemcitabine. 
ANC  0.5  109/L (500/L) but 
 1.0  109/L (1000/L) 
and/or 
Platelet count  50  109/L 
(50,000/L) but  75  109/L 
(75,000/L) 
 Continue nab-paclitaxel and gemcitabine with dose reduced 
by one level. b 
ANC  0.5  109/L (500/L) 
and/or 
Platelet count  50  109/L 
(50,000/L) 
 Withhold nab-paclitaxel and gemcitabine. 
 If nab-paclitaxel and gemcitabine are withheld  56 days after 
event onset, permanently discontinue nab-paclitaxel and 
gemcitabine. a 
Atezo  Chemo  Tira  atezolizumab plus chemotherapy (nab-paclitaxel and gemcitabine) plus 
tiragolumab; CRS  cytokine release syndrome; IRR  infusion-related reaction; 
nab-paclitaxel  nanoparticle albuminbound paclitaxel; TSH  thyroid-stimulating hormone. 
a Resumption of treatment may be considered if the investigator believes the patient is likely to 
derive clinical benefit.  The decision to re-challenge patients should be based on investigator's 
assessment of benefitrisk and documented by the investigator (or an appropriate delegate).  
The Medical Monitor is available to advise as needed. 
b The dose of nab-paclitaxel may be reduced by 25 mg/m2 (one dose level) up to two times and 
the dose of gemcitabine may be reduced by 200 mg/m2 (one dose level) up to two times 
(see Section A145.1.6.1 for details). 

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Table A14‑5 Guidelines for Management of Patients Who Experience 
Specific Adverse Events in Atezo  Chemo  Tira Arm (cont.) 
Event 
Action to Be Taken 
Hematologic toxicity at Day 15 (excluding febrile neutropenia):  Day 8 doses given without 
modification 
ANC  1.0  109/L (1000/L) 
and 
Platelet count  75  109/L 
(75,000/L) 
 Continue atezolizumab, tiragolumab, nab-paclitaxel, and 
gemcitabine. 
ANC  0.5  109/L (500/L) but 
 1.0  109/L (1000/L) 
and/or 
Platelet count  50  109/L 
(50,000/L) but  75  109/L 
(75,000/L) 
 Continue atezolizumab and tiragolumab.  Continue 
nab-paclitaxel and gemcitabine at current dose followed by 
WBC growth factors or with dose reduced by one level. b 
 
ANC  0.5  109/L (500/L) 
and/or 
Platelet count  50  109/L 
(50,000/L) 
 Withhold atezolizumab, tiragolumab, nab-paclitaxel, and 
gemcitabine. 
 If event improves, atezolizumab, tiragolumab, nab-paclitaxel, 
and/or gemcitabine can be resumed. a 
 If nab-paclitaxel and gemcitabine are withheld  56 days after 
event onset, permanently discontinue nab-paclitaxel and 
gemcitabine. a 
 If atezolizumab and tiragolumab are withheld  12 weeks after 
event onset, permanently discontinue atezolizumab and 
tiragolumab. a 
Atezo  Chemo  Tira  atezolizumab plus chemotherapy (nab-paclitaxel and gemcitabine) plus 
tiragolumab; CRS  cytokine release syndrome; IRR  infusion-related reaction; 
nab-paclitaxel  nanoparticle albuminbound paclitaxel; TSH  thyroid-stimulating hormone. 
a Resumption of treatment may be considered if the investigator believes the patient is likely to 
derive clinical benefit.  The decision to re-challenge patients should be based on investigator's 
assessment of benefitrisk and documented by the investigator (or an appropriate delegate).  
The Medical Monitor is available to advise as needed. 
b The dose of nab-paclitaxel may be reduced by 25 mg/m2 (one dose level) up to two times and 
the dose of gemcitabine may be reduced by 200 mg/m2 (one dose level) up to two times 
(see Section A145.1.6.1 for details). 

Appendix 14:  Study Details Specific to Atezo  Chemo  Tira Arm (Cohort 1) 
  
Pancreatic Immunotherapy Combinations—F. Hoffmann-La Roche Ltd 
203/Protocol WO39608, Version 16
 
 
Table A14‑5 Guidelines for Management of Patients Who Experience 
Specific Adverse Events in Atezo  Chemo  Tira Arm (cont.) 
Event 
Action to Be Taken 
Hematologic toxicity at Day 15 (excluding febrile neutropenia):  Day 8 doses reduced 
ANC  1.0  109/L (1000/L) 
and 
Platelet count  75  109/L 
(75,000/L) 
 Continue atezolizumab and tiragolumab.  Continue 
nab-paclitaxel and gemcitabine at Day 1 doses followed by 
WBC growth factors or at current dose. 
ANC  0.5  109/L (500/L) but 
 1.0  109/L (1000/L) 
and/or 
Platelet count  50  109/L 
(50,000/L) but  75  109/L 
(75,000/L) 
 Continue atezolizumab and tiragolumab.  Continue 
nab-paclitaxel and gemcitabine at current dose followed by 
WBC growth factors or with dose reduced by one level. b 
ANC  0.5  109/L (500/L) 
and/or 
Platelet count  50  109/L 
(50,000/L) 
 Withhold atezolizumab, tiragolumab, nab-paclitaxel, and 
gemcitabine. 
 If event improves, atezolizumab, tiragolumab, nab-paclitaxel, 
and/or gemcitabine can be resumed. a 
 If nab-paclitaxel and gemcitabine are withheld  56 days after 
event onset, permanently discontinue nab-paclitaxel and 
gemcitabine. a 
 If atezolizumab and tiragolumab are withheld  12 weeks after 
event onset, permanently discontinue atezolizumab and 
tiragolumab. a 
Atezo  Chemo  Tira  atezolizumab plus chemotherapy (nab-paclitaxel and gemcitabine) plus 
tiragolumab; CRS  cytokine release syndrome; IRR  infusion-related reaction; 
nab-paclitaxel  nanoparticle albuminbound paclitaxel; TSH  thyroid-stimulating hormone. 
a Resumption of treatment may be considered if the investigator believes the patient is likely to 
derive clinical benefit.  The decision to re-challenge patients should be based on investigator's 
assessment of benefitrisk and documented by the investigator (or an appropriate delegate).  
The Medical Monitor is available to advise as needed. 
b The dose of nab-paclitaxel may be reduced by 25 mg/m2 (one dose level) up to two times and 
the dose of gemcitabine may be reduced by 200 mg/m2 (one dose level) up to two times 
(see Section A145.1.6.1 for details). 

Appendix 14:  Study Details Specific to Atezo  Chemo  Tira Arm (Cohort 1) 
  
Pancreatic Immunotherapy Combinations—F. Hoffmann-La Roche Ltd 
204/Protocol WO39608, Version 16
 
 
Table A14‑5 Guidelines for Management of Patients Who Experience 
Specific Adverse Events in Atezo  Chemo  Tira Arm (cont.) 
Event 
Action to Be Taken 
Hematologic toxicity at Day 15 (excluding febrile neutropenia):  Day 8 treatment was withheld 
ANC  1.0  109/L (1000/L) 
and 
Platelet count  75  109/L 
(75,000/L) 
 Continue atezolizumab and tiragolumab.  Continue 
nab-paclitaxel and gemcitabine at current dose followed by 
WBC growth factors or with dose reduced by one level. b 
ANC  0.5  109/L (500/L) but 
 1.0  109/L (1000/L) 
and/or 
Platelet count  50  109/L 
(50,000/L) but  75  109/L 
(75,000/L) 
 Continue atezolizumab and tiragolumab.  Continue 
nab-paclitaxel and gemcitabine with dose reduced by one level 
followed by WBC growth factors or with dose reduced by two 
levels. b 
ANC  0.5  109/L (500/L) 
and/or 
Platelet count  50  109/L 
(50,000/L) 
 Withhold atezolizumab, tiragolumab, nab-paclitaxel, and 
gemcitabine. 
 If event improves, atezolizumab, tiragolumab, nab-paclitaxel, 
and/or gemcitabine can be resumed. a 
 If nab-paclitaxel and gemcitabine are withheld  56 days after 
event onset, permanently discontinue nab-paclitaxel and 
gemcitabine. a 
 If atezolizumab and tiragolumab are withheld  12 weeks after 
event onset, permanently discontinue atezolizumab and 
tiragolumab. a 
Atezo  Chemo  Tira  atezolizumab plus chemotherapy (nab-paclitaxel and gemcitabine) plus 
tiragolumab; CRS  cytokine release syndrome; IRR  infusion-related reaction; 
nab-paclitaxel  nanoparticle albuminbound paclitaxel; TSH  thyroid-stimulating hormone. 
a Resumption of treatment may be considered if the investigator believes the patient is likely to 
derive clinical benefit.  The decision to re-challenge patients should be based on investigator's 
assessment of benefitrisk and documented by the investigator (or an appropriate delegate).  
The Medical Monitor is available to advise as needed. 
b The dose of nab-paclitaxel may be reduced by 25 mg/m2 (one dose level) up to two times and 
the dose of gemcitabine may be reduced by 200 mg/m2 (one dose level) up to two times 
(see Section A145.1.6.1 for details). 
 
 

Appendix 14:  Study Details Specific to Atezo  Chemo  Tira Arm (Cohort 1) 
  
Pancreatic Immunotherapy Combinations—F. Hoffmann-La Roche Ltd 
205/Protocol WO39608, Version 16
 
 
Table A14‑5 Guidelines for Management of Patients Who Experience 
Specific Adverse Events in Atezo  Chemo  Tira Arm (cont.) 
Event 
Action to Be Taken 
Neurologic disorder 
 
Immune-mediated neuropathy, 
Grade 1 or 2 
 Follow guidelines for atezolizumab and tiragolumab in 
Appendix 2. 
 Continue nab-paclitaxel and gemcitabine. 
Immune-mediated neuropathy, 
Grade 3 or 4 
 Follow guidelines for atezolizumab and tiragolumab in 
Appendix 2. 
 Continue gemcitabine.  Withhold nab-paclitaxel. 
 If event resolves to Grade 1 or better  56 days after event 
onset, resume nab-paclitaxel with dose reduced by one level. b  
If not, permanently discontinue nab-paclitaxel. a 
Nonimmune-mediated 
neuropathy, Grade 1 or 2 
 Continue atezolizumab, tiragolumab, nab-paclitaxel, and 
gemcitabine. 
Nonimmune-mediated 
neuropathy, Grade 3 or 4 
 Continue atezolizumab, tiragolumab, and gemcitabine.  
Withhold nab-paclitaxel. 
 If event resolves to Grade 1 or better  56 days after event 
onset, resume nab-paclitaxel with dose reduced by one level. b  
If not, permanently discontinue nab-paclitaxel. a 
Immune-mediated 
meningoencephalitis, any grade 
 Follow guidelines for atezolizumab and tiragolumab in 
Appendix 2. 
 Withhold nab-paclitaxel and gemcitabine. 
 If event stabilizes  56 days after event onset, resume 
nab-paclitaxel and gemcitabine.  If not, permanently 
discontinue nab-paclitaxel and gemcitabine.  The Medical 
Monitor is available to advise as needed. 
Atezo  Chemo  Tira  atezolizumab plus chemotherapy (nab-paclitaxel and gemcitabine) plus 
tiragolumab; CRS  cytokine release syndrome; IRR  infusion-related reaction; 
nab-paclitaxel  nanoparticle albuminbound paclitaxel; TSH  thyroid-stimulating hormone. 
a Resumption of treatment may be considered if the investigator believes the patient is likely to 
derive clinical benefit.  The decision to re-challenge patients should be based on investigator's 
assessment of benefitrisk and documented by the investigator (or an appropriate delegate).  
The Medical Monitor is available to advise as needed. 
b The dose of nab-paclitaxel may be reduced by 25 mg/m2 (one dose level) up to two times and 
the dose of gemcitabine may be reduced by 200 mg/m2 (one dose level) up to two times 
(see Section A145.1.6.1 for details). 

Appendix 14:  Study Details Specific to Atezo  Chemo  Tira Arm (Cohort 1) 
  
Pancreatic Immunotherapy Combinations—F. Hoffmann-La Roche Ltd 
206/Protocol WO39608, Version 16
 
 
Table A14‑5 Guidelines for Management of Patients Who Experience 
Specific Adverse Events in Atezo  Chemo  Tira Arm (cont.) 
Event 
Action to Be Taken 
Posterior reversible encephalopathy syndrome 
Posterior reversible 
encephalopathy syndrome, 
any grade 
 Withhold atezolizumab, tiragolumab, and nab-paclitaxel.  
Permanently discontinue gemcitabine. a 
 If event improves, atezolizumab, tiragolumab, and/or 
nab-paclitaxel can be resumed. a 
 If nab-paclitaxel is withheld  56 days after event onset, 
permanently discontinue nab-paclitaxel. a 
 If atezolizumab and tiragolumab are withheld  12 weeks after 
event onset, permanently discontinue atezolizumab and 
tiragolumab. a 
Dermatologic events (other than injection-site reaction) 
Dermatologic event, Grade 1 
 Follow guidelines for atezolizumab and tiragolumab in 
Appendix 2. 
 Continue nab-paclitaxel and gemcitabine. 
Dermatologic event, 
Grade 2 or 3 
 Follow guidelines for atezolizumab and tiragolumab in 
Appendix 2. 
 Continue nab-paclitaxel and gemcitabine with dose reduced by 
one level. b 
 If event persists, permanently discontinue nab-paclitaxel and 
gemcitabine. a 
Atezo  Chemo  Tira  atezolizumab plus chemotherapy (nab-paclitaxel and gemcitabine) plus 
tiragolumab; CRS  cytokine release syndrome; IRR  infusion-related reaction; 
nab-paclitaxel  nanoparticle albuminbound paclitaxel; TSH  thyroid-stimulating hormone. 
a Resumption of treatment may be considered if the investigator believes the patient is likely to 
derive clinical benefit.  The decision to re-challenge patients should be based on investigator's 
assessment of benefitrisk and documented by the investigator (or an appropriate delegate).  
The Medical Monitor is available to advise as needed. 
b The dose of nab-paclitaxel may be reduced by 25 mg/m2 (one dose level) up to two times and 
the dose of gemcitabine may be reduced by 200 mg/m2 (one dose level) up to two times 
(see Section A145.1.6.1 for details). 
 

Appendix 14:  Study Details Specific to Atezo  Chemo  Tira Arm (Cohort 1) 
  
Pancreatic Immunotherapy Combinations—F. Hoffmann-La Roche Ltd 
207/Protocol WO39608, Version 16
 
 
Table A14‑5 Guidelines for Management of Patients Who Experience 
Specific Adverse Events in Atezo  Chemo  Tira Arm (cont.) 
Event 
Action to Be Taken 
Dermatologic events (other than injection-site reaction) (cont.) 
Dermatologic event, Grade 4 
 Follow guidelines for atezolizumab and tiragolumab in 
Appendix 2. 
 Permanently discontinue nab-paclitaxel and gemcitabine. a 
Stevens-Johnson syndrome or 
toxic epidermal necrolysis 
(any grade) 
 Withhold atezolizumab, nab-paclitaxel, gemcitabine, and 
tiragolumab 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, 
nab-paclitaxel, gemcitabine, and tiragolumab. 
Atezo  Chemo  Tira  atezolizumab plus chemotherapy (nab-paclitaxel and gemcitabine) plus 
tiragolumab; CRS  cytokine release syndrome; IRR  infusion-related reaction; 
nab-paclitaxel  nanoparticle albuminbound paclitaxel; TSH  thyroid-stimulating hormone. 
a Resumption of treatment may be considered if the investigator believes the patient is likely to 
derive clinical benefit.  The decision to re-challenge patients should be based on investigator's 
assessment of benefitrisk and documented by the investigator (or an appropriate delegate).  
The Medical Monitor is available to advise as needed. 
b The dose of nab-paclitaxel may be reduced by 25 mg/m2 (one dose level) up to two times and 
the dose of gemcitabine may be reduced by 200 mg/m2 (one dose level) up to two times 
(see Section A145.1.6.1 for details). 
 
 

Appendix 14:  Study Details Specific to Atezo  Chemo  Tira Arm (Cohort 1) 
  
Pancreatic Immunotherapy Combinations—F. Hoffmann-La Roche Ltd 
208/Protocol WO39608, Version 16
 
 
Table A14‑5 Guidelines for Management of Patients Who Experience 
Specific Adverse Events in Atezo  Chemo  Tira Arm (cont.) 
Event 
Action to Be Taken 
Pulmonary events 
 
Pulmonary event, Grade 1  
 Follow guidelines for atezolizumab and tiragolumab in 
Appendix 2. 
 Continue nab-paclitaxel and gemcitabine. 
 If confirmed diagnosis of pneumonitis, permanently discontinue 
nab-paclitaxel and gemcitabine. a 
Pulmonary event, Grade 2 
 Follow guidelines for atezolizumab and tiragolumab in 
Appendix 2. 
 Withhold nab-paclitaxel and gemcitabine. 
 If confirmed diagnosis of pneumonitis, permanently discontinue 
nab-paclitaxel and gemcitabine. a 
 If event resolves to Grade 1 or better  56 days after event 
onset, resume nab-paclitaxel and gemcitabine.  If not, 
permanently discontinue nab-paclitaxel and gemcitabine. a 
 For recurrent events, treat as a Grade 3 or 4 event. 
Pulmonary event, Grade 3 or 4 
 Follow guidelines for atezolizumab and tiragolumab in 
Appendix 2. 
 Permanently discontinue nab-paclitaxel and gemcitabine. a 
Atezo  Chemo  Tira  atezolizumab plus chemotherapy (nab-paclitaxel and gemcitabine) plus 
tiragolumab; CRS  cytokine release syndrome; IRR  infusion-related reaction; 
nab-paclitaxel  nanoparticle albuminbound paclitaxel; TSH  thyroid-stimulating hormone. 
a Resumption of treatment may be considered if the investigator believes the patient is likely to 
derive clinical benefit.  The decision to re-challenge patients should be based on investigator's 
assessment of benefitrisk and documented by the investigator (or an appropriate delegate).  
The Medical Monitor is available to advise as needed. 
b The dose of nab-paclitaxel may be reduced by 25 mg/m2 (one dose level) up to two times and 
the dose of gemcitabine may be reduced by 200 mg/m2 (one dose level) up to two times 
(see Section A145.1.6.1 for details). 

Appendix 14:  Study Details Specific to Atezo  Chemo  Tira Arm (Cohort 1) 
  
Pancreatic Immunotherapy Combinations—F. Hoffmann-La Roche Ltd 
209/Protocol WO39608, Version 16
 
 
Table A14‑5 Guidelines for Management of Patients Who Experience 
Specific Adverse Events in Atezo  Chemo  Tira Arm (cont.) 
Event 
Action to Be Taken 
Hepatic event 
 
Hepatic event, Grade 1 
 Follow guidelines for atezolizumab and tiragolumab in 
Appendix 2. 
 Continue nab-paclitaxel and gemcitabine. 
Hepatic event, Grade 2 
 Follow guidelines for atezolizumab and tiragolumab in 
Appendix 2. 
 Withhold nab-paclitaxel and gemcitabine for hepatic event 
other than Grade 2 elevation of AST, ALT, or ALP. 
 If chemotherapy is withheld and event resolves to Grade 1 or 
better  56 days after event onset, resume nab-paclitaxel and 
gemcitabine.  If not, permanently discontinue nab-paclitaxel 
and gemcitabine. a 
Hepatic event, Grade 3 or 4 
 Follow guidelines for atezolizumab and tiragolumab in 
Appendix 2. 
 Withhold nab-paclitaxel and gemcitabine. 
 If event resolves to Grade 1 or better  56 days after event 
onset, resume nab-paclitaxel and gemcitabine and consider 
reducing the dose by one level. b  If not, permanently 
discontinue nab-paclitaxel and gemcitabine. a 
Atezo  Chemo  Tira  atezolizumab plus chemotherapy (nab-paclitaxel and gemcitabine) plus 
tiragolumab; CRS  cytokine release syndrome; IRR  infusion-related reaction; 
nab-paclitaxel  nanoparticle albuminbound paclitaxel; TSH  thyroid-stimulating hormone. 
a Resumption of treatment may be considered if the investigator believes the patient is likely to 
derive clinical benefit.  The decision to re-challenge patients should be based on investigator's 
assessment of benefitrisk and documented by the investigator (or an appropriate delegate).  
The Medical Monitor is available to advise as needed. 
b The dose of nab-paclitaxel may be reduced by 25 mg/m2 (one dose level) up to two times and 
the dose of gemcitabine may be reduced by 200 mg/m2 (one dose level) up to two times 
(see Section A145.1.6.1 for details). 
 
 

Appendix 14:  Study Details Specific to Atezo  Chemo  Tira Arm (Cohort 1) 
  
Pancreatic Immunotherapy Combinations—F. Hoffmann-La Roche Ltd 
210/Protocol WO39608, Version 16
 
 
Table A14‑5 Guidelines for Management of Patients Who Experience 
Specific Adverse Events in Atezo  Chemo  Tira Arm (cont.) 
Event 
Action to Be Taken 
Endocrine 
 events 
 
Asymptomatic hypothyroidism 
 Follow guidelines for atezolizumab and tiragolumab in 
Appendix 2. 
 Continue nab-paclitaxel and gemcitabine. 
Symptomatic hypothyroidism 
 Follow guidelines for atezolizumab and tiragolumab in 
Appendix 2. 
 Withhold nab-paclitaxel and gemcitabine. 
 When symptoms are controlled and thyroid function is 
improving, resume nab-paclitaxel and gemcitabine. 
Asymptomatic hyperthyroidism 
TSH  0.1 mU/L and  0.5 mU/L: 
 Follow guidelines for atezolizumab and tiragolumab in 
Appendix 2. 
 Continue nab-paclitaxel and gemcitabine. 
TSH  0.1 mU/L: 
 Follow guidelines for symptomatic hyperthyroidism. 
Symptomatic hyperthyroidism 
 Follow guidelines for atezolizumab and tiragolumab in 
Appendix 2. 
 Withhold nab-paclitaxel and gemcitabine. 
 When symptoms are controlled and thyroid function is 
improving, resume nab-paclitaxel and gemcitabine. 
Atezo  Chemo  Tira  atezolizumab plus chemotherapy (nab-paclitaxel and gemcitabine) plus 
tiragolumab; CRS  cytokine release syndrome; IRR  infusion-related reaction; 
nab-paclitaxel  nanoparticle albuminbound paclitaxel; TSH  thyroid-stimulating hormone. 
a Resumption of treatment may be considered if the investigator believes the patient is likely to 
derive clinical benefit.  The decision to re-challenge patients should be based on investigator's 
assessment of benefitrisk and documented by the investigator (or an appropriate delegate).  
The Medical Monitor is available to advise as needed. 
b The dose of nab-paclitaxel may be reduced by 25 mg/m2 (one dose level) up to two times and 
the dose of gemcitabine may be reduced by 200 mg/m2 (one dose level) up to two times 
(see Section A145.1.6.1 for details). 

Appendix 14:  Study Details Specific to Atezo  Chemo  Tira Arm (Cohort 1) 
  
Pancreatic Immunotherapy Combinations—F. Hoffmann-La Roche Ltd 
211/Protocol WO39608, Version 16
 
 
Table A14‑5 Guidelines for Management of Patients Who Experience 
Specific Adverse Events in Atezo  Chemo  Tira Arm (cont.) 
Event 
Action to Be Taken 
Hemolytic-uremic syndrome 
 
Hemolytic-uremic syndrome, 
any grade 
 Permanently discontinue gemcitabine. a  Withhold 
atezolizumab, tiragolumab, and nab-paclitaxel. 
 If event improves, resume atezolizumab, tiragolumab, and nab-
paclitaxel.  If not, permanently discontinue atezolizumab, 
tiragolumab, and nab-paclitaxel. a 
Capillary leak syndrome 
 
Capillary leak syndrome, 
any grade 
 Permanently discontinue gemcitabine. a  Withhold 
atezolizumab, tiragolumab, and nab-paclitaxel. 
 If event improves, resume atezolizumab, tiragolumab, and nab-
paclitaxel.  If not, permanently discontinue atezolizumab, 
tiragolumab, and nab-paclitaxel. a 
Chemotherapy-related toxicities not described above 
Grade 1 or 2 
 Continue atezolizumab, tiragolumab, nab-paclitaxel, and 
gemcitabine. 
Grade 3 
 Continue atezolizumab and tiragolumab.  Withhold 
nab-paclitaxel and gemcitabine. 
 If event resolves to Grade 2 or better  56 days after event 
onset, resume nab-paclitaxel and gemcitabine and consider 
reducing dose by one level. b  If not, permanently discontinue 
nab-paclitaxel and gemcitabine. a 
Grade 4 
 Withhold atezolizumab, tiragolumab, nab-paclitaxel, and 
gemcitabine. 
 If event improves, resume atezolizumab and tiragolumab.  
If not, permanently discontinue atezolizumab and 
tiragolumab. a 
 If event resolves to Grade 2 or better  56 days after event 
onset, resume nab-paclitaxel and gemcitabine and consider 
reducing dose by one level. b  If not, permanently discontinue 
nab-paclitaxel and gemcitabine. a 
Atezo  Chemo  Tira  atezolizumab plus chemotherapy (nab-paclitaxel and gemcitabine) plus 
tiragolumab; CRS  cytokine release syndrome; IRR  infusion-related reaction; 
nab-paclitaxel  nanoparticle albuminbound paclitaxel; TSH  thyroid-stimulating hormone. 
a Resumption of treatment may be considered if the investigator believes the patient is likely to 
derive clinical benefit.  The decision to re-challenge patients should be based on investigator's 
assessment of benefitrisk and documented by the investigator (or an appropriate delegate).  
The Medical Monitor is available to advise as needed. 
b The dose of nab-paclitaxel may be reduced by 25 mg/m2 (one dose level) up to two times and 
the dose of gemcitabine may be reduced by 200 mg/m2 (one dose level) up to two times 
(see Section A145.1.6.1 for details). 

Appendix 14:  Study Details Specific to Atezo  Chemo  Tira Arm (Cohort 1) 
  
Pancreatic Immunotherapy Combinations—F. Hoffmann-La Roche Ltd 
212/Protocol WO39608, Version 16
 
 
Table A14‑5 Guidelines for Management of Patients Who Experience 
Specific Adverse Events in Atezo  Chemo  Tira Arm (cont.) 
Event 
Action to Be Taken 
Atezolizumab and tiragolumab-related toxicities not described above 
Grade 1 or 2 
 Follow guidelines for atezolizumab and tiragolumab in Appendix 2. 
 Continue nab-paclitaxel and gemcitabine. 
Grade 3 or 4 
 Follow guidelines for atezolizumab and tiragolumab in Appendix 2. 
 Withhold nab-paclitaxel and gemcitabine. 
 If event resolves to Grade 2 or better  56 days after event onset, resume 
nab-paclitaxel and gemcitabine and consider reducing dose by one level. b  
If not, permanently discontinue nab-paclitaxel and gemcitabine. a 
Atezo  Chemo  Tira  atezolizumab plus chemotherapy (nab-paclitaxel and gemcitabine) plus 
tiragolumab; CRS  cytokine release syndrome; IRR  infusion-related reaction; 
nab-paclitaxel  nanoparticle albuminbound paclitaxel; TSH  thyroid-stimulating hormone. 
a Resumption of treatment may be considered if the investigator believes the patient is likely to 
derive clinical benefit.  The decision to re-challenge patients should be based on investigator's 
assessment of benefitrisk and documented by the investigator (or an appropriate delegate).  
The Medical Monitor is available to advise as needed. 
b The dose of nab-paclitaxel may be reduced by 25 mg/m2 (one dose level) up to two times and 
the dose of gemcitabine may be reduced by 200 mg/m2 (one dose level) up to two times 
(see Section A145.1.6.1 for details). 
 
A14–5.2 
ADVERSE EVENTS OF SPECIAL INTEREST FOR 
ATEZO  CHEMO  TIRA ARM (IMMEDIATELY REPORTABLE 
TO THE SPONSOR) 
Adverse events of special interest are required to be reported by the investigator to the 
Sponsor immediately (i.e., no more than 24 hours after learning of the event; see 
Section 5.4.2 for reporting instructions).  Adverse events of special interest for the 
Atezo  Chemo  Tira arm are as follows: 
 
 
 
 
 

Appendix 14:  Study Details Specific to Atezo  Chemo  Tira Arm (Cohort 1) 
  
Pancreatic Immunotherapy Combinations—F. Hoffmann-La Roche Ltd 
213/Protocol WO39608, Version 16
 
 
 
Pneumonitis 
 
Colitis 
 
Endocrinopathies:  diabetes mellitus, pancreatitis, adrenal insufficiency, 
hyperthyroidism, and hypophysitis 
 
Hepatitis, including AST or ALT  10  upper limit of normal 
 
Systemic lupus erythematosus 
 
Neurologic disorders:  Guillain-Barré syndrome, myasthenic syndrome or 
myasthenia gravis, and meningoencephalitis 
 
Events suggestive of hypersensitivity, IRRs, cytokine release syndrome, 
influenza-like illness, HLH, and MAS 
 
Nephritis 
 
Ocular toxicities (e.g., uveitis, retinitis) 
 
Myositis 
 
Myopathies, including rhabdomyolysis 
 
Grade  2 cardiac disorders (e.g., atrial fibrillation, myocarditis, pericarditis) 
 
 
 
 
 
Severe cutaneous reactions (e.g., Stevens-Johnson syndrome, dermatitis bullous, 
toxic epidermal necrolysis) 
 
Myelitis 
 
Facial paresis  
 
A14–5.3 
REPORTING REQUIREMENTS FOR PREGNANCIES IN 
ATEZO  CHEMO  TIRA ARM 
A14–5.3.1 
Pregnancies in Female Patients 
Female patients of childbearing potential will be instructed to immediately inform the 
investigator if they become pregnant during the study or within 5 months after the last 
dose of atezolizumab, 90 days after the last dose of tiragolumab, or 6 months after the 
last dose of nab-paclitaxel or gemcitabine.  A 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 

Appendix 14:  Study Details Specific to Atezo  Chemo  Tira Arm (Cohort 1) 
  
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214/Protocol WO39608, Version 16
 
 
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. 
A14–5.3.2 
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 
90 days after the last dose of tiragolumab or 6 months after the last dose of 
nab-paclitaxel or gemcitabine.  A 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.  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 when updated information on the course and outcome of the 
pregnancy 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 
investigator and/or obstetrician. 
A14–5.3.3 
Abortions 
Any 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). 
A14–5.3.4 
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). 
 

Appendix 14:  Study Details Specific to Atezo  Chemo  Tira Arm (Cohort 1) 
  
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215/Protocol WO39608, Version 16
 
 
A14–6 
SCHEDULES OF ACTIVITIES AND SAMPLE COLLECTION FOR ATEZO  CHEMO  TIRA ARM 
Table A14-6 
Schedule of Activities for Atezo  Chemo  Tira Arm (Cohort 1) 
 
Screening  
(see 
Appendix 6) 
Treatment Cycles (28-day cycles) a 
Treat. 
Discon. c 
Follow-Up c 
Cycle 1 b 
Cycles  2 
Day –28 
to –1 
Day 1 
 
Day 8 
(3 days) 
Day 15 
( 3 days) 
Day 1 
( 3 days) 
Day 8 
( 3 days) 
Day 15 
( 3 days) 
Every 
3 Months 
Molecular profile of pancreatic cancer 
(if available) 
See 
Appendix 6 
Whenever updated information becomes available  
 
Vital signs d 
x 
x  
x 
x 
x  
x 
x 
 
Weight 
x e 
x e 
x e 
x e 
x e 
x e 
x 
 
Complete physical examination f 
 
 
 
 
 
 
x 
 
Limited physical examination g 
x e 
x e 
x e 
x e 
x e 
x e 
 
 
ECOG Performance Status 
x e 
 
 
x e 
 
 
x 
 
ECG h 
Perform as clinically indicated e 
 
 
Hematology i 
x j, k 
x j 
x j 
x j 
x j 
x j 
x 
 
Chemistry l 
x j, k 
x j 
x j 
x j 
x j 
x j 
x 
 
Coagulation (INR and aPTT) 
x j, k 
Perform as clinically indicated 
x 
 
TSH, free T3 (or total T3), free T4 m 
x j, k, m 
x 
 
C-reactive protein 
x j, k 
 
 
x j 
 
 
 
 
CA19-9 
x j 
 
 
x j 
 
 
x 
 
Pregnancy test o 
x j, k 
 
 
x j 
 
 
x 
x o 

Appendix 14:  Study Details Specific to Atezo  Chemo  Tira Arm (Cohort 1) 
  
Table A14-6 
Schedule of Activities for Atezo  Chemo  Tira Arm (Cohort 1) (cont.) 
Pancreatic Immunotherapy Combinations—F. Hoffmann-La Roche Ltd 
216/Protocol WO39608, Version 16
 
 
 
Screening  
(see 
Appendix 6) 
Treatment Cycles (28-day cycles) a 
Treat. 
Discon. c 
Follow-Up c 
Cycle 1 b 
Cycles  2 
Day –28 
to –1 
Day 1 
 
Day 8 
(3 days) 
Day 15 
( 3 days) 
Day 1 
( 3 days) 
Day 8 
( 3 days) 
Day 15 
( 3 days) 
Every 
3 Months 
Urinalysis p 
See 
Appendix 6 
Perform as clinically indicated 
 
 
Tumor response assessments 
x v, w 
Concomitant medications x 
x 
x 
x 
x 
x 
x 
x 
 
Adverse events y 
x 
x 
x 
x 
x 
x 
x y 
x y 
Atezolizumab administration z, aa 
x 
 
x 
x 
 
x 
 
 
Tiragolumab administration aa, bb 
x 
 
x 
x 
 
x 
 
 
Nab-paclitaxel and gemcitabine 
administration aa, cc 
x 
x 
x 
x 
x 
x 
 
 
Survival follow-up and anti-cancer 
treatment 
 
 
 
 
 
 
 
x dd 

Appendix 14:  Study Details Specific to Atezo  Chemo  Tira Arm (Cohort 1) 
  
Table A14-6 
Schedule of Activities for Atezo  Chemo  Tira Arm (Cohort 1) (cont.) 
Pancreatic Immunotherapy Combinations—F. Hoffmann-La Roche Ltd 
217/Protocol WO39608, Version 16
 
 
ADA  anti-drug antibody; Atezo  Chemo  Tira  atezolizumab plus chemotherapy (nab-paclitaxel and gemcitabine) plus tiragolumab ; CIT  cancer 
immunotherapy; CT  computed tomography; Discon.  discontinuation; ECOG  Eastern Cooperative Oncology Group; eCRF  electronic Case 
Report Form; 
; nab-paclitaxel  nanoparticle albuminbound paclitaxel; PK  pharmacokinetic; RBR  Research Biosample 
Repository; RECIST v1.1  Response Evaluation Criteria in Solid Tumors, Version 1.1; T3  triiodothyronine; T4  thyroxine; Treat.  treatment; 
TSH  thyroid-stimulating hormone. 
Note:  On treatment days, all assessments should be performed prior to dosing, unless otherwise specified. 
a If a visit is precluded because of a holiday, vacation, or other circumstance, it can occur outside of the specified window. 
b It is recommended that treatment be initiated no later than 7 days after randomization. 
c Patients will return to the clinic for a treatment discontinuation visit not more than 30 days after the last dose of study treatment.  The visit at 
which disease progression is confirmed may be used as the treatment discontinuation visit.  Patients will then undergo follow-up assessments. 
d Vital signs include respiratory rate, pulse rate, and systolic and diastolic blood pressure while the patient is in a seated position, pulse oximetry, 
and temperature.  Record new or worsened clinically significant abnormalities on the Adverse Event eCRF.  For the first infusion of 
atezolizumab, vital signs should be measured within 60 minutes prior to the infusion and, if clinically indicated, every 15 ( 5) minutes during and 
30 ( 10) minutes after the infusion.  For subsequent infusions, vital signs should be measured within 60 minutes prior to the infusion and, if 
clinically indicated or if symptoms occurred during the previous infusion, during and 30 ( 10) minutes after the infusion. For the first infusion of 
tiragolumab, vital signs should be measured within
minutes prior to the infusion and 
 after 
the infusion.  For subsequent infusions of tiragolumab, vital signs should be measured within 
 minutes prior to the infusion and, if clinically 
indicated or if symptoms occurred during the previous infusion, during and 
minutes after the infusion. 
e Assessment may be performed within 24 hours prior to dosing during the treatment period. 
f Complete physical examination includes evaluation of the head, eyes, ears, nose, and throat, and the cardiovascular, dermatologic, 
musculoskeletal, respiratory, gastrointestinal, genitourinary, and neurologic systems.  Record new or worsened clinically significant 
abnormalities on the Adverse Event eCRF. 
g Perform a limited, symptom-directed examination at specified timepoints and as clinically indicated at other timepoints.  Record new or worsened 
clinically significant abnormalities on the Adverse Event eCRF. 
h It is recommended that patients be resting in a supine position for at least 10 minutes prior to ECG recording. 
i Hematology includes WBC count, RBC count, hemoglobin, hematocrit, platelet count, and differential count (neutrophils, eosinophils, basophils, 
monocytes, lymphocytes, other cells). 
j Laboratory tests must be performed within 96 hours prior to dosing during the treatment period. 
k If screening laboratory assessments were performed within 96 hours prior to Day 1 of Cycle 1, they do not have to be repeated. 

Appendix 14:  Study Details Specific to Atezo  Chemo  Tira Arm (Cohort 1) 
  
Table A14-6 
Schedule of Activities for Atezo  Chemo  Tira Arm (Cohort 1) (cont.) 
Pancreatic Immunotherapy Combinations—F. Hoffmann-La Roche Ltd 
218/Protocol WO39608, Version 16
 
 
l Chemistry panel (serum or plasma) includes bicarbonate or total carbon dioxide (if considered standard of care for the region), sodium, 
potassium, magnesium, chloride, glucose, BUN or urea, creatinine, total protein, albumin, phosphorus, calcium, total bilirubin, ALP, ALT, and 
AST. 
m TSH, free T3 (or total T3 for sites where free T3 is not performed), and free T4 will be assessed at screening and on Day 1 of Cycle 1 and every 
third cycle thereafter (i.e., Cycles 4, 7, 10, etc.). 
n 
o All women of childbearing potential will have urine or serum pregnancy tests performed at specified visits during treatment and at 3 months and 
6 months after the last dose of study treatment.  If a urine pregnancy test is positive, it must be confirmed by a serum pregnancy test. 
p Includes pH, specific gravity, glucose, protein, ketones, and blood; dipstick permitted. 
q Autoantibody analysis includes anti-nuclear antibody, antidouble-stranded DNA, circulating anti-neutrophil cytoplasmic antibody, and 
perinuclear anti-neutrophil cytoplasmic antibody. 
r Autoantibody analysis should be repeated for patients who develop signs or symptoms suggestive of autoimmune disease (e.g., lupus 
erythematosus). 
s Not applicable for a site that has not been granted approval for RBR sampling.  Performed only for patients at participating sites who have 
provided written informed consent to participate. 
t 
u 
 

Appendix 14:  Study Details Specific to Atezo  Chemo  Tira Arm (Cohort 1) 
  
Table A14-6 
Schedule of Activities for Atezo  Chemo  Tira Arm (Cohort 1) (cont.) 
Pancreatic Immunotherapy Combinations—F. Hoffmann-La Roche Ltd 
219/Protocol WO39608, Version 16
 
 
v Patients will undergo tumor assessments at baseline, every 6 weeks ( 1 week) for the first 48 weeks following treatment initiation, and every 
12 weeks ( 2 weeks) thereafter, regardless of dose delays, until radiographic disease progression according to RECIST v1.1, except in the case 
of patients who continue treatment after radiographic disease progression; such patients will undergo tumor assessments every 6 weeks 
( 1 week) until loss of clinical benefit as determined by the investigator (see Section 3.1.2 for details).  Thus, tumor assessments are to 
continue according to schedule in patients who discontinue treatment for reasons other than disease progression, even if they start new 
nonprotocol-specified anti-cancer therapy. 
w All measurable and/or evaluable lesions identified at baseline should be re-assessed at each subsequent tumor evaluations according to the 
tumor assessment schedule described above (see footnote “v”).  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).  Refer to Section 4.5.5 for further details on 
tumor assessments. 
x Includes 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 study treatment from 10 days prior to initiation of study treatment until the treatment 
discontinuation visit. 
y 
After this period, all deaths, regardless of cause, should be reported.  In addition, the Sponsor should be notified if the investigator becomes 
aware of any serious adverse event that is believed to be related to prior exposure to study treatment (see Section 5.6).  The investigator should 
follow each adverse event until the event has resolved to baseline grade or better, the event is assessed as stable by the investigator, 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. 
z Atezolizumab will be administered by IV infusion at a fixed dose of 840 mg on Days 1 and 15 of each 28-day cycle.  The initial dose of 
atezolizumab will be delivered over 60 ( 15) minutes.  Subsequent infusions will be delivered over 30 ( 10) minutes if the previous infusion was 
tolerated without infusion-associated adverse events, or 60 ( 15) minutes if the patient experienced an infusion-associated adverse event with 
the previous infusion.  Refer to Section A144.1.2.1, Table A14-2, for details on atezolizumab infusions (including measurement of vital signs). 
aa Treatment will continue until unacceptable toxicity or loss of clinical benefit as determined by the investigator (see Section 3.1.2 for details). 
 
 
 
 

Appendix 14:  Study Details Specific to Atezo  Chemo  Tira Arm (Cohort 1) 
  
Table A14-6 
Schedule of Activities for Atezo  Chemo  Tira Arm (Cohort 1) (cont.) 
Pancreatic Immunotherapy Combinations—F. Hoffmann-La Roche Ltd 
220/Protocol WO39608, Version 16
 
 
bb Tiragolumab will be administered by IV infusion at a fixed dose of 420 mg on Days 1 and 15 of each 28-day cycle.  The initial dose of 
tiragolumab will be delivered over
 minutes.  Subsequent infusions will be delivered over
minutes if the previous infusion was 
tolerated without infusion-associated adverse events, or
minutes if the patient experienced an infusion-associated adverse event with 
the previous infusion.  On Day 1 of Cycle 1, tiragolumab will be administered 
minutes after completion of the atezolizumab infusion.  
The interval between subsequent infusions will be 
minutes if the previous atezolizumab infusion was tolerated without an IRR or 
minutes if 
the patient experienced an IRR with the previous atezolizumab infusion.  Refer to Section A144.1.2.2, Table A14-3, for details on tiragolumab 
infusions (including measurement of vital signs and patient observation after infusions). 
cc On Days 1, 8, and 15, patients will receive nab-paclitaxel 125 mg/m2, administered by IV infusion over 30 ( 5) minutes, followed by gemcitabine 
1000 mg/m2, administered by IV infusion over 30 ( 5) minutes.  On Day 1 of Cycle 1, nab-paclitaxel will be administered 60 minutes after 
completion of the tiragolumab infusion to allow for observation after tiragolumab administration.  The interval between subsequent infusions will 
be 30 minutes if the previous tiragolumab infusion was tolerated without an IRR or 60 minutes if the patient experienced an IRR with the previous 
tiragolumab infusion. 
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 only.  For an experimental arm in which all patients discontinued 
treatment and passed the safety follow-up window, as well as approximately 80% of patients discontinued the study, the Sponsor may conclude 
the arm (the remaining approximately 20% of patients will be discontinued from the study). 

Appendix 14:  Study Details Specific to Atezo  Chemo  Tira Arm (Cohort 1) 
  
Pancreatic Immunotherapy Combinations—F. Hoffmann-La Roche Ltd 
221/Protocol WO39608, Version 16
 
 
Table A14-7 Schedule of Pharmacokinetic, Immunogenicity, and 
Biomarker Samples for Atezo  Chemo  Tira Arm (Cohort 1):  
Preliminary and Expansion Phases 
ADA  anti-drug antibody; Atezo  Chemo  Tira  atezolizumab plus chemotherapy 
(nab-paclitaxel and gemcitabine) plus tiragolumab; nab-paclitaxel  nanoparticle 
albuminbound paclitaxel; PBMC  peripheral blood mononuclear cell; 
PK  pharmacokinetic. 
Note:  On the basis of emerging safety or efficacy data, the number of PK and ADA 
samples may be reduced or sample collection may cease altogether.  Additionally, collected 
samples may not be analyzed if not warranted.  On the basis of emerging biomarker data, 
the number of biomarker samples may be reduced or sample collection may cease 
altogether. 

Appendix 14:  Study Details Specific to Atezo  Chemo  Tira Arm (Cohort 1) 
  
Pancreatic Immunotherapy Combinations—F. Hoffmann-La Roche Ltd 
222/Protocol WO39608, Version 16
 
 
Table A14-7 Schedule of Pharmacokinetic, Immunogenicity, and 
Biomarker Samples for Atezo  Chemo  Tira Arm (Cohort 1):  
Preliminary and Expansion Phases (cont.)  
ADA  anti-drug antibody; Atezo  Chemo  Tira  atezolizumab plus chemotherapy 
(nab-paclitaxel and gemcitabine) plus tiragolumab; nab-paclitaxel  nanoparticle 
albuminbound paclitaxel; PBMC  peripheral blood mononuclear cell; 
PK  pharmacokinetic. 
Note:  On the basis of emerging safety or efficacy data, the number of PK and ADA 
samples may be reduced or sample collection may cease altogether.  Additionally, collected 
samples may not be analyzed if not warranted.  On the basis of emerging biomarker data, 
the number of biomarker samples may be reduced or sample collection may cease 
altogether. 
 

Appendix 14:  Study Details Specific to Atezo  Chemo  Tira Arm (Cohort 1) 
  
Pancreatic Immunotherapy Combinations—F. Hoffmann-La Roche Ltd 
223/Protocol WO39608, Version 16
 
 
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Yang Z. Expression and function of tigit in B-cell non-hodgkin lymphoma. Blood 
2016;128:4138. 
Yoshida J, Ishikawa T, Doi T, et al. Clinical significance of soluble forms of immune 
checkpoint molecules in advanced esophageal cancer. Med Oncol 2019;36(7):60. 
Yu X, Harden K, Gonzalez LC, et al. The surface protein TIGIT suppresses T cell 
activation by promoting the generation of mature immunoregulatory dendritic cells. 
Nat Immunol 2009;10:4857. 

 
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Appendix 15  
Study Details Specific to Atezo  Chemo  Bev Arm (Cohort 1) 
TABLE OF CONTENTS 
A15–1 
Background on Atezo  Chemo  Bev Arm ............................. 230 
A15–1.1 
Background on Atezolizumab ................................................ 230 
A15–1.2 
Background on Nab‑Paclitaxel and Gemcitabine in 
Pancreatic Cancer ................................................................. 230 
A15–1.3 
Background on Bevacizumab ................................................ 231 
A15–2 
Rationale for Atezo  Chemo  Bev Arm ................................. 231 
A15–2.1 
The PD-L1 Pathway ............................................................... 231 
A15–2.2 
Anti-VEGF Cancer Treatment ................................................ 232 
A15–2.3 
Combined Inhibition of the PD-L1 and VEGF Pathways as 
Potential anti-Cancer Therapy ............................................... 233 
A15–2.4 
Clinical Studies of Atezolizumab In Combination with 
Bevacizumab ......................................................................... 234 
A15–2.5 
Clinical Study of Atezolizumab in Combination with Nab-
Paclitaxel and Gemcitabine ................................................... 235 
A15–2.6 
Benefit–Risk Assessment ...................................................... 235 
A15–3 
Rationale for Dose and Schedule for Atezo  Chemo  Bev 
Arm ........................................................................................ 236 
A15–3.1 
Rationale for Atezolizumab Dose and Schedule .................... 236 
A15–3.2 
Rationale for Bevacizumab Dose and Schedule .................... 236 
A15–4 
Materials and Methods Specific to Atezo  Chemo  Bev 
Arm ........................................................................................ 237 
A15–4.1 
Treatment in Atezo  Chemo  Bev Arm ................................. 237 
A15–4.1.1 
Formulation, Packaging, and Handling .................................. 237 
A15–4.1.1.1 Atezolizumab ......................................................................... 237 
A15–4.1.1.2 Bevacizumab ......................................................................... 237 
A15–4.1.1.3 Nab-Paclitaxel ........................................................................ 237 
A15–4.1.1.4 Gemcitabine ........................................................................... 237 
A15–4.1.2 
Dosage, Administration, and Compliance .............................. 237 
A15–4.1.2.1 Atezolizumab ......................................................................... 238 
A15–4.1.2.2 Bevacizumab ......................................................................... 239 
A15–4.1.2.3 Nab-Paclitaxel and Gemcitabine ............................................ 240 
A15–4.2 
Concomitant Therapy for Atezo  Chemo  Bev Arm .............. 241 

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A15–4.2.1 
Permitted Therapy for Atezo  Chemo  Bev Arm ................... 241 
A15–4.2.2 
Cautionary Therapy for Atezo  Chemo  Bev Arm ................. 243 
A15–4.2.2.1 Corticosteroids, Immunosuppressive Medications, and 
Tumor Necrosis Factor‑ Inhibitors ....................................... 243 
A15–4.2.2.2 Medications Given with Precaution due to Effects Related 
to Cytochrome P450 Enzymes .............................................. 243 
A15–4.2.2.3 Herbal Therapies ................................................................... 243 
A15–4.2.2.4 Bisphosphonates ................................................................... 244 
A15–4.2.3 
Prohibited Therapy for Atezo  Chemo  Bev Arm .................. 244 
A15–4.3 
contraception Requirements for Atezo  Chemo  Bev Arm .... 244 
A15–5 
Assessment of Safety for Atezo  Chemo  Bev Arm .............. 245 
A15–5.1 
Safety Plan for Atezo  Chemo  Bev Arm .............................. 245 
A15–5.1.1 
Risks Associated with Atezolizumab ...................................... 246 
A15–5.1.2 
Risks Associated with Nab-Paclitaxel .................................... 246 
A15–5.1.3 
Risks Associated with Gemcitabine ....................................... 246 
A15–5.1.4 
Risks Associated with Bevacizumab ...................................... 247 
A15–5.1.4.1 Perforations and Fistulae ....................................................... 247 
A15–5.1.4.2 Hemorrhage ........................................................................... 248 
A15–5.1.4.3 Hypertension .......................................................................... 248 
A15–5.1.4.4 Posterior Reversible Encephalopathy Syndrome ................... 248 
A15–5.1.4.5 Thromboembolism ................................................................. 249 
A15–5.1.4.6 Congestive Heart Failure ....................................................... 249 
A15–5.1.4.7 Other Cardiac Disorders ........................................................ 250 
A15–5.1.4.8 Neutropenia and Infection ...................................................... 250 
A15–5.1.4.9 Wound-Healing Complications ............................................... 250 
A15–5.1.4.10 Proteinuria ............................................................................. 250 
A15–5.1.4.11 Hypersensitivity or Infusion-Related Reactions...................... 251 
A15–5.1.4.12 Osteonecrosis of the Jaw ...................................................... 251 
A15–5.1.4.13 Ovarian Failure ...................................................................... 251 
A15–5.1.4.14 Pulmonary Hypertension ....................................................... 251 
A15–5.1.5 
Risks Associated with Combination Use of Atezolizumab, 
Nab‑Paclitaxel, Gemcitabine, and Bevacizumab ................... 251 

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A15–5.1.6 
Management of Patients Who Experience Specific 
Adverse Events in Atezo  Chemo  Bev Arm ......................... 252 
A15–5.1.6.1 Dose Modifications ................................................................ 252 
A15–5.1.6.2 Treatment Interruption for Toxicities ...................................... 252 
A15–5.1.6.3 Management Guidelines for Adverse Events ......................... 253 
A15–5.2 
Adverse Events of Special Interest for 
Atezo  Chemo  Bev Arm (Immediately Reportable 
to the Sponsor) ...................................................................... 278 
A15–5.3 
Reporting Requirements for Pregnancies in 
Atezo  Chemo  Bev Arm ...................................................... 280 
A15–5.3.1 
Pregnancies in Female Patients ............................................ 280 
A15–5.3.2 
Pregnancies in Female Partners of Male Patients ................. 280 
A15–5.3.3 
Abortions................................................................................ 281 
A15–5.3.4 
Congenital Anomalies/Birth Defects ...................................... 281 
A15–6 
Schedules of Activities and Sample Collection for 
Atezo  Chemo  Bev Arm ...................................................... 282 
 

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A15–1 
BACKGROUND ON ATEZO  CHEMO  BEV ARM 
A15–1.1 
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 
and quality of tumor-specific T-cell responses, resulting in improved anti-tumor activity 
(Fehrenbacher et al. 2016; Rosenberg et al. 2016).  Atezolizumab has minimal binding 
to Fc receptors, thus eliminating detectable Fc-effector function and associated 
antibody-mediated clearance of activated effector T cells. 
Atezolizumab shows anti-tumor activity in both nonclinical models and cancer patients 
and is being investigated as a potential therapy in a wide variety of malignancies.  
Atezolizumab is being studied as a single agent in the advanced cancer and adjuvant 
therapy settings, as well as in combination with chemotherapy, targeted therapy, and 
cancer immunotherapy. 
Atezolizumab has been generally well tolerated.  Adverse events with potentially 
immune-mediated causes consistent with an immunotherapeutic agent, including rash, 
influenza-like illness, endocrinopathies, hepatitis or transaminitis, pneumonitis, colitis, 
and myasthenia gravis, have been observed (see Atezolizumab Investigator's Brochure 
for detailed safety results).  To date, these events have been manageable with 
treatment. 
Atezolizumab is approved for the treatment of urothelial carcinoma, nonsmall cell lung 
cancer, small-cell lung cancer, triple-negative breast cancer, hepatocellular carcinoma, 
melanoma, and alveolar soft part sarcoma. 
Refer to the Atezolizumab Investigator's Brochure for details on nonclinical and 
clinical studies. 
A15–1.2 
BACKGROUND ON NAB‑PACLITAXEL AND GEMCITABINE IN 
PANCREATIC CANCER  
Nanoparticle albuminbound paclitaxel (nab-paclitaxel) is a microtubule inhibitor that is 
approved in combination with gemcitabine for the first-line treatment of patients with 
metastatic adenocarcinoma of the pancreas.  Gemcitabine is a nucleoside metabolic 
inhibitor that is approved for the treatment of locally advanced or metastatic 
adenocarcinoma of the pancreas. 
The combination of nab-paclitaxel and gemcitabine has been established as the 
standard-of-care chemotherapy regimen for metastatic pancreatic cancer and is 

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classified as Category 1 (intervention is appropriate based upon high-level evidence) by 
the National Comprehensive Cancer Network for this indication (Von Hoff et al. 2013; 
NCCN 2017). 
A15–1.3 
BACKGROUND ON BEVACIZUMAB  
Vascular endothelial growth factor (VEGF) is the most important pro-angiogenic factor 
and a key regulator of physiological angiogenesis.  It is also implicated in pathological 
angiogenesis such as that associated with tumor growth.  Increased levels of VEGF 
have been found in many tumors examined to date, including pancreatic cancer tumors 
where overexpression is associated with a poorer prognosis (Seo et al. 2000; 
Kuwahara et al. 2003; Costache et al. 2015).  
Bevacizumab is a recombinant humanized monoclonal antibody that recognizes all 
isoforms of VEGF.  It may exert a direct anti-angiogenic effect by binding to and clearing 
VEGF from the tumor microenvironment.  Additional anti-tumor activity may be on tumor 
vasculature, interstitial pressure, and blood vessel permeability, providing for enhanced 
chemotherapy delivery to tumor cells (Jain 2001). 
Bevacizumab is approved worldwide for the first-line and second-line treatment of 
metastatic colorectal cancer (mCRC), first-line treatment of advanced NSCLC, 
metastatic breast cancer, advanced renal cell carcinoma, and ovarian cancer, and 
treatment of recurrent glioblastoma.  Bevacizumab is currently being tested in 
combination with atezolizumab in Phase I and Phase II clinical trials.  Bevacizumab 
has been generally well tolerated, and adverse events have been manageable. 
Refer to the Bevacizumab Investigator’s Brochure for details on nonclinical and 
clinical studies. 
A15–2 
RATIONALE FOR ATEZO  CHEMO  BEV ARM 
A15–2.1 
THE PD-L1 PATHWAY 
Encouraging clinical data emerging in the field of tumor immunotherapy have 
demonstrated that therapies focused on enhancing T-cell responses against cancer can 
result in a significant survival benefit in patients with advanced malignancies 
(Hodi et al. 2010; Kantoff et al. 2010; Chen et al. 2012). 
The PD-L1 pathway serves as an immune checkpoint to temporarily dampen immune 
responses in states of chronic antigen stimulation, such as chronic infection or cancer.  
PD-L1 is an extracellular protein that downregulates immune responses through binding 
to its two receptors, PD-1 and B7-1.  PD-1 is an inhibitory receptor expressed on T cells 
following T-cell activation, and expression is sustained in states of chronic stimulation 
(Blank et al. 2005; Keir et al. 2008).  B7-1 is a molecule expressed on 

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antigen-presenting cells and activated T cells.  Binding of PD-L1 to PD-1 and B7-1 
inhibits T-cell proliferation and activation, cytokine production, and cytolytic activity, 
leading to the functional inactivation or exhaustion of T cells (Butte et al. 2007; 
Yang et al. 2011).  Overexpression of PD-L1 on tumor cells has been reported to impede 
anti-tumor immunity, resulting in immune evasion (Blank and Mackensen 2007).  
Therefore, interruption of the PD-L1 pathway represents an attractive strategy for 
restoring tumor-specific T-cell immunity. 
Targeting the PD-L1 pathway with atezolizumab has demonstrated activity in patients 
with advanced malignancies who have failed standard-of-care therapies.  Objective 
responses have been observed across a broad range of malignancies, including 
NSCLC, urothelial carcinoma, renal cell carcinoma, melanoma, colorectal cancer, head 
and neck cancer, gastric cancer, breast cancer, and sarcoma (see Atezolizumab 
Investigator's Brochure for detailed efficacy results).   
It has been shown that in pancreatic cancer tissues, both PD-L1 and PD-L2 are 
expressed and that tumor PD-L1, but not PD-L2, expression significantly correlates with 
postoperative prognosis.  Moreover, PD-L1 expression is inversely correlated with 
tumor-infiltrating lymphocytes, particularly CD8 T cells (Nomi et al. 2007).  However, no 
clinically significant response to single-agent checkpoint inhibitors has been observed in 
patients with pancreatic cancer (Royal et al. 2010; Brahmer et al. 2012). 
A15–2.2 
ANTI-VEGF CANCER TREATMENT 
VEGF, a diffusible glycoprotein produced by normal and neoplastic cells, is an important 
regulator of physiological and pathological angiogenesis.  Increased levels of VEGF 
expression have been found in most human malignancies examined to date, including 
tumors of the lung, breast, thyroid, gastrointestinal (GI) tract, kidney, bladder, ovary, 
cervix, and pancreas, as well as angiosarcomas and glioblastomas (Ferrara and 
Davis-Smyth 1997; von Marschall et al. 2000; Luo et al. 2001).  Increased VEGF serum 
levels have been correlated with poor survival.  Targeting the VEGF pathway with 
bevacizumab has demonstrated activity in patients across a broad range of advanced 
malignancies when used in combination with chemotherapy. 
The role of bevacizumab in pancreatic cancer remains controversial.  An earlier 
single-arm Phase II study (NCI-2675) indicated that the addition of bevacizumab to 
gemcitabine chemotherapy may be beneficial in patients with advanced pancreatic 
cancer.  However, the National Cancer Institutesponsored Phase III trial CALGB80303 
could not confirm the Phase II findings (see Bevacizumab Investigator's Brochure for 
detailed efficacy results).  In a Phase II study of bevacizumab combined with 
gemcitabine followed by infusional 5-fluorouracil (5-FU) in patients with advanced 
pancreatic cancer, a statistically significant benefit was demonstrated for 

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progression-free survival (PFS), the primary endpoint (Martin et al. 2012).  In a Phase III 
study of bevacizumab combined with gemcitabine and erlotinib in patients with 
metastatic pancreatic adenocarcinoma (Study BO17706), a statistically significant 
benefit was not demonstrated for overall survival, the primary endpoint.  However, PFS 
was significantly longer in the bevacizumab group compared with the placebo group 
(see Bevacizumab Investigator's Brochure for detailed efficacy results). 
A15–2.3 
COMBINED INHIBITION OF THE PD-L1 AND VEGF PATHWAYS 
AS POTENTIAL ANTI-CANCER THERAPY 
A strong scientific rationale and emerging clinical data suggest that the combined 
PD-L1/VEGF blockade may be clinically beneficial in a number of tumor types. 
T-cell activation results in expression of PD-L1 as an adaptive response of tumor cells to 
interferon- that is released as a consequence of the immune response within the tumor 
microenvironment (Kim et al. 2005; Lee et al. 2005; Wilke et al. 2011).  The result is that 
effector T cells can be suppressed by PD-L1 produced by the tumor or tumor-associated 
macrophages.  This negative feedback loop can be nullified by blocking PD-L1 from 
binding its receptor through atezolizumab.  Moreover, on the basis of the experimental 
data, blockade of PD-L1 or PD-1 is not expected to stimulate de novo immune 
responses but rather to enhance ongoing immune responses against tumor antigens 
because this axis is mostly implicated in the effector phase and not during priming of the 
cellular immune response (Merelli et al. 2014). 
Overexpression of VEGF and its receptors occurs in  90% of pancreatic cancer cases 
and correlates with vascular density, tumor invasiveness and metastasis, and poor 
prognosis (Itakura et al. 1997; Seo et al. 2000; Kuwahara et al. 2003).  VEGF-A is a 
pro-angiogenic molecule produced by endothelium, tumors, and tumor-associated 
macrophages.  The VEGF pathway also plays a crucial role in exerting and 
maintaining an immunosuppressive tumor microenvironment through several 
mechanisms.  For example, VEGF-A inhibits the maturation of dendritic cells (DCs) 
(Gabrilovich et al. 1996), promotes the expression of inhibitory immune checkpoint 
molecules on intratumoral CD8 T-cells that express VEGF-R2 (Voron et al. 2015), and 
induces Fas ligand (FasL) expression on endothelial cells, which acquired the ability to 
kill effector CD8 T cells, but not regulatory T cells (Motz et al. 2014).  Anti-VEGF agents 
such as bevacizumab are well known to promote the normalization of tumor vasculature 
and thereby increase access of therapeutic agents (Jain 2005).  Furthermore, 
bevacizumab can restore and/or maintain the antigen-presentation capacity of DCs, 
leading to enhanced T-cell infiltration in tumors (Oelkrug and Ramage 2014; Wallin et al. 
2016).  Administration of antiVEGF-A has been shown to attenuate tumor endothelial 
FasL expression and produce a significant increase in the influx of tumor-rejecting CD8 
T cells, leading to tumor growth suppression (Motz et al. 2014).  In addition, anti-VEGF 

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therapies can reduce the frequency of myeloid-derived suppressor cells, decrease 
production of suppressive cytokines, and lower expression of inhibitory checkpoints on 
CD8 T cells in tumors (Roland et al. 2009; Voron et al. 2015).  The immunomodulatory 
effect of bevacizumab is expected to increase CD8 T-cell recruitment and relieve 
intratumoral immunosuppression, thereby boosting the effects of atezolizumab. 
There is precedent for a beneficial effect of anti-angiogenesis in the context of 
immunotherapy.  In a murine melanoma model, VEGF blockade was shown to synergize 
with adoptive immunotherapy, as evidenced by improved anti-tumor activity, prolonged 
survival, and increased trafficking of T cells into tumors (Shrimali et al. 2010).  High 
pretreatment serum VEGF was associated with poor survival following ipilimumab 
(anti-CTLA-4) monotherapy (Yuan et al. 2014), and synergistic effects were observed in 
a clinical study combining ipilimumab and bevacizumab, as shown by increased T-cell 
frequency in post-treatment biopsies, as well as marked increases in central memory 
cells in peripheral blood in the majority of patients (Hodi et al. 2014). 
The above-described data suggest that combined treatment with atezolizumab and 
bevacizumab may augment the anti-tumor immune response, resulting in improved and 
more durable clinical benefit.  
A15–2.4 
CLINICAL STUDIES OF ATEZOLIZUMAB IN COMBINATION 
WITH BEVACIZUMAB 
Study GP28328 is an ongoing, Phase Ib, open-label, multicenter study combining 
atezolizumab (1200 mg Q3W) with bevacizumab (15 mg/kg Q3W) in patients with 
advanced solid tumors, with expansion arms for patients with renal cell carcinoma, 
mCRC, gastric cancer, and ovarian cancer.  Safety findings have been consistent with 
the known single-agent safety profiles for each drug; no new safety signals have been 
identified.  The regimen has been well tolerated, and adverse events have been 
manageable.  Another Phase Ib, open-label, multicenter study (GO30140) is 
investigating a similar dose of atezolizumab combined with bevacizumab in patients with 
hepatocellular carcinoma. 
Study WO29637 is an ongoing, Phase III, randomized study in which atezolizumab plus 
bevacizumab is compared with sunitinib in patients with untreated metastatic renal cell 
carcinoma.  As of 29 September 2017, the data cutoff date, 915 patients (454 receiving 
atezolizumab plus bevacizumab and 461 receiving sunitinib) had been enrolled and 
were evaluable for efficacy.  The objective response rate was 37% in the atezolizumab 
plus bevacizumab arm and 33% in the sunitinib arm.  Median PFS based on investigator 
assessment was 11.2 months in the atezolizumab plus bevacizumab arm and 
8.4 months in the sunitinib arm, with a hazard ratio of 0.83 (95% CI 0.70, 0.97).  Patients 
in the atezolizumab plus bevacizumab arm had fewer high-grade treatment-related 

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adverse events and delayed symptom interference with daily life compared with patients 
in the sunitinib arm. 
Study GO29436 is an ongoing, Phase III, randomized study of bevacizumab plus 
chemotherapy (carboplatin and paclitaxel) with or without atezolizumab in patients with 
untreated non-squamous metastatic NSCLC.  As of 15 September 2017, the data cutoff 
date, 356 patients had been enrolled in the bevacizumab plus chemotherapy plus 
atezolizumab (Bev  Chemo  Atezo) arm and 336 had been enrolled in the bevacizumab 
plus chemotherapy (Bev  Chemo) arm.  In the primary analysis population, the objective 
response rate and median duration of response were 64% and 9.0 months, respectively, 
for the Bev  Chemo  Atezo arm, compared with 48% and 5.7 months, respectively, for 
the Bev  Chemo arm.  Median PFS was 8.3 months for the Bev  Chemo  Atezo arm 
and 6.8 months for the Bev  Chemo arm, with a hazard ratio of 0.62 (p  0.0001).  
The combination of bevacizumab, carboplatin, paclitaxel, and atezolizumab appears to 
be well tolerated. 
Detailed clinical study results for atezolizumab and bevacizumab can be found in the 
Atezolizumab Investigator's Brochure and the Bevacizumab Investigator's Brochure, 
respectively. 
A15–2.5 
CLINICAL STUDY OF ATEZOLIZUMAB IN COMBINATION WITH 
NAB-PACLITAXEL AND GEMCITABINE 
An ongoing Phase I study (GO30140) includes an arm that is evaluating atezolizumab in 
combination with nab-paclitaxel and gemcitabine in treatment-naive patients with 
metastatic pancreatic cancer. 
Adverse events observed to date are consistent with the known risks of atezolizumab, 
nab-paclitaxel, and gemcitabine.  Atezolizumab in combination with cytotoxic 
chemotherapy has not been associated with additive severe (Grade  3) toxicities, 
indicating that atezolizumab can be safely combined with standard chemotherapy.  
As of the data cutoff date of 24 October 2017, the confirmed objective response rate 
was 41.7%, the median progression-free survival was 7 months, and the median 
overall survival was 10.6 months for 24 efficacy-evaluable patients with metastatic 
pancreatic cancer. 
A15–2.6 
BENEFIT–RISK ASSESSMENT 
Metastatic pancreatic ductal adenocarcinoma (PDAC) is an incurable disease with a 
high unmet need for improved medical intervention.  As described above, bevacizumab 
has immunomodulatory properties that include increased T-cell trafficking into tumors 
and the reduction of suppressive cytokines and infiltrating regulatory T cells (Hodi et al. 
2010; Wallin et al. 2016).  These data, in combination with nonclinical and clinical data 
for bevacizumab plus an immune checkpoint inhibitor, suggest a potential added benefit 

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when combining bevacizumab and atezolizumab.  In addition, combination treatment 
with bevacizumab and atezolizumab has shown improved efficacy over atezolizumab 
alone in patients with renal cell carcinoma (McDermott et al. 2017).  Therefore, 
combining the anti-VEGF effects of bevacizumab with blockade of the PD-L1/PD-1 
pathway by atezolizumab may result in an enhanced protective anti-tumor immune 
response in patients with PDAC. 
COVID-19 Benefit‒Risk Assessment 
In the setting of the coronavirus disease 2019 (COVID-19) pandemic, patients with 
comorbidities, including those patients with pancreatic cancer, are a more vulnerable 
population.  In some retrospective analyses, infection with severe acute respiratory 
syndrome coronavirus 2 (SARS-CoV-2) has been associated with higher mortality in 
patients with cancer.  It is unclear whether or how cancer therapies such as 
chemotherapy, targeted therapy, or immunotherapy impact the incidence or severity of 
COVID-19.  At this time, there is insufficient evidence for a causal association between 
atezolizumab and an increased risk of COVID-19.  Neutropenia and lymphopenia 
associated with chemotherapy may increase the risk for developing an infection in 
patients receiving atezolizumab in combination with chemotherapy; however, this is not 
specific to the risk of infection with SARS-CoV-2 (see Section A155.1).  Based on the 
safety profiles and mechanism of action, it is not anticipated that bevacizumab will 
increase the risk of infection with SARS-CoV-2.  Additionally, an interaction of 
bevacizumab with the COVID-19 vaccines is unlikely. 
For the evaluation of the impact of the COVID-19 pandemic and COVID-19 vaccination 
on the benefitrisk assessment, please refer to Section 1.5. 
A15–3 
RATIONALE FOR DOSE AND SCHEDULE FOR 
ATEZO  CHEMO  BEV ARM 
A15–3.1 
RATIONALE FOR ATEZOLIZUMAB DOSE AND SCHEDULE 
Atezolizumab will be administered at a fixed dose of 840 mg every 2 weeks (Q2W) 
(840 mg on Days 1 and 15 of each 28-day cycle), which is an approved dosage for 
atezolizumab. 
A15–3.2 
RATIONALE FOR BEVACIZUMAB DOSE AND SCHEDULE 
Bevacizumab will be administered at a dose of 10 mg/kg Q2W (10 mg/kg on Days 1 
and 15 of each 28-day cycle).  This treatment regimen was selected on the basis of 
nonclinical studies, available clinical data, and the doses recommended for use for 
indications in which bevacizumab is approved (refer to the Bevacizumab Investigator’s 
Brochure for details). 

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A15–4 
MATERIALS AND METHODS SPECIFIC TO 
ATEZO  CHEMO  BEV ARM 
A15–4.1 
TREATMENT IN ATEZO  CHEMO  BEV ARM 
A15–4.1.1 
Formulation, Packaging, and Handling 
A15–4.1.1.1 Atezolizumab 
The atezolizumab drug product 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 formulation and handling of atezolizumab, see the pharmacy 
manual and the Atezolizumab Investigator's Brochure. 
A15–4.1.1.2 Bevacizumab 
The bevacizumab drug product will be supplied by the Sponsor as a sterile solution in a 
single-use, 4-mL or 16-mL, preservative-free glass vial.  The 4-mL vial contains 100 mg 
of bevacizumab (25 mg/mL), and the 16-mL vial contains 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. 
A15–4.1.1.3 Nab-Paclitaxel 
For information on the formulation, packaging, and handling of nab-paclitaxel, refer to 
the local prescribing information. 
A15–4.1.1.4 Gemcitabine 
For information on the formulation, packaging, and handling of gemcitabine, refer to the 
local prescribing information. 
A15–4.1.2 
Dosage, Administration, and Compliance 
Patients in the atezolizumab plus chemotherapy (nab-paclitaxel and gemcitabine) plus 
bevacizumab (Atezo  Chemo  Bev) arm will receive treatment as outlined in  
Table A15-1 until unacceptable toxicity or loss of clinical benefit as determined by the 
investigator after an integrated assessment of radiographic and biochemical data, local 
biopsy results (if available), and clinical status (e.g., symptomatic deterioration such as 
pain secondary to disease) (see Section 3.1.2 for details).  It is recommended that 
treatment be initiated no later than 7 days after randomization. 

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Table A15-1 
Treatment Regimen for Atezo  Chemo  Bev Arm 
Cycle Length 
Dose, Route, and Regimen 
(drugs listed in order of administration) 
28 days 
 Atezolizumab 840 mg IV on Days 1 and 15 of each cycle 
 Bevacizumab 10 mg/kg IV on Days 1 and 15 of each cycle a  
 Nab-paclitaxel 125 mg/m2 IV on Days 1, 8, and 15 of each cycle b 
 Gemcitabine 1000 mg/m2 IV on Days 1, 8, and 15 of each cycle 
Atezo  Chemo  Bev  atezolizumab plus chemotherapy (nab-paclitaxel and gemcitabine) 
plus bevacizumab; nab-paclitaxel  nanoparticle albuminbound paclitaxel. 
a Bevacizumab will be administered after completion of the atezolizumab infusion. 
b On Days 1 and 15 of each cycle, nab-paclitaxel will be administered after completion of 
the bevacizumab infusion. 
 
Refer to the pharmacy manual for detailed instructions on drug preparation, storage, and 
administration. 
Medication errors 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.  
No safety data related to overdosing of atezolizumab or bevacizumab are available.  
For information on overdosing of gemcitabine or nab-paclitaxel, refer to the local 
prescribing information for each agent. 
A15–4.1.2.1 Atezolizumab 
Atezolizumab will be administered by IV infusion at a fixed dose of 840 mg on Days 1 
and 15 of each 28-day cycle. 
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 5.  
Atezolizumab infusions will be administered per the instructions outlined in Table A15-2. 

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Table A15-2 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, pulse oximetry, and 
temperature) should be recorded within 
60 minutes prior to the infusion. 
 
Atezolizumab should be infused over 
60 ( 15) minutes. 
 
If clinically indicated, vital signs should be 
recorded every 15 ( 5) minutes during the 
infusion and 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 recorded 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 recorded during the infusion and 
at 30 ( 10) minutes after the infusion. 
 
Guidelines for medical management of infusion-related reactions (IRRs) for 
atezolizumab are provided in Appendix 2. 
No dose modification for atezolizumab is allowed.  Guidelines for treatment interruption 
or discontinuation because of toxicities are provided in Section A155.1.6.  
Atezolizumab treatment may be interrupted for reasons other than toxicity (e.g., surgical 
procedures).  The acceptable length of treatment interruption must be based on an 
assessment of benefitrisk by the investigator and in alignment with the protocol 
requirements for the duration of treatment and documented by the investigator.  
The Medical Monitor is available to advise as needed. 
A15–4.1.2.2 Bevacizumab 
Bevacizumab will be administered by IV infusion at a dose of 10 mg/kg on Days 1 
and 15 of each 28-day cycle.  On Days 1 and 15 of each cycle, bevacizumab will be 
administered after completion of the atezolizumab infusion. 
Administration of bevacizumab will be performed in a monitored setting where there is 
immediate access to trained personnel and adequate equipment and medicine to 

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manage potentially serious reactions.  For anaphylaxis precautions, see Appendix 5.  
Bevacizumab infusions will be administered per the instructions outlined in Table A15-3. 
Table A15-3 Administration of First and Subsequent Bevacizumab 
Infusions 
First Infusion 
Subsequent Infusions 
 
No premedication is permitted prior to the 
bevacizumab infusion. 
 
Vital signs (pulse rate, respiratory rate, 
blood pressure, pulse oximetry, and 
temperature) should be measured within 
60 minutes prior to the infusion. 
 
Bevacizumab should be infused over 
90 ( 15) minutes. 
 
Vital signs should be measured within 
30 minutes after completion of 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 recorded within 
60 minutes prior to the infusion. 
 
Bevacizumab should be infused over 
60 ( 10) minutes if the previous 
90-minute 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 may be infused over 
30 ( 5) minutes thereafter. 
 
Vital signs should be measured within 
30 minutes after completion of the 
infusion. 
 
No dose modification for bevacizumab is allowed.  Guidelines for treatment interruption 
or discontinuation because of toxicities are provided in Section A155.1.6.  
Bevacizumab treatment may be interrupted for reasons other than toxicity (e.g., surgical 
procedures).  The acceptable length of treatment interruption must be based on an 
assessment of benefitrisk by the investigator and in alignment with the protocol 
requirements for the duration of treatment and documented by the investigator.  
The Medical Monitor is available to advise as needed. 
A15–4.1.2.3 Nab-Paclitaxel and Gemcitabine 
On Days 1, 8, and 15, patients will receive nab-paclitaxel 125 mg/m2, administered by IV 
infusion over 30 ( 5) minutes, followed by gemcitabine 1000 mg/m2, administered by IV 
infusion over 30 ( 5) minutes.  On Days 1 and 15 of each cycle, nab-paclitaxel will be 
administered after completion of the bevacizumab infusion. 

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Nab-paclitaxel and gemcitabine will be administered according to institutional standards 
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 5.   
Guidelines for nab-paclitaxel and gemcitabine dose modification and treatment 
interruption or discontinuation because of toxicities are provided in Section A155.1.6.  
Nab-paclitaxel and gemcitabine treatment may be interrupted for reasons other than 
toxicity (e.g., surgical procedures).  The acceptable length of treatment interruption must 
be based on an assessment of benefitrisk by the investigator and in alignment with the 
protocol requirements for the duration of treatment and documented by the 
investigator.  The Medical Monitor is available to advise as needed. 
A15–4.2 
CONCOMITANT THERAPY FOR ATEZO  CHEMO  BEV ARM 
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 study treatment from 
10 days prior to initiation of study treatment to the treatment discontinuation visit.  
All such medications should be reported to the investigator and recorded on the 
Concomitant Medications eCRF. 
A15–4.2.1 
Permitted Therapy for Atezo  Chemo  Bev Arm 
Patients are permitted to use the following therapies during the study: 
 
Colony-stimulating factors (CSFs), such as granulocyte colony-stimulating factors 
(G-CSFs), and erythropoiesis-stimulating agents (ESAs) per local 
practice/institutional guidelines or the American Society of Clinical Oncology 
guidelines for hematopoietic CSFs (Smith et al. 2006) and American Society of 
Hematology/American Society of Clinical Oncology guidelines for ESAs 
(Rizzo et al. 2010) 
Evidence supporting the use of long-acting (PEGylated) forms of G-CSF in 
patients receiving weekly chemotherapy (i.e., nab-paclitaxel) is limited.  
Thus, investigators should consider giving preference to conventional 
formulations of G-CSF. 
 
Oral contraceptives 
 
Hormone-replacement therapy 
 
Prophylactic or therapeutic anticoagulation therapy (such as warfarin at a stable 
dose or low-molecular-weight heparin) 
 
Vaccinations (such as influenza, COVID-19) 
Live, attenuated vaccines are not permitted (see Section A154.2.3). 

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 
Megestrol acetate administered as an appetite stimulant after initiation of study 
treatment 
 
Mineralocorticoids (e.g., fludrocortisone) 
 
Inhaled corticosteroids administered for chronic obstructive pulmonary disease 
or asthma 
 
Low-dose corticosteroids administered for orthostatic hypotension or adrenocortical 
insufficiency 
 
Hormonal therapy with gonadotropinreleasing hormone agonists or antagonists for 
prostate cancer 
 
Palliative radiotherapy (e.g., treatment of known bony metastases or symptomatic 
relief of pain) as outlined below: 
Palliative radiotherapy is permitted, provided it does not interfere with the 
assessment of tumor target lesions (e.g., the lesion to be irradiated must not be 
the only site of measurable disease).  Treatment with atezolizumab, 
nab-paclitaxel, gemcitabine, and bevacizumab should be withheld during 
palliative radiotherapy. 
 
Radiotherapy to the brain as outlined below: 
Patients whose extracranial tumor burden is stable or responding to study 
treatment and who are subsequently found to have three or fewer brain 
metastases may receive radiotherapy to the brain (either stereotactic 
radiosurgery or whole-brain radiation therapy) provided that all of the following 
criteria are met: 
– 
The patient has no evidence of progression or 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. 
Note:  Treatment with atezolizumab, nab-paclitaxel, gemcitabine, and 
bevacizumab should be withheld during CNS-directed radiation therapy. 
 
Premedication with antihistamines, antipyretics, and/or analgesics may be administered 
for the second and subsequent atezolizumab and bevacizumab infusions only, at the 
discretion of the investigator. 
In general, investigators should manage a patient’s care with supportive therapies as 
clinically indicated, per local standard practice.  Patients who experience infusion-
associated symptoms may be treated symptomatically with acetaminophen, ibuprofen, 

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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 5). 
A15–4.2.2 
Cautionary Therapy for Atezo  Chemo  Bev Arm 
A15–4.2.2.1 Corticosteroids, Immunosuppressive Medications, and Tumor 
Necrosis Factor‑ Inhibitors 
Systemic corticosteroids, immunosuppressive medications, and tumor necrosis factor- 
(TNF-) inhibitors may attenuate potential beneficial immunologic effects of treatment 
with atezolizumab.  Therefore, in situations in which systemic corticosteroids, 
immunosuppressive medications, or TNF- inhibitors would be routinely administered, 
alternatives, including antihistamines, should be considered.  If the alternatives are not 
feasible, systemic corticosteroids, immunosuppressive medications, and TNF- 
inhibitors may be administered at the discretion of the investigator. 
Systemic corticosteroids or immunosuppressive medications are recommended, at the 
discretion of the investigator, for the treatment of specific adverse events when 
associated with atezolizumab therapy (refer to Appendix 2 for details). 
A15–4.2.2.2 Medications Given with Precaution due to Effects Related to 
Cytochrome P450 Enzymes 
The metabolism of nab-paclitaxel is catalyzed by CYP2C8 and CYP3A4.  Caution should 
be exercised when nab-paclitaxel is concomitantly administered with known CYP2C8 or 
CYP3A4 inhibitors (e.g., atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, 
nefazodone, nelfinavir, ritonavir, saquinavir, and telithromycin) or inducers (e.g., rifampin 
and carbamazepine). 
The above lists of cautionary medications are not necessarily comprehensive.  The 
investigator should consult the prescribing information when determining whether a 
concomitant medication can be safety administered with study treatment.  In addition, 
the Medical Monitor is available to advise if questions arise regarding medications not 
listed above. 
A15–4.2.2.3 Herbal Therapies 
Concomitant use of herbal therapies is not recommended because their 
pharmacokinetics, safety profiles, and potential drug-drug interactions are generally 
unknown.  However, herbal therapies not intended for the treatment of cancer 
(see Section A154.2.3) may be used during the study at the discretion of the 
investigator. 

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A15–4.2.2.4 Bisphosphonates 
Osteonecrosis of the jaw has been reported in patients receiving bevacizumab, mainly in 
combination with bisphosphonates.  Thus, caution must be exercised in using 
bevacizumab in patients receiving concomitant bisphosphonates. 
A15–4.2.3 
Prohibited Therapy for Atezo  Chemo  Bev Arm 
Use of the following concomitant therapies is prohibited as described below: 
 
Concomitant therapy intended for the treatment of cancer (including, but not limited 
to, chemotherapy, hormonal therapy, immunotherapy, radiotherapy, and herbal 
therapy), whether health authorityapproved or experimental, is prohibited for 
various time periods prior to starting study treatment, depending on the agent 
(see Section 4.1.2), and during study treatment until disease progression is 
documented and the patient has discontinued study treatment, with the exception of 
palliative radiotherapy and radiotherapy to the brain under circumstances outlined 
above in Section A154.2.1. 
 
Investigational therapy (other than protocol-mandated study treatment) is prohibited 
within 28 days prior to initiation of study treatment and during study treatment. 
 
Live, attenuated vaccines (e.g., FluMist) are prohibited within 4 weeks prior to 
initiation of study treatment, during treatment with atezolizumab, and for 5 months 
after the last dose of atezolizumab. 
 
Systemic immunostimulatory agents (including, but not limited to, interferons and 
interleukin-2) are prohibited within 4 weeks or 5 half-lives of the drug, whichever is 
longer, prior to initiation of study treatment and during study treatment because 
these agents could potentially increase the risk for autoimmune conditions when 
given in combination with atezolizumab. 
 
Anti-thrombotic treatment with aspirin ( 325 mg/dL) and clopidogrel ( 75 mg/day) 
or equivalent are prohibited within 10 days prior to initiation of study treatment and 
during study treatment. 
 
A15–4.3 
CONTRACEPTION REQUIREMENTS FOR 
ATEZO  CHEMO  BEV ARM 
Contraception requirements for women and men in the Atezo  Chemo  Bev arm are 
outlined below: 
 
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 during the treatment period and for 5 months after the last 
dose of atezolizumab, 6 months after the last dose of nab-paclitaxel or 
gemcitabine, and 6 months after the last dose of bevacizumab.  Women must 
refrain from donating eggs during this same period. 

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A woman is considered to be of childbearing potential if she is postmenarcheal, 
has not reached a postmenopausal state ( 12 continuous months of 
amenorrhea with no identified cause other than menopause), and has not 
undergone surgical sterilization (removal of ovaries and/or uterus). 
Examples of contraceptive methods with a failure rate of  1% per year include 
bilateral tubal ligation, male sterilization, hormonal contraceptives that inhibit 
ovulation, hormone-releasing intrauterine devices, and copper intrauterine 
devices. 
The reliability of sexual abstinence should be evaluated in relation to the 
duration of the clinical trial and the preferred and usual lifestyle of the patient.  
Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation 
methods) and withdrawal are not acceptable methods of contraception. 
 
For men:  agreement to remain abstinent (refrain from heterosexual intercourse) or 
use contraceptive methods, and agreement to refrain from donating sperm, as 
defined below: 
With female partners of childbearing potential, men who are receiving 
chemotherapy must remain abstinent or use a condom plus an additional 
contraceptive method that together result in a failure rate of  1% per year 
during the treatment period and for 6 months after the last dose of 
nab-paclitaxel or gemcitabine and men who are not receiving chemotherapy 
must remain abstinent or use a condom during the treatment period and for 
6 months after the last dose of bevacizumab.  Men must refrain from donating 
sperm during this same period. 
With pregnant female partners, men must remain abstinent or use a condom 
during the treatment period and for 6 months after the last dose of 
nab-paclitaxel, gemcitabine, or bevacizumab to avoid exposing the embryo. 
The reliability of sexual abstinence should be evaluated in relation to the 
duration of the clinical trial and the preferred and usual lifestyle of the patient.  
Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation 
methods) and withdrawal are not acceptable methods of contraception. 
 
A15–5 
ASSESSMENT OF SAFETY FOR ATEZO  CHEMO  BEV ARM 
A15–5.1 
SAFETY PLAN FOR ATEZO  CHEMO  BEV ARM 
The safety plan for patients in this study is based on clinical experience with 
atezolizumab, nab-paclitaxel, gemcitabine, and bevacizumab in completed and 
ongoing studies.  The anticipated important safety risks are outlined below 
(see Sections A155.1.1, A155.1.2, A155.1.3, A155.1.4, and A155.1.5).  Guidelines 
for management of patients who experience specific adverse events are provided in 
Section A155.1.6. 

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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 study treatment 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.  Adverse events will 
be reported as described in Sections 5.25.6. 
A15–5.1.1 
Risks Associated with Atezolizumab 
Atezolizumab has been associated with risks such as the following:  IRRs and 
immune-mediated hepatitis, pneumonitis, colitis, pancreatitis, diabetes mellitus, 
hypothyroidism, hyperthyroidism, adrenal insufficiency, hypophysitis, Guillain-Barré 
syndrome, myasthenic syndrome or myasthenia gravis, facial paresis, myelitis, 
meningoencephalitis, myocarditis, pericardial disorders, nephritis, myositis, and severe 
cutaneous adverse reactions.  In addition, immune-mediated reactions may involve any 
organ system and may lead to hemophagocytic lymphohistiocytosis (HLH).  Refer to 
Appendix 2 of the protocol and Section 6 of the Atezolizumab Investigator's Brochure for 
a detailed description of anticipated safety risks for atezolizumab.   
A15–5.1.2 
Risks Associated with Nab-Paclitaxel 
The following are the most common adverse events observed with nab-paclitaxel in 
patients with PDAC:  neutropenia, fatigue, peripheral neuropathy, nausea, alopecia, 
peripheral edema, diarrhea, pyrexia, vomiting, decreased appetite, rash, and 
dehydration.  The following adverse events have also been observed:  
myelosuppression (primarily neutropenia, anemia, thrombocytopenia), cranial nerve 
palsies, hypersensitivity reactions, pneumonitis, myalgia, arthralgia, cardiotoxicity 
(myocardial disorders, cardiac failure, angina, tachycardia, ventricular arrhythmia), 
cystoid macular edema, Stevens-Johnson syndrome/toxic epidermal necrolysis, sepsis, 
infusion-site reactions/extravasation, hepatic toxicity (drug-induced liver injury), acute 
renal failure, scleroderma, and drug-induced lupus erythematous. 
For more details regarding the safety profile for nab-paclitaxel, refer to the nab-paclitaxel 
prescribing information. 
A15–5.1.3 
Risks Associated with Gemcitabine  
The most common adverse events observed with gemcitabine are nausea/vomiting, 
anemia, hepatic transaminitis, neutropenia, increased ALP, proteinuria, fever, hematuria, 
rash, thrombocytopenia, dyspnea, and peripheral edema.  The following adverse events 
have also been observed:  renal failure, hemolytic-uremic syndrome, interstitial 
pneumonitis, myocardial infarction, arrhythmia, and heart failure. 

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For more details regarding the safety profile for gemcitabine, refer to the gemcitabine 
prescribing information. 
A15–5.1.4 
Risks Associated with Bevacizumab 
Bevacizumab has been associated with risks such as the following:  GI perforations, 
fistulae, hemorrhage, hypertension, posterior reversible encephalopathy syndrome 
(PRES), arterial and venous thromboembolic events, congestive heart failure (CHF), 
other cardiac disorders, neutropenia and infection, wound-healing complications, 
proteinuria, hypersensitivity or IRRs, osteonecrosis of the jaw, ovarian failure, and 
pulmonary hypertension.  Refer to Section 6 of the Bevacizumab Investigator's Brochure 
for a detailed description of all anticipated risks for bevacizumab.   
A15–5.1.4.1 Perforations and Fistulae 
Guidelines for management of patients who develop a perforation or fistula are provided 
in Table A15-5. 
Gastrointestinal Perforation and Fistula 
Bevacizumab has been associated with serious cases of GI perforation in patients with 
mCRC, and a few reports of gallbladder perforation have been reported from the 
postmarketing experience.  Presentation of these events has varied in type and severity, 
ranging from free air seen only on the plain abdominal X-ray, which resolved without 
treatment, to a colonic perforation with abdominal abscess and fatal outcome.  In some 
cases, the underlying intra-abdominal inflammation was present, either from gastric ulcer 
disease, tumor necrosis, diverticulitis, or chemotherapy-associated colitis.  A causal 
association of an intra-abdominal inflammatory process and GI perforation to treatment 
with bevacizumab has not been established.  However, caution should be exercised 
when treating patients with intra-abdominal inflammatory process with bevacizumab.  
Patients treated with bevacizumab for persistent, recurrent, or metastatic cervical cancer 
may be at increased risk of fistulae between the vagina and any part of the GI tract.  
Fatal outcomes have been reported in cases of GI perforations. 
Bevacizumab use has been associated with serious cases of fistula, including events 
resulting in death.  Fistulae within the GI tract are common in patients with mCRC and 
ovarian cancer, but are uncommon or rare in other indications.  Patients who develop 
GIvaginal fistulae may also have bowel obstructions and may require surgical 
intervention as well as diverting ostomies. 

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Non-Gastrointestinal Fistula 
Bevacizumab use has been associated with serious cases of non-GI fistula, including 
events resulting in death.  Patients may be at increased risk for the development of 
non-GI fistulae when treated with bevacizumab.  Other fistulae (e.g., bronchopleural, 
tracheoesophageal, urogenital, biliary) have been reported uncommonly in bevacizumab 
clinical trials patients and in postmarketing reports. 
A15–5.1.4.2 Hemorrhage 
In clinical trials, an increased incidence of bleeding events has been observed in 
patients treated with bevacizumab compared with control.  The hemorrhagic events 
observed in bevacizumab studies were predominantly tumor-associated hemorrhage 
and minor mucocutaneous hemorrhage.  Patients with untreated CNS metastases were 
routinely excluded from clinical trials with bevacizumab, on the basis of imaging 
procedures or signs and symptoms.  Therefore, the risk of CNS hemorrhage in such 
patients has not been prospectively evaluated in randomized clinical studies.  Patients 
should be monitored for signs and symptoms of CNS bleeding. 
Guidelines for management of patients who develop a hemorrhage are provided 
in Table A15-5. 
A15–5.1.4.3 Hypertension 
An increased incidence of hypertension has been observed in patients treated with 
bevacizumab.  Clinical safety data suggest the incidence of hypertension is likely to be 
dose dependent.  Preexisting hypertension should be adequately controlled before 
starting bevacizumab treatment.  There is no information on the effect of bevacizumab in 
patients with uncontrolled hypertension at the time of initiating therapy.  In most cases, 
hypertension is controlled adequately by standard anti-hypertensive treatment.  Very 
rare cases of hypertensive encephalopathy have been reported, some of which were 
fatal.  Blood pressure must be assessed before each bevacizumab administration. 
Guidelines for management of patients who develop hypertension are provided in 
Table A15-5. 
A15–5.1.4.4 Posterior Reversible Encephalopathy Syndrome 
There have been rare reports of patients treated with bevacizumab developing signs and 
symptoms that are consistent with PRES, a rare neurologic disorder (also known as 
reversible posterior leukoencephalopathy syndrome).  PRES can present with the 
following signs and symptoms (among others):  seizures, headache, altered mental 
status, or visual disturbance or cortical blindness, with or without associated 
hypertension.  A diagnosis of PRES requires confirmation by magnetic resonance 
imaging (MRI) of the brain.  In patients developing PRES, treatment of specific 
symptoms, including control of hypertension, is recommended.  The safety of re-initiating 

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bevacizumab therapy in patients previously experiencing PRES is not known.  Adequate 
brain imaging through use of MRI must be performed as a follow-up measurement for 
patients with PRES. 
Guidelines for management of patients who develop PRES are provided in Table A15-5. 
A15–5.1.4.5 Thromboembolism 
Guidelines for management of patients who develop a thromboembolism are provided in 
Table A15-5. 
Arterial Thromboembolism 
In clinical trials, the incidence of arterial thromboembolism reactions, including 
cerebrovascular accidents, transient ischemic attack, and myocardial infarction, was 
higher in patients receiving bevacizumab in combination with chemotherapy compared 
with those receiving chemotherapy alone.  Patients receiving bevacizumab plus 
chemotherapy with a history of arterial thromboembolism, diabetes, or age  65 years 
have an increased risk of developing arterial thromboembolic events during 
bevacizumab therapy.  Caution should be taken when treating these patients with 
bevacizumab.  
Venous Thromboembolism 
Patients may be at risk of developing venous thromboembolic reactions, including 
pulmonary embolism, while receiving bevacizumab.  An increased risk of venous 
thromboembolic events and bleeding has been observed in bevacizumab-treated 
patients receiving anticoagulation therapy after an initial venous thromboembolic event.  
Patients with venous thromboembolisms should be managed and monitored with 
appropriate medical therapy. 
A15–5.1.4.6 Congestive Heart Failure 
Events consistent with CHF have been reported in clinical trials.  The findings ranged 
from asymptomatic declines in left ventricular ejection fraction to symptomatic CHF 
requiring treatment or hospitalization.  Most of the patients who experienced CHF had 
metastatic breast cancer and had received previous treatment with anthracyclines, has 
received prior radiotherapy to the left chest wall, or had other risk factors for CHF.  
Caution should be exercised when administering bevacizumab to patients with clinically 
significant cardiovascular disease, such as preexisting coronary artery disease, 
concomitant cardiotoxic therapy, or CHF. 
Guidelines for management of patients who develop CHF are provided in Table A15-5. 

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A15–5.1.4.7 Other Cardiac Disorders 
Cardiac disorders, including arrhythmias, have been seen in clinical trials using 
bevacizumab in combination with 5-FU and leucovorin or bevacizumab in combination 
with capecitabine and oxaliplatin.  However, for the vast majority of cases, the patient’s 
history included preexisting underlying cardiovascular diseases, concomitant treatment 
with potentially arrhythmogenic medications, or severe intercurrent illnesses. 
A15–5.1.4.8 Neutropenia and Infection 
Increased rates of severe neutropenia, febrile neutropenia, or infection with severe 
neutropenia (including some fatalities) have been observed in patients treated with 
some myelotoxic chemotherapy regimens plus bevacizumab compared with 
chemotherapy alone. 
Guidelines for management of patients who develop neutropenia are provided in 
Table A15-5. 
A15–5.1.4.9 Wound-Healing Complications 
Bevacizumab may adversely affect the wound-healing process.  Serious wound-healing 
complications with a fatal outcome have been reported.  Bevacizumab therapy should 
not be initiated in patients who have had major surgery within the previous 28 days or 
patients with a surgical wound that has not fully healed.  Bevacizumab therapy should be 
withheld for a minimum of 28 days prior to major elective surgery.  Emergency surgery 
should be performed as appropriate without delay after a careful benefitrisk 
assessment. 
Necrotizing fasciitis, including fatal cases, has rarely been reported in patients treated 
with bevacizumab, usually secondary to wound-healing complications, GI perforation, or 
fistula formation. 
Guidelines for management of patients who develop necrotizing fasciitis or wound 
dehiscence are provided in Table A15-5. 
A15–5.1.4.10 
Proteinuria 
In clinical studies, the incidence of proteinuria was higher in patients receiving 
bevacizumab in combination with chemotherapy compared with those receiving 
chemotherapy alone.  Proteinuria reported in patients receiving bevacizumab has 
ranged in severity from clinically asymptomatic, transient, trace proteinuria to nephrotic 
syndrome.  Nephrotic syndrome was seen in up to 1.4% of treated patients.  Patients 
with a history of hypertension may be at increased risk for the development of 
proteinuria when treated with bevacizumab.  Patients with proteinuria will be excluded 
from bevacizumab-containing arms. 

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Guidelines for management of patients who develop proteinuria are provided in 
Table A15-5. 
A15–5.1.4.11 
Hypersensitivity or Infusion-Related Reactions 
Patients may be at risk of developing hypersensitivity or IRRs to bevacizumab.  Patients 
will be closely monitored during and following administration of bevacizumab.  
Systematic premedication is not warranted. 
Guidelines for management of patients who develop hypersensitivity reactions or IRRs 
are provided in Table A15-5. 
A15–5.1.4.12 
Osteonecrosis of the Jaw 
Osteonecrosis of the jaw has been reported in patients receiving bevacizumab, mainly in 
combination with bisphosphonates in the postmarketing setting.  The pathogenesis of 
the osteonecrosis is unclear.  Caution must be exercised in using bevacizumab in 
patients receiving concomitant bisphosphonates.   
A15–5.1.4.13 
Ovarian Failure 
Bevacizumab may impair female fertility.  Ovarian function recovered in the majority of 
women after bevacizumab discontinuation.  Fertility preservation strategies should be 
discussed with women of childbearing potential prior to starting treatment with 
bevacizumab. 
A15–5.1.4.14 
Pulmonary Hypertension 
Pulmonary hypertension has been seen in patients treated with bevacizumab, primarily 
in the postmarketing setting.  Patients at risk included those with preexisting cardiac 
disease, pulmonary disease, thromboembolic disease, metastasis to the lungs, or use of 
other medications associated with pulmonary hypertension. 
Guidelines for management of patients who develop hypertension are provided in 
Table A15-5. 
A15–5.1.5 
Risks Associated with Combination Use of Atezolizumab, 
Nab‑Paclitaxel, Gemcitabine, and Bevacizumab 
The following adverse events are potential overlapping toxicities associated with 
combination use of atezolizumab, nab-paclitaxel, gemcitabine, and bevacizumab:  IRRs, 
dermatologic reactions, hepatic toxicity, diarrhea/colitis, pneumonitis, neutropenia, and 
proteinuria. 

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A15–5.1.6 
Management of Patients Who Experience Specific Adverse 
Events in Atezo  Chemo  Bev Arm 
On Day 1 of each cycle, patients are required to have an ANC of  1.5  109/L (1500/L) 
and a platelet count of  100  109/L (100,000/L) to receive treatment with nab-paclitaxel 
and gemcitabine.  Guidelines for management of hematologic toxicities and other 
toxicities (including guidelines for dose modification and treatment interruption or 
discontinuation) are provided in Table A15-5. 
A15–5.1.6.1 Dose Modifications 
There will be no dose modifications for atezolizumab or bevacizumab in this study. 
For management of drug-related toxicities, the dose of nab-paclitaxel may be reduced by 
25 mg/m2 (one dose level) up to two times and the dose of gemcitabine may be reduced 
by 200 mg/m2 (one dose level) up to two times, as outlined in Table A15-4: 
Table A15-4 Recommended Dose Reductions for Nab-Paclitaxel and 
Gemcitabine 
 
Initial Dose 
First Dose Reduction 
Second Dose Reduction 
Nab-paclitaxel 
125 mg/m2 
100 mg/m2 
75 mg/m2 
Gemcitabine 
1000 mg/m2 
800 mg/m2 
600 mg/m2 
Nab-paclitaxel  nanoparticle albuminbound paclitaxel. 
 
If further dose reduction is indicated for nab-paclitaxel and/or gemcitabine after two dose 
reductions, that drug (or both drugs, if applicable) should be discontinued, but the patient 
may continue other study treatments at the investigator's discretion.  After dose 
reduction, the dose may be escalated during subsequent administrations at the 
investigator's discretion. 
A15–5.1.6.2 Treatment Interruption for Toxicities 
Atezolizumab treatment may be temporarily suspended in patients experiencing toxicity 
considered to be related to study treatment.  If corticosteroids are initiated for treatment 
of the toxicity, they must be tapered over  1 month to  10 mg/day oral prednisone or 
equivalent before atezolizumab can be resumed.  If atezolizumab is withheld for 
 12 weeks, the patient will be discontinued from atezolizumab.  However, atezolizumab 
may be withheld for  12 weeks to allow for patients to taper off corticosteroids prior to 
resuming treatment.  Atezolizumab can be resumed after being withheld for  12 weeks if 
the patient is likely to derive clinical benefit.  The decision to re-challenge patients with 
atezolizumab should be based on investigator's assessment of benefitrisk and 
documented by the investigator.  The Medical Monitor is available to advise as needed. 

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Nab-paclitaxel and/or gemcitabine treatment may be temporarily suspended in patients 
experiencing toxicity considered to be related to study treatment (see Table A15-5).  
If nab-paclitaxel or gemcitabine have been withheld for  56 days because of toxicity, 
the patient should be discontinued from both chemotherapy agents.  However, 
nab-paclitaxel or gemcitabine can be resumed after being withheld for  56 days if the 
patient is likely to derive clinical benefit.  The decision to re-challenge patients with nab-
paclitaxel and/or gemcitabine should be based on investigator's assessment of 
benefitrisk and documented by the investigator.  The Medical Monitor is available to 
advise as needed. 
Bevacizumab treatment may be temporarily suspended in patients experiencing toxicity 
considered to be related to study treatment.  If bevacizumab is withheld for  56 days, 
the patient will be discontinued from bevacizumab.  Bevacizumab can be resumed after 
being withheld for  56 days if the patient is likely to derive clinical benefit.  The decision 
to re-challenge patients bevacizumab should be based on investigator's assessment of 
benefitrisk and documented by the investigator.  The Medical Monitor is available to 
advise as needed. 
If atezolizumab, nab-paclitaxel, gemcitabine, or bevacizumab is discontinued, the other 
drugs can be continued if the patient is likely to derive clinical benefit, as determined by 
the investigator. 
Refer to Section A154.1.2 for information on dose interruptions for reasons other 
than toxicity. 
A15–5.1.6.3 Management Guidelines for Adverse Events 
Guidelines for management of patients who experience specific adverse events are 
provided in Table A15-5.  These guidelines are intended to inform rather than supersede 
an investigator's clinical judgment and assessment of the benefitrisk balance when 
managing individual cases. 
The investigator may use discretion in adhering to the guidelines for nab-paclitaxel and 
gemcitabine described below, taking into account the severity of the event and benefit 
versus risk for the patient, with the goal of maximizing patient compliance and access to 
supportive care.  Additionally, the prescribing information, as well as local hospital or 
clinical practice, must be followed. 
 
 

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Table A15-5 Guidelines for Management of Patients Who Experience 
Specific Adverse Events in Atezo  Chemo  Bev Arm 
Event 
Action to Be Taken 
IRRs, CRS, anaphylaxis, and hypersensitivity reactions 
General guidance 
 Guidelines for management of IRRs and CRS for atezolizumab 
are provided in Appendix 2  
 Guidelines for management of IRRs for bevacizumab and 
chemotherapy are provided below. 
 For anaphylaxis precautions, see Appendix 5. 
 For severe hypersensitivity reactions, permanently discontinue 
the causative agent. 
IRR to bevacizumab, Grade 1 
or 2 
 Reduce infusion rate to  50%. 
 After symptoms have adequately resolved, increase in 50% 
increments up to the full rate if well tolerated.  Infusions may be 
restarted at the full rate during the next cycle. 
 For subsequent infusions, monitor closely for IRRs. 
IRR to bevacizumab, Grade 3   Interrupt infusion. 
 Administer aggressive symptomatic treatment (e.g., oral or IV 
antihistamine, antipyretic, glucocorticoids, epinephrine, 
bronchodilators, oxygen) if clinically indicated. 
 After symptoms have resolved to baseline, resume infusion at 
 50% of the rate prior to the reaction after the patient’s 
symptoms have adequately resolved, and increase in 
50% increments up to the full rate if well tolerated.  Infusions 
may be restarted at the full rate during the next cycle. 
 For subsequent infusions, monitor closely for IRRs. 
IRR to bevacizumab, Grade 4  Stop infusion and permanently discontinue bevacizumab. a 
 Administer aggressive symptomatic treatment (e.g., oral or IV 
antihistamine, antipyretic, glucocorticoids, epinephrine, 
bronchodilators, oxygen) if clinically indicated. 
Atezo  Chemo  Bev  atezolizumab plus chemotherapy (nab-paclitaxel and gemcitabine) plus 
bevacizumab; CRS  cytokine release syndrome; IRR  infusion-related reaction; 
nab-paclitaxel  nanoparticle albuminbound paclitaxel. 
a Resumption of treatment may be considered if the investigator believes the patient is likely to 
derive clinical benefit.  The decision to re-challenge patients should be based on investigator's 
assessment of benefitrisk and documented by the investigator (or an appropriate delegate).  
The Medical Monitor is available to advise as needed. 
b The dose of nab-paclitaxel may be reduced by 25 mg/m2 (one dose level) up to two times and 
the dose of gemcitabine may be reduced by 200 mg/m2 (one dose level) up to two times 
(see Section A155.1.6.1 for details). 

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Table A15‑5 Guidelines for Management of Patients Who Experience 
Specific Adverse Events in Atezo  Chemo  Bev Arm (cont.) 
Event 
Action to Be Taken 
IRRs, CRS, anaphylaxis, and hypersensitivity reactions (cont.) 
IRR to chemotherapy, 
Grade 1  
 Reduce infusion rate to half the rate being given at the time of 
event onset. 
 After the event has resolved, the investigator should wait for 
30 minutes while delivering the infusion at the reduced rate. 
 If the infusion is tolerated at the reduced rate for 30 minutes after 
symptoms have resolved, the infusion rate may be increased to 
the original rate. 
IRR to chemotherapy, 
Grade 2 
 Interrupt infusion. 
 Administer aggressive symptomatic treatment (e.g., oral or IV 
antihistamine, antipyretic, glucocorticoids, epinephrine, 
bronchodilators, oxygen). 
 After symptoms have resolved to baseline, resume infusion at half 
the rate being given at the time of event onset. 
 For subsequent infusions, administer oral premedication with 
antihistamine and antipyretic and monitor closely for IRRs. 
IRR to chemotherapy, 
Grade 3 or 4 
 Stop infusion. 
 Administer aggressive symptomatic treatment (e.g., oral or IV 
antihistamine, antipyretic, glucocorticoids, epinephrine, 
bronchodilators, oxygen). 
 Permanently discontinue treatment and contact Medical Monitor. a 
Hemophagocytic 
lymphohistiocytosis  
 Follow guidelines for atezolizumab in Appendix 2. 
 Withhold all treatment and contact Medical Monitor. 
Atezo  Chemo  Bev  atezolizumab plus chemotherapy (nab-paclitaxel and gemcitabine) plus 
bevacizumab; CRS  cytokine release syndrome; IRR  infusion-related reaction; 
nab-paclitaxel  nanoparticle albuminbound paclitaxel. 
a Resumption of treatment may be considered if the investigator believes the patient is likely to 
derive clinical benefit.  The decision to re-challenge patients should be based on investigator's 
assessment of benefitrisk and documented by the investigator (or an appropriate delegate).  
The Medical Monitor is available to advise as needed. 
b The dose of nab-paclitaxel may be reduced by 25 mg/m2 (one dose level) up to two times and 
the dose of gemcitabine may be reduced by 200 mg/m2 (one dose level) up to two times 
(see Section A155.1.6.1 for details). 

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Table A15‑5 Guidelines for Management of Patients Who Experience 
Specific Adverse Events in Atezo  Chemo  Bev Arm (cont.) 
Event 
Action to Be Taken 
Gastrointestinal toxicity 
Diarrhea or colitis, 
Grade 1 
 Follow guidelines for atezolizumab in Appendix 2. 
 Continue nab-paclitaxel, gemcitabine, and bevacizumab. 
Diarrhea or colitis, 
Grade 2 
 Follow guidelines for atezolizumab in Appendix 2. 
 Continue nab-paclitaxel and gemcitabine.  Bevacizumab may be continued 
at the discretion of the investigator. 
 If bevacizumab is withheld and event resolves to Grade 1 or better 
 56 days after event onset, resume bevacizumab.  If not, permanently 
discontinue bevacizumab. a 
Diarrhea or colitis, 
Grade 3 
 Follow guidelines for atezolizumab in Appendix 2. 
 Withhold nab-paclitaxel and gemcitabine.  Bevacizumab may be continued 
at the discretion of the investigator. 
 If event resolves to Grade 1 or better  56 days after event onset, resume 
nab-paclitaxel and gemcitabine with dose reduced by one level. b  If not, 
permanently discontinue nab-paclitaxel and gemcitabine. a 
 If bevacizumab is withheld and event resolves to Grade 1 or better 
 56 days after event onset, resume bevacizumab.  If not, permanently 
discontinue bevacizumab. a 
Diarrhea or colitis, 
Grade 4 
 Follow guidelines for atezolizumab in Appendix 2. 
 Permanently discontinue nab-paclitaxel and gemcitabine.  Bevacizumab 
may be continued at the discretion of the investigator. 
 If bevacizumab is withheld and event resolves to Grade 1 or better 
 56 days after event onset, resume bevacizumab.  If not, permanently 
discontinue bevacizumab. a 
Atezo  Chemo  Bev  atezolizumab plus chemotherapy (nab-paclitaxel and gemcitabine) plus 
bevacizumab; CRS  cytokine release syndrome; IRR  infusion-related reaction; 
nab-paclitaxel  nanoparticle albuminbound paclitaxel. 
a Resumption of treatment may be considered if the investigator believes the patient is likely to 
derive clinical benefit.  The decision to re-challenge patients should be based on investigator's 
assessment of benefitrisk and documented by the investigator (or an appropriate delegate).  
The Medical Monitor is available to advise as needed. 
b The dose of nab-paclitaxel may be reduced by 25 mg/m2 (one dose level) up to two times and 
the dose of gemcitabine may be reduced by 200 mg/m2 (one dose level) up to two times 
(see Section A155.1.6.1 for details). 

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Table A15‑5 Guidelines for Management of Patients Who Experience 
Specific Adverse Events in Atezo  Chemo  Bev Arm (cont.) 
Event 
Action to Be Taken 
Gastrointestinal toxicity (cont.) 
Mucositis, Grade 1 or 2  Continue atezolizumab, nab-paclitaxel, gemcitabine, and bevacizumab. 
Mucositis, Grade 3 
 Continue atezolizumab and bevacizumab.  Withhold nab-paclitaxel and 
gemcitabine. 
 If event resolves to Grade 1 or better  56 days after event onset, 
resume nab-paclitaxel and gemcitabine with dose reduced by one 
level. b  If not, permanently discontinue nab-paclitaxel and gemcitabine. a 
Mucositis, Grade 4 
 Permanently discontinue atezolizumab, nab-paclitaxel, gemcitabine, and 
bevacizumab. a 
Gastrointestinal 
perforation, any grade 
 Withhold atezolizumab, nab-paclitaxel and gemcitabine.  Permanently 
discontinue bevacizumab. a 
 Initiate treatment per institutional guidelines. 
 If event improves, resume atezolizumab, nab-paclitaxel, and 
gemcitabine.  If not, permanently discontinue atezolizumab, 
nab-paclitaxel, and gemcitabine. a 
Bowel obstruction, 
Grade 2 
 Withhold atezolizumab, nab-paclitaxel, gemcitabine, and bevacizumab 
for obstruction requiring medical intervention. 
 If event resolves completely, resume atezolizumab, nab-paclitaxel, 
gemcitabine, and bevacizumab.  If not, permanently discontinue 
atezolizumab, nab-paclitaxel, gemcitabine, and bevacizumab. a 
Bowel obstruction, 
Grade 3 or 4 
 Withhold atezolizumab, nab-paclitaxel, gemcitabine, and bevacizumab. 
 If event resolves completely (including recovery from any surgery), 
resume atezolizumab, nab-paclitaxel, gemcitabine, and bevacizumab.  If 
not, permanently discontinue atezolizumab, nab-paclitaxel, gemcitabine, 
and bevacizumab. a 
Atezo  Chemo  Bev  atezolizumab plus chemotherapy (nab-paclitaxel and gemcitabine) plus 
bevacizumab; CRS  cytokine release syndrome; IRR  infusion-related reaction; 
nab-paclitaxel  nanoparticle albuminbound paclitaxel. 
a Resumption of treatment may be considered if the investigator believes the patient is likely to 
derive clinical benefit.  The decision to re-challenge patients should be based on investigator's 
assessment of benefitrisk and documented by the investigator (or an appropriate delegate).  
The Medical Monitor is available to advise as needed. 
b The dose of nab-paclitaxel may be reduced by 25 mg/m2 (one dose level) up to two times and 
the dose of gemcitabine may be reduced by 200 mg/m2 (one dose level) up to two times 
(see Section A155.1.6.1 for details). 

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Table A15‑5 Guidelines for Management of Patients Who Experience 
Specific Adverse Events in Atezo  Chemo  Bev Arm (cont.) 
Event 
Action to Be Taken 
Capillary leak syndrome 
Capillary leak syndrome, 
any grade 
 Permanently discontinue gemcitabine. a  Withhold 
atezolizumab, nab-paclitaxel, and bevacizumab. 
 If event improves, resume atezolizumab, nab-paclitaxel, and 
bevacizumab.  If not, permanently discontinue atezolizumab, 
nab-paclitaxel, and bevacizumab. a 
Dermatologic toxicity 
Dermatologic event, Grade 1 
 Follow guidelines for atezolizumab in Appendix 2. 
 Continue nab-paclitaxel, gemcitabine, and bevacizumab. 
Dermatologic event, Grade 2 
 Follow guidelines for atezolizumab in Appendix 2. 
 Continue nab-paclitaxel and gemcitabine with dose reduced 
by one level. b  Continue bevacizumab. 
 If event persists, permanently discontinue nab-paclitaxel and 
gemcitabine. a 
Dermatologic event, Grade 3 
 Follow guidelines for atezolizumab in Appendix 2. 
 Continue nab-paclitaxel and gemcitabine with dose reduced 
by one level. b  Bevacizumab may be continued at the 
discretion of the investigator. 
 If event persists, permanently discontinue nab-paclitaxel and 
gemcitabine. a 
 If bevacizumab is withheld and event resolves to Grade 2 or 
better  56 days after event onset, resume bevacizumab.  
If not, permanently discontinue bevacizumab. a 
Atezo  Chemo  Bev  atezolizumab plus chemotherapy (nab-paclitaxel and gemcitabine) plus 
bevacizumab; CRS  cytokine release syndrome; IRR  infusion-related reaction; 
nab-paclitaxel  nanoparticle albuminbound paclitaxel. 
a Resumption of treatment may be considered if the investigator believes the patient is likely to 
derive clinical benefit.  The decision to re-challenge patients should be based on investigator's 
assessment of benefitrisk and documented by the investigator (or an appropriate delegate).  
The Medical Monitor is available to advise as needed. 
b The dose of nab-paclitaxel may be reduced by 25 mg/m2 (one dose level) up to two times and 
the dose of gemcitabine may be reduced by 200 mg/m2 (one dose level) up to two times 
(see Section A155.1.6.1 for details). 
 

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Table A15‑5 Guidelines for Management of Patients Who Experience 
Specific Adverse Events in Atezo  Chemo  Bev Arm (cont.) 
Event 
Action to Be Taken 
Dermatologic toxicity (cont.) 
Dermatologic event, Grade 4 
 Follow guidelines for atezolizumab in Appendix 2. 
 Permanently discontinue nab-paclitaxel, gemcitabine, and 
bevacizumab. a 
Stevens-Johnson syndrome or 
toxic epidermal necrolysis (any 
grade) 
 Withhold atezolizumab, nab-paclitaxel, gemcitabine, and 
bevacizumab 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, 
nab-paclitaxel, gemcitabine, and bevacizumab. 
Atezo  Chemo  Bev  atezolizumab plus chemotherapy (nab-paclitaxel and gemcitabine) plus 
bevacizumab; CRS  cytokine release syndrome; IRR  infusion-related reaction; 
nab-paclitaxel  nanoparticle albuminbound paclitaxel. 
a Resumption of treatment may be considered if the investigator believes the patient is likely to 
derive clinical benefit.  The decision to re-challenge patients should be based on investigator's 
assessment of benefitrisk and documented by the investigator (or an appropriate delegate).  
The Medical Monitor is available to advise as needed. 
b The dose of nab-paclitaxel may be reduced by 25 mg/m2 (one dose level) up to two times and 
the dose of gemcitabine may be reduced by 200 mg/m2 (one dose level) up to two times 
(see Section A155.1.6.1 for details). 

Appendix 15:  Study Details Specific to Atezo  Chemo  Bev Arm (Cohort 1) 
  
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260/Protocol WO39608, Version 16
 
 
Table A15‑5 Guidelines for Management of Patients Who Experience 
Specific Adverse Events in Atezo  Chemo  Bev Arm (cont.) 
Event 
Action to Be Taken 
Febrile neutropenia 
Grade 3 or 4 
 Withhold atezolizumab, nab-paclitaxel, gemcitabine, and 
bevacizumab. 
 If fever resolves and ANC improves to  1.5  109/L (1500/L) 
 56 days after event onset, resume nab-paclitaxel and 
gemcitabine with dose reduced by one level b and resume and 
bevacizumab.  If not, permanently discontinue nab-paclitaxel, 
gemcitabine, and bevacizumab. a 
 If fever resolves and ANC improves to  1.5  109/L (1500/L) 
 12 weeks after event onset, resume atezolizumab.  If not, 
permanently discontinue atezolizumab. a 
Hematologic toxicity at Day 1 (excluding febrile neutropenia) 
ANC  1.5  109/L (1500/L) 
and 
Platelet count  100  109/L 
(100,000/L) 
 Continue atezolizumab, nab-paclitaxel, gemcitabine, and 
bevacizumab. 
ANC  1.5  109/L (1500/L) 
and/or 
Platelet count  100  109/L 
(100,000/L) 
 Continue atezolizumab and bevacizumab.  Withhold 
nab-paclitaxel and gemcitabine. 
 Permanently discontinue nab-paclitaxel or gemcitabine if 
withheld  56 days after event onset. a  
Atezo  Chemo  Bev  atezolizumab plus chemotherapy (nab-paclitaxel and gemcitabine) plus 
bevacizumab; CRS  cytokine release syndrome; IRR  infusion-related reaction; 
nab-paclitaxel  nanoparticle albuminbound paclitaxel. 
a Resumption of treatment may be considered if the investigator believes the patient is likely to 
derive clinical benefit.  The decision to re-challenge patients should be based on investigator's 
assessment of benefitrisk and documented by the investigator (or an appropriate delegate).  
The Medical Monitor is available to advise as needed. 
b The dose of nab-paclitaxel may be reduced by 25 mg/m2 (one dose level) up to two times and 
the dose of gemcitabine may be reduced by 200 mg/m2 (one dose level) up to two times 
(see Section A155.1.6.1 for details). 

Appendix 15:  Study Details Specific to Atezo  Chemo  Bev Arm (Cohort 1) 
  
Pancreatic Immunotherapy Combinations—F. Hoffmann-La Roche Ltd 
261/Protocol WO39608, Version 16
 
 
Table A15‑5 Guidelines for Management of Patients Who Experience 
Specific Adverse Events in Atezo  Chemo  Bev Arm (cont.) 
Event 
Action to Be Taken 
Hematologic toxicity at Day 8 (excluding febrile neutropenia) 
ANC  1.0  109/L (1000/L) 
and 
Platelet count  75  109/L 
(75,000/L) 
 Continue nab-paclitaxel and gemcitabine. 
ANC  0.5  109/L (500/L) but 
 1.0  109/L (1000/L) 
and/or 
Platelet count  50  109/L 
(50,000/L) but  75  109/L 
(75,000/L) 
 Continue nab-paclitaxel and gemcitabine with dose reduced 
by one level. b 
ANC  0.5  109/L (500/L) 
and/or 
Platelet count  50  109/L 
(50,000/L) 
 Withhold nab-paclitaxel and gemcitabine. 
 If nab-paclitaxel and gemcitabine are withheld  56 days after 
event onset, permanently discontinue nab-paclitaxel and 
gemcitabine. a 
Atezo  Chemo  Bev  atezolizumab plus chemotherapy (nab-paclitaxel and gemcitabine) plus 
bevacizumab; CRS  cytokine release syndrome; IRR  infusion-related reaction; 
nab-paclitaxel  nanoparticle albuminbound paclitaxel. 
a Resumption of treatment may be considered if the investigator believes the patient is likely to 
derive clinical benefit.  The decision to re-challenge patients should be based on investigator's 
assessment of benefitrisk and documented by the investigator (or an appropriate delegate).  
The Medical Monitor is available to advise as needed. 
b The dose of nab-paclitaxel may be reduced by 25 mg/m2 (one dose level) up to two times and 
the dose of gemcitabine may be reduced by 200 mg/m2 (one dose level) up to two times 
(see Section A155.1.6.1 for details). 

Appendix 15:  Study Details Specific to Atezo  Chemo  Bev Arm (Cohort 1) 
  
Pancreatic Immunotherapy Combinations—F. Hoffmann-La Roche Ltd 
262/Protocol WO39608, Version 16
 
 
Table A15‑5 Guidelines for Management of Patients Who Experience 
Specific Adverse Events in Atezo  Chemo  Bev Arm (cont.) 
Event 
Action to Be Taken 
Hematologic toxicity at Day 15 (excluding febrile neutropenia):  Day 8 doses given without 
modification 
ANC  1.0  109/L (1000/L) 
and 
Platelet count  75  109/L 
(75,000/L) 
 Continue atezolizumab, nab-paclitaxel, gemcitabine, and 
bevacizumab. 
ANC  0.5  109/L (500/L) but 
 1.0  109/L (1000/L) 
and/or 
Platelet count  50  109/L 
(50,000/L) but  75  109/L 
(75,000/L) 
 Continue atezolizumab and bevacizumab.  Continue 
nab-paclitaxel and gemcitabine at current dose followed by 
WBC growth factors or with dose reduced by one level. b 
ANC  0.5  109/L (500/L) 
and/or 
Platelet count  50  109/L 
(50,000/L) 
 Withhold atezolizumab, nab-paclitaxel, gemcitabine, and 
bevacizumab. 
 If event improves, atezolizumab, nab-paclitaxel, gemcitabine, 
and/or bevacizumab can be resumed. a 
 If nab-paclitaxel, gemcitabine, and bevacizumab are withheld 
 56 days after event onset, permanently discontinue 
nab-paclitaxel, gemcitabine, and bevacizumab. a 
Atezo  Chemo  Bev  atezolizumab plus chemotherapy (nab-paclitaxel and gemcitabine) plus 
bevacizumab; CRS  cytokine release syndrome; IRR  infusion-related reaction; 
nab-paclitaxel  nanoparticle albuminbound paclitaxel. 
a Resumption of treatment may be considered if the investigator believes the patient is likely to 
derive clinical benefit.  The decision to re-challenge patients should be based on investigator's 
assessment of benefitrisk and documented by the investigator (or an appropriate delegate).  
The Medical Monitor is available to advise as needed. 
b The dose of nab-paclitaxel may be reduced by 25 mg/m2 (one dose level) up to two times and 
the dose of gemcitabine may be reduced by 200 mg/m2 (one dose level) up to two times 
(see Section A155.1.6.1 for details). 

Appendix 15:  Study Details Specific to Atezo  Chemo  Bev Arm (Cohort 1) 
  
Pancreatic Immunotherapy Combinations—F. Hoffmann-La Roche Ltd 
263/Protocol WO39608, Version 16
 
 
Table A15‑5 Guidelines for Management of Patients Who Experience 
Specific Adverse Events in Atezo  Chemo  Bev Arm (cont.) 
Event 
Action to Be Taken 
Hematologic toxicity at Day 15 (excluding febrile neutropenia):  Day 8 doses reduced 
ANC  1.0  109/L (1000/L) 
and 
Platelet count  75  109/L 
(75,000/L) 
 Continue atezolizumab and bevacizumab.  Continue 
nab-paclitaxel and gemcitabine at Day 1 doses followed by 
WBC growth factors or at current dose. 
ANC  0.5  109/L (500/L) but 
 1.0  109/L (1000/L) 
and/or 
Platelet count  50  109/L 
(50,000/L) but  75  109/L 
(75,000/L) 
 Continue atezolizumab and bevacizumab.  Continue 
nab-paclitaxel and gemcitabine at current dose followed by 
WBC growth factors or with dose reduced by one level. b 
ANC  0.5  109/L (500/L) 
and/or 
Platelet count  50  109/L 
(50,000/L) 
 Withhold atezolizumab, nab-paclitaxel, gemcitabine, and 
bevacizumab. 
 If event improves, atezolizumab, nab-paclitaxel, gemcitabine, 
and/or bevacizumab can be resumed. a 
 If nab-paclitaxel, gemcitabine, and bevacizumab are withheld 
 56 days after event onset, permanently discontinue 
nab-paclitaxel, gemcitabine, and bevacizumab. a 
Atezo  Chemo  Bev  atezolizumab plus chemotherapy (nab-paclitaxel and gemcitabine) plus 
bevacizumab; CRS  cytokine release syndrome; IRR  infusion-related reaction; 
nab-paclitaxel  nanoparticle albuminbound paclitaxel. 
a Resumption of treatment may be considered if the investigator believes the patient is likely to 
derive clinical benefit.  The decision to re-challenge patients should be based on investigator's 
assessment of benefitrisk and documented by the investigator (or an appropriate delegate).  
The Medical Monitor is available to advise as needed. 
b The dose of nab-paclitaxel may be reduced by 25 mg/m2 (one dose level) up to two times and 
the dose of gemcitabine may be reduced by 200 mg/m2 (one dose level) up to two times 
(see Section A155.1.6.1 for details). 

Appendix 15:  Study Details Specific to Atezo  Chemo  Bev Arm (Cohort 1) 
  
Pancreatic Immunotherapy Combinations—F. Hoffmann-La Roche Ltd 
264/Protocol WO39608, Version 16
 
 
Table A15‑5 Guidelines for Management of Patients Who Experience 
Specific Adverse Events in Atezo  Chemo  Bev Arm (cont.) 
Event 
Action to Be Taken 
Hematologic toxicity at Day 15 (excluding febrile neutropenia):  Day 8 treatment was withheld 
ANC  1.0  109/L (1000/L) 
and 
Platelet count  75  109/L 
(75,000/L) 
 Continue atezolizumab and bevacizumab.  Continue 
nab-paclitaxel and gemcitabine at current dose followed by 
WBC growth factors or with dose reduced by one level. b 
ANC  0.5  109/L (500/L) but 
 1.0  109/L (1000/L) 
and/or 
Platelet count  50  109/L 
(50,000/L) but  75  109/L 
(75,000/L) 
 Continue atezolizumab and bevacizumab.  Continue 
nab-paclitaxel and gemcitabine with dose reduced by one level 
followed by WBC growth factors or with dose reduced by two 
levels. b 
ANC  0.5  109/L (500/L) 
and/or 
Platelet count  50  109/L 
(50,000/L) 
 Withhold atezolizumab, nab-paclitaxel, gemcitabine, and 
bevacizumab. 
 If event improves, atezolizumab, nab-paclitaxel, gemcitabine, 
and/or bevacizumab can be resumed. a 
 If nab-paclitaxel, gemcitabine, and bevacizumab are withheld 
 56 days after event onset, permanently discontinue 
nab-paclitaxel, gemcitabine, and bevacizumab. a 
Atezo  Chemo  Bev  atezolizumab plus chemotherapy (nab-paclitaxel and gemcitabine) plus 
bevacizumab; CRS  cytokine release syndrome; IRR  infusion-related reaction; 
nab-paclitaxel  nanoparticle albuminbound paclitaxel. 
a Resumption of treatment may be considered if the investigator believes the patient is likely to 
derive clinical benefit.  The decision to re-challenge patients should be based on investigator's 
assessment of benefitrisk and documented by the investigator (or an appropriate delegate).  
The Medical Monitor is available to advise as needed. 
b The dose of nab-paclitaxel may be reduced by 25 mg/m2 (one dose level) up to two times and 
the dose of gemcitabine may be reduced by 200 mg/m2 (one dose level) up to two times 
(see Section A155.1.6.1 for details). 

Appendix 15:  Study Details Specific to Atezo  Chemo  Bev Arm (Cohort 1) 
  
Pancreatic Immunotherapy Combinations—F. Hoffmann-La Roche Ltd 
265/Protocol WO39608, Version 16
 
 
Table A15‑5 Guidelines for Management of Patients Who Experience 
Specific Adverse Events in Atezo  Chemo  Bev Arm (cont.) 
Event 
Action to Be Taken 
Pulmonary events 
Pulmonary event, Grade 1  
 Follow guidelines for atezolizumab in Appendix 2. 
 Continue nab-paclitaxel, gemcitabine, and bevacizumab. 
 If confirmed diagnosis of pneumonitis, permanently discontinue 
nab-paclitaxel and gemcitabine. a 
Pulmonary event, Grade 2 
 Follow guidelines for atezolizumab in Appendix 2. 
 Withhold nab-paclitaxel, and gemcitabine.  Bevacizumab may 
be continued at the discretion of the investigator. 
 If confirmed diagnosis of pneumonitis, permanently discontinue 
nab-paclitaxel and gemcitabine. a 
 If event resolves to Grade 1 or better  56 days after event 
onset, resume nab-paclitaxel and gemcitabine.  If not, 
permanently discontinue nab-paclitaxel and gemcitabine. a 
 If bevacizumab is withheld and event resolves to Grade 1 or 
better  56 days after event onset, resume bevacizumab.  
If not, permanently discontinue bevacizumab. a 
 For recurrent events, treat as a Grade 3 or 4 event. 
Pulmonary event, Grade 3 or 4 
 Follow guidelines for atezolizumab in Appendix 2. 
 Permanently discontinue nab-paclitaxel and gemcitabine. a  
Bevacizumab may be continued at the discretion of the 
investigator. 
 If bevacizumab is withheld and event resolves to Grade 1 or 
better  56 days after event onset, resume bevacizumab.  
If not, permanently discontinue bevacizumab. a 
Atezo  Chemo  Bev  atezolizumab plus chemotherapy (nab-paclitaxel and gemcitabine) plus 
bevacizumab; CRS  cytokine release syndrome; IRR  infusion-related reaction; 
nab-paclitaxel  nanoparticle albuminbound paclitaxel. 
a Resumption of treatment may be considered if the investigator believes the patient is likely to 
derive clinical benefit.  The decision to re-challenge patients should be based on investigator's 
assessment of benefitrisk and documented by the investigator (or an appropriate delegate).  
The Medical Monitor is available to advise as needed. 
b The dose of nab-paclitaxel may be reduced by 25 mg/m2 (one dose level) up to two times and 
the dose of gemcitabine may be reduced by 200 mg/m2 (one dose level) up to two times 
(see Section A155.1.6.1 for details). 

Appendix 15:  Study Details Specific to Atezo  Chemo  Bev Arm (Cohort 1) 
  
Pancreatic Immunotherapy Combinations—F. Hoffmann-La Roche Ltd 
266/Protocol WO39608, Version 16
 
 
Table A15‑5 Guidelines for Management of Patients Who Experience 
Specific Adverse Events in Atezo  Chemo  Bev Arm (cont.) 
Event 
Action to Be Taken 
Hepatic event 
 
Hepatic event, 
Grade 1 
 Follow guidelines for atezolizumab in Appendix 2. 
 Continue nab-paclitaxel, gemcitabine, and bevacizumab. 
Hepatic event, 
Grade 2 
 Follow guidelines for atezolizumab in Appendix 2. 
 Withhold nab-paclitaxel and gemcitabine for hepatic event other than Grade 2 
elevation of AST, ALT, or ALP.  Continue bevacizumab.  
 If chemotherapy is withheld and event resolves to Grade 1 or better  56 days 
after event onset, resume nab-paclitaxel and gemcitabine.  If not, permanently 
discontinue nab-paclitaxel and gemcitabine. a 
Hepatic event, 
Grade 3 or 4 
 Follow guidelines for atezolizumab in Appendix 2. 
 Withhold nab-paclitaxel, gemcitabine, and bevacizumab. 
 If event resolves to Grade 1 or better  56 days after event onset, resume 
nab-paclitaxel, gemcitabine, and bevacizumab and consider reducing the 
nab-paclitaxel and gemcitabine dose by one level. b  If not, permanently 
discontinue nab-paclitaxel, gemcitabine, and bevacizumab. a 
Atezo  Chemo  Bev  atezolizumab plus chemotherapy (nab-paclitaxel and gemcitabine) plus 
bevacizumab; CRS  cytokine release syndrome; IRR  infusion-related reaction; 
nab-paclitaxel  nanoparticle albuminbound paclitaxel. 
a Resumption of treatment may be considered if the investigator believes the patient is likely to 
derive clinical benefit.  The decision to re-challenge patients should be based on investigator's 
assessment of benefitrisk and documented by the investigator (or an appropriate delegate).  
The Medical Monitor is available to advise as needed. 
b The dose of nab-paclitaxel may be reduced by 25 mg/m2 (one dose level) up to two times and 
the dose of gemcitabine may be reduced by 200 mg/m2 (one dose level) up to two times 
(see Section A155.1.6.1 for details). 

Appendix 15:  Study Details Specific to Atezo  Chemo  Bev Arm (Cohort 1) 
  
Pancreatic Immunotherapy Combinations—F. Hoffmann-La Roche Ltd 
267/Protocol WO39608, Version 16
 
 
Table A15‑5 Guidelines for Management of Patients Who Experience 
Specific Adverse Events in Atezo  Chemo  Bev Arm (cont.) 
Event 
Action to Be Taken 
Neurologic disorder 
Immune-mediated neuropathy, 
Grade 1 or 2 
 Follow guidelines for atezolizumab in Appendix 2. 
 Continue nab-paclitaxel, gemcitabine, and bevacizumab. 
Immune-mediated neuropathy, 
Grade 3 or 4 
 Follow guidelines for atezolizumab in Appendix 2. 
 Continue gemcitabine and bevacizumab.  Withhold 
nab-paclitaxel. 
 If event resolves to Grade 1 or better  56 days after event onset, 
resume nab-paclitaxel with dose reduced by one level. b  If not, 
permanently discontinue nab-paclitaxel. a 
Nonimmune-mediated 
neuropathy, Grade 1 or 2 
 Continue atezolizumab, nab-paclitaxel, gemcitabine, and 
bevacizumab. 
Nonimmune-mediated 
neuropathy, Grade 3 or 4 
 Continue atezolizumab, gemcitabine, and bevacizumab.  
Withhold nab-paclitaxel. 
 If event resolves to Grade 1 or better  56 days after event onset, 
resume nab-paclitaxel with dose reduced by one level. b  If not, 
permanently discontinue nab-paclitaxel. a 
Immune-mediated 
meningoencephalitis, any 
grade 
 Follow guidelines for atezolizumab in Appendix 2. 
 Withhold nab-paclitaxel, gemcitabine, and bevacizumab. 
 If event stabilizes  56 days after event onset, resume 
nab-paclitaxel, gemcitabine, and bevacizumab.  If not, 
permanently discontinue nab-paclitaxel, gemcitabine, and 
bevacizumab. a 
Posterior reversible encephalopathy syndrome 
Posterior reversible 
encephalopathy syndrome, 
any grade confirmed by 
magnetic resonance imaging 
 Withhold atezolizumab and nab-paclitaxel.  Permanently 
discontinue gemcitabine and bevacizumab. a 
 If event improves, atezolizumab and/or nab-paclitaxel can be 
resumed. a 
 If nab-paclitaxel is withheld  56 days after event onset, 
permanently discontinue nab-paclitaxel. a 
 If atezolizumab is withheld  12 weeks after event onset, 
permanently discontinue atezolizumab. a 
Atezo  Chemo  Bev  atezolizumab plus chemotherapy (nab-paclitaxel and gemcitabine) plus 
bevacizumab; CRS  cytokine release syndrome; IRR  infusion-related reaction; 
nab-paclitaxel  nanoparticle albuminbound paclitaxel. 
a Resumption of treatment may be considered if the investigator believes the patient is likely to 
derive clinical benefit.  The decision to re-challenge patients should be based on investigator's 
assessment of benefitrisk and documented by the investigator (or an appropriate delegate).  
The Medical Monitor is available to advise as needed. 
b The dose of nab-paclitaxel may be reduced by 25 mg/m2 (one dose level) up to two times and 
the dose of gemcitabine may be reduced by 200 mg/m2 (one dose level) up to two times 
(see Section A155.1.6.1 for details). 

Appendix 15:  Study Details Specific to Atezo  Chemo  Bev Arm (Cohort 1) 
  
Pancreatic Immunotherapy Combinations—F. Hoffmann-La Roche Ltd 
268/Protocol WO39608, Version 16
 
 
Table A15‑5 Guidelines for Management of Patients Who Experience 
Specific Adverse Events in Atezo  Chemo  Bev Arm (cont.) 
Event 
Action to Be Taken 
Hypertension 
Hypertension, Grade 1 
 Continue atezolizumab, nab-paclitaxel, gemcitabine, and 
bevacizumab. 
Hypertension,  
Grade 2 or 3 
 Atezolizumab, nab-paclitaxel, and gemcitabine may be continued at 
the discretion of the investigator.  Withhold bevacizumab. 
 Initiate anti-hypertensive therapy. 
 If treatment is withheld and event resolves to Grade 1 or better 
 56 days after event onset, resume nab-paclitaxel and gemcitabine.  
If not, permanently discontinue nab-paclitaxel and gemcitabine. a 
 If treatment is withheld and event resolves to Grade 1 or better 
 12 weeks after event onset, resume atezolizumab.  If not, 
permanently discontinue atezolizumab. a 
 If event resolves to Grade 1 or better  56 days after event onset, 
resume bevacizumab.  If not, permanently discontinue bevacizumab. a 
Hypertension, Grade 4 
 Withhold atezolizumab, nab-paclitaxel, and gemcitabine.  Permanently 
discontinue bevacizumab. a 
 Initiate anti-hypertensive therapy. 
 If event improves  56 days after event onset, resume nab-paclitaxel 
and gemcitabine.  If not, permanently discontinue nab-paclitaxel and 
gemcitabine. a 
 If event improves  12 weeks after event onset, resume atezolizumab.  
If not, permanently discontinue atezolizumab. a 
Atezo  Chemo  Bev  atezolizumab plus chemotherapy (nab-paclitaxel and gemcitabine) plus 
bevacizumab; CRS  cytokine release syndrome; IRR  infusion-related reaction; 
nab-paclitaxel  nanoparticle albuminbound paclitaxel. 
a Resumption of treatment may be considered if the investigator believes the patient is likely to 
derive clinical benefit.  The decision to re-challenge patients should be based on investigator's 
assessment of benefitrisk and documented by the investigator (or an appropriate delegate).  
The Medical Monitor is available to advise as needed. 
b The dose of nab-paclitaxel may be reduced by 25 mg/m2 (one dose level) up to two times and 
the dose of gemcitabine may be reduced by 200 mg/m2 (one dose level) up to two times 
(see Section A155.1.6.1 for details). 
 
 

Appendix 15:  Study Details Specific to Atezo  Chemo  Bev Arm (Cohort 1) 
  
Pancreatic Immunotherapy Combinations—F. Hoffmann-La Roche Ltd 
269/Protocol WO39608, Version 16
 
 
Table A15‑5 Guidelines for Management of Patients Who Experience 
Specific Adverse Events in Atezo  Chemo  Bev Arm (cont.) 
Event 
Action to Be Taken 
Hemorrhage 
Hemorrhage, Grade 1 
(excluding cerebral 
hemorrhage) 
All patients: 
 Continue atezolizumab, nab-paclitaxel, and gemcitabine. 
Patients not receiving full-dose anticoagulation: 
 Withhold bevacizumab. 
 If the bleeding resolves, hemoglobin levels are stable, there is no 
bleeding diathesis, and there is no anatomic or pathologic condition 
that would significantly increase the risk of hemorrhage recurrence 
 56 days after event onset, resume bevacizumab.  If not, permanently 
discontinue bevacizumab. a 
 For recurrent pulmonary or CNS (including intracranial) hemorrhage 
events, permanently discontinue bevacizumab. a 
Patients receiving full-dose anticoagulation: 
 Permanently discontinue bevacizumab. a 
Hemorrhage, Grade 2 
(excluding cerebral 
hemorrhage) 
All patients: 
 Continue atezolizumab.  Withhold nab-paclitaxel and gemcitabine. 
 If event resolves to Grade 1 or better  56 days after event onset, 
resume nab-paclitaxel and gemcitabine and consider reducing the 
dose by one level. b  If not, permanently discontinue nab-paclitaxel and 
gemcitabine. a 
Patients not receiving full-dose anticoagulation: 
 Withhold bevacizumab. 
 If the bleeding resolves, hemoglobin levels are stable, there is no 
bleeding diathesis, and there is no anatomic or pathologic condition 
that would significantly increase the risk of hemorrhage recurrence 
 56 days after event onset, resume bevacizumab.  If not, permanently 
discontinue bevacizumab. a 
 For recurrent pulmonary or CNS (including intracranial) hemorrhage 
events, permanently discontinue bevacizumab. a 
Patients receiving full-dose anticoagulation: 
 Permanently discontinue bevacizumab. a 
Atezo  Chemo  Bev  atezolizumab plus chemotherapy (nab-paclitaxel and gemcitabine) plus 
bevacizumab; CRS  cytokine release syndrome; IRR  infusion-related reaction; 
nab-paclitaxel  nanoparticle albuminbound paclitaxel. 
a Resumption of treatment may be considered if the investigator believes the patient is likely to 
derive clinical benefit.  The decision to re-challenge patients should be based on investigator's 
assessment of benefitrisk and documented by the investigator (or an appropriate delegate).  
The Medical Monitor is available to advise as needed. 
b The dose of nab-paclitaxel may be reduced by 25 mg/m2 (one dose level) up to two times and 
the dose of gemcitabine may be reduced by 200 mg/m2 (one dose level) up to two times 
(see Section A155.1.6.1 for details). 

Appendix 15:  Study Details Specific to Atezo  Chemo  Bev Arm (Cohort 1) 
  
Pancreatic Immunotherapy Combinations—F. Hoffmann-La Roche Ltd 
270/Protocol WO39608, Version 16
 
 
Table A15‑5 Guidelines for Management of Patients Who Experience 
Specific Adverse Events in Atezo  Chemo  Bev Arm (cont.) 
Event 
Action to Be Taken 
Hemorrhage (cont.) 
Hemorrhage, Grade 3 (excluding 
cerebral hemorrhage) 
 Continue atezolizumab.  Withhold nab-paclitaxel and 
gemcitabine.  Permanently discontinue bevacizumab. a 
 If event resolves to Grade 1 or better  56 days after event 
onset, resume nab-paclitaxel and gemcitabine and consider 
reducing the dose by one level. b  If not, permanently 
discontinue nab-paclitaxel and gemcitabine. a 
Hemorrhage, Grade 4, or 
cerebral hemorrhage, any grade 
 Withhold atezolizumab, nab-paclitaxel, and gemcitabine.  
Permanently discontinue bevacizumab. a 
 If event improves, resume atezolizumab, nab-paclitaxel, and 
gemcitabine.  If not, permanently discontinue atezolizumab, 
nab-paclitaxel, and gemcitabine. a 
Thromboembolic events 
Venous thromboembolic event, 
Grade 1 
 Continue atezolizumab, nab-paclitaxel, gemcitabine, and 
bevacizumab. 
Venous thromboembolic event, 
Grade 2 
 Withhold atezolizumab, nab-paclitaxel, and gemcitabine.  
Continue bevacizumab. 
 Initiate anticoagulant treatment per institutional guidelines. 
 If patient becomes asymptomatic  56 days after event onset, 
resume nab-paclitaxel and gemcitabine.  If not, permanently 
discontinue nab-paclitaxel and gemcitabine. a 
 If patient becomes asymptomatic  12 weeks after event onset, 
resume atezolizumab.  If not, permanently discontinue 
atezolizumab. a 
Atezo  Chemo  Bev  atezolizumab plus chemotherapy (nab-paclitaxel and gemcitabine) plus 
bevacizumab; CRS  cytokine release syndrome; IRR  infusion-related reaction; 
nab-paclitaxel  nanoparticle albuminbound paclitaxel. 
a Resumption of treatment may be considered if the investigator believes the patient is likely to 
derive clinical benefit.  The decision to re-challenge patients should be based on investigator's 
assessment of benefitrisk and documented by the investigator (or an appropriate delegate).  
The Medical Monitor is available to advise as needed. 
b The dose of nab-paclitaxel may be reduced by 25 mg/m2 (one dose level) up to two times and 
the dose of gemcitabine may be reduced by 200 mg/m2 (one dose level) up to two times 
(see Section A155.1.6.1 for details). 

Appendix 15:  Study Details Specific to Atezo  Chemo  Bev Arm (Cohort 1) 
  
Pancreatic Immunotherapy Combinations—F. Hoffmann-La Roche Ltd 
271/Protocol WO39608, Version 16
 
 
Table A15‑5 Guidelines for Management of Patients Who Experience 
Specific Adverse Events in Atezo  Chemo  Bev Arm (cont.) 
Event 
Action to Be Taken 
Thromboembolic events (cont.) 
Venous thromboembolic event, 
Grade 3 
 Withhold atezolizumab, nab-paclitaxel, and gemcitabine.  
Withhold bevacizumab for at least 3 weeks. 
 Initiate anticoagulant treatment per institutional guidelines. 
 If patient becomes asymptomatic  56 days after event onset, 
resume nab-paclitaxel and gemcitabine.  If not, permanently 
discontinue nab-paclitaxel and gemcitabine. a 
 If patient becomes asymptomatic  12 weeks after event onset, 
resume atezolizumab.  If not, permanently discontinue 
atezolizumab. a 
 If anticoagulation therapy is stabilized  56 days after event 
onset, resume bevacizumab (provided that bevacizumab has 
been withheld for at least 3 weeks).  If not, permanently 
discontinue bevacizumab. a 
 For recurrent events, permanently discontinue bevacizumab. a 
Venous thromboembolic event, 
Grade 4 
 Withhold atezolizumab, nab-paclitaxel, and gemcitabine.  
Permanently discontinue bevacizumab. a 
 Initiate anticoagulant treatment per institutional guidelines. 
 If patient becomes asymptomatic  56 days after event onset, 
resume nab-paclitaxel and gemcitabine.  If not, permanently 
discontinue nab-paclitaxel and gemcitabine. a 
 If patient becomes asymptomatic  12 weeks after event onset, 
resume atezolizumab.  If not, permanently discontinue 
atezolizumab. a 
Arterial thromboembolic event, 
any grade 
 Withhold atezolizumab, nab-paclitaxel, and gemcitabine.  
Permanently discontinue bevacizumab. a 
 If patient becomes asymptomatic  56 days after event onset, 
resume nab-paclitaxel and gemcitabine.  If not, permanently 
discontinue nab-paclitaxel and gemcitabine. a 
 If patient becomes asymptomatic  12 weeks after event onset, 
resume atezolizumab.  If not, permanently discontinue 
atezolizumab. a 
Atezo  Chemo  Bev  atezolizumab plus chemotherapy (nab-paclitaxel and gemcitabine) plus 
bevacizumab; CRS  cytokine release syndrome; IRR  infusion-related reaction; 
nab-paclitaxel  nanoparticle albuminbound paclitaxel. 
a Resumption of treatment may be considered if the investigator believes the patient is likely to 
derive clinical benefit.  The decision to re-challenge patients should be based on investigator's 
assessment of benefitrisk and documented by the investigator (or an appropriate delegate).  
The Medical Monitor is available to advise as needed. 
b The dose of nab-paclitaxel may be reduced by 25 mg/m2 (one dose level) up to two times and 
the dose of gemcitabine may be reduced by 200 mg/m2 (one dose level) up to two times 
(see Section A155.1.6.1 for details). 
 
 

Appendix 15:  Study Details Specific to Atezo  Chemo  Bev Arm (Cohort 1) 
  
Pancreatic Immunotherapy Combinations—F. Hoffmann-La Roche Ltd 
272/Protocol WO39608, Version 16
 
 
Table A15‑5 Guidelines for Management of Patients Who Experience 
Specific Adverse Events in Atezo  Chemo  Bev Arm (cont.) 
Event 
Action to Be Taken 
Hemolytic-uremic syndrome 
Hemolytic-uremic syndrome, 
any grade 
 Permanently discontinue gemcitabine. a  Withhold atezolizumab, 
nab-paclitaxel, and bevacizumab. 
 If event improves, resume atezolizumab, nab-paclitaxel, and 
bevacizumab.  If not, permanently discontinue atezolizumab, 
nab-paclitaxel, and bevacizumab. 
Proteinuria 
Proteinuria, Grade 1 
(1+ by dipstick; urinary 
protein  1.0 g/24 hr) 
 Continue atezolizumab, nab-paclitaxel, gemcitabine, and 
bevacizumab. 
Proteinuria, Grade 2 
(2+ by dipstick; urinary 
protein 1.03.4 g/24 hr) 
 Continue atezolizumab, nab-paclitaxel, and gemcitabine. 
 If 24-hour urine protein results are not available, continue 
bevacizumab.  If 24-hour urine protein results are available, 
continue bevacizumab if urine protein is  2 g/24 hr and withhold 
bevacizumab if urine protein is  2 g/24 hr. 
 If bevacizumab is withheld and urine protein improves to 
 2 g/24 hr  56 days after event onset, resume bevacizumab.  
If not, permanently discontinue bevacizumab. a 
 Collect 24-hour urine for determination of total protein within 
3 days prior to subsequent scheduled bevacizumab 
administrations until proteinuria has improved to  1 g/24 hr. 
Atezo  Chemo  Bev  atezolizumab plus chemotherapy (nab-paclitaxel and gemcitabine) plus 
bevacizumab; CRS  cytokine release syndrome; IRR  infusion-related reaction; 
nab-paclitaxel  nanoparticle albuminbound paclitaxel. 
a Resumption of treatment may be considered if the investigator believes the patient is likely to 
derive clinical benefit.  The decision to re-challenge patients should be based on investigator's 
assessment of benefitrisk and documented by the investigator (or an appropriate delegate).  
The Medical Monitor is available to advise as needed. 
b The dose of nab-paclitaxel may be reduced by 25 mg/m2 (one dose level) up to two times and 
the dose of gemcitabine may be reduced by 200 mg/m2 (one dose level) up to two times 
(see Section A155.1.6.1 for details). 

Appendix 15:  Study Details Specific to Atezo  Chemo  Bev Arm (Cohort 1) 
  
Pancreatic Immunotherapy Combinations—F. Hoffmann-La Roche Ltd 
273/Protocol WO39608, Version 16
 
 
Table A15‑5 Guidelines for Management of Patients Who Experience 
Specific Adverse Events in Atezo  Chemo  Bev Arm (cont.) 
Event 
Action to Be Taken 
Proteinuria (cont.) 
Proteinuria, Grade 3 
(urinary protein 
 3.5 g/24 hr) with no 
diagnosis of nephrotic 
syndrome 
 Atezolizumab, nab-paclitaxel, and gemcitabine may be continued at 
the discretion of the investigator. 
 Collect 24-hour urine (if not already available) to determine if 
bevacizumab can be administered.  Continue bevacizumab if urine 
protein is  2 g/24 hr and withhold bevacizumab if urine protein is 
 2 g/24 hr. 
 If urine protein improves to  2 g/24 hr  56 days after event onset, 
resume bevacizumab.  If not, permanently discontinue 
bevacizumab. a 
 If treatment is withheld and event improves  56 days after event 
onset, resume nab-paclitaxel and gemcitabine.  If not, permanently 
discontinue nab-paclitaxel and gemcitabine. a 
 If treatment is withheld and event improves  12 weeks after event 
onset, resume atezolizumab.  If not, permanently discontinue 
atezolizumab. a 
 Collect 24-hour urine for determination of total protein within 3 days 
prior to subsequent scheduled bevacizumab administrations until 
proteinuria has improved to  1 g/24 hr. 
Nephrotic syndrome 
 Atezolizumab, nab-paclitaxel, and gemcitabine may be continued at 
the discretion of the investigator.  Permanently discontinue 
bevacizumab. a 
 If treatment is withheld and event improves  56 days after event 
onset, resume nab-paclitaxel and gemcitabine.  If not, permanently 
discontinue nab-paclitaxel and gemcitabine. a 
 If treatment is withheld and event improves  12 weeks after event 
onset, resume atezolizumab.  If not, permanently discontinue 
atezolizumab. a 
Atezo  Chemo  Bev  atezolizumab plus chemotherapy (nab-paclitaxel and gemcitabine) plus 
bevacizumab; CRS  cytokine release syndrome; IRR  infusion-related reaction; 
nab-paclitaxel  nanoparticle albuminbound paclitaxel. 
a Resumption of treatment may be considered if the investigator believes the patient is likely to 
derive clinical benefit.  The decision to re-challenge patients should be based on investigator's 
assessment of benefitrisk and documented by the investigator (or an appropriate delegate).  
The Medical Monitor is available to advise as needed. 
b The dose of nab-paclitaxel may be reduced by 25 mg/m2 (one dose level) up to two times and 
the dose of gemcitabine may be reduced by 200 mg/m2 (one dose level) up to two times 
(see Section A155.1.6.1 for details). 

Appendix 15:  Study Details Specific to Atezo  Chemo  Bev Arm (Cohort 1) 
  
Pancreatic Immunotherapy Combinations—F. Hoffmann-La Roche Ltd 
274/Protocol WO39608, Version 16
 
 
Table A15‑5 Guidelines for Management of Patients Who Experience 
Specific Adverse Events in Atezo  Chemo  Bev Arm (cont.) 
Event 
Action to Be Taken 
Fistula 
Tracheoesophageal 
fistula, any grade 
 Withhold atezolizumab, nab-paclitaxel, and gemcitabine.  Permanently 
discontinue bevacizumab. a 
 If event improves, resume atezolizumab, nab-paclitaxel, and 
gemcitabine.  If not, permanently discontinue atezolizumab, 
nab-paclitaxel, and gemcitabine. a 
Fistula (non-
tracheoesophageal), 
Grade 1, 2, or 3 
 Atezolizumab, nab-paclitaxel, and gemcitabine may be continued at the 
discretion of the investigator.  Consider withholding bevacizumab. 
 If treatment is withheld and event improves, resume bevacizumab.  If not, 
permanently discontinue bevacizumab. a 
 If treatment is withheld and event improves  56 days after event onset, 
resume nab-paclitaxel and gemcitabine.  If not, permanently discontinue 
nab-paclitaxel and gemcitabine. a 
 If treatment is withheld and event improves  12 weeks after event onset, 
resume atezolizumab.  If not, permanently discontinue atezolizumab. a 
Fistula (non-
tracheoesophageal), 
Grade 4 
 Withhold atezolizumab, nab-paclitaxel, and gemcitabine.  Permanently 
discontinue bevacizumab. a 
 If event improves, resume atezolizumab, nab-paclitaxel, and 
gemcitabine.  If not, permanently discontinue atezolizumab, 
nab-paclitaxel, and gemcitabine. a 
Necrotizing fasciitis 
Necrotizing fasciitis, 
any grade 
 Withhold atezolizumab, nab-paclitaxel, and gemcitabine.  Permanently 
discontinue bevacizumab. 
 If event improves, resume atezolizumab, nab-paclitaxel, and 
gemcitabine.  If not, permanently discontinue atezolizumab, 
nab-paclitaxel, and gemcitabine. a 
Atezo  Chemo  Bev  atezolizumab plus chemotherapy (nab-paclitaxel and gemcitabine) plus 
bevacizumab; CRS  cytokine release syndrome; IRR  infusion-related reaction; 
nab-paclitaxel  nanoparticle albuminbound paclitaxel. 
a Resumption of treatment may be considered if the investigator believes the patient is likely to 
derive clinical benefit.  The decision to re-challenge patients should be based on investigator's 
assessment of benefitrisk and documented by the investigator (or an appropriate delegate).  
The Medical Monitor is available to advise as needed. 
b The dose of nab-paclitaxel may be reduced by 25 mg/m2 (one dose level) up to two times and 
the dose of gemcitabine may be reduced by 200 mg/m2 (one dose level) up to two times 
(see Section A155.1.6.1 for details). 

Appendix 15:  Study Details Specific to Atezo  Chemo  Bev Arm (Cohort 1) 
  
Pancreatic Immunotherapy Combinations—F. Hoffmann-La Roche Ltd 
275/Protocol WO39608, Version 16
 
 
Table A15‑5 Guidelines for Management of Patients Who Experience 
Specific Adverse Events in Atezo  Chemo  Bev Arm (cont.) 
Event 
Action to Be Taken 
Wound dehiscence 
Wound dehiscence, any grade 
requiring medical or surgical 
therapy 
 Atezolizumab, nab-paclitaxel, and gemcitabine may be 
continued at the discretion of the investigator.  Permanently 
discontinue bevacizumab. a 
 If treatment is withheld and event improves  56 days after 
event onset, resume nab-paclitaxel and gemcitabine.  If not, 
permanently discontinue nab-paclitaxel and gemcitabine. a 
 If treatment is withheld and event improves  12 weeks after 
event onset, resume atezolizumab.  If not, permanently 
discontinue atezolizumab. a 
Congestive heart failure 
Congestive heart failure, Grade 1 
or 2 
 Atezolizumab, nab-paclitaxel, gemcitabine, and 
bevacizumab may be continued at the discretion of the 
investigator. 
 If treatment is withheld and event improves  56 days after 
event onset, resume nab-paclitaxel, gemcitabine, and 
bevacizumab.  If not, permanently discontinue 
nab-paclitaxel, gemcitabine, and bevacizumab. a 
 If treatment is withheld and event improves  12 weeks after 
event onset, resume atezolizumab.  If not, permanently 
discontinue atezolizumab. a 
Congestive heart failure, Grade 3 
or 4 
 Atezolizumab, nab-paclitaxel, and gemcitabine may be 
continued at the discretion of the investigator.  Permanently 
discontinue bevacizumab. a 
 If treatment is withheld and event improves, resume 
atezolizumab, nab-paclitaxel, and gemcitabine.  If not, 
permanently discontinue atezolizumab, nab-paclitaxel, and 
gemcitabine. a 
Atezo  Chemo  Bev  atezolizumab plus chemotherapy (nab-paclitaxel and gemcitabine) plus 
bevacizumab; CRS  cytokine release syndrome; IRR  infusion-related reaction; 
nab-paclitaxel  nanoparticle albuminbound paclitaxel. 
a Resumption of treatment may be considered if the investigator believes the patient is likely to 
derive clinical benefit.  The decision to re-challenge patients should be based on investigator's 
assessment of benefitrisk and documented by the investigator (or an appropriate delegate).  
The Medical Monitor is available to advise as needed. 
b The dose of nab-paclitaxel may be reduced by 25 mg/m2 (one dose level) up to two times and 
the dose of gemcitabine may be reduced by 200 mg/m2 (one dose level) up to two times 
(see Section A155.1.6.1 for details). 

Appendix 15:  Study Details Specific to Atezo  Chemo  Bev Arm (Cohort 1) 
  
Pancreatic Immunotherapy Combinations—F. Hoffmann-La Roche Ltd 
276/Protocol WO39608, Version 16
 
 
Table A15‑5 Guidelines for Management of Patients Who Experience 
Specific Adverse Events in Atezo  Chemo  Bev Arm (cont.) 
Event 
Action to Be Taken 
Chemotherapy-related toxicities not described above 
Grade 1 or 2 
 Continue atezolizumab, nab-paclitaxel, gemcitabine, and 
bevacizumab. 
Grade 3 
 Continue atezolizumab and bevacizumab.  Withhold 
nab-paclitaxel and gemcitabine. 
 If event resolves to Grade 2 or better  56 days after event 
onset, resume nab-paclitaxel and gemcitabine and consider 
reducing dose by one level. b  If not, permanently discontinue 
nab-paclitaxel and gemcitabine. a 
Grade 4 
 Withhold atezolizumab, nab-paclitaxel, gemcitabine, and 
bevacizumab. 
 If event improves, resume atezolizumab.  If not, permanently 
discontinue atezolizumab. a 
 If event resolves to Grade 2 or better  56 days after event 
onset, resume nab-paclitaxel and gemcitabine and consider 
reducing dose by one level. b  If not, permanently discontinue 
nab-paclitaxel and gemcitabine. a 
 If event improves, resume bevacizumab.  If not, permanently 
discontinue bevacizumab. a 
Atezo  Chemo  Bev  atezolizumab plus chemotherapy (nab-paclitaxel and gemcitabine) plus 
bevacizumab; CRS  cytokine release syndrome; IRR  infusion-related reaction; 
nab-paclitaxel  nanoparticle albuminbound paclitaxel. 
a Resumption of treatment may be considered if the investigator believes the patient is likely to 
derive clinical benefit.  The decision to re-challenge patients should be based on investigator's 
assessment of benefitrisk and documented by the investigator (or an appropriate delegate).  
The Medical Monitor is available to advise as needed. 
b The dose of nab-paclitaxel may be reduced by 25 mg/m2 (one dose level) up to two times and 
the dose of gemcitabine may be reduced by 200 mg/m2 (one dose level) up to two times 
(see Section A155.1.6.1 for details). 

Appendix 15:  Study Details Specific to Atezo  Chemo  Bev Arm (Cohort 1) 
  
Pancreatic Immunotherapy Combinations—F. Hoffmann-La Roche Ltd 
277/Protocol WO39608, Version 16
 
 
Table A15‑5 Guidelines for Management of Patients Who Experience 
Specific Adverse Events in Atezo  Chemo  Bev Arm (cont.) 
Event 
Action to Be Taken 
Bevacizumab-related toxicities not described above 
Grade 1 or 2 
 Continue atezolizumab, nab-paclitaxel, gemcitabine, and 
bevacizumab. 
Grade 3 
 Continue atezolizumab.  Withhold bevacizumab, 
nab-paclitaxel, and gemcitabine. 
 If event resolves to Grade 2 or better  56 days after event 
onset, resume nab-paclitaxel, gemcitabine, and bevacizumab 
and consider reducing nab-paclitaxel and gemcitabine dose by 
one level. b  If not, permanently discontinue nab-paclitaxel, 
gemcitabine, and bevacizumab. a 
Grade 4 
 Withhold atezolizumab, nab-paclitaxel, gemcitabine, and 
bevacizumab. 
 If event improves, resume atezolizumab.  If not, permanently 
discontinue atezolizumab. a 
 If event resolves to Grade 2 or better  56 days after event 
onset, resume nab-paclitaxel, gemcitabine, and bevacizumab 
and consider reducing nab-paclitaxel and gemcitabine dose by 
one level. b  If not, permanently discontinue nab-paclitaxel, 
gemcitabine, and bevacizumab. a 
Atezo  Chemo  Bev  atezolizumab plus chemotherapy (nab-paclitaxel and gemcitabine) plus 
bevacizumab; CRS  cytokine release syndrome; IRR  infusion-related reaction; 
nab-paclitaxel  nanoparticle albuminbound paclitaxel. 
a Resumption of treatment may be considered if the investigator believes the patient is likely to 
derive clinical benefit.  The decision to re-challenge patients should be based on investigator's 
assessment of benefitrisk and documented by the investigator (or an appropriate delegate).  
The Medical Monitor is available to advise as needed. 
b The dose of nab-paclitaxel may be reduced by 25 mg/m2 (one dose level) up to two times and 
the dose of gemcitabine may be reduced by 200 mg/m2 (one dose level) up to two times 
(see Section A155.1.6.1 for details). 

Appendix 15:  Study Details Specific to Atezo  Chemo  Bev Arm (Cohort 1) 
  
Pancreatic Immunotherapy Combinations—F. Hoffmann-La Roche Ltd 
278/Protocol WO39608, Version 16
 
 
Table A15‑5 Guidelines for Management of Patients Who Experience 
Specific Adverse Events in Atezo  Chemo  Bev Arm (cont.) 
Event 
Action to Be Taken 
Atezolizumab-related toxicities not described above 
Grade 1 or 2 
 Follow guidelines for atezolizumab in Appendix 2. 
 Continue nab-paclitaxel, gemcitabine, and bevacizumab. 
Grade 3 or 4 
 Follow guidelines for atezolizumab in Appendix 2. 
 Withhold nab-paclitaxel, gemcitabine, and bevacizumab. 
 If event resolves to Grade 2 or better  56 days after event 
onset, resume nab-paclitaxel, gemcitabine, and bevacizumab 
and consider reducing nab-paclitaxel and gemcitabine dose by 
one level. b  If not, permanently discontinue nab-paclitaxel, 
gemcitabine, and bevacizumab. a 
Atezo  Chemo  Bev  atezolizumab plus chemotherapy (nab-paclitaxel and gemcitabine) plus 
bevacizumab; CRS  cytokine release syndrome; IRR  infusion-related reaction; 
nab-paclitaxel  nanoparticle albuminbound paclitaxel. 
a Resumption of treatment may be considered if the investigator believes the patient is likely to 
derive clinical benefit.  The decision to re-challenge patients should be based on investigator's 
assessment of benefitrisk and documented by the investigator (or an appropriate delegate).  
The Medical Monitor is available to advise as needed. 
b The dose of nab-paclitaxel may be reduced by 25 mg/m2 (one dose level) up to two times and 
the dose of gemcitabine may be reduced by 200 mg/m2 (one dose level) up to two times 
(see Section A155.1.6.1 for details). 
 
A15–5.2 
ADVERSE EVENTS OF SPECIAL INTEREST FOR 
ATEZO  CHEMO  BEV ARM (IMMEDIATELY REPORTABLE 
TO THE SPONSOR) 
Adverse events of special interest are required to be reported by the investigator to 
the Sponsor immediately (i.e., no more than 24 hours after learning of the event; 
see Section 5.4.2 for reporting instructions).  Adverse events of special interest for the 
Atezo  Chemo  Bev arm are as follows: 
 
Cases of potential drug-induced liver injury that include an elevated ALT or AST in 
combination with either 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. 

Appendix 15:  Study Details Specific to Atezo  Chemo  Bev Arm (Cohort 1) 
  
Pancreatic Immunotherapy Combinations—F. Hoffmann-La Roche Ltd 
279/Protocol WO39608, Version 16
 
 
 
Pneumonitis 
 
Colitis 
 
Endocrinopathies:  diabetes mellitus, pancreatitis, adrenal insufficiency, 
hyperthyroidism, and hypophysitis 
 
Hepatitis, including AST or ALT  10  upper limit of normal 
 
Systemic lupus erythematosus 
 
Neurologic disorders:  Guillain-Barré syndrome, myasthenic syndrome or 
myasthenia gravis, and meningoencephalitis 
 
Events suggestive of hypersensitivity, IRRs, cytokine release syndrome, 
influenza-like illness, HLH, and MAS 
 
Nephritis 
 
Ocular toxicities (e.g., uveitis, retinitis) 
 
Myositis 
 
Myopathies, including rhabdomyolysis 
 
Grade  2 cardiac disorders (e.g., atrial fibrillation, myocarditis, pericarditis) 
 
 
 
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 grade arterial thromboembolic event 
 
Grade  3 venous thromboembolic event 
 
Any grade PRES 
 
Grade 3 CHF/left ventricular systolic dysfunction 
 
 
 
Severe cutaneous reactions (e.g., Stevens-Johnson syndrome, dermatitis bullous, 
toxic epidermal necrolysis) 
 
Myelitis 
 
Facial paresis  

Appendix 15:  Study Details Specific to Atezo  Chemo  Bev Arm (Cohort 1) 
  
Pancreatic Immunotherapy Combinations—F. Hoffmann-La Roche Ltd 
280/Protocol WO39608, Version 16
 
 
 
A15–5.3 
REPORTING REQUIREMENTS FOR PREGNANCIES IN 
ATEZO  CHEMO  BEV ARM 
A15–5.3.1 
Pregnancies in Female Patients 
Female patients of childbearing potential will be instructed to immediately inform the 
investigator if they become pregnant during the study or within 5 months after the last 
dose of atezolizumab, 6 months after the last dose of bevacizumab, or 6 months after 
the last dose of nab-paclitaxel or gemcitabine.  A 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. 
A15–5.3.2 
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 last dose of bevacizumab, nab-paclitaxel, or gemcitabine.  A 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.  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 when updated information on 
the course and outcome of the pregnancy 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 investigator and/or obstetrician. 

Appendix 15:  Study Details Specific to Atezo  Chemo  Bev Arm (Cohort 1) 
  
Pancreatic Immunotherapy Combinations—F. Hoffmann-La Roche Ltd 
281/Protocol WO39608, Version 16
 
 
A15–5.3.3 
Abortions 
Any 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). 
A15–5.3.4 
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). 
 

Appendix 15:  Study Details Specific to Atezo  Chemo  Bev Arm (Cohort 1) 
  
Pancreatic Immunotherapy Combinations—F. Hoffmann-La Roche Ltd 
282/Protocol WO39608, Version 16
 
 
A15–6 
SCHEDULES OF ACTIVITIES AND SAMPLE COLLECTION FOR ATEZO  CHEMO  BEV ARM 
Table A15-6 
Schedule of Activities for Atezo  Chemo  Bev Arm (Cohort 1) 
 
Stage 1 
Screening  
(see 
Appendix 6) 
Treatment Cycles (28-day cycles) a 
Treat. 
Discon. c 
Follow-Up c 
Cycle 1 b 
Cycles  2 
Day –28 
to –1 
Day 1 
 
Day 8 
(3 days) 
Day 15 
( 3 days) 
Day 1 
( 3 days) 
Day 8 
( 3 days) 
Day 15 
( 3 days) 
Every 
3 Months 
Molecular profile of pancreatic cancer 
(if available) 
See 
Appendix 6 
Whenever updated information becomes available  
 
Vital signs d 
x 
x  
x 
x 
x  
x 
x 
 
Weight 
x e 
x e 
x e 
x e 
x e 
x e 
x 
 
Complete physical examination f 
 
 
 
 
 
 
x 
 
Limited physical examination g 
x e 
x e 
x e 
x e 
x e 
x e 
 
 
ECOG Performance Status 
x e 
 
 
x e 
 
 
x 
 
ECG h 
Perform as clinically indicated e 
 
 
Hematology i 
x j, k 
x j 
x j 
x j 
x j 
x j 
x 
 
Chemistry l 
x j, k 
x j 
x j 
x j 
x j 
x j 
x 
 
Coagulation (INR and aPTT) 
x j, k 
 
 
x j 
 
 
x 
 
TSH, free T3 (or total T3), free T4 m 
x j, k, m 
x 
 
CA19-9 
x j 
 
 
x j 
 
 
x 
 
Pregnancy test o 
x j, k 
 
 
x j 
 
 
x 
x o 

Appendix 15:  Study Details Specific to Atezo  Chemo  Bev Arm (Cohort 1) 
  
Table A15‑6 
Schedule of Activities for Atezo  Chemo  Bev Arm (Cohort 1) (cont.) 
Pancreatic Immunotherapy Combinations—F. Hoffmann-La Roche Ltd 
283/Protocol WO39608, Version 16
 
 
 
Stage 1 
Screening  
(see 
Appendix 6) 
Treatment Cycles (28-day cycles) a 
Treat. 
Discon. c 
Follow-Up c 
Cycle 1 b 
Cycles  2 
Day –28 
to –1 
Day 1 
 
Day 8 
(3 days) 
Day 15 
( 3 days) 
Day 1 
( 3 days) 
Day 8 
( 3 days) 
Day 15 
( 3 days) 
Every 
3 Months 
Urinalysis p 
See 
Appendix 6 
x q 
 
 
x r 
 
 
x 
 
Serum autoantibody sample s 
Perform as clinically indicated t 
 
 
Tumor response assessments 
x y, z 
Concomitant medications aa 
x 
x 
x 
x 
x 
x 
x 
 
Adverse events bb 
x 
x 
x 
x 
x 
x 
x bb 
x bb 
Atezolizumab administration cc, dd 
x 
 
x 
x 
 
x 
 
 
Bevacizumab administration dd, ee 
x 
 
x 
x 
 
x 
 
 
Nab-paclitaxel and gemcitabine 
administration dd, ff 
x 
x 
x 
x 
x 
x 
 
 
Survival follow-up and anti-cancer 
treatment 
 
 
 
 
 
 
 
x gg 

Appendix 15:  Study Details Specific to Atezo  Chemo  Bev Arm (Cohort 1) 
  
Table A15‑6 
Schedule of Activities for Atezo  Chemo  Bev Arm (Cohort 1) (cont.) 
Pancreatic Immunotherapy Combinations—F. Hoffmann-La Roche Ltd 
284/Protocol WO39608, Version 16
 
 
ADA  anti-drug antibody; Atezo  Chemo  Bev  atezolizumab plus chemotherapy (nab-paclitaxel and gemcitabine) plus bevacizumab; CIT  cancer 
immunotherapy; CT  computed tomography; Discon.  discontinuation; ECOG  Eastern Cooperative Oncology Group; eCRF  electronic Case 
Report Form; 
; nab-paclitaxel  nanoparticle albuminbound paclitaxel; PK  pharmacokinetic; RBR  Research Biosample 
Repository; RECIST v1.1  Response Evaluation Criteria in Solid Tumors, Version 1.1; T3  triiodothyronine; T4  thyroxine; Treat.  treatment; 
TSH  thyroid-stimulating hormone. 
Note:  On treatment days, all assessments should be performed prior to dosing, unless otherwise specified. 
a 
If a visit is precluded because of a holiday, vacation, or other circumstance, it can occur outside of the specified window. 
b 
Treatment must be initiated at least 7 days after the baseline tumor biopsy (performed at study entry if deemed feasible by the investigator), 
and it is recommended that treatment be initiated no later than 7 days after randomization. 
c 
Patients will return to the clinic for a treatment discontinuation visit not more than 30 days after the last dose of study treatment.  The visit at 
which disease progression is confirmed may be used as the treatment discontinuation visit.  Patients will then undergo follow-up assessments. 
d 
Vital signs include respiratory rate, pulse rate, and systolic and diastolic blood pressure while the patient is in a seated position, pulse oximetry, 
and temperature.  Record new or worsened clinically significant abnormalities on the Adverse Event eCRF.  For the first infusion of 
atezolizumab, vital signs should be measured within 60 minutes prior to the infusion and, if clinically indicated, every 15 ( 5) minutes during 
and 30 ( 10) minutes after the infusion.  For subsequent infusions, vital signs should be measured within 60 minutes prior to the infusion and, if 
clinically indicated or if symptoms occurred during the previous infusion, during and 30 ( 10) minutes after the infusion.  For bevacizumab, vital 
signs should be measured within 60 minutes prior to and within 30 minutes after the infusion. 
e 
Assessment may be performed within 24 hours prior to dosing during the treatment period. 
f 
Complete physical examination includes evaluation of the head, eyes, ears, nose, and throat, and the cardiovascular, dermatologic, 
musculoskeletal, respiratory, gastrointestinal, genitourinary, and neurologic systems.  Record new or worsened clinically significant 
abnormalities on the Adverse Event eCRF. 
g 
Perform a limited, symptom-directed examination at specified timepoints and as clinically indicated at other timepoints.  Record new or 
worsened clinically significant abnormalities on the Adverse Event eCRF. 
h 
It is recommended that patients be resting in a supine position for at least 10 minutes prior to ECG recording. 
i 
Hematology includes WBC count, RBC count, hemoglobin, hematocrit, platelet count, and differential count (neutrophils, eosinophils, basophils, 
monocytes, lymphocytes, other cells). 
j 
Laboratory tests must be performed within 96 hours prior to dosing during the treatment period. 
k 
If screening laboratory assessments were performed within 96 hours prior to Day 1 of Cycle 1, they do not have to be repeated. 
 

Appendix 15:  Study Details Specific to Atezo  Chemo  Bev Arm (Cohort 1) 
  
Table A15‑6 
Schedule of Activities for Atezo  Chemo  Bev Arm (Cohort 1) (cont.) 
Pancreatic Immunotherapy Combinations—F. Hoffmann-La Roche Ltd 
285/Protocol WO39608, Version 16
 
 
l 
Chemistry panel (serum or plasma) includes bicarbonate or total carbon dioxide (if considered standard of care for the region), sodium, 
potassium, magnesium, chloride, glucose, BUN or urea, creatinine, total protein, albumin, phosphorus, calcium, total bilirubin, ALP, ALT, 
and AST. 
m TSH, free T3 (or total T3 for sites where free T3 is not performed), and free T4 will be assessed on Day 1 of Cycle 1 and every third cycle 
thereafter (i.e., Cycles 4, 7, 10, etc.). 
n 
o 
All women of childbearing potential will have urine or serum pregnancy tests performed at specified visits during treatment and at 3 months and 
6 months after the last dose of study treatment.  If a urine pregnancy test is positive, it must be confirmed by a serum pregnancy test. 
p 
Includes pH, specific gravity, glucose, protein, ketones, and blood; dipstick permitted. 
q 
Baseline urinalysis to be performed only if screening urinalysis is not performed within 7 days prior to initiation of study treatment.  Patients with 
 2+ protein on dipstick urinalysis must undergo a 24-hour urine collection and demonstrate  1 g of protein in 24 hours. 
r 
Urinalysis may be performed up to 72 hours prior to Day 1 of each cycle, as results must be available prior to treatment administration.  
Patients with Grade 2 proteinuria must undergo a 24-hour urine collection prior to the subsequent bevacizumab infusion.  Patients with Grade 3 
proteinuria must undergo a 24-hour urine collection prior to the current bevacizumab infusion.  Refer to Table A15-5 for details on management 
of proteinuria. 
s 
Autoantibody analysis includes anti-nuclear antibody, antidouble-stranded DNA, circulating anti-neutrophil cytoplasmic antibody, and 
perinuclear anti-neutrophil cytoplasmic antibody. 
t 
Autoantibody analysis should be repeated for patients who develop signs or symptoms suggestive of autoimmune disease (e.g., lupus 
erythematosus). 
u 
Not applicable for a site that has not been granted approval for RBR sampling.  Performed only for patients at participating sites who have 
provided written informed consent to participate. 
 
 
 
 

Appendix 15:  Study Details Specific to Atezo  Chemo  Bev Arm (Cohort 1) 
  
Table A15‑6 
Schedule of Activities for Atezo  Chemo  Bev Arm (Cohort 1) (cont.) 
Pancreatic Immunotherapy Combinations—F. Hoffmann-La Roche Ltd 
286/Protocol WO39608, Version 16
 
 
v 
w 
x 
y 
Patients will undergo tumor assessments at baseline, every 6 weeks ( 1 week) for the first 48 weeks following treatment initiation, and every 
12 weeks ( 2 weeks) thereafter, regardless of dose delays, until radiographic disease progression according to RECIST v1.1, except in the 
case of patients who continue treatment after radiographic disease progression; such patients will undergo tumor assessments every 6 weeks 
( 1 week) until loss of clinical benefit as determined by the investigator (see Section 3.1.2 for details).  Thus, tumor assessments are to 
continue according to schedule in patients who discontinue treatment for reasons other than disease progression, even if they start new 
nonprotocol-specified anti-cancer therapy. 
z 
All measurable and/or evaluable lesions identified at baseline should be re-assessed at subsequent tumor evaluations according to the tumor 
assessment schedule described above (see footnote “y”).  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).  Refer to Section 4.5.5 for further details on tumor 
assessments. 
aa Includes 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 study treatment from 10 days prior to initiation of study treatment until the treatment 
discontinuation visit. 
 
 

Appendix 15:  Study Details Specific to Atezo  Chemo  Bev Arm (Cohort 1) 
  
Table A15‑6 
Schedule of Activities for Atezo  Chemo  Bev Arm (Cohort 1) (cont.) 
Pancreatic Immunotherapy Combinations—F. Hoffmann-La Roche Ltd 
287/Protocol WO39608, Version 16
 
 
bb 
After this period, all deaths, regardless of cause, should be reported.  In addition, the Sponsor should be notified if the investigator becomes 
aware of any serious adverse event that is believed to be related to prior exposure to study treatment (see Section 5.6).  The investigator 
should follow each adverse event until the event has resolved to baseline grade or better, the event is assessed as stable by the investigator, 
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. 
cc Atezolizumab will be administered by IV infusion at a fixed dose of 840 mg on Days 1 and 15 of each 28-day cycle.  The initial dose of 
atezolizumab will be delivered over 60 ( 15) minutes.  Subsequent infusions will be delivered over 30 ( 10) minutes if the previous infusion 
was tolerated without infusion-associated adverse events, or 60 ( 15) minutes if the patient experienced an infusion-associated adverse event 
with the previous infusion.  Refer to Section A154.1.2.1, Table A15-2, for details on atezolizumab infusions (including measurement of vital 
signs). 
dd Treatment will continue until unacceptable toxicity or loss of clinical benefit as determined by the investigator (see Section 3.1.2 for details). 
ee Bevacizumab will be administered by IV infusion at a dose of 10 mg/kg on Days 1 and 15 of each 28-day cycle.  The initial dose of 
bevacizumab will be delivered over 90 ( 15) minutes.  Bevacizumab should be infused over 60 ( 10) minutes if the previous 90-minute 
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 may be infused over 30 ( 5) minutes thereafter.  Bevacizumab will 
be administered after completion of the atezolizumab infusion.  Bevacizumab must be administered  3 days after any on-treatment biopsy, but 
only after adequate wound healing has been demonstrated.  Refer to Section A154.1.2.2, Table A15-3, for details on bevacizumab infusions 
(including measurement of vital signs). 
ff 
On Days 1, 8, and 15, patients will receive nab-paclitaxel 125 mg/m2, administered by IV infusion over 30 ( 5) minutes, followed by 
gemcitabine 1000 mg/m2, administered by IV infusion over 30 ( 5) minutes.  On Days 1 and 15 of each cycle, nab-paclitaxel will be 
administered after completion of the bevacizumab infusion. 
 
 
 
 
 

Appendix 15:  Study Details Specific to Atezo  Chemo  Bev Arm (Cohort 1) 
  
Table A15‑6 
Schedule of Activities for Atezo  Chemo  Bev Arm (Cohort 1) (cont.) 
Pancreatic Immunotherapy Combinations—F. Hoffmann-La Roche Ltd 
288/Protocol WO39608, Version 16
 
 
gg 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 only.  For an experimental arm in which all patients discontinued 
treatment and passed the safety follow-up window, as well as approximately 80% of patients discontinued the study, the Sponsor may conclude 
the arm (the remaining approximately 20% of patients will be discontinued from the study). 

Appendix 15:  Study Details Specific to Atezo  Chemo  Bev Arm (Cohort 1) 
  
Pancreatic Immunotherapy Combinations—F. Hoffmann-La Roche Ltd 
289/Protocol WO39608, Version 16
 
 
Table A15-7 Schedule of Pharmacokinetic, Immunogenicity, and 
Biomarker Samples for Atezo  Chemo  Bev Arm (Cohort 1):  
Preliminary and Expansion Phases 
Visit 
Time 
Sample Type 
ADA  anti-drug antibody; Atezo  Chemo  Bev  atezolizumab plus chemotherapy 
(nab-paclitaxel and gemcitabine) plus bevacizumab; nab-paclitaxel  nanoparticle 
albuminbound paclitaxel; PBMC  peripheral blood mononuclear cell; 
PK  pharmacokinetic. 
Note:  On the basis of emerging safety or efficacy data, the number of PK and ADA 
samples may be reduced or sample collection may cease altogether.  Additionally, collected 
samples may not be analyzed if not warranted.  On the basis of emerging biomarker data, 
the number of biomarker samples may be reduced or sample collection may cease 
altogether. 

Appendix 15:  Study Details Specific to Atezo  Chemo  Bev Arm (Cohort 1) 
  
Pancreatic Immunotherapy Combinations—F. Hoffmann-La Roche Ltd 
290/Protocol WO39608, Version 16
 
 
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Appendix 15:  Study Details Specific to Atezo  Chemo  Bev Arm (Cohort 1) 
  
Pancreatic Immunotherapy Combinations—F. Hoffmann-La Roche Ltd 
293/Protocol WO39608, Version 16
 
 
Yang J, Riella LV, Chock S, et al. The novel costimulatory programmed death ligand 
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Pancreatic Immunotherapy Combinations—F. Hoffmann-La Roche Ltd 
294/Protocol WO39608, Version 16
 
 
Appendix 16  
Study Details Specific to Atezo  Chemo  TCZ Arm (Cohort 1) 
TABLE OF CONTENTS 
A16–1 
Background on Atezo  Chemo  TCZ Arm ............................. 297 
A16–1.1 
Background on Atezolizumab ................................................ 297 
A16–1.2 
Background on Nab‑Paclitaxel and Gemcitabine in 
Pancreatic Cancer ................................................................. 297 
A16–1.3 
Background on Tocilizumab................................................... 298 
A16–2 
Rationale for Atezo  Chemo  TCZ Arm ................................ 298 
A16–2.1 
The PD-L1 Pathway ............................................................... 298 
A16–2.2 
The IL-6 Pathway and Pancreatic Cancer ............................. 299 
A16–2.3 
Combined Inhibition OF the PD-L1 and antiIL-6 Pathways 
as Potential anti-Cancer Therapy .......................................... 300 
A16–2.4 
Clinical studies of atezolizumab In Combination with 
Tocilizumab............................................................................ 301 
A16–2.5 
Clinical Study of Atezolizumab in Combination with Nab-
Paclitaxel and Gemcitabine ................................................... 301 
A16–2.6 
Clinical Studies of Tocilizumab in Combination with 
Chemotherapy ....................................................................... 302 
A16–2.7 
Benefit–Risk Assessment ...................................................... 303 
A16–2.8 
COVID-19 Benefit–Risk Assessment ..................................... 303 
A16–3 
Rationale for Dose and Schedule for Atezo  Chemo  TCZ 
Arm ........................................................................................ 304 
A16–3.1 
Rationale for Atezolizumab Dose and Schedule .................... 304 
A16–3.2 
Rationale for Tocilizumab Dose and Schedule ...................... 304 
A16–4 
Materials and Methods Specific to Atezo  Chemo  TCZ 
Arm ........................................................................................ 305 
A16–4.1 
Treatment in Atezo  Chemo  TCZ Arm................................. 305 
A16–4.1.1 
Formulation, Packaging, and Handling .................................. 305 
A16–4.1.1.1 Atezolizumab ......................................................................... 305 
A16–4.1.1.2 Tocilizumab............................................................................ 305 
A16–4.1.1.3 Nab-Paclitaxel ........................................................................ 305 
A16–4.1.1.4 Gemcitabine ........................................................................... 305 
A16–4.1.2 
Dosage, Administration, and Compliance .............................. 305 
A16–4.1.2.1 Tocilizumab............................................................................ 306 

Appendix 16:  Study Details Specific to Atezo  Chemo  TCZ Arm (Cohort 1) 
  
Pancreatic Immunotherapy Combinations—F. Hoffmann-La Roche Ltd 
295/Protocol WO39608, Version 16
 
 
A16–4.1.2.2 Atezolizumab ......................................................................... 307 
A16–4.1.2.3 Nab-Paclitaxel and Gemcitabine ............................................ 309 
A16–4.2 
Concomitant Therapy for Atezo  Chemo  TCZ Arm ............. 309 
A16–4.2.1 
Permitted Therapy for Atezo  Chemo  TCZ Arm .................. 310 
A16–4.2.2 
Cautionary Therapy for Atezo  Chemo  TCZ Arm ................ 311 
A16–4.2.2.1 Corticosteroids ....................................................................... 311 
A16–4.2.2.2 Medications Given with Precaution due to Effects Related 
to Cytochrome P450 Enzymes .............................................. 312 
A16–4.2.2.3 Herbal Therapies ................................................................... 312 
A16–4.2.3 
Prohibited Therapy for Atezo  Chemo  TCZ Arm ................. 313 
A16–4.3 
Contraception Requirements for Atezo  Chemo  TCZ Arm .. 314 
A16–5 
Assessment of Safety for Atezo  Chemo  TCZ Arm ............. 315 
A16–5.1 
Safety Plan for Atezo  Chemo  TCZ Arm ............................. 315 
A16–5.1.1 
Risks Associated with Atezolizumab ...................................... 315 
A16–5.1.2 
Risks Associated with Nab-Paclitaxel .................................... 315 
A16–5.1.3 
Risks Associated with Gemcitabine ....................................... 316 
A16–5.1.4 
Risks Associated with Tocilizumab ........................................ 316 
A16–5.1.5 
Risks Associated with Combination Use of Atezolizumab, 
Nab‑Paclitaxel, Gemcitabine, and Tocilizumab...................... 317 
A16–5.1.6 
Management of Patients Who Experience Specific 
Adverse Events in Atezo  Chemo  TCZ Arm ........................ 317 
A16–5.1.6.1 Dose Modifications ................................................................ 317 
A16–5.1.6.2 Treatment Interruption for Toxicities ...................................... 318 
A16–5.1.6.3 Management Guidelines for Adverse Events ......................... 319 
A16–5.2 
Adverse Events of Special Interest for 
Atezo  Chemo  TCZ Arm (Immediately Reportable 
to the Sponsor) ...................................................................... 339 
A16–5.3 
Reporting Requirements for Pregnancies in 
Atezo  Chemo  TCZ Arm ...................................................... 341 
A16–5.3.1 
Pregnancies in Female Patients ............................................ 341 
A16–5.3.2 
Pregnancies in Female Partners of Male Patients ................. 341 
A16–5.3.3 
Abortions................................................................................ 342 
A16–5.3.4 
Congenital Anomalies/Birth Defects ...................................... 342 

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A16–6 
Schedules of Activities and Sample Collection for 
Atezo  Chemo  TCZ Arm ...................................................... 343 
 

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A16–1 
BACKGROUND ON ATEZO  CHEMO  TCZ ARM 
A16–1.1 
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 
and quality of tumor-specific T-cell responses, resulting in improved anti-tumor activity 
(Fehrenbacher et al. 2016; Rosenberg et al. 2016).  Atezolizumab has minimal binding 
to Fc receptors, thus eliminating detectable Fc-effector function and associated 
antibody-mediated clearance of activated effector T cells. 
Atezolizumab shows anti-tumor activity in both nonclinical models and cancer patients 
and is being investigated as a potential therapy in a wide variety of malignancies.  
Atezolizumab is being studied as a single agent in the advanced cancer and adjuvant 
therapy settings, as well as in combination with chemotherapy, targeted therapy, and 
cancer immunotherapy. 
Atezolizumab has been generally well tolerated.  Adverse events with potentially 
immune-mediated causes consistent with an immunotherapeutic agent, including rash, 
influenza-like illness, endocrinopathies, hepatitis or transaminitis, pneumonitis, colitis, 
and myasthenia gravis, have been observed (see Atezolizumab Investigator's Brochure 
for detailed safety results).  To date, these events have been manageable with 
treatment. 
Atezolizumab is approved for the treatment of urothelial carcinoma, nonsmall cell lung 
cancer, small-cell lung cancer, triple-negative breast cancer, hepatocellular carcinoma, 
melanoma, and alveolar soft part sarcoma. 
Refer to the Atezolizumab Investigator's Brochure for details on nonclinical and 
clinical studies. 
A16–1.2 
BACKGROUND ON NAB‑PACLITAXEL AND GEMCITABINE IN 
PANCREATIC CANCER  
Nanoparticle albuminbound paclitaxel (nab-paclitaxel) is a microtubule inhibitor that is 
approved in combination with gemcitabine for the first-line treatment of patients with 
metastatic adenocarcinoma of the pancreas.  Gemcitabine is a nucleoside metabolic 
inhibitor that is approved for the treatment of locally advanced or metastatic 
adenocarcinoma of the pancreas. 

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The combination of nab-paclitaxel and gemcitabine has been established as the 
standard-of-care chemotherapy regimen for metastatic pancreatic cancer and is 
classified as Category 1 (intervention is appropriate based upon high-level evidence) by 
the National Comprehensive Cancer Network for this indication (Von Hoff et al. 2013; 
NCCN 2017). 
A16–1.3 
BACKGROUND ON TOCILIZUMAB 
Tocilizumab is a recombinant humanized, anti-human monoclonal antibody of the 
IgG1 subclass directed against the soluble and membrane-bound interleukin 6 
receptor (IL-6R).  Tocilizumab binds specifically to both soluble IL-6R (sIL-6R) and 
membrane-bound IL-6R (mIL-6R) and has been shown to inhibit sIL-6R and 
mIL-6R-mediated signaling. 
Interleukin 6 (IL-6) is a pleiotropic pro-inflammatory, multifunctional cytokine produced by 
a variety of cell types.  It has been shown to be involved in such diverse physiological 
processes as T-cell activation; induction of acute-phase proteins; stimulation of 
hematopoietic precursor cell growth and differentiation; proliferation of hepatic, dermal, 
and neural cells; bone metabolism; lipid metabolism; hepatoprotection; and fibrosis.  
Elevated tissue and serum levels of IL-6 have been implicated in the disease pathology 
of several inflammatory and autoimmune disorders. 
Tocilizumab is approved for the treatment of rheumatoid arthritis, systemic juvenile 
idiopathic arthritis, polyarticular juvenile idiopathic arthritis, cytokine release syndrome 
(CRS), Castleman disease, giant cell arteritis, and Takayasu arteritis. 
Refer to the Tocilizumab Investigator’s Brochure for details on the nonclinical and 
clinical studies. 
A16–2 
RATIONALE FOR ATEZO  CHEMO  TCZ ARM 
A16–2.1 
THE PD-L1 PATHWAY 
Encouraging clinical data emerging in the field of tumor immunotherapy have 
demonstrated that therapies focused on enhancing T-cell responses against cancer can 
result in a significant survival benefit in patients with advanced malignancies 
(Hodi et al. 2010; Kantoff et al. 2010; Chen et al. 2012). 
The PD-L1 pathway serves as an immune checkpoint to temporarily dampen immune 
responses in states of chronic antigen stimulation, such as chronic infection or cancer.  
PD-L1 is an extracellular protein that downregulates immune responses through binding 
to its two receptors, PD-1 and B7-1.  PD-1 is an inhibitory receptor expressed on T cells 
following T-cell activation, and expression is sustained in states of chronic stimulation 
(Blank et al. 2005; Keir et al. 2008).  B7-1 is a molecule expressed on 

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antigen-presenting cells and activated T cells.  Binding of PD-L1 to PD-1 and B7-1 
inhibits T-cell proliferation and activation, cytokine production, and cytolytic activity, 
leading to the functional inactivation or exhaustion of T cells (Butte et al. 2007; 
Yang et al. 2011).  Overexpression of PD-L1 on tumor cells has been reported to impede 
anti-tumor immunity, resulting in immune evasion (Blank and Mackensen 2007).  
Therefore, interruption of the PD-L1 pathway represents an attractive strategy for 
restoring tumor-specific T-cell immunity. 
Targeting the PD-L1 pathway with atezolizumab has demonstrated activity in patients 
with advanced malignancies who have failed standard-of-care therapies.  Objective 
responses have been observed across a broad range of malignancies, including 
NSCLC, urothelial carcinoma, renal cell carcinoma, melanoma, colorectal cancer, head 
and neck cancer, gastric cancer, breast cancer, and sarcoma (see Atezolizumab 
Investigator's Brochure for detailed efficacy results). 
It has been shown that in pancreatic cancer tissues, both PD-L1 and PD-L2 are 
expressed and that tumor PD-L1 expression significantly correlates with postoperative 
prognosis.  Moreover, PD-L1 expression is inversely correlated with tumor-infiltrating 
lymphocytes, particularly CD8 T cells (Nomi et al. 2007).  However, no clinically 
significant response to single-agent checkpoint inhibitors has been observed in patients 
with pancreatic cancer (Royal et al. 2010; Brahmer et al. 2012). 
A16–2.2 
THE IL-6 PATHWAY AND PANCREATIC CANCER 
IL-6 regulates the proliferation, migration, activation, morphology, and metabolic state of 
virtually all cells that partake in cancer formation and progression (Chang et al. 2014).  
The IL-6 signaling pathway is abnormally regulated in a variety of malignancies 
through numerous mechanisms, including the overexpression of IL-6, IL-6R, sIL-6R, 
glycoprotein 130 (gp130), JAK, and STAT3 (Chang et al. 2014). 
Binding to gp130 initiates the activation of JAK/STAT3, MAPK, and PI3K pathways 
(Fisher et al. 2014).  sIL-6 and sIL-6R binding to gp130 (trans-signaling) is associated 
with the transition from acute to chronic inflammation and development of a pro-tumor 
state with shifts in the tumor microenvironment to include more tumor-associated 
macrophages, regulatory T cells, and myeloid-derived suppressor cells (Rose-John et al. 
2006; Scheller et al. 2011; Fisher et al. 2014). 
IL-6 is the major regulator of the acute phase response, an innate defense mechanism in 
response to inflammation and injury including cancer.  Importantly, C-reactive protein 
(CRP) is a prominent marker of the acute phase response and IL-6 production 
(Heinrich et al. 1990).  In cancer, there is a significant and direct correlation between 
serum IL-6 and CRP levels, with both correlating high levels to poor prognosis and lower 
overall survival (Mahmoud and Rivera 2002). 

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In pancreatic cancer, activating KRAS mutations that occur in 90% of patients induce an 
inflammatory response leading to the upregulation of IL-6 (Almoguera et al. 1988; 
Ancrile et al. 2007).  IL-6 signaling is required for tumor maintenance and progression 
(Fukuda et al. 2011; Lesina et al. 2011; Zhang et al. 2013), with high serum IL-6 and 
CRP levels correlating with advanced tumor stage and poor overall survival 
(Falconer et al. 1995; Talar-Wojnarowska et al. 2009; Farren et al. 2016).  
Additional data indicates that IL-6 interacts with the tumor microenvironment to promote 
tumor progression in multiple ways.  The pancreatic cancer tumor microenvironment is 
characterized as highly hypoxic and rich with a dense desmoplastic stroma that includes 
the extracellular matrix, growth factors, enzymes, and cytokines, in addition to 
fibroblasts, stellate cells, and immune cells (Feig et al. 2012).  In pancreatic cancer, IL-6 
expression is enhanced by hypoxia (Feurino et al. 2007; Bao et al. 2012), a condition 
that supports resistance to chemotherapy and radiotherapy, increasing the potential for a 
more invasive and aggressive disease (Le et al. 2004; Brown 2007).  Current data 
indicate that in pancreatic cancer, IL-6 is produced by several cells including 
immunosuppressive tumor-associated macrophages and pancreatic stellate cells 
resident in the tumor stroma (Lesina et al. 2011; Nagathihalli et al. 2016; Wu et al. 
2016).  Increased IL-6 secretion induces expression of vascular endothelial growth factor 
(VEGF) and matrix metalloproteinase-2 (MMP2), which can promote angiogenesis and 
tumor invasion (Masui et al. 2002; Tang et al. 2005; Huang et al. 2010).  Moreover, IL-6 
may promote a pro-tumorigenic environment by stimulating secretion of Th2 cytokines 
and suppressing dendritic cell differentiation and activation (Feurino et al. 2007; 
Bharadwaj et al. 2007).  Together, these data indicate that IL-6 contributes to a 
pro-tumorigenic microenvironment in pancreatic cancer.  
A16–2.3 
COMBINED INHIBITION OF THE PD-L1 AND ANTIIL-6 
PATHWAYS AS POTENTIAL ANTI-CANCER THERAPY 
Preclinical studies show that dual blockade of IL-6 and PD-L1 improved efficacy 
compared with blockade of either PD-L1 or IL-6 alone in mice bearing subcutaneous 
tumors of pancreatic cancer (Mace et al. 2018).  Observed tumor regression was 
dependent on the T-effector CD8+ lymphocyte population, and was associated with a 
concomitant increase in infiltrating T cells and a decrease in fibrotic stroma in the 
pancreas.  Moreover, the combined inhibition of both IL-6 and PD-L1 resulted in more 
circulating T cells with Th1 phenotypic characteristics and intratumoral effector T cells, 
suggesting that the tumor microenvironment was becoming less immunosuppressive 
and more anti-tumorigenic (Mace et al. 2018).  Likewise, similar results demonstrating 
the synergistic effects of IL-6 and PD-L1/PD-1 dual blockade providing improved 
efficacy have been observed in preclinical tumor lung and melanoma models 
(Tsukamoto et al. 2018; Ramos-Castaneda et al. 2019). 

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A16–2.4 
CLINICAL STUDIES OF ATEZOLIZUMAB IN COMBINATION 
WITH TOCILIZUMAB 
There are many therapies targeting the IL-6 pathway.  However, only tocilizumab and 
siltuximab are being evaluated in combination with anti-PD-L1/PD-1 therapies in cancer.  
Tocilizumab, an IL-6 receptor inhibitor, is a drug approved for autoimmune disorders, 
severe inflammation, and others.  Although there have been few evaluations of 
tocilizumab in patients with cancer, the efficacy and safety of atezolizumab in 
combination with tocilizumab as a treatment for patients with metastatic urothelial cancer 
is currently being investigated in Study WO39613.  A recent Internal Monitoring 
Committee (IMC) review of safety data from 10 safety evaluable patients randomized to 
the atezolizumab plus tocilizumab treatment arm concluded that the combination was 
well-tolerated, and safety findings were consistent with the known safety profile of each 
agent.  In addition, no new safety signals were identified (Roche data on file). 
Two additional on-going studies are evaluating dual IL6 and PD-L1/PD-1 blockade in 
pancreatic cancer: tocilizumab in combination with nivolumab, ipilimumab, and radiation 
in patients with advanced pancreatic cancer (NCT04258150); and siltuximab in 
combination with spartalizumab in patients with metastatic pancreatic cancer 
(NCT04191421). 
A16–2.5 
CLINICAL STUDY OF ATEZOLIZUMAB IN COMBINATION WITH 
NAB-PACLITAXEL AND GEMCITABINE 
An ongoing Phase I study (GO30140) includes an arm that is evaluating atezolizumab in 
combination with nab-paclitaxel and gemcitabine in treatment-naive patients with 
metastatic pancreatic cancer. 
Adverse events observed to date are consistent with the known risks of atezolizumab, 
nab-paclitaxel, and gemcitabine.  Atezolizumab in combination with cytotoxic 
chemotherapy has not been associated with additive severe (Grade  3) toxicities, 
indicating that atezolizumab can be safely combined with standard chemotherapy.  
As of the data cutoff date of 24 October 2017, the confirmed objective response rate 
was 41.7%, the median progression-free survival was 7 months, and the median 
overall survival was 10.6 months for 24 efficacy-evaluable patients with metastatic 
pancreatic cancer. 

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A16–2.6 
CLINICAL STUDIES OF TOCILIZUMAB IN COMBINATION WITH 
CHEMOTHERAPY 
Although there have been few evaluations of tocilizumab in patients with cancer, a 
Phase I dose-escalation study evaluated tocilizumab in combination with carboplatin and 
doxorubicin in patients with recurrent epithelial ovarian cancer (Dijkgraaf et al. 2015).  
Patients receiving the 8 mg/kg dose of tocilizumab in combination with carboplatin ad 
doxorubicin (with and without interferon-2b) showed a functional blockade of IL-6R with 
increased levels of serum IL-6 (p  0.02) and sIL-6R (p  0.008).  In addition, effects were 
seen in the immune cells with T cells showing higher levels of activation and increased 
secretion of interferon- and tumor necrosis factor (TNF-).  There were no 
dose-limiting toxicities among the 18 patients treated with tocilizumab at doses of up to 
8 mg/kg, administered by IV infusion every 4 weeks (Q4W).  The most frequent 
treatment-related events were fatigue, nausea or vomiting, and anorexia, and the 
most frequent Grade 3 or 4 events were neutropenia, febrile neutropenia, and ileus.  
There were no treatment-related deaths. 
Study JapicCTI-090889 is a Phase I/II multicenter, open-label study that evaluated 
tocilizumab in combination with gemcitabine in patients with treatment-naive advanced 
pancreatic cancer and high inflammatory burden (CRP  2 mg/dL) (Mitsunaga et al. 
2017).  Fifteen patients received tocilizumab at a dose of 8 mg/kg every 2 weeks (Q2W) 
with gemcitabine.  CRP levels initially decreased in all patients to below baseline levels 
after tocilizumab administration; decreases were sustained in 2 patients with partial 
response and 2 patients with stable disease.  Patients with modest CRP elevations 
( 2 to 10 mg/dL) tended to have better median overall survival compared with patients 
with high CRP ( 10 mg/dL) (5.8 vs. 1.6 months respectively; p  0.0937).  While changes 
in serum IL-6 were negligible in patients who achieved disease control, serum IL-6 levels 
tended to increase in patients who experienced disease progression.  In general, the 
Q2W tocilizumab regimen combined with gemcitabine was tolerable, with all treated 
patients experiencing an adverse event and 13 out of 15 patients (87%) experiencing 
Grade  3 adverse events.  The most frequent Grade  3 adverse events were 
thrombocytopenia (40%), leukopenia (40%), and neutropenia (33%).  Given that this 
study enrolled patients with advanced disease with a median CRP of 10.64 mg/dL and a 
poorer prognosis, the number of patient deaths (6), study drug withdrawals (1), and 
treatment interruptions (11) that were observed, irrespective of study treatment 
relatedness, were not unexpected.  
Additionally, there is an ongoing Phase II study evaluating tocilizumab in combination 
with nab-paclitaxel and gemcitabine in patients with unresectable pancreatic cancer 
(PACTO; NCT02767557), and a Phase Ib/II study evaluating tocilizumab in combination 
with nab-paclitaxel and atezolizumab in patients with metastatic triple-negative breast 
cancer (MORPHEUS-TNBC; NCT03424005). 

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A16–2.7 
BENEFIT–RISK ASSESSMENT 
Metastatic pancreatic ductal adenocarcinoma (PDAC) is an incurable disease with a 
high unmet need for improved medical intervention.  As described above, tocilizumab 
offers the potential to re-set the immune system by decreasing regulatory T cells, 
increasing effector T cells, and decreasing tumor-associated macrophages and 
myeloid-derived suppressor cells.  Additionally, tocilizumab may be able to reshape the 
tumor microenvironment to be less fibrotic, a major barrier to treatment in pancreatic 
cancer.  Taking into account the potentially synergistic mechanisms of action of 
tocilizumab with atezolizumab and chemotherapy based on preclinical and clinical data, 
as well as the manageable safety profiles of the above-described combinations, 
treatment with atezolizumab, chemotherapy (nab-paclitaxel and gemcitabine), and 
tocilizumab (Atezo  Chemo  TCZ) appears to have therapeutic potential in PDAC. 
Because of the potential for overlapping toxicities, a minimum of 6 patients in the 
Atezo  Chemo  TCZ arm must complete a safety evaluation before additional patients 
can be enrolled in that arm (see Section 3.1.3). 
A16–2.8 
COVID-19 BENEFIT–RISK ASSESSMENT 
In the setting of the coronavirus disease 2019 (COVID-19) pandemic, patients with 
comorbidities, including those patients with cancer, are a more vulnerable population.  
Infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been 
associated with higher morbidity and mortality in patients with cancer in some 
retrospective analyses.  It is unclear whether or how cancer therapies such as 
chemotherapy, targeted therapy, or immunotherapy impact the incidence or severity of 
COVID-19. 
Multiple clinical trials using atezolizumab, both as monotherapy and in different 
combinations, are ongoing during the COVID-19 pandemic.  At this time, there is 
insufficient evidence for a causal association between atezolizumab and an increased 
risk of COVID-19. 
Although the combination of atezolizumab, chemotherapy, and tocilizumab may 
potentially increase the risk of developing an infection, this is not specific to the risk of 
infection with SARS-CoV-2 (see Section A165.1).  Severe COVID-19 is associated with 
a CRS involving the inflammatory cytokines IL-6, IL-10, IL-2, and interferon- (IFN-).  
Tocilizumab, as an inhibitor of IL-6, may therefore reduce levels of IL-6, which are 
thought to be partially responsible for the enhanced inflammatory response if a patient 
develops SARS-Co-2 infection.  A single clinical trial with atezolizumab and tocilizumab 
is ongoing during this COVID-19 pandemic and, although the patient numbers are small, 
no increased risk of developing COVID-19 or of having a worse outcome has been 

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observed in patients receiving this combination.  Additionally, an interaction of 
tocilizumab with the COVID-19 vaccines is unlikely. 
For additional information on the evaluation of the impact of the COVID-19 pandemic 
and COVID-19 vaccination on the benefitrisk assessment, please refer to Section 1.5. 
A16–3 
RATIONALE FOR DOSE AND SCHEDULE FOR 
ATEZO  CHEMO  TCZ ARM 
A16–3.1 
RATIONALE FOR ATEZOLIZUMAB DOSE AND SCHEDULE 
Atezolizumab will be administered at a fixed dose of 1680 mg Q4W (1680 mg on Day 1 
of each 28-day cycle), which is an approved dosage for atezolizumab. 
A16–3.2 
RATIONALE FOR TOCILIZUMAB DOSE AND SCHEDULE 
Tocilizumab will be administered at a dose of 8 mg/kg Q4W (8 mg/kg on Day 1 of each 
28-day cycle), which is the approved dosage for tocilizumab for the treatment of 
rheumatoid arthritis.  In a Phase I dose-escalation study in patients with recurrent 
epithelial ovarian cancer (Dijkgraaf et al. 2015), pharmacodynamic effects were 
observed in patients receiving the 8 mg/kg Q4W dose of tocilizumab in combination 
with carboplatin and doxorubicin (with and without interferon-2b).  There were no 
dose-limiting or unexpected toxicities among the 18 patients treated with tocilizumab 
doses of up to 8 mg/kg Q4W (see Section A162.6). 
The available information, although not specifically addressing the combination of 
tocilizumab, checkpoint inhibitors, and chemotherapy, suggests that IV administration of 
tocilizumab 8 mg/kg Q4W in combination with atezolizumab and chemotherapy is 
reasonable and expected to result in an acceptable safety profile. 
This study contains all the safety measures of an early development study in that it 
enrolls only a well-defined patient population with good performance status that is 
selected based on the known safety profile of the combination partners.  At the same 
time, the study implements close safety monitoring, including frequent visits of patients 
to the site, strict inclusion/exclusion criteria, regular investigator calls, and the 
implementation of an IMC and a Scientific Oversight Committee. 

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A16–4 
MATERIALS AND METHODS SPECIFIC TO 
ATEZO  CHEMO  TCZ ARM 
A16–4.1 
TREATMENT IN ATEZO  CHEMO  TCZ ARM 
A16–4.1.1 
Formulation, Packaging, and Handling 
A16–4.1.1.1 Atezolizumab 
The atezolizumab drug product 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 formulation and handling of atezolizumab, see the pharmacy 
manual and the Atezolizumab Investigator's Brochure. 
A16–4.1.1.2 Tocilizumab 
The tocilizumab drug product will be supplied by the Sponsor as a sterile solution at a 
concentration of 20 mg/mL in a single-use vials containing 10 mL. 
For information on the formulation and handling of tocilizumab, see the pharmacy 
manual and the Tocilizumab Investigator's Brochure. 
A16–4.1.1.3 Nab-Paclitaxel 
For information on the formulation, packaging, and handling of nab-paclitaxel, refer to 
the local prescribing information. 
A16–4.1.1.4 Gemcitabine 
For information on the formulation, packaging, and handling of gemcitabine, refer to the 
local prescribing information. 
A16–4.1.2 
Dosage, Administration, and Compliance 
Patients in the Atezo  Chemo  TCZ arm will receive treatment as outlined in  
Table A16-1 until unacceptable toxicity or loss of clinical benefit as determined by the 
investigator after an integrated assessment of radiographic and biochemical data, local 
biopsy results (if available), and clinical status (e.g., symptomatic deterioration such as 
pain secondary to disease) (see Section 3.1.2 for details).  It is recommended that 
treatment be initiated no later than 7 days after randomization. 

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Table A16-1 
Treatment Regimen for Atezo  Chemo  TCZ Arm 
Cycle Length 
Dose, Route, and Regimen 
(drugs listed in order of administration) 
28 days 
 Tocilizumab 8 mg/kg IV on Day 1 of each cycle 
 Atezolizumab 1680 mg IV on Day 1 of each cycle a 
 Nab-paclitaxel 125 mg/m2 IV on Days 1, 8, and 15 of each cycle b 
 Gemcitabine 1000 mg/m2 IV on Days 1, 8, and 15 of each cycle 
Atezo  Chemo  TCZ  atezolizumab plus chemotherapy (nab-paclitaxel and gemcitabine) 
plus tocilizumab; nab-paclitaxel  nanoparticle albuminbound paclitaxel. 
a Atezolizumab should be administered 2 hours after completion of the tocilizumab 
infusion on Day 1 of the first two cycles.  On Day 1 of subsequent cycles, atezolizumab 
can be administered after completion of the tocilizumab infusion, as per instructions 
outlined in Section A164.1.2.2. 
b Nab-paclitaxel will be administered after completion of the atezolizumab infusion. 
 
Refer to the pharmacy manual for detailed instructions on drug preparation, storage, and 
administration. 
Medication errors 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.  
No safety data related to overdosing of atezolizumab is available.  For information on 
overdosing of gemcitabine or nab-paclitaxel, refer to the local prescribing information for 
each agent.  There are limited data available on overdose with tocilizumab.  One case of 
accidental overdose was reported in which a patient with multiple myeloma received a 
single IV dose of 40 mg/kg.  No adverse drug reactions were observed.  No serious 
adverse drug reactions were observed in healthy volunteers who received a single IV 
dose of up to 28 mg/kg; however, dose-related neutropenia was observed. 
A16–4.1.2.1 Tocilizumab 
Tocilizumab will be administered by IV infusion at a dose of 8 mg/kg on Day 1 of each 
28-day cycle.  The maximum dose is 800 mg (for patients weighing  100 kg).  The last 
recorded body weight of a patient should be used for calculating tocilizumab volumes for 
each infusion.  The dose administered should be within 10% of the calculated dose.  
No premedication is required before tocilizumab infusions.  
Administration of tocilizumab 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 5. 

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Tocilizumab should be infused over 60 ( 15) minutes.  The infusion speed must be 
10 mL/hr for 15 minutes and the increased to 130 mL/hr to complete the dosing over 
60 minutes.  In exceptional cases of infusion reactions, the infusion time may be 
extended to up to 6 hours.  Vital signs are recommended to be measured within 
60 minutes prior to the infusion, during the infusion if clinically indicated, and at 
30 ( 10) minutes after the infusion. 
Guidelines for medical management of IRRs for tocilizumab are provided in 
Section A165.1.6. 
Guidelines for tocilizumab dose modification and treatment interruption or 
discontinuation because of toxicities are provided in Section A165.1.6.  Tocilizumab 
treatment may be interrupted for reasons other than toxicity (e.g., surgical procedures).  
The acceptable length of treatment interruption must be based on an assessment of 
benefitrisk by the investigator and in alignment with the protocol requirements for the 
duration of treatment and documented by the investigator.  The Medical Monitor is 
available to advise as needed. 
A16–4.1.2.2 Atezolizumab 
Atezolizumab will be administered by IV infusion at a fixed dose of 1680 mg on Day 1 of 
each 28-day cycle.  Atezolizumab should be administered 2 hours after completion of 
the tocilizumab infusion on Day 1 of the first two cycles.  On Day 1 of subsequent cycles, 
if the patient has not experienced an infusion-related reaction with the previous infusion, 
atezolizumab can be administered 30 minutes after completion of the tocilizumab 
infusion.  If the patient has experienced an infusion-related reaction with the previous 
infusion, atezolizumab should be administered 2 hours after completion of the 
tocilizumab infusion. 
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 5.  
Atezolizumab infusions will be administered per the instructions outlined in Table A16-2. 

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Table A16-2 Administration of First and Subsequent Atezolizumab 
Infusions 
 
First Infusion 
Subsequent Infusions 
Atezolizumab 
infusion 
 
No premedication is permitted 
prior to the atezolizumab 
infusion. 
 
Vital signs (pulse rate, 
respiratory rate, blood pressure, 
pulse oximetry, and 
temperature) should be 
recorded within 60 minutes prior 
to the infusion. 
 
Atezolizumab should be infused 
over 60 ( 15) minutes. 
 
If clinically indicated, vital signs 
should be recorded every 
15 ( 5) minutes during the 
infusion. 
 
 
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 recorded 
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 
recorded during the infusion. 
Observation 
period after 
atezolizumab 
infusion 
 
After the atezolizumab infusion, 
patient should be observed for 
60 minutes.  
 
Vital signs should be recorded 
at 30 ( 10) minutes after the 
infusion. 
 
Patients will 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 tolerated the 
previous atezolizumab infusion 
well without infusion-associated 
adverse events, the observation 
period after the next and 
following infusions may be 
reduced to 30 minutes. 
 
If the patient experienced 
infusion-associated adverse 
events in the previous infusion, 
the observation period should be 
60 minutes.  
 
If clinically indicated, vital signs 
should be recorded at 
30 ( 10) minutes after the 
infusion. 
 
Guidelines for medical management of infusion-related reactions (IRRs) for 
atezolizumab are provided in Appendix 2.  

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No dose modification for atezolizumab is allowed.  Guidelines for treatment interruption 
or discontinuation because of toxicities are provided in Section A165.1.6.  
Atezolizumab treatment may be interrupted for reasons other than toxicity (e.g., surgical 
procedures).  The acceptable length of treatment interruption must be based on an 
assessment of benefitrisk by the investigator and in alignment with the protocol 
requirements for the duration of treatment and documented by the investigator.  The 
Medical Monitor is available to advise as needed. 
A16–4.1.2.3 Nab-Paclitaxel and Gemcitabine 
On Days 1, 8, and 15, patients will receive nab-paclitaxel 125 mg/m2, administered by IV 
infusion over 30 ( 5) minutes, followed by gemcitabine 1000 mg/m2, administered by IV 
infusion over 30 ( 5) minutes.  On Days 1 and 15 of each cycle, nab-paclitaxel will be 
administered after completion of the atezolizumab infusion. 
Nab-paclitaxel and gemcitabine will be administered according to institutional 
standards 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 5.   
Guidelines for nab-paclitaxel and gemcitabine dose modification and treatment 
interruption or discontinuation because of toxicities are provided in Section A165.1.6.  
Nab-paclitaxel and gemcitabine treatment may be interrupted for reasons other than 
toxicity (e.g., surgical procedures).  The acceptable length of treatment interruption must 
be based on an assessment of benefitrisk by the investigator and in alignment with the 
protocol requirements for the duration of treatment and documented by the 
investigator.  The Medical Monitor is available to advise as needed. 
A16–4.2 
CONCOMITANT THERAPY FOR ATEZO  CHEMO  TCZ ARM 
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 study treatment from 
10 days prior to initiation of study treatment 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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A16–4.2.1 
Permitted Therapy for Atezo  Chemo  TCZ Arm 
Patients are permitted to use the following therapies during the study: 
 
Colony-stimulating factors (CSFs), such as granulocyte colony-stimulating factors 
(G-CSFs), and erythropoiesis-stimulating agents (ESAs) per local 
practice/institutional guidelines or the American Society of Clinical Oncology 
guidelines for hematopoietic CSFs (Smith et al. 2006) and American Society of 
Hematology/American Society of Clinical Oncology guidelines for ESAs 
(Rizzo et al. 2010) 
Evidence supporting the use of long-acting (PEGylated) forms of G-CSF in 
patients receiving weekly chemotherapy (i.e., nab-paclitaxel) is limited.  
Thus, investigators should consider giving preference to conventional 
formulations of G-CSF. 
 
Oral contraceptives 
 
Hormone-replacement therapy 
 
Prophylactic or therapeutic anticoagulation therapy (such as warfarin at a stable 
dose or low-molecular-weight heparin) 
 
Vaccinations (such as influenza, COVID-19) 
Live, attenuated vaccines are not permitted (see Section A164.2.3). 
 
Megestrol acetate administered as an appetite stimulant after initiation of study 
treatment 
 
Mineralocorticoids (e.g., fludrocortisone) 
 
Inhaled corticosteroids administered for chronic obstructive pulmonary disease 
or asthma 
 
Low-dose corticosteroids administered for orthostatic hypotension or adrenocortical 
insufficiency 
 
Hormonal therapy with gonadotropinreleasing hormone agonists or antagonists for 
prostate cancer 
 
Palliative radiotherapy (e.g., treatment of known bony metastases or symptomatic 
relief of pain) as outlined below: 
Palliative radiotherapy is permitted, provided it does not interfere with the 
assessment of tumor target lesions (e.g., the lesion to be irradiated must not be 
the only site of measurable disease).  Treatment with atezolizumab, 
nab-paclitaxel, gemcitabine, and tocilizumab should be withheld during 
palliative radiotherapy. 

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311/Protocol WO39608, Version 16
 
 
 
Radiotherapy to the brain as outlined below: 
Patients whose extracranial tumor burden is stable or responding to study 
treatment and who are subsequently found to have three or fewer brain 
metastases may receive radiotherapy to the brain (either stereotactic 
radiosurgery or whole-brain radiation therapy) provided that all of the following 
criteria are met: 
– 
The patient has no evidence of progression or 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. 
Note:  Treatment with atezolizumab, nab-paclitaxel, gemcitabine, and 
tocilizumab should be withheld during CNS-directed radiation therapy. 
 
Premedication with antihistamines, antipyretics, and/or analgesics may be administered 
for the second and subsequent atezolizumab infusions only, at the discretion of the 
investigator. 
In general, investigators should manage a patient’s care with supportive therapies as 
clinically indicated, per local standard practice.  Patients who experience 
infusion-associated symptoms may be treated symptomatically with acetaminophen, 
ibuprofen, diphenhydramine, and/or H2-receptor antagonists (e.g., famotidine, 
cimetidine), or equivalent medications per local standard practice.  Serious 
infusion-associated events manifested by dyspnea, hypotension, wheezing, 
bronchospasm, tachycardia, reduced oxygen saturation, or respiratory distress should 
be managed with supportive therapies as clinically indicated (e.g., supplemental oxygen 
and 2-adrenergic agonists; see Appendix 5).   
A16–4.2.2 
Cautionary Therapy for Atezo  Chemo  TCZ Arm 
A16–4.2.2.1 Corticosteroids 
Systemic corticosteroids may attenuate potential beneficial immunologic effects of 
treatment with atezolizumab.  Therefore, in situations in which systemic corticosteroids 
would be routinely administered, alternatives, including antihistamines, should be 
considered.  If the alternatives are not feasible, systemic corticosteroids may be 
administered at the discretion of the investigator. 

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Systemic corticosteroids are recommended, at the discretion of the investigator, for the 
treatment of specific adverse events when associated with atezolizumab therapy 
(refer to Appendix 2 for details). 
A16–4.2.2.2 Medications Given with Precaution due to Effects Related to 
Cytochrome P450 Enzymes 
The formation of CYP450 enzymes may be suppressed by increased levels of cytokines 
(e.g., IL-6) during chronic inflammation.  Therefore, it is expected that for molecules that 
antagonize cytokine activity, such as tocilizumab, the formation of CYP450 enzymes 
could be normalized.  When starting or stopping therapy, patients taking medications 
that are individually dose adjusted and metabolized via CYP3A4, CYP1A2, or CYP2C9 
(e.g., atorvastatin, calcium channel blockers, theophylline, warfarin, phenytoin, 
cyclosporin, or benzodiazepines) should be monitored as doses may need to be 
adjusted to maintain therapeutic effect.  Given its long elimination half-life, the effect of 
tocilizumab on CYP450 enzyme activity may persist for several weeks after stopping 
therapy. 
The metabolism of nab-paclitaxel is catalyzed by CYP2C8 and CYP3A4.  Caution should 
be exercised when nab-paclitaxel is concomitantly administered with known CYP2C8 or 
CYP3A4 inhibitors (e.g., atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, 
nefazodone, nelfinavir, ritonavir, saquinavir, and telithromycin) or inducers (e.g., rifampin 
and carbamazepine). 
The above lists of cautionary medications are not necessarily comprehensive.  
The investigator should consult the prescribing information when determining whether a 
concomitant medication can be safety administered with study treatment.  In addition, 
the Medical Monitor is available to advise if questions arise regarding medications not 
listed above. 
A16–4.2.2.3 Herbal Therapies 
Concomitant use of herbal therapies is not recommended because their 
pharmacokinetics, safety profiles, and potential drug-drug interactions are generally 
unknown.  However, herbal therapies not intended for the treatment of cancer 
(see Section A164.2.3) may be used during the study at the discretion of the 
investigator. 

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313/Protocol WO39608, Version 16
 
 
A16–4.2.3 
Prohibited Therapy for Atezo  Chemo  TCZ Arm 
Use of the following concomitant therapies is prohibited as described below: 
 
Concomitant therapy intended for the treatment of cancer (including, but not limited 
to, chemotherapy, hormonal therapy, immunotherapy, radiotherapy, and herbal 
therapy), whether health authorityapproved or experimental, is prohibited for 
various time periods prior to starting study treatment, depending on the agent 
(see Section 4.1.2), and during study treatment until disease progression is 
documented and the patient has discontinued study treatment, with the exception of 
palliative radiotherapy and radiotherapy to the brain under circumstances outlined 
above in Section A164.2.1. 
 
Investigational therapy (other than protocol-mandated study treatment) is prohibited 
within 28 days prior to initiation of study treatment and during study treatment. 
 
Live, attenuated vaccines (e.g., FluMist) are prohibited within 4 weeks prior to 
initiation of study treatment, during treatment with atezolizumab and tocilizumab, 
and for 5 months after the last dose of atezolizumab or tocilizumab. 
 
Systemic immunostimulatory agents (including, but not limited to, interferons and 
interleukin-2) are prohibited within 4 weeks or 5 half-lives of the drug, whichever is 
longer, prior to initiation of study treatment and during study treatment because 
these agents could potentially increase the risk for autoimmune conditions when 
given in combination with atezolizumab. 
 
Systemic immunosuppressive medications, including, but not limited to, the 
following are prohibited during study treatment because these agents could 
potentially alter the efficacy and safety of atezolizumab and tocilizumab: 
– 
Thalidomide 
– 
TNF- inhibitors (e.g., etanercept, infliximab, adalimumab, certolizumab pegol, 
golimumab) 
– 
Anti-IL-1 medications (e.g., anakinra, canakinumab) 
– 
Abatacept 
– 
Rituximab 
– 
Anti-IL6 medications other than tocilizumab (e.g., sarilumab, siltuximab) 
– 
Oral JAKs (e.g., tofacitinib, baricitinib, ruxolitinib) 
– 
Conventional synthetic disease-modifying anti-rheumatic drugs 
(e.g., azathioprine, chlorambucil, chloroquine, hydroxychloroquine, 
cyclophosphamide, gold, leflunomide, methotrexate, minocycline, 
mycophenolate mofetil, mycophenolic acid, d-penicillamine, sulfasalazine) 
– 
Calcineurin inhibitors (e.g., tacrolimus and cyclosporine) 
 

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A16–4.3 
CONTRACEPTION REQUIREMENTS FOR 
ATEZO  CHEMO  TCZ ARM 
Contraception requirements for women and men in the Atezo  Chemo  TCZ arm are 
outlined below: 
 
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 during the treatment period and for 3 months after the last 
dose of tocilizumab, 5 months after the last dose of atezolizumab, 6 months 
after the last dose of nab-paclitaxel or gemcitabine.  Women must refrain from 
donating eggs during this same period. 
A woman is considered to be of childbearing potential if she is postmenarcheal, 
has not reached a postmenopausal state ( 12 continuous months of 
amenorrhea with no identified cause other than menopause), and has not 
undergone surgical sterilization (removal of ovaries and/or uterus). 
Examples of contraceptive methods with a failure rate of  1% per year include 
bilateral tubal ligation, male sterilization, hormonal contraceptives that inhibit 
ovulation, hormone-releasing intrauterine devices, and copper intrauterine 
devices. 
The reliability of sexual abstinence should be evaluated in relation to the 
duration of the clinical trial and the preferred and usual lifestyle of the patient.  
Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation 
methods) and withdrawal are not acceptable methods of contraception. 
 
For men:  agreement to remain abstinent (refrain from heterosexual intercourse) or 
use contraceptive methods, and agreement to refrain from donating sperm, as 
defined below: 
With female partners of childbearing potential, men who are receiving 
chemotherapy must remain abstinent or use a condom plus an additional 
contraceptive method that together result in a failure rate of  1% per year 
during the treatment period and for 6 months after the last dose of 
nab-paclitaxel or gemcitabine and men who are not receiving chemotherapy 
must remain abstinent or use a condom during the treatment period and for 
2 months after the last dose of tocilizumab.  Men must refrain from donating 
sperm during this same period. 
With pregnant female partners, men must remain abstinent or use a condom 
during the treatment period and for 2 months after the last dose of tocilizumab 
and 6 months after the last dose of nab-paclitaxel and gemcitabine to avoid 
exposing the embryo. 
The reliability of sexual abstinence should be evaluated in relation to the 
duration of the clinical trial and the preferred and usual lifestyle of the patient.  

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Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation 
methods) and withdrawal are not acceptable methods of contraception. 
 
A16–5 
ASSESSMENT OF SAFETY FOR ATEZO  CHEMO  TCZ ARM 
A16–5.1 
SAFETY PLAN FOR ATEZO  CHEMO  TCZ ARM 
The safety plan for patients in this study is based on clinical experience with 
atezolizumab, nab-paclitaxel, gemcitabine, and tocilizumab in completed and 
ongoing studies.  The anticipated important safety risks are outlined below 
(see Sections A165.1.1, A165.1.2, A165.1.3, A165.1.4, and A165.1.5).  Guidelines 
for management of patients who experience specific adverse events are provided in 
Section A165.1.6. 
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 study treatment 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.  Adverse events will 
be reported as described in Sections 5.25.6. 
A16–5.1.1 
Risks Associated with Atezolizumab 
Atezolizumab has been associated with risks such as the following:  IRRs and 
immune-mediated hepatitis, pneumonitis, colitis, pancreatitis, diabetes mellitus, 
hypothyroidism, hyperthyroidism, adrenal insufficiency, hypophysitis, Guillain-Barré 
syndrome, myasthenic syndrome or myasthenia gravis, facial paresis, myelitis, 
meningoencephalitis, myocarditis, pericardial disorders, nephritis, myositis, and severe 
cutaneous adverse reactions.  In addition, immune-mediated reactions may involve any 
organ system and may lead to hemophagocytic lymphohistiocytosis (HLH).  Refer to 
Appendix 2 of the protocol and Section 6 of the Atezolizumab Investigator's Brochure for 
a detailed description of anticipated safety risks for atezolizumab. 
A16–5.1.2 
Risks Associated with Nab-Paclitaxel 
The following are the most common adverse events observed with nab-paclitaxel in 
patients with PDAC:  neutropenia, fatigue, peripheral neuropathy, nausea, alopecia, 
peripheral edema, diarrhea, pyrexia, vomiting, decreased appetite, rash, and 
dehydration.  The following adverse events have also been observed:  
myelosuppression (primarily neutropenia, anemia, thrombocytopenia), cranial nerve 
palsies, hypersensitivity reactions, pneumonitis, myalgia, arthralgia, cardiotoxicity 
(myocardial disorders, cardiac failure, angina, tachycardia, ventricular arrhythmia), 
cystoid macular edema, Stevens-Johnson syndrome/toxic epidermal necrolysis, sepsis, 
infusion-site reactions/extravasation, hepatic toxicity (drug-induced liver injury), acute 
renal failure, scleroderma, and drug-induced lupus erythematous. 

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For more details regarding the safety profile for nab-paclitaxel, refer to the nab-paclitaxel 
prescribing information. 
A16–5.1.3 
Risks Associated with Gemcitabine 
The most common adverse events observed with gemcitabine are nausea/vomiting, 
anemia, hepatic transaminitis, neutropenia, increased ALP, proteinuria, fever, hematuria, 
rash, thrombocytopenia, dyspnea, and peripheral edema.  The following adverse events 
have also been observed:  renal failure, hemolytic-uremic syndrome, interstitial 
pneumonitis, myocardial infarction, arrhythmia, and heart failure. 
For more details regarding the safety profile for gemcitabine, refer to the gemcitabine 
prescribing information. 
A16–5.1.4 
Risks Associated with Tocilizumab 
Clinical experience to date focuses on the non-oncology disease setting.  On the basis 
of the safety data from the tocilizumab prescribing information, adverse drug reactions 
include infections (including opportunistic and serious infections), hypersensitivity 
(including anaphylaxis and fatal IRRs), GI disorders (including GI perforation), skin and 
subcutaneous tissue disorders (rash, pruritus, urticaria), nervous system disorders 
(including headache and dizziness), hematologic abnormalities (neutropenia, 
thrombocytopenia), elevated lipids (cholesterol, triglycerides), hepatotoxicity (hepatitis, 
jaundice, and serious drug-induced liver injury, including acute liver failure), respiratory 
events (cough, dyspnea), hypertension, conjunctivitis, nephrolithiasis, and 
hypothyroidism.  Additional potential risks include demyelinating disorders, 
Stevens-Johnson syndrome, malignancies, CYP450 enzyme normalization, and 
immunogenicity. 
Serious and sometimes fatal infections due to bacterial, mycobacterial, invasive fungal, 
viral, protozoal, or other opportunistic pathogens have been reported in patients 
receiving tocilizumab.  The effects of tocilizumab on high-sensitivity CRP, neutrophils, 
and the signs and symptoms of infection should be considered when evaluating a patient 
for potential infection.  Vigilance for timely detection of serious infection is recommended 
for patients receiving tocilizumab, as signs and symptoms of acute inflammation may be 
lessened due to suppression of the acute phase reaction.  Patients must be instructed to 
contact their physician immediately when any symptoms suggesting infection appear. 
Patients should be made aware of the symptoms potentially indicative of diverticular 
disease, and they should be instructed to alert their doctor as soon as possible if these 
symptoms arise. 

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The effect of treatment with tocilizumab on demyelinating disorder is not known; events 
have rarely been reported.  Patients should be closely monitored for signs and 
symptoms potentially indicative of central demyelinating disorders. 
Refer to the Tocilizumab Investigator's Brochure for a detailed description of all 
anticipated risks for tocilizumab. 
A16–5.1.5 
Risks Associated with Combination Use of Atezolizumab, 
Nab‑Paclitaxel, Gemcitabine, and Tocilizumab 
The following adverse events are potential overlapping toxicities associated with 
combination use of atezolizumab, nab-paclitaxel, gemcitabine, and tocilizumab:  IRRs, 
dermatologic events, hepatic events, hypersensitivity, pneumonitis, infections, GI events, 
neutropenia, and thrombocytopenia.  
A16–5.1.6 
Management of Patients Who Experience Specific Adverse 
Events in Atezo  Chemo  TCZ Arm 
On Day 1 of each cycle, patients are required to have an ANC of  1.5  109/L (1500/L) 
and a platelet count of  100  109/L (100,000/L) to receive treatment with nab-paclitaxel 
and gemcitabine.  Guidelines for management of hematologic toxicities and other 
toxicities (including guidelines for dose modification and treatment interruption or 
discontinuation) are provided in Table A16-4. 
A16–5.1.6.1 Dose Modifications 
There will be no dose modifications for atezolizumab in this study. 
For management of drug-related toxicities, the dose of nab-paclitaxel may be reduced by 
25 mg/m2 (one dose level) up to two times, the dose of gemcitabine may be reduced by 
200 mg/m2 (one dose level) up to two times, and the dose of tocilizumab may be 
reduced by 4 mg/kg (one dose level) up to one time, as outlined in Table A16-3. 
Table A16-3 Recommended Dose Reductions for Nab-Paclitaxel, 
Gemcitabine and Tocilizumab 
 
Initial Dose 
First Dose Reduction 
Second Dose Reduction 
Nab-paclitaxel 
125 mg/m2 
100 mg/m2 
75 mg/m2 
Gemcitabine 
1000 mg/m2 
800 mg/m2 
600 mg/m2 
Tocilizumab 
8 mg/kg 
4 mg/kg 
NA 
NA = not applicable; Nab-paclitaxel  nanoparticle albuminbound paclitaxel. 
 
If further dose reduction is indicated for nab-paclitaxel and/or gemcitabine after two dose 
reductions, that drug (or both drugs, if applicable) should be discontinued, but the patient 

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may continue other study treatments at the investigator’s discretion.  If further dose 
reduction is indicated for tocilizumab after one dose reduction, tocilizumab should be 
discontinued, but the patient may continue other study treatments at the investigator's 
discretion. 
After any dose reduction, the dose may be escalated during subsequent administrations 
at the investigator's discretion. 
A16–5.1.6.2 Treatment Interruption for Toxicities 
Atezolizumab treatment may be temporarily suspended in patients experiencing toxicity 
considered to be related to study treatment.  If corticosteroids are initiated for treatment 
of the toxicity, they must be tapered over  1 month to  10 mg/day oral prednisone or 
equivalent before atezolizumab can be resumed.  If atezolizumab is withheld for 
 12 weeks, the patient will be discontinued from atezolizumab.  However, atezolizumab 
may be withheld for  12 weeks to allow for patients to taper off corticosteroids prior to 
resuming treatment.  Atezolizumab can be resumed after being withheld for  12 weeks if 
the patient is likely to derive clinical benefit.  The decision to re-challenge patients with 
atezolizumab should be based on investigator's assessment of benefitrisk and 
documented by the investigator.  The Medical Monitor is available to advise as needed. 
Nab-paclitaxel and/or gemcitabine treatment may be temporarily suspended in patients 
experiencing toxicity considered to be related to study treatment (see Table A16-4).  
If nab-paclitaxel or gemcitabine have been withheld for  56 days because of toxicity, the 
patient should be discontinued from both chemotherapy agents.  However, 
nab-paclitaxel or gemcitabine can be resumed after being withheld for  56 days if the 
patient is likely to derive clinical benefit.  The decision to re-challenge patients with nab-
paclitaxel and/or gemcitabine should be based on investigator's assessment of 
benefitrisk and documented by the investigator.  The Medical Monitor is available to 
advise as needed. 
Tocilizumab treatment may be temporarily suspended in patients experiencing toxicity 
considered to be related to study treatment.  If tocilizumab has been withheld for 
 12 weeks, the patient should be discontinued from tocilizumab.  However, tocilizumab 
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 tocilizumab should be based 
on investigator's assessment of benefitrisk and documented by the investigator.  
The Medical Monitor is available to advise as needed. 
If atezolizumab, nab-paclitaxel, gemcitabine, or tocilizumab is discontinued, the other 
drugs can be continued if the patient is likely to derive clinical benefit, as determined by 
the investigator, with one exception: if atezolizumab, nab-paclitaxel and gemcitabine are 
discontinued, tocilizumab should also be discontinued. 

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Refer to Section A164.1.2 for information on dose interruptions for reasons other 
than toxicity. 
A16–5.1.6.3 Management Guidelines for Adverse Events 
Guidelines for management of patients who experience specific adverse events are 
provided in Table A16-4.  These guidelines are intended to inform rather than supersede 
an investigator's clinical judgment and assessment of the benefitrisk balance when 
managing individual cases. 
The investigator may use discretion in adhering to the guidelines for nab-paclitaxel and 
gemcitabine described below, taking into account the severity of the event and benefit 
versus risk for the patient, with the goal of maximizing patient compliance and access to 
supportive care.  Additionally, the prescribing information, as well as local hospital or 
clinical practice, must be followed. 

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Table A16-4 Guidelines for Management of Patients Who Experience 
Specific Adverse Events in Atezo  Chemo  TCZ Arm 
Event 
Action to Be Taken 
IRRs, CRS, anaphylaxis, and hypersensitivity reactions 
General guidance 
 Guidelines for management of IRRs and CRS for atezolizumab 
are provided in Appendix 2. 
 Guidelines for management of IRRs for tocilizumab and 
chemotherapy are provided below. 
 For anaphylaxis precautions, see Appendix 5. 
 For severe hypersensitivity reactions, permanently discontinue 
the causative agent. 
IRR to chemotherapy, 
Grade 1  
 Reduce infusion rate to half the rate being given at the time of 
event onset. 
 After the event has resolved, the investigator should wait for 
30 minutes while delivering the infusion at the reduced rate. 
 If the infusion is tolerated at the reduced rate for 30 minutes after 
symptoms have resolved, the infusion rate may be increased to 
the original rate. 
IRR to chemotherapy, 
Grade 2 
 Interrupt infusion. 
 Administer aggressive symptomatic treatment (e.g., oral or IV 
antihistamine, antipyretic, glucocorticoids, epinephrine, 
bronchodilators, oxygen). 
 After symptoms have resolved to baseline, resume infusion at 
half the rate being given at the time of event onset. 
 For subsequent infusions, administer oral premedication with 
antihistamine and antipyretic and monitor closely for IRRs. 
Atezo  Chemo  TCZ  atezolizumab plus chemotherapy (nab-paclitaxel and gemcitabine) plus 
tocilizumab; CRS  cytokine release syndrome; G-CSF  granulocyte colony-stimulating factor; 
IRR  infusion-related reaction; LFT  liver function test; nab-paclitaxel  nanoparticle 
albuminbound paclitaxel; ULN  upper limit of normal. 
a Resumption of treatment may be considered if the investigator believes the patient is likely to 
derive clinical benefit.  The decision to re-challenge patients should be based on investigator's 
assessment of benefitrisk and documented by the investigator (or an appropriate delegate).  
The Medical Monitor is available to advise as needed. 
b The dose of nab-paclitaxel may be reduced by 25 mg/m2 (one dose level) up to two times and 
the dose of gemcitabine may be reduced by 200 mg/m2 (one dose level) up to two times 
(see Section A165.1.6.1 for details). 

Appendix 16:  Study Details Specific to Atezo  Chemo  TCZ Arm (Cohort 1) 
  
Pancreatic Immunotherapy Combinations—F. Hoffmann-La Roche Ltd 
321/Protocol WO39608, Version 16
 
 
Table A16‑4 Guidelines for Management of Patients Who Experience 
Specific Adverse Events in Atezo  Chemo  TCZ Arm (cont.) 
Event 
Action to Be Taken 
IRRs, CRS, anaphylaxis, and hypersensitivity reactions (cont.) 
IRR to chemotherapy, 
Grade 3 or 4 
 Stop infusion. 
 Administer aggressive symptomatic treatment (e.g., oral or IV 
antihistamine, antipyretic, glucocorticoids, epinephrine, 
bronchodilators, oxygen). 
 Permanently discontinue treatment and contact Medical 
Monitor. a 
IRR to tocilizumab 
 If patient has symptoms of anaphylaxis or serious hypersensitivity 
or requires an interruption of tocilizumab because of symptoms of 
anaphylaxis or hypersensitivity, permanently discontinue 
tocilizumab. a  Obtain blood samples at the time of the event and 
8 weeks after the final dose of tocilizumab to enable 
pharmacokinetic, immunogenicity, and biomarker testing. 
 For lower grade IRR, initiate treatment as per institutional 
guidelines for management of IRRs and/or hypersensitivity 
reactions. 
Hemophagocytic 
lymphohistiocytosis  
 Follow guidelines for atezolizumab in Appendix 2. 
 Withhold all treatment and contact Medical Monitor. 
Atezo  Chemo  TCZ  atezolizumab plus chemotherapy (nab-paclitaxel and gemcitabine) plus 
tocilizumab; CRS  cytokine release syndrome; G-CSF  granulocyte colony-stimulating factor; 
IRR  infusion-related reaction; LFT  liver function test; nab-paclitaxel  nanoparticle 
albuminbound paclitaxel; ULN  upper limit of normal. 
a Resumption of treatment may be considered if the investigator believes the patient is likely to 
derive clinical benefit.  The decision to re-challenge patients should be based on investigator's 
assessment of benefitrisk and documented by the investigator (or an appropriate delegate).  
The Medical Monitor is available to advise as needed. 
b The dose of nab-paclitaxel may be reduced by 25 mg/m2 (one dose level) up to two times and 
the dose of gemcitabine may be reduced by 200 mg/m2 (one dose level) up to two times 
(see Section A165.1.6.1 for details). 

Appendix 16:  Study Details Specific to Atezo  Chemo  TCZ Arm (Cohort 1) 
  
Pancreatic Immunotherapy Combinations—F. Hoffmann-La Roche Ltd 
322/Protocol WO39608, Version 16
 
 
Table A16‑4 Guidelines for Management of Patients Who Experience 
Specific Adverse Events in Atezo  Chemo   TCZ Arm (cont.) 
Event 
Action to Be Taken 
Gastrointestinal toxicity 
Diarrhea or colitis, Grade 1 
 Follow guidelines for atezolizumab in Appendix 2. 
 Continue nab-paclitaxel, gemcitabine, and tocilizumab. 
Diarrhea or colitis, Grade 2 
 Follow guidelines for atezolizumab in Appendix 2. 
 Continue nab-paclitaxel and gemcitabine.  Continue tocilizumab for 
Grade 2 diarrhea.  Withhold tocilizumab for Grade 2 colitis. 
 If colitis resolved to Grade 1 or better  12 weeks after event onset, 
resume tocilizumab.  If not, permanently discontinue tocilizumab. a 
Diarrhea or colitis, Grade 3 
 Follow guidelines for atezolizumab in Appendix 2. 
 Withhold nab-paclitaxel, gemcitabine, and tocilizumab. 
 If event resolves to Grade 1 or better  56 days after event onset, 
resume nab-paclitaxel and gemcitabine with dose reduced by one 
level. b  If not, permanently discontinue nab-paclitaxel and 
gemcitabine. a 
 If event resolves to Grade 1 or better  12 weeks after event onset, 
resume tocilizumab.  If not, permanently discontinue tocilizumab. a 
Diarrhea or colitis, Grade 4 
 Follow guidelines for atezolizumab in Appendix 2. 
 Permanently discontinue nab-paclitaxel, gemcitabine, and 
tocilizumab. a  
Atezo  Chemo  TCZ  atezolizumab plus chemotherapy (nab-paclitaxel and gemcitabine) plus 
tocilizumab; CRS  cytokine release syndrome; G-CSF  granulocyte colony-stimulating factor; 
IRR  infusion-related reaction; LFT  liver function test; nab-paclitaxel  nanoparticle albuminbound 
paclitaxel; ULN  upper limit of normal. 
a Resumption of treatment may be considered if the investigator believes the patient is likely to 
derive clinical benefit.  The decision to re-challenge patients should be based on investigator's 
assessment of benefitrisk and documented by the investigator (or an appropriate delegate).  
The Medical Monitor is available to advise as needed. 
b The dose of nab-paclitaxel may be reduced by 25 mg/m2 (one dose level) up to two times and 
the dose of gemcitabine may be reduced by 200 mg/m2 (one dose level) up to two times 
(see Section A165.1.6.1 for details). 

Appendix 16:  Study Details Specific to Atezo  Chemo  TCZ Arm (Cohort 1) 
  
Pancreatic Immunotherapy Combinations—F. Hoffmann-La Roche Ltd 
323/Protocol WO39608, Version 16
 
 
Table A16‑4 Guidelines for Management of Patients Who Experience 
Specific Adverse Events in Atezo  Chemo  TCZ Arm (cont.) 
Event 
Action to Be Taken 
Gastrointestinal toxicity (cont.) 
Mucositis, Grade 1 or 2 
 Continue atezolizumab, nab-paclitaxel, gemcitabine, and 
tocilizumab. 
Mucositis, Grade 3 
 Continue atezolizumab.  Withhold nab-paclitaxel, gemcitabine, and 
tocilizumab. 
 If event resolves to Grade 1 or better  56 days after event onset, 
resume nab-paclitaxel and gemcitabine with dose reduced by one 
level. b  If not, permanently discontinue nab-paclitaxel and 
gemcitabine. a 
 If event resolved to Grade 1 or better  12 weeks after event onset, 
resume tocilizumab.  If not, permanently discontinue tocilizumab. a 
Mucositis, Grade 4 
 Permanently discontinue atezolizumab, nab-paclitaxel, 
gemcitabine, and tocilizumab. a 
Hemolytic-uremic syndrome 
Hemolytic-uremic syndrome, 
any grade 
 Permanently discontinue gemcitabine. a  Withhold atezolizumab, 
nab-paclitaxel, and tocilizumab. 
 If event improves, resume atezolizumab, nab-paclitaxel, and 
tocilizumab.  If not, permanently discontinue atezolizumab, 
nab-paclitaxel, and tocilizumab. a 
Capillary leak syndrome 
Capillary leak syndrome, 
any grade 
 Permanently discontinue gemcitabine. a  Withhold atezolizumab, 
nab-paclitaxel, and tocilizumab. 
 If event improves, resume atezolizumab, nab-paclitaxel, and 
tocilizumab.  If not, permanently discontinue atezolizumab, 
nab-paclitaxel, and tocilizumab. a 
Atezo  Chemo  TCZ  atezolizumab plus chemotherapy (nab-paclitaxel and gemcitabine) plus 
tocilizumab; CRS  cytokine release syndrome; G-CSF  granulocyte colony-stimulating factor; 
IRR  infusion-related reaction; LFT  liver function test; nab-paclitaxel  nanoparticle albuminbound 
paclitaxel; ULN  upper limit of normal. 
a Resumption of treatment may be considered if the investigator believes the patient is likely to 
derive clinical benefit.  The decision to re-challenge patients should be based on investigator's 
assessment of benefitrisk and documented by the investigator (or an appropriate delegate).  
The Medical Monitor is available to advise as needed. 
b The dose of nab-paclitaxel may be reduced by 25 mg/m2 (one dose level) up to two times and 
the dose of gemcitabine may be reduced by 200 mg/m2 (one dose level) up to two times 
(see Section A165.1.6.1 for details). 

Appendix 16:  Study Details Specific to Atezo  Chemo  TCZ Arm (Cohort 1) 
  
Pancreatic Immunotherapy Combinations—F. Hoffmann-La Roche Ltd 
324/Protocol WO39608, Version 16
 
 
Table A16‑4 Guidelines for Management of Patients Who Experience 
Specific Adverse Events in Atezo  Chemo  TCZ Arm (cont.) 
Event 
Action to Be Taken 
Dermatologic toxicity 
Dermatologic event, Grade 1  Follow guidelines for atezolizumab in Appendix 2. 
 Continue nab-paclitaxel, gemcitabine, and tocilizumab. 
Dermatologic event, Grade 2  Follow guidelines for atezolizumab in Appendix 2. 
 Continue nab-paclitaxel and gemcitabine with dose reduced by 
one level. b  Continue tocilizumab. 
 If event persists, permanently discontinue nab-paclitaxel and 
gemcitabine. a 
Dermatologic event, Grade 3  Follow guidelines for atezolizumab in Appendix 2. 
 Continue nab-paclitaxel and gemcitabine with dose reduced by 
one level. b  Withhold tocilizumab. 
 If event persists, permanently discontinue nab-paclitaxel and 
gemcitabine. a 
 If event resolves to Grade 1 or better  12 weeks after event 
onset, resume tocilizumab.  If not, permanently discontinue 
tocilizumab. a 
Dermatologic event, Grade 4  Follow guidelines for atezolizumab in Appendix 2. 
 Permanently discontinue nab-paclitaxel, gemcitabine, and 
tocilizumab. a 
Stevens-Johnson syndrome 
or toxic epidermal necrolysis 
(any grade) 
 Withhold atezolizumab, nab-paclitaxel, gemcitabine, and 
tocilizumab 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, nab-paclitaxel, 
gemcitabine, and tocilizumab. 
Atezo  Chemo  TCZ  atezolizumab plus chemotherapy (nab-paclitaxel and gemcitabine) plus 
tocilizumab; CRS  cytokine release syndrome; G-CSF  granulocyte colony-stimulating factor; 
IRR  infusion-related reaction; LFT  liver function test; nab-paclitaxel  nanoparticle 
albuminbound paclitaxel; ULN  upper limit of normal. 
a Resumption of treatment may be considered if the investigator believes the patient is likely to 
derive clinical benefit.  The decision to re-challenge patients should be based on investigator's 
assessment of benefitrisk and documented by the investigator (or an appropriate delegate).  
The Medical Monitor is available to advise as needed. 
b The dose of nab-paclitaxel may be reduced by 25 mg/m2 (one dose level) up to two times and 
the dose of gemcitabine may be reduced by 200 mg/m2 (one dose level) up to two times 
(see Section A165.1.6.1 for details). 

Appendix 16:  Study Details Specific to Atezo  Chemo  TCZ Arm (Cohort 1) 
  
Pancreatic Immunotherapy Combinations—F. Hoffmann-La Roche Ltd 
325/Protocol WO39608, Version 16
 
 
Table A16‑4 Guidelines for Management of Patients Who Experience 
Specific Adverse Events in Atezo  Chemo  TCZ Arm (cont.) 
Event 
Action to Be Taken 
Serious Infection 
 
Any grade 
 Withhold atezolizumab, nab-paclitaxel, gemcitabine, and 
tocilizumab. 
 If infection resolves, atezolizumab, nab-paclitaxel, gemcitabine, and 
tocilizumab may be continued at the discretion of the investigator. 
 If nab-paclitaxel and gemcitabine are withheld  56 days after event 
onset, permanently discontinue nab-paclitaxel and gemcitabine. a 
 If atezolizumab has been withheld for  12 weeks after event onset, 
permanently discontinue atezolizumab. a 
 If tocilizumab has been withheld for  12 weeks after event onset, 
permanently discontinue tocilizumab. a 
Febrile neutropenia 
Grade 3 or 4 
 Withhold atezolizumab, nab-paclitaxel, gemcitabine, and 
tocilizumab. 
 If fever resolves and ANC improves to  1.5  109/L (1500/L) 
 56 days after event onset, resume nab-paclitaxel and 
gemcitabine with dose reduced by one level b.  If not, permanently 
discontinue nab-paclitaxel and gemcitabine. a 
 If fever resolves and ANC improves to  1.5  109/L (1500/L) 
 12 weeks after event onset, resume atezolizumab and 
tocilizumab.  If not, permanently discontinue atezolizumab and 
tocilizumab. a 
 If treatment is resumed, G-CSF should be strongly considered for 
subsequent cycles. 
Atezo  Chemo  TCZ  atezolizumab plus chemotherapy (nab-paclitaxel and gemcitabine) plus 
tocilizumab; CRS  cytokine release syndrome; G-CSF  granulocyte colony-stimulating factor; 
IRR  infusion-related reaction; LFT  liver function test; nab-paclitaxel  nanoparticle albuminbound 
paclitaxel; ULN  upper limit of normal. 
a Resumption of treatment may be considered if the investigator believes the patient is likely to 
derive clinical benefit.  The decision to re-challenge patients should be based on investigator's 
assessment of benefitrisk and documented by the investigator (or an appropriate delegate).  
The Medical Monitor is available to advise as needed. 
b The dose of nab-paclitaxel may be reduced by 25 mg/m2 (one dose level) up to two times and 
the dose of gemcitabine may be reduced by 200 mg/m2 (one dose level) up to two times 
(see Section A165.1.6.1 for details). 
 

Appendix 16:  Study Details Specific to Atezo  Chemo  TCZ Arm (Cohort 1) 
  
Pancreatic Immunotherapy Combinations—F. Hoffmann-La Roche Ltd 
326/Protocol WO39608, Version 16
 
 
Table A16‑4 Guidelines for Management of Patients Who Experience 
Specific Adverse Events in Atezo  Chemo  TCZ Arm (cont.) 
Event 
Action to Be Taken 
Hematologic toxicity at Day 1 (excluding febrile neutropenia) 
ANC  1.5  109/L (1500/L) 
and 
Platelet count  100  109/L 
(100,000/L) 
 Continue atezolizumab, nab-paclitaxel, gemcitabine, and 
tocilizumab. 
ANC  0.5  109/L (500/L) but 
 1.5  109/L (1500/µL) 
And/or 
Platelet count  50  109/L 
(50,000/L) but <100  109/L 
(100,000/L) 
 Continue atezolizumab.  Withhold nab-paclitaxel, gemcitabine, 
and tocilizumab. 
 Permanently discontinue nab-paclitaxel and gemcitabine if 
withheld  56 days after event onset. a 
 If event improves, resume tocilizumab at 4 mg/kg.  If not, 
permanently discontinue tocilizumab. a 
 For recurrent neutropenia, permanently discontinue tocilizumab. a  
G-CSF should be strongly considered for subsequent cycles. 
ANC  0.5  109/L (500/L) 
and/or 
Platelet count  50  109/L 
(50,000/L) 
 Continue atezolizumab.  Withhold nab-paclitaxel and gemcitabine. 
Permanently discontinue tocilizumab. a 
 Permanently discontinue nab-paclitaxel or gemcitabine if withheld 
 56 days after event onset. a  
 For recurrent neutropenia, G-CSF should be strongly considered 
for subsequent cycles. 
Atezo  Chemo  TCZ  atezolizumab plus chemotherapy (nab-paclitaxel and gemcitabine) plus 
tocilizumab; CRS  cytokine release syndrome; G-CSF  granulocyte colony-stimulating factor; 
IRR  infusion-related reaction; LFT  liver function test; nab-paclitaxel  nanoparticle albuminbound 
paclitaxel; ULN  upper limit of normal. 
a Resumption of treatment may be considered if the investigator believes the patient is likely to 
derive clinical benefit.  The decision to re-challenge patients should be based on investigator's 
assessment of benefitrisk and documented by the investigator (or an appropriate delegate).  
The Medical Monitor is available to advise as needed. 
b The dose of nab-paclitaxel may be reduced by 25 mg/m2 (one dose level) up to two times and 
the dose of gemcitabine may be reduced by 200 mg/m2 (one dose level) up to two times 
(see Section A165.1.6.1 for details). 
 

Appendix 16:  Study Details Specific to Atezo  Chemo  TCZ Arm (Cohort 1) 
  
Pancreatic Immunotherapy Combinations—F. Hoffmann-La Roche Ltd 
327/Protocol WO39608, Version 16
 
 
Table A16‑4 Guidelines for Management of Patients Who Experience 
Specific Adverse Events in Atezo  Chemo  TCZ Arm (cont.) 
Event 
Action to Be Taken 
Hematologic toxicity at Day 8 (excluding febrile neutropenia) 
ANC  1.0  109/L (1000/L) 
and 
Platelet count  75  109/L 
(75,000/L) 
 Continue nab-paclitaxel, gemcitabine, and tocilizumab. 
ANC  0.5  109/L (500/L) 
but  1.0  109/L (1000/L) 
and/or 
Platelet count  50  109/L 
(50,000/L) but  75  109/L 
(75,000/L) 
 Continue nab-paclitaxel and gemcitabine with dose reduced by one 
level. b 
 Continue tocilizumab. 
 For recurrent neutropenia, permanently discontinue tocilizumab. a  
G-CSF should be strongly considered for subsequent cycles. 
ANC  0.5  109/L (500/L) 
and/or 
Platelet count  50  109/L 
(50,000/L) 
 Withhold nab-paclitaxel and gemcitabine. 
 Permanently discontinue tocilizumab. a 
 If nab-paclitaxel and gemcitabine are withheld  56 days after event 
onset, permanently discontinue nab-paclitaxel and gemcitabine. a 
 For recurrent neutropenia, G-CSF should be strongly considered 
for subsequent cycles. 
Atezo  Chemo  TCZ  atezolizumab plus chemotherapy (nab-paclitaxel and gemcitabine) plus 
tocilizumab; CRS  cytokine release syndrome; G-CSF  granulocyte colony-stimulating factor; 
IRR  infusion-related reaction; LFT  liver function test; nab-paclitaxel  nanoparticle albuminbound 
paclitaxel; ULN  upper limit of normal. 
a Resumption of treatment may be considered if the investigator believes the patient is likely to 
derive clinical benefit.  The decision to re-challenge patients should be based on investigator's 
assessment of benefitrisk and documented by the investigator (or an appropriate delegate).  
The Medical Monitor is available to advise as needed. 
b The dose of nab-paclitaxel may be reduced by 25 mg/m2 (one dose level) up to two times and 
the dose of gemcitabine may be reduced by 200 mg/m2 (one dose level) up to two times 
(see Section A165.1.6.1 for details). 
 

Appendix 16:  Study Details Specific to Atezo  Chemo  TCZ Arm (Cohort 1) 
  
Pancreatic Immunotherapy Combinations—F. Hoffmann-La Roche Ltd 
328/Protocol WO39608, Version 16
 
 
Table A16‑4 Guidelines for Management of Patients Who Experience 
Specific Adverse Events in Atezo  Chemo  TCZ Arm (cont.) 
Event 
Action to Be Taken 
Hematologic toxicity at Day 15 (excluding febrile neutropenia):  Day 8 doses given without 
modification 
ANC  1.0  109/L (1000/L) 
and 
Platelet count  75  109/L 
(75,000/L) 
 Continue atezolizumab, nab-paclitaxel, gemcitabine, and 
tocilizumab. 
ANC  0.5  109/L (500/L) but 
 1.0  109/L (1000/L) 
and/or 
Platelet count  50  109/L 
(50,000/L) but  75  109/L 
(75,000/L) 
 Continue atezolizumab.  Continue nab-paclitaxel and gemcitabine 
at current dose followed by G-CSF support or with dose reduced 
by one level. b 
 Withhold tocilizumab. 
 If event improves, resume tocilizumab at 4 mg/kg.  If not, 
permanently discontinue tocilizumab. a 
 For recurrent neutropenia, permanently discontinue tocilizumab. a  
G-CSF should be strongly considered for subsequent cycles. 
ANC  0.5  109/L (500/L) 
and/or 
Platelet count  50  109/L 
(50,000/L) 
 Withhold atezolizumab, nab-paclitaxel, and gemcitabine. 
 Permanently discontinue tocilizumab. a 
 If event improves, resume atezolizumab.  If not, permanently 
discontinue atezolizumab. a  
 If nab-paclitaxel and gemcitabine are withheld  56 days after 
event onset, permanently discontinue nab-paclitaxel, and 
gemcitabine. a 
 For recurrent neutropenia, G-CSF should be strongly considered 
for subsequent cycles. 
Atezo  Chemo  TCZ  atezolizumab plus chemotherapy (nab-paclitaxel and gemcitabine) plus 
tocilizumab; CRS  cytokine release syndrome; G-CSF  granulocyte colony-stimulating factor; 
IRR  infusion-related reaction; LFT  liver function test; nab-paclitaxel  nanoparticle albuminbound 
paclitaxel; ULN  upper limit of normal. 
a Resumption of treatment may be considered if the investigator believes the patient is likely to 
derive clinical benefit.  The decision to re-challenge patients should be based on investigator's 
assessment of benefitrisk and documented by the investigator (or an appropriate delegate).  
The Medical Monitor is available to advise as needed. 
b The dose of nab-paclitaxel may be reduced by 25 mg/m2 (one dose level) up to two times and 
the dose of gemcitabine may be reduced by 200 mg/m2 (one dose level) up to two times 
(see Section A165.1.6.1 for details). 

Appendix 16:  Study Details Specific to Atezo  Chemo  TCZ Arm (Cohort 1) 
  
Pancreatic Immunotherapy Combinations—F. Hoffmann-La Roche Ltd 
329/Protocol WO39608, Version 16
 
 
Table A16‑4 Guidelines for Management of Patients Who Experience 
Specific Adverse Events in Atezo  Chemo  TCZ Arm (cont.) 
Event 
Action to Be Taken 
Hematologic toxicity at Day 15 (excluding febrile neutropenia):  Day 8 doses reduced 
ANC  1.0  109/L (1000/L) 
and 
Platelet count  75  109/L 
(75,000/L) 
 Continue atezolizumab. 
 Continue nab-paclitaxel and gemcitabine at Day 1 doses followed 
by G-CSF support or at current dose. 
 Continue tocilizumab. 
ANC  0.5  109/L (500/L) but 
 1.0  109/L (1000/L) 
and/or 
Platelet count  50  109/L 
(50,000/L) but  75  109/L 
(75,000/L) 
 Continue atezolizumab.  Continue nab-paclitaxel and gemcitabine 
at current dose followed by G-CSF support or with dose reduced 
by one level. b 
 Withhold tocilizumab. 
 If event improves, resume tocilizumab at 4 mg/kg.  If not, 
permanently discontinue tocilizumab. a  
 For recurrent neutropenia, permanently discontinue tocilizumab. a  
G-CSF should be strongly considered for subsequent cycles. 
ANC  0.5  109/L (500/L) 
and/or 
Platelet count  50  109/L 
(50,000/L) 
 Withhold atezolizumab, nab-paclitaxel, and gemcitabine. 
 Permanently discontinue tocilizumab. a 
 If event improves, resume atezolizumab.  If not, permanently 
discontinue atezolizumab. a 
 If nab-paclitaxel and gemcitabine are withheld  56 days after 
event onset, permanently discontinue nab-paclitaxel and 
gemcitabine. a 
 For recurrent neutropenia, G-CSF should be strongly considered 
for subsequent cycles. 
Atezo  Chemo  TCZ  atezolizumab plus chemotherapy (nab-paclitaxel and gemcitabine) plus 
tocilizumab; CRS  cytokine release syndrome; G-CSF  granulocyte colony-stimulating factor; 
IRR  infusion-related reaction; LFT  liver function test; nab-paclitaxel  nanoparticle albuminbound 
paclitaxel; ULN  upper limit of normal. 
a Resumption of treatment may be considered if the investigator believes the patient is likely to 
derive clinical benefit.  The decision to re-challenge patients should be based on investigator's 
assessment of benefitrisk and documented by the investigator (or an appropriate delegate).  
The Medical Monitor is available to advise as needed. 
b The dose of nab-paclitaxel may be reduced by 25 mg/m2 (one dose level) up to two times and 
the dose of gemcitabine may be reduced by 200 mg/m2 (one dose level) up to two times 
(see Section A165.1.6.1 for details). 

Appendix 16:  Study Details Specific to Atezo  Chemo  TCZ Arm (Cohort 1) 
  
Pancreatic Immunotherapy Combinations—F. Hoffmann-La Roche Ltd 
330/Protocol WO39608, Version 16
 
 
Table A16‑4 Guidelines for Management of Patients Who Experience 
Specific Adverse Events in Atezo  Chemo  TCZ Arm (cont.) 
Event 
Action to Be Taken 
Hematologic toxicity at Day 15 (excluding febrile neutropenia):  Day 8 treatment was withheld 
ANC  1.0  109/L (1000/L) 
and 
Platelet count  75  109/L 
(75,000/L) 
 Continue atezolizumab.  Continue nab-paclitaxel and gemcitabine 
at current dose followed by G-CSF support or with dose reduced 
by one level. b 
 Continue tocilizumab. 
ANC  0.5  109/L (500/L) but 
 1.0  109/L (1000/L) 
and/or 
Platelet count  50  109/L 
(50,000/L) but  75  109/L 
(75,000/L) 
 Continue atezolizumab.  Continue nab-paclitaxel and gemcitabine 
with dose reduced by one level followed by G-CSF support or 
with dose reduced by two levels. b 
 Withhold tocilizumab. 
 If event improves, resume tocilizumab at 4 mg/kg.  If not, 
permanently discontinue tocilizumab. a  
 For recurrent neutropenia, permanently discontinue tocilizumab. a  
G-CSF should be strongly considered for subsequent cycles. 
ANC  0.5  109/L (500/L) 
and/or 
Platelet count  50  109/L 
(50,000/L) 
 Withhold atezolizumab, nab-paclitaxel, and gemcitabine. 
 Permanently discontinue tocilizumab. a 
 If event improves, resume atezolizumab.  If not, permanently 
discontinue atezolizumab. a 
 If nab-paclitaxel and gemcitabine are withheld  56 days after 
event onset, permanently discontinue nab-paclitaxel and 
gemcitabine. a 
 For recurrent neutropenia, G-CSF should be strongly considered 
for subsequent cycles. 
Atezo  Chemo  TCZ  atezolizumab plus chemotherapy (nab-paclitaxel and gemcitabine) plus 
tocilizumab; CRS  cytokine release syndrome; G-CSF  granulocyte colony-stimulating factor; 
IRR  infusion-related reaction; LFT  liver function test; nab-paclitaxel  nanoparticle albuminbound 
paclitaxel; ULN  upper limit of normal. 
a Resumption of treatment may be considered if the investigator believes the patient is likely to 
derive clinical benefit.  The decision to re-challenge patients should be based on investigator's 
assessment of benefitrisk and documented by the investigator (or an appropriate delegate).  
The Medical Monitor is available to advise as needed. 
b The dose of nab-paclitaxel may be reduced by 25 mg/m2 (one dose level) up to two times and 
the dose of gemcitabine may be reduced by 200 mg/m2 (one dose level) up to two times 
(see Section A165.1.6.1 for details). 
 

Appendix 16:  Study Details Specific to Atezo  Chemo  TCZ Arm (Cohort 1) 
  
Pancreatic Immunotherapy Combinations—F. Hoffmann-La Roche Ltd 
331/Protocol WO39608, Version 16
 
 
Table A16‑4 Guidelines for Management of Patients Who Experience 
Specific Adverse Events in Atezo  Chemo  TCZ Arm (cont.) 
Event 
Action to Be Taken 
Pulmonary events 
Pulmonary event, Grade 1  
 Follow guidelines for atezolizumab in Appendix 2. 
 Continue nab-paclitaxel, gemcitabine, and tocilizumab. 
 If diagnosis of pneumonitis is confirmed, permanently discontinue 
nab-paclitaxel and gemcitabine. a 
Pulmonary event, Grade 2 
 Follow guidelines for atezolizumab in Appendix 2. 
 Withhold nab-paclitaxel, gemcitabine, and tocilizumab. 
 If diagnosis of pneumonitis is confirmed, permanently discontinue 
nab-paclitaxel and gemcitabine. a 
 If non-pneumonitis event resolves to Grade 1 or better  56 days 
after event onset, resume nab-paclitaxel and gemcitabine.  If not, 
permanently discontinue nab-paclitaxel and gemcitabine. a 
 If event resolves to Grade 1 or better  12 weeks after event 
onset, resume tocilizumab.  If not, permanently discontinue 
tocilizumab. a 
 For recurrent events, treat as a Grade 3 or 4 event. 
Pulmonary event, Grade 3 
or 4 
 Follow guidelines for atezolizumab in Appendix 2. 
 Permanently discontinue nab-paclitaxel, gemcitabine, and 
tocilizumab. a 
Atezo  Chemo  TCZ  atezolizumab plus chemotherapy (nab-paclitaxel and gemcitabine) plus 
tocilizumab; CRS  cytokine release syndrome; G-CSF  granulocyte colony-stimulating factor; 
IRR  infusion-related reaction; LFT  liver function test; nab-paclitaxel  nanoparticle albuminbound 
paclitaxel; ULN  upper limit of normal. 
a Resumption of treatment may be considered if the investigator believes the patient is likely to 
derive clinical benefit.  The decision to re-challenge patients should be based on investigator's 
assessment of benefitrisk and documented by the investigator (or an appropriate delegate).  
The Medical Monitor is available to advise as needed. 
b The dose of nab-paclitaxel may be reduced by 25 mg/m2 (one dose level) up to two times and 
the dose of gemcitabine may be reduced by 200 mg/m2 (one dose level) up to two times 
(see Section A165.1.6.1 for details). 

Appendix 16:  Study Details Specific to Atezo  Chemo  TCZ Arm (Cohort 1) 
  
Pancreatic Immunotherapy Combinations—F. Hoffmann-La Roche Ltd 
332/Protocol WO39608, Version 16
 
 
Table A16‑4 Guidelines for Management of Patients Who Experience 
Specific Adverse Events in Atezo  Chemo  TCZ Arm (cont.) 
Event 
Action to Be Taken 
Elevations in AST, ALT, and/or bilirubin 
General Guidance  
 In patients experiencing elevations in AST/ALT and/or bilirubin, 
concurrent medications, viral hepatitis, and other possible 
etiologies should be considered and addressed as appropriate. 
AST/ALT > ULN to 
 3  ULN with total bilirubin 
 2  ULN 
 Continue atezolizumab, nab-paclitaxel, gemcitabine, and 
tocilizumab. 
 For persistent increases (two or more consecutive assessments 
at least 1 month apart) in patients who did not have elevated 
screening values, either reduce tocilizumab dose to 4 mg/kg or 
withhold tocilizumab. 
 If tocilizumab is withheld and values return to baseline within 
12 weeks, resume tocilizumab.  If not, consult with Medical 
Monitor to determine if tocilizumab should be permanently 
discontinued. 
AST/ALT  3 ULN to 
5  ULN with total bilirubin 
 ULN to  2  ULN 
 Continue atezolizumab, nab-paclitaxel, and gemcitabine.  
Withhold tocilizumab if AST/ALT and total bilirubin are elevated 
from baseline values. 
 For persistent increases (two or more consecutive assessments 
at least 1 month apart) in patients who did not have elevated 
screening values, permanently discontinue tocilizumab. a 
 Monitor LFTs at least weekly. 
 Consider patient referral to a hepatologist and liver biopsy. 
 If event resolves to AST/ALT  3  ULN with total bilirubin  2  ULN 
(or to baseline for patients who had elevated screening values) 
within 8 weeks, resume tocilizumab and consider reduction the 
dose to 4 mg/kg if AST/ALT is  ULN.  If not, permanently 
discontinue tocilizumab. a 
Suspected immune-mediated events of  5 days' duration: 
 Consider withholding atezolizumab. 
 Consider initiation of treatment with 12 mg/kg/day oral 
prednisone or equivalent. 
 If atezolizumab is withheld and event resolves to AST/ALT 
 3  ULN with total bilirubin  2  ULN within 12 weeks, resume 
atezolizumab at fixed dose.  If not, permanently discontinue 
atezolizumab and contact Medical Monitor. a 
Atezo  Chemo  TCZ  atezolizumab plus chemotherapy (nab-paclitaxel and gemcitabine) plus 
tocilizumab; CRS  cytokine release syndrome; G-CSF  granulocyte colony-stimulating factor; 
IRR  infusion-related reaction; LFT  liver function test; nab-paclitaxel  nanoparticle albuminbound 
paclitaxel; ULN  upper limit of normal. 
a Resumption of treatment may be considered if the investigator believes the patient is likely to 
derive clinical benefit.  The decision to re-challenge patients should be based on investigator's 
assessment of benefitrisk and documented by the investigator (or an appropriate delegate).  
The Medical Monitor is available to advise as needed. 
b The dose of nab-paclitaxel may be reduced by 25 mg/m2 (one dose level) up to two times and 
the dose of gemcitabine may be reduced by 200 mg/m2 (one dose level) up to two times 
(see Section A165.1.6.1 for details). 

Appendix 16:  Study Details Specific to Atezo  Chemo  TCZ Arm (Cohort 1) 
  
Pancreatic Immunotherapy Combinations—F. Hoffmann-La Roche Ltd 
333/Protocol WO39608, Version 16
 
 
Table A16‑4 Guidelines for Management of Patients Who Experience 
Specific Adverse Events in Atezo  Chemo  TCZ Arm (cont.) 
Event 
Action to Be Taken 
Elevations in AST, ALT, and/or bilirubin (cont.) 
AST/ALT  5  ULN to 
 10  ULN with total bilirubin 
 ULN to  2  ULN 
 Continue atezolizumab, nab-paclitaxel, and gemcitabine. 
Permanently discontinue tocilizumab. a 
 Monitor LFTs at least weekly. 
 Consider patient referral to hepatologist and liver biopsy. 
Suspected immune-mediated events: 
 Withhold atezolizumab. 
 Consider initiation of treatment with 12 mg/kg/day oral 
prednisone or equivalent.  
 If corticosteroids are initiated and event does not improve within 
48 hours, consider adding an immunosuppressive agent. 
 If event resolves to AST/ALT  3  ULN with total bilirubin 
 2  ULN within 12 weeks, resume atezolizumab at fixed dose.  
If not, permanently discontinue atezolizumab and contact Medical 
Monitor. a 
AST/ALT  ULN to 
 3  ULN with total bilirubin 
 2  ULN 
 Withhold atezolizumab, nab-paclitaxel, gemcitabine, and 
tocilizumab. 
 If event resolves to total bilirubin  2  ULN within 56 days, resume 
nab-paclitaxel and gemcitabine with the dose reduced by one 
level.  If not, permanently discontinue nab-paclitaxel and 
gemcitabine. a 
 If event resolves to total bilirubin  2  ULN within 12 weeks, 
resume atezolizumab and tocilizumab.  If not, permanently 
discontinue atezolizumab and tocilizumab and contact Medical 
Monitor. a 
 For persistent increases (two or more consecutive assessments 
at least 1 month apart) in patients who did not have elevated 
screening values, permanently discontinue tocilizumab. a 
Atezo  Chemo  TCZ  atezolizumab plus chemotherapy (nab-paclitaxel and gemcitabine) plus 
tocilizumab; CRS  cytokine release syndrome; G-CSF  granulocyte colony-stimulating factor; 
IRR  infusion-related reaction; LFT  liver function test; nab-paclitaxel  nanoparticle albuminbound 
paclitaxel; ULN  upper limit of normal. 
a Resumption of treatment may be considered if the investigator believes the patient is likely to 
derive clinical benefit.  The decision to re-challenge patients should be based on investigator's 
assessment of benefitrisk and documented by the investigator (or an appropriate delegate).  
The Medical Monitor is available to advise as needed. 
b The dose of nab-paclitaxel may be reduced by 25 mg/m2 (one dose level) up to two times and 
the dose of gemcitabine may be reduced by 200 mg/m2 (one dose level) up to two times 
(see Section A165.1.6.1 for details). 
 
 

Appendix 16:  Study Details Specific to Atezo  Chemo  TCZ Arm (Cohort 1) 
  
Pancreatic Immunotherapy Combinations—F. Hoffmann-La Roche Ltd 
334/Protocol WO39608, Version 16
 
 
Table A16‑4 Guidelines for Management of Patients Who Experience 
Specific Adverse Events in Atezo  Chemo  TCZ Arm (cont.) 
Event 
Action to Be Taken 
Elevations in AST, ALT, and/or bilirubin (cont.) 
AST/ALT  3  ULN to 
 10  ULN with total bilirubin 
 2  ULN 
 Withhold atezolizumab, nab-paclitaxel, and gemcitabine. 
Permanently discontinue tocilizumab. a 
 Monitor LFTs every 4872 hours until decreasing and then 
monitor weekly. 
 Refer patient to hepatologist and consider liver biopsy. 
 Consider initiation of treatment with 12 mg/kg/day oral 
prednisone or equivalent. 
 If corticosteroids are initiation and event does not improve within 
48 hours, considering adding an immunosuppressive agent. 
 If event resolves to AST/ALT  3  ULN with total bilirubin 
 2  ULN  56 days after event onset, resume nab-paclitaxel and 
gemcitabine with the dose reduced by one level.  If not, 
permanently discontinue nab-paclitaxel and gemcitabine. a 
 If event resolves to AST/ALT  3  ULN with total bilirubin 
 2  ULN within 12 weeks, resume atezolizumab.  If not, 
permanently discontinue atezolizumab and contact Medical 
Monitor. a 
 Permanently discontinue atezolizumab, nab-paclitaxel, and 
gemcitabine for life-threatening hepatic events and contact the 
Medical Monitor. a 
AST/ALT  10  ULN 
 Permanently discontinue nab-paclitaxel, gemcitabine, and 
tocilizumab, and contact Medical Monitor. a 
 Monitor LFTs every 4872 hours until decreasing and then 
monitor weekly. 
 Refer patient to hepatologist and consider liver biopsy. 
 Consider initiation of treatment with 12 mg/kg/day oral 
prednisone or equivalent. 
 If corticosteroids are initiated and event does not improve within 
48 hours, considering adding an immunosuppressive agent or 
escalating the corticosteroid dose. 
 If event resolved to AST/ALT  3  ULN with total bilirubin 
 2  ULN, taper corticosteroids over  1 month. 
Atezo  Chemo  TCZ  atezolizumab plus chemotherapy (nab-paclitaxel and gemcitabine) plus 
tocilizumab; CRS  cytokine release syndrome; G-CSF  granulocyte colony-stimulating factor; 
IRR  infusion-related reaction; LFT  liver function test; nab-paclitaxel  nanoparticle albuminbound 
paclitaxel; ULN  upper limit of normal. 
a Resumption of treatment may be considered if the investigator believes the patient is likely to 
derive clinical benefit.  The decision to re-challenge patients should be based on investigator's 
assessment of benefitrisk and documented by the investigator (or an appropriate delegate).  
The Medical Monitor is available to advise as needed. 
b The dose of nab-paclitaxel may be reduced by 25 mg/m2 (one dose level) up to two times and 
the dose of gemcitabine may be reduced by 200 mg/m2 (one dose level) up to two times 
(see Section A165.1.6.1 for details). 

Appendix 16:  Study Details Specific to Atezo  Chemo  TCZ Arm (Cohort 1) 
  
Pancreatic Immunotherapy Combinations—F. Hoffmann-La Roche Ltd 
335/Protocol WO39608, Version 16
 
 
Table A16‑4 Guidelines for Management of Patients Who Experience 
Specific Adverse Events in Atezo  Chemo  TCZ Arm (cont.) 
Event 
Action to Be Taken 
Endocrine events 
Asymptomatic 
hypothyroidism 
 Follow guidelines for atezolizumab in Appendix 2. 
 Continue nab-paclitaxel, gemcitabine, and tocilizumab. 
Symptomatic 
hypothyroidism 
 Follow guidelines for atezolizumab in Appendix 2. 
 Withhold nab-paclitaxel, gemcitabine and tocilizumab. 
 When symptoms are controlled and thyroid function is improving, 
resume nab-paclitaxel, gemcitabine, and tocilizumab. 
Asymptomatic hyperthyroidism TSH  1.0 mU/L and  0.5 mU/L: 
 Follow guidelines for atezolizumab in Appendix 2. 
 Continue nab-paclitaxel, gemcitabine, and tocilizumab. 
TSH  1.0 mU/L: 
 Follow guidelines for symptomatic hyperthyroidism. 
Symptomatic 
hyperthyroidism 
 Follow guidelines for atezolizumab in Appendix 2. 
 Withhold nab-paclitaxel, gemcitabine, and tocilizumab. 
 When symptoms are controlled and thyroid function is improving, 
resume nab-paclitaxel, gemcitabine, and tocilizumab. 
Atezo  Chemo  TCZ  atezolizumab plus chemotherapy (nab-paclitaxel and gemcitabine) plus 
tocilizumab; CRS  cytokine release syndrome; G-CSF  granulocyte colony-stimulating factor; 
IRR  infusion-related reaction; LFT  liver function test; nab-paclitaxel  nanoparticle albuminbound 
paclitaxel; ULN  upper limit of normal. 
a Resumption of treatment may be considered if the investigator believes the patient is likely to 
derive clinical benefit.  The decision to re-challenge patients should be based on investigator's 
assessment of benefitrisk and documented by the investigator (or an appropriate delegate).  
The Medical Monitor is available to advise as needed. 
b The dose of nab-paclitaxel may be reduced by 25 mg/m2 (one dose level) up to two times and 
the dose of gemcitabine may be reduced by 200 mg/m2 (one dose level) up to two times 
(see Section A165.1.6.1 for details). 
 
 

Appendix 16:  Study Details Specific to Atezo  Chemo  TCZ Arm (Cohort 1) 
  
Pancreatic Immunotherapy Combinations—F. Hoffmann-La Roche Ltd 
336/Protocol WO39608, Version 16
 
 
Table A16‑4 Guidelines for Management of Patients Who Experience 
Specific Adverse Events in Atezo  Chemo  TCZ Arm (cont.) 
Event 
Action to Be Taken 
Neurologic disorder 
General guidance 
 If the patient has a potential demyelination event, withhold 
tocilizumab to assess for a demyelinating disorder. 
 Tocilizumab may be resumed at the discretion of the investigator. 
Immune-mediated neuropathy, 
Grade 1 or 2 
 Follow guidelines for atezolizumab in Appendix 2. 
 Continue nab-paclitaxel, gemcitabine, and tocilizumab. 
Immune-mediated neuropathy, 
Grade 3 or 4 
 Follow guidelines for atezolizumab in Appendix 2. 
 Continue gemcitabine and tocilizumab.  Withhold nab-paclitaxel. 
 If event resolves to Grade 1 or better  56 days after event onset, 
resume nab-paclitaxel with dose reduced by one level and 
resume tocilizumab. b  If not, permanently discontinue 
nab-paclitaxel and tocilizumab. a 
Nonimmune-mediated 
neuropathy, Grade 1 or 2 
 Continue atezolizumab, nab-paclitaxel, gemcitabine, and 
tocilizumab. 
Nonimmune-mediated 
neuropathy, Grade 3 or 4 
 Continue atezolizumab, gemcitabine, and tocilizumab. Withhold 
nab-paclitaxel. 
 If event resolves to Grade 1 or better  56 days after event onset, 
resume nab-paclitaxel with dose reduction by one level. b  If not, 
permanently discontinue nab-paclitaxel. a 
Immune-mediated 
meningoencephalitis, 
any grade 
 Follow guidelines for atezolizumab in Appendix 2. 
 Withhold nab-paclitaxel, gemcitabine, and tocilizumab. 
 If event stabilizes  56 days after event onset, resume 
nab-paclitaxel, gemcitabine, and tocilizumab.  If not, permanently 
discontinue nab-paclitaxel, gemcitabine, and tocilizumab. a 
Atezo  Chemo  TCZ  atezolizumab plus chemotherapy (nab-paclitaxel and gemcitabine) plus 
tocilizumab; CRS  cytokine release syndrome; G-CSF  granulocyte colony-stimulating factor; 
IRR  infusion-related reaction; LFT  liver function test; nab-paclitaxel  nanoparticle albuminbound 
paclitaxel; ULN  upper limit of normal. 
a Resumption of treatment may be considered if the investigator believes the patient is likely to 
derive clinical benefit. The decision to re-challenge patients should be based on investigator's 
assessment of benefitrisk and documented by the investigator (or an appropriate delegate).  
The Medical Monitor is available to advise as needed. 
b The dose of nab-paclitaxel may be reduced by 25 mg/m2 (one dose level) up to two times and 
the dose of gemcitabine may be reduced by 200 mg/m2 (one dose level) up to two times 
(see Section A165.1.6.1 for details). 
 

Appendix 16:  Study Details Specific to Atezo  Chemo  TCZ Arm (Cohort 1) 
  
Pancreatic Immunotherapy Combinations—F. Hoffmann-La Roche Ltd 
337/Protocol WO39608, Version 16
 
 
Table A16‑4 Guidelines for Management of Patients Who Experience 
Specific Adverse Events in Atezo  Chemo  TCZ Arm (cont.) 
Event 
Action to Be Taken 
Chemotherapy-related toxicities not described above 
Grade 1 or 2 
 Continue atezolizumab, nab-paclitaxel, gemcitabine, and 
tocilizumab. 
Grade 3 
 Continue atezolizumab.  Withhold nab-paclitaxel, gemcitabine, and 
tocilizumab. 
 If event resolves to Grade 2 or better  56 days after event onset, 
resume nab-paclitaxel and gemcitabine and consider reducing 
dose by one level. b  If not, permanently discontinue nab-paclitaxel 
and gemcitabine. a 
 If event resolves to Grade 2 or better  12 weeks after event onset, 
resume tocilizumab and consider reducing dose to 4 mg/kg.  If not, 
permanently discontinue tocilizumab. a 
Grade 4 
 Withhold atezolizumab, tocilizumab, nab-paclitaxel, and 
gemcitabine. 
 If event improves, resume atezolizumab.  If not, permanently 
discontinue atezolizumab. a 
 If event resolves to Grade 2 or better  56 days after event onset, 
resume nab-paclitaxel and gemcitabine and consider reducing 
dose by one level. b  If not, permanently discontinue nab-paclitaxel 
and gemcitabine. a 
 If event resolves to Grade 2 or better  12 weeks after event onset, 
resume tocilizumab and consider reducing dose to 4 mg/kg.  If not, 
permanently discontinue tocilizumab. a 
Atezo  Chemo  TCZ  atezolizumab plus chemotherapy (nab-paclitaxel and gemcitabine) plus 
tocilizumab; CRS  cytokine release syndrome; G-CSF  granulocyte colony-stimulating factor; 
IRR  infusion-related reaction; LFT  liver function test; nab-paclitaxel  nanoparticle albuminbound 
paclitaxel; ULN  upper limit of normal. 
a Resumption of treatment may be considered if the investigator believes the patient is likely to 
derive clinical benefit.  The decision to re-challenge patients should be based on investigator's 
assessment of benefitrisk and documented by the investigator (or an appropriate delegate).  
The Medical Monitor is available to advise as needed. 
b The dose of nab-paclitaxel may be reduced by 25 mg/m2 (one dose level) up to two times and 
the dose of gemcitabine may be reduced by 200 mg/m2 (one dose level) up to two times 
(see Section A165.1.6.1 for details). 

Appendix 16:  Study Details Specific to Atezo  Chemo  TCZ Arm (Cohort 1) 
  
Pancreatic Immunotherapy Combinations—F. Hoffmann-La Roche Ltd 
338/Protocol WO39608, Version 16
 
 
Table A16‑4 Guidelines for Management of Patients Who Experience 
Specific Adverse Events in Atezo  Chemo  TCZ Arm (cont.) 
Event 
Action to Be Taken 
Tocilizumab-related toxicities not described above 
Grade 1 or 2 
 Continue atezolizumab, nab-paclitaxel, gemcitabine, and 
tocilizumab. 
Grade 3 
 Continue atezolizumab.  Withhold tocilizumab, nab-paclitaxel, and 
gemcitabine. 
 If event resolves to Grade 2 or better  56 days after event onset, 
resume nab-paclitaxel and gemcitabine, and consider reducing 
nab-paclitaxel and gemcitabine dose by one level. b  If not, 
permanently discontinue nab-paclitaxel and gemcitabine. a 
First event: 
 If event resolves to Grade 2 or better  12 weeks after event onset, 
resume tocilizumab and consider reducing dose to 4 mg/kg.  If not, 
permanently discontinue tocilizumab. a 
Second and subsequent events: 
 If event resolves to Grade 1 or better  12 weeks after event onset, 
resume tocilizumab and consider reducing dose to 4 mg/kg.  If not, 
permanently discontinue tocilizumab. a 
Grade 4 
 Withhold atezolizumab, tocilizumab, nab-paclitaxel, and 
gemcitabine. 
 If event improves, resume atezolizumab.  If not, permanently 
discontinue atezolizumab. a 
 If event resolves to Grade 2 or better  56 days after event onset, 
resume nab-paclitaxel and gemcitabine, and consider reducing 
nab-paclitaxel and gemcitabine dose by one level. b  If not, 
permanently discontinue nab-paclitaxel and gemcitabine. a 
First event: 
 If event resolves to Grade 2 or better  12 weeks after event onset, 
resume tocilizumab and consider reducing dose to 4 mg/kg.  If not, 
permanently discontinue tocilizumab. a 
Second and subsequent events: 
 If event resolves to Grade 1 or better  12 weeks after event onset, 
resume tocilizumab and consider reducing dose to 4 mg/kg.  If not, 
permanently discontinue tocilizumab. a 
Atezo  Chemo  TCZ  atezolizumab plus chemotherapy (nab-paclitaxel and gemcitabine) plus 
tocilizumab; CRS  cytokine release syndrome; G-CSF  granulocyte colony-stimulating factor; 
IRR  infusion-related reaction; LFT  liver function test; nab-paclitaxel  nanoparticle albuminbound 
paclitaxel; ULN  upper limit of normal. 
a Resumption of treatment may be considered if the investigator believes the patient is likely to 
derive clinical benefit.  The decision to re-challenge patients should be based on investigator's 
assessment of benefitrisk and documented by the investigator (or an appropriate delegate).  
The Medical Monitor is available to advise as needed. 
b The dose of nab-paclitaxel may be reduced by 25 mg/m2 (one dose level) up to two times and 
the dose of gemcitabine may be reduced by 200 mg/m2 (one dose level) up to two times 
(see Section A165.1.6.1 for details). 

Appendix 16:  Study Details Specific to Atezo  Chemo  TCZ Arm (Cohort 1) 
  
Pancreatic Immunotherapy Combinations—F. Hoffmann-La Roche Ltd 
339/Protocol WO39608, Version 16
 
 
Table A16‑4 Guidelines for Management of Patients Who Experience 
Specific Adverse Events in Atezo  Chemo  TCZ Arm (cont.) 
Event 
Action to Be Taken 
Atezolizumab-related toxicities not described above 
Grade 1 or 2 
 Follow guidelines for atezolizumab in Appendix 2. 
 Continue nab-paclitaxel, gemcitabine, and tocilizumab. 
Grade 3 or 4 
 Follow guidelines for atezolizumab in Appendix 2. 
 Withhold nab-paclitaxel, gemcitabine, and tocilizumab. 
 If event resolves to Grade 2 or better  56 days after event onset, 
resume nab-paclitaxel and gemcitabine, and consider reducing 
nab-paclitaxel and gemcitabine dose by one level. b  If not, 
permanently discontinue nab-paclitaxel and gemcitabine. a 
First event: 
 If event resolves to Grade 2 or better  12 weeks after event 
onset, resume tocilizumab and consider reducing dose to 
4 mg/kg.  If not, permanently discontinue tocilizumab. a 
Second and subsequent events: 
 If event resolves to Grade 1 or better  12 weeks after event 
onset, resume tocilizumab and consider reducing dose to 
4 mg/kg.  If not, permanently discontinue tocilizumab. a 
Atezo  Chemo  TCZ  atezolizumab plus chemotherapy (nab-paclitaxel and gemcitabine) plus 
tocilizumab; CRS  cytokine release syndrome; G-CSF  granulocyte colony-stimulating factor; 
IRR  infusion-related reaction; LFT  liver function test; nab-paclitaxel  nanoparticle albuminbound 
paclitaxel; ULN  upper limit of normal. 
a Resumption of treatment may be considered if the investigator believes the patient is likely to 
derive clinical benefit.  The decision to re-challenge patients should be based on investigator's 
assessment of benefitrisk and documented by the investigator (or an appropriate delegate).  
The Medical Monitor is available to advise as needed. 
b The dose of nab-paclitaxel may be reduced by 25 mg/m2 (one dose level) up to two times and 
the dose of gemcitabine may be reduced by 200 mg/m2 (one dose level) up to two times 
(see Section A165.1.6.1 for details). 
 
A16–5.2 
ADVERSE EVENTS OF SPECIAL INTEREST FOR 
ATEZO  CHEMO  TCZ ARM (IMMEDIATELY REPORTABLE 
TO THE SPONSOR) 
Adverse events of special interest are required to be reported by the investigator to the 
Sponsor immediately (i.e., no more than 24 hours after learning of the event; see 
Section 5.4.2 for reporting instructions).  Adverse events of special interest for the 
Atezo  Chemo  TCZ arm are as follows: 
 
Cases of potential drug-induced liver injury that include an elevated ALT or AST in 
combination with either elevated bilirubin or clinical jaundice, as defined by Hy's Law 
(see Section 5.3.5.7) 

Appendix 16:  Study Details Specific to Atezo  Chemo  TCZ Arm (Cohort 1) 
  
Pancreatic Immunotherapy Combinations—F. Hoffmann-La Roche Ltd 
340/Protocol WO39608, Version 16
 
 
 
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. 
 
Pneumonitis 
 
Colitis 
 
Endocrinopathies:  diabetes mellitus, pancreatitis, adrenal insufficiency, 
hyperthyroidism, and hypophysitis 
 
Hepatitis, including AST or ALT  10  upper limit of normal 
 
Systemic lupus erythematosus 
 
Neurologic disorders:  Guillain-Barré syndrome, myasthenic syndrome or 
myasthenia gravis, and meningoencephalitis 
 
Events suggestive of hypersensitivity, IRRs, CRS, influenza-like illness, HLH, and 
MAS 
 
Nephritis 
 
Ocular toxicities (e.g., uveitis, retinitis) 
 
Myositis 
 
Myopathies, including rhabdomyolysis 
 
Grade  2 cardiac disorders (e.g., atrial fibrillation, myocarditis, pericarditis) 
 
 
 
Serious and/or medically significant infections 
 
Myocardial infarction or acute coronary syndrome 
 
GI perforations 
 
Malignancies 
 
Demyelinating disorders 
 
Stroke 
 
Serious and/or medically significant bleeding events 
 
Serious and/or medically significant hepatic events 
 
 
 
Severe cutaneous reactions (e.g., Stevens-Johnson syndrome, dermatitis bullous, 
toxic epidermal necrolysis) 

Appendix 16:  Study Details Specific to Atezo  Chemo  TCZ Arm (Cohort 1) 
  
Pancreatic Immunotherapy Combinations—F. Hoffmann-La Roche Ltd 
341/Protocol WO39608, Version 16
 
 
 
Myelitis 
 
Facial paresis  
 
A16–5.3 
REPORTING REQUIREMENTS FOR PREGNANCIES IN 
ATEZO  CHEMO  TCZ ARM 
A16–5.3.1 
Pregnancies in Female Patients 
Female patients of childbearing potential will be instructed to immediately inform the 
investigator if they become pregnant during the study or within 3 months after the last 
dose of tocilizumab, 5 months after the last dose of atezolizumab, or 6 months after the 
last dose of nab-paclitaxel or gemcitabine.  A 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. 
A16–5.3.2 
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 
2 months after the last dose of tocilizumab, or 6 months after the last dose of 
nab-paclitaxel or gemcitabine.  A 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.  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 when updated information on the course and outcome of the 
pregnancy 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 
investigator and/or obstetrician. 

Appendix 16:  Study Details Specific to Atezo  Chemo  TCZ Arm (Cohort 1) 
  
Pancreatic Immunotherapy Combinations—F. Hoffmann-La Roche Ltd 
342/Protocol WO39608, Version 16
 
 
A16–5.3.3 
Abortions 
Any 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). 
A16–5.3.4 
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). 
 

Appendix 16:  Study Details Specific to Atezo  Chemo  TCZ Arm (Cohort 1) 
  
Pancreatic Immunotherapy Combinations—F. Hoffmann-La Roche Ltd 
343/Protocol WO39608, Version 16
 
 
A16–6 
SCHEDULES OF ACTIVITIES AND SAMPLE COLLECTION FOR ATEZO  CHEMO  TCZ ARM 
Table A16-5 
Schedule of Activities for Atezo  Chemo  TCZ Arm (Cohort 1) 
 
Stage 1 
Screening  
(see 
Appendix 6) 
Treatment Cycles (28-day cycles) a 
Treat. 
Discon. c 
Follow-Up c 
Cycle 1 b 
Cycles  2 
Day –28 
to –1 
Day 1 
 
Day 8 
(3 days) 
Day 15 
( 3 days) 
Day 1 
( 3 days) 
Day 8 
( 3 days) 
Day 15 
( 3 days) 
Every 
3 Months 
Molecular profile of pancreatic cancer 
(if available) 
See 
Appendix 6 
Whenever updated information becomes available  
 
Vital signs d 
x 
x 
x 
x 
x 
x 
x 
 
Weight 
x e 
x e 
x e 
x e 
x e 
x e 
x 
 
Complete physical examination f 
 
 
 
 
 
 
x 
 
Limited physical examination g 
x e 
x e 
x e 
x e 
x e 
x e 
 
 
ECOG Performance Status 
x e 
 
 
x e 
 
 
x 
 
ECG h 
Perform as clinically indicated e 
 
 
Hematology i 
x j, k 
x j 
x j 
x j 
x j 
x j 
x 
 
Chemistry l 
x j, k 
x j 
x j 
x j 
x j 
x j 
x 
 
Coagulation (INR and aPTT) 
Perform as clinically indicated 
x 
 
TSH, free T3 (or total T3), free T4 m 
x j, k, m 
x 
 
CA19-9 
x j 
 
 
x j 
 
 
x 
 
C-reactive protein 
x j 
x j 
x j 
x j 
 
 
x 
 

Appendix 16:  Study Details Specific to Atezo  Chemo  TCZ Arm (Cohort 1) 
  
Table A16‑5 
Schedule of Activities for Atezo  Chemo  TCZ Arm (Cohort 1) (cont.) 
Pancreatic Immunotherapy Combinations—F. Hoffmann-La Roche Ltd 
344/Protocol WO39608, Version 16
 
 
 
Stage 1 
Screening  
(see 
Appendix 6) 
Treatment Cycles (28-day cycles) a 
Treat. 
Discon. c 
Follow-Up c 
Cycle 1 b 
Cycles  2 
Day –28 
to –1 
Day 1 
 
Day 8 
(3 days) 
Day 15 
( 3 days) 
Day 1 
( 3 days) 
Day 8 
( 3 days) 
Day 15 
( 3 days) 
Every 
3 Months 
Pregnancy test o 
See 
Appendix 6
x j, k 
 
 
x j 
 
 
x 
x o 
Urinalysis p 
Perform as clinically indicated 
 
 
Tumor response assessments 
x v, w 
Concomitant medications x 
x 
x 
x 
x 
x 
x 
x 
 
Adverse events y 
x 
x 
x 
x 
x 
x 
x y 
x y 
Tocilizumab administration z, aa 
x 
 
 
x 
 
 
 
 
Atezolizumab administration aa, bb 
x 
 
 
x 
 
 
 
 
Nab-paclitaxel and gemcitabine 
administration aa, cc 
x 
x 
x 
x 
x 
x 
 
 
Survival follow-up and anti-cancer treatment 
 
 
 
 
 
 
 
x dd 

Appendix 16:  Study Details Specific to Atezo  Chemo  TCZ Arm (Cohort 1) 
  
Table A16‑5 
Schedule of Activities for Atezo  Chemo  TCZ Arm (Cohort 1) (cont.) 
Pancreatic Immunotherapy Combinations—F. Hoffmann-La Roche Ltd 
345/Protocol WO39608, Version 16
 
 
 
ADA  anti-drug antibody; Atezo  Chemo  TCZ  atezolizumab plus chemotherapy (nab-paclitaxel and gemcitabine) plus tocilizumab; CIT  cancer 
immunotherapy; CT  computed tomography; Discon.  discontinuation; ECOG  Eastern Cooperative Oncology Group; eCRF  electronic Case 
Report Form;
 nab-paclitaxel  nanoparticle albuminbound paclitaxel; PK  pharmacokinetic; RBR  Research Biosample 
Repository; RECIST v1.1  Response Evaluation Criteria in Solid Tumors, Version 1.1; T3  triiodothyronine; T4  thyroxine; Treat.  treatment; 
TSH  thyroid-stimulating hormone. 
Note:  On treatment days, all assessments should be performed prior to dosing, unless otherwise specified. 
a 
If a visit is precluded because of a holiday, vacation, or other circumstance, it can occur outside of the specified window. 
b 
It is recommended that treatment be initiated no later than 7 days after randomization. 
c 
Patients will return to the clinic for a treatment discontinuation visit not more than 30 days after the last dose of study treatment.  The visit at 
which disease progression is confirmed may be used as the treatment discontinuation visit.  Patients will then undergo follow-up assessments. 
d 
Vital signs include respiratory rate, pulse rate, and systolic and diastolic blood pressure while the patient is in a seated position, pulse oximetry, 
and temperature.  Record new or worsened clinically significant abnormalities on the Adverse Event eCRF.  For the first infusion of 
atezolizumab, vital signs should be measured within 60 minutes prior to the infusion and, if clinically indicated, every 15 ( 5) minutes during 
and 30 ( 10) minutes after the infusion.  For subsequent infusions, vital signs should be measured within 60 minutes prior to the infusion and, if 
clinically indicated or if symptoms occurred during the previous infusion, during and 30 ( 10) minutes after the infusion.  For tocilizumab, vital 
signs should be measured within 60 minutes prior to, during the infusion if clinically indicated, and within 30 ( 10) minutes after the infusion. 
e 
Assessment may be performed within 24 hours prior to dosing during the treatment period. 
f 
Complete physical examination includes evaluation of the head, eyes, ears, nose, and throat, and the cardiovascular, dermatologic, 
musculoskeletal, respiratory, gastrointestinal, genitourinary, and neurologic systems.  Record new or worsened clinically significant 
abnormalities on the Adverse Event eCRF. 
g 
Perform a limited, symptom-directed examination at specified timepoints and as clinically indicated at other timepoints.  Record new or 
worsened clinically significant abnormalities on the Adverse Event eCRF. 
h 
It is recommended that patients be resting in a supine position for at least 10 minutes prior to ECG recording. 
i 
Hematology includes WBC count, RBC count, hemoglobin, hematocrit, platelet count, and differential count (neutrophils, eosinophils, basophils, 
monocytes, lymphocytes, other cells). 
j 
Laboratory tests must be performed within 96 hours prior to dosing during the treatment period. 

Appendix 16:  Study Details Specific to Atezo  Chemo  TCZ Arm (Cohort 1) 
  
Table A16‑5 
Schedule of Activities for Atezo  Chemo  TCZ Arm (Cohort 1) (cont.) 
Pancreatic Immunotherapy Combinations—F. Hoffmann-La Roche Ltd 
346/Protocol WO39608, Version 16
 
 
k 
If screening laboratory assessments were performed within 96 hours prior to Day 1 of Cycle 1, they do not have to be repeated. 
l 
Chemistry panel (serum or plasma) includes bicarbonate or total carbon dioxide (if considered standard of care for the region), sodium, 
potassium, magnesium, chloride, glucose, BUN or urea, creatinine, total protein, albumin, phosphorus, calcium, total bilirubin, ALP, ALT, 
and AST. 
m TSH, free T3 (or total T3 for sites where free T3 is not performed), and free T4 will be assessed on Day 1 of Cycle 1 and every third cycle 
thereafter (i.e., Cycles 4, 7, 10, etc.). 
n 
o 
All women of childbearing potential will have urine or serum pregnancy tests performed at specified visits during treatment and at 3 months and 
6 months after the last dose of study treatment.  If a urine pregnancy test is positive, it must be confirmed by a serum pregnancy test. 
p 
Includes pH, specific gravity, glucose, protein, ketones, and blood; dipstick permitted. 
q 
Autoantibody analysis includes anti-nuclear antibody, antidouble-stranded DNA, circulating anti-neutrophil cytoplasmic antibody, and 
perinuclear anti-neutrophil cytoplasmic antibody. 
r 
Autoantibody analysis should be repeated for patients who develop signs or symptoms suggestive of autoimmune disease (e.g., lupus 
erythematosus). 
s 
Not applicable for a site that has not been granted approval for RBR sampling.  Performed only for patients at participating sites who have 
provided written informed consent to participate. 
t 
u 

Appendix 16:  Study Details Specific to Atezo  Chemo  TCZ Arm (Cohort 1) 
  
Table A16‑5 
Schedule of Activities for Atezo  Chemo  TCZ Arm (Cohort 1) (cont.) 
Pancreatic Immunotherapy Combinations—F. Hoffmann-La Roche Ltd 
347/Protocol WO39608, Version 16
 
 
v Patients will undergo tumor assessments at baseline, every 6 weeks ( 1 week) for the first 48 weeks following treatment initiation, and every 
12 weeks ( 2 weeks) thereafter, regardless of dose delays, until radiographic disease progression according to RECIST v1.1, except in the case 
of patients who continue treatment after radiographic disease progression; such patients will undergo tumor assessments every 6 weeks 
( 1 week) until loss of clinical benefit as determined by the investigator (see Section 3.1.2 for details).  Thus, tumor assessments are to 
continue according to schedule in patients who discontinue treatment for reasons other than disease progression, even if they start new 
nonprotocol-specified anti-cancer therapy. 
w All measurable and/or evaluable lesions identified at baseline should be re-assessed at subsequent tumor evaluations according to the tumor 
assessment schedule described above (see footnote “v”).  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).  Refer to Section 4.5.5 for further details on tumor 
assessments. 
x 
Includes 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 study treatment from 10 days prior to initiation of study treatment until the treatment 
discontinuation visit. 
y 
 
 
 After 
this period, all deaths, regardless of cause, should be reported.  In addition, the Sponsor should be notified if the investigator becomes aware of 
any serious adverse event that is believed to be related to prior exposure to study treatment (see Section 5.6).  The investigator should follow 
each adverse event until the event has resolved to baseline grade or better, the event is assessed as stable by the investigator, 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. 
z 
Tocilizumab will be administered by IV infusion at a dose of 8 mg/kg on Day 1 of each 28-day cycle, with a maximum dose of 800 mg 
tocilizumab (for patients weighing  100 kg).  Tocilizumab should be infused over 60 ( 15) minutes.  The infusion speed must be 10 mL/hr for 
15 minutes and then increased to 130 mL/hr to complete the dosing over 60 minutes.  In exceptional cases of infusion reactions, the infusion 
time may be extended to up to 6 hours. 
aa Treatment will continue until unacceptable toxicity or loss of clinical benefit as determined by the investigator (see Section 3.1.2 for details). 
 

Appendix 16:  Study Details Specific to Atezo  Chemo  TCZ Arm (Cohort 1) 
  
Table A16‑5 
Schedule of Activities for Atezo  Chemo  TCZ Arm (Cohort 1) (cont.) 
Pancreatic Immunotherapy Combinations—F. Hoffmann-La Roche Ltd 
348/Protocol WO39608, Version 16
 
 
bb Atezolizumab will be administered by IV infusion at a fixed dose of 1680 mg on Day 1 of each 28-day cycle.  The initial dose of atezolizumab will 
be delivered over 60 ( 15) minutes.  Subsequent infusions will be delivered over 30 ( 10) minutes if the previous infusion was tolerated without 
infusion-associated adverse events, or 60 ( 15) minutes if the patient experienced an infusion-associated adverse event with the previous 
infusion.  Refer to Section A164.1.2.2, Table A16-2, for details on atezolizumab infusions (including measurement of vital signs). 
cc On Days 1, 8, and 15 of each cycle, patients will receive nab-paclitaxel 125 mg/m2, administered by IV infusion over 30 ( 5) minutes, followed 
by gemcitabine 1000 mg/m2, administered by IV infusion over 30 ( 5) minutes.  On Days 1 and 15 of each cycle, nab-paclitaxel will be 
administered after completion of the atezolizumab infusion. 
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 only.  For an experimental arm in which all patients discontinued 
treatment and passed the safety follow-up window, as well as approximately 80% of patients discontinued the study, the Sponsor may conclude 
the arm (the remaining approximately 20% of patients will be discontinued from the study). 

Appendix 16:  Study Details Specific to Atezo  Chemo  TCZ Arm (Cohort 1) 
  
Pancreatic Immunotherapy Combinations—F. Hoffmann-La Roche Ltd 
349/Protocol WO39608, Version 16
 
 
Table A16-6 Schedule of Pharmacokinetic, Immunogenicity, and 
Biomarker Samples for Atezo  Chemo  TCZ Arm (Cohort 1):  
Preliminary and Expansion Phases 
 
 

Appendix 16:  Study Details Specific to Atezo  Chemo  TCZ Arm (Cohort 1) 
  
Pancreatic Immunotherapy Combinations—F. Hoffmann-La Roche Ltd 
350/Protocol WO39608, Version 16
 
 
Table A16-6 Schedule of Pharmacokinetic, Immunogenicity, and 
Biomarker Samples for Atezo  Chemo  TCZ Arm (Cohort 1):  
Preliminary and Expansion Phases (cont.) 
Visit 
Time 
Sample Type 
ADA  anti-drug antibody; Atezo  Chemo  TCZ  atezolizumab plus chemotherapy 
(nab-paclitaxel and gemcitabine) plus tocilizumab; nab-paclitaxel  nanoparticle 
albuminbound paclitaxel; PBMC  peripheral blood mononuclear cell; 
PK  pharmacokinetic; TCZ  tocilizumab. 
Note: On the basis of emerging safety or efficacy data, the number of PK and ADA samples 
may be reduced or sample collection may cease altogether.  Additionally, collected samples 
may not be analyzed if not warranted.  On the basis of emerging biomarker data, the 
number of biomarker samples may be reduced or sample collection may cease altogether. 
 

Appendix 16:  Study Details Specific to Atezo  Chemo  TCZ Arm (Cohort 1) 
  
Pancreatic Immunotherapy Combinations—F. Hoffmann-La Roche Ltd 
351/Protocol WO39608, Version 16
 
 
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Rosenberg JE, Hoffman-Censits J, Powles T, et al. Atezolizumab in patients with locally 
advanced and metastatic urothelial carcinoma who have progressed following 
treatment with platinum-based chemotherapy: a single-arm, multicentre, phase 2 
trial. Lancet 2016;387:190920. 
Royal RE, Levy C, Turner K, et al. Phase 2 trial of single agent Ipilimumab (anti-CTLA-4) 
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Scheller J, Chalaris A, Schmidt-Arras D, et al.. The pro- and anti-inflammatory properties 
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Appendix 16:  Study Details Specific to Atezo  Chemo  TCZ Arm (Cohort 1) 
  
Pancreatic Immunotherapy Combinations—F. Hoffmann-La Roche Ltd 
354/Protocol WO39608, Version 16
 
 
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progression by promoting MAPK signaling activation and oxidative stress 
resistance. Cancer Res 2013;773:635974. 
 

  
Pancreatic Immunotherapy Combinations—F. Hoffmann-La Roche Ltd 
355/Protocol WO39608, Version 16
 
 
Appendix 17  
Investigational Medicinal Product Designations (for Use in European 
Economic Area) 
Table A17-1 
Investigational Medicinal Product Designations for European 
Economic Area 
Product Name 
IMP Designation 
Marketing Authorization 
Status in EEA  
Used within 
Marketing 
Authorization 
Atezolizumab 
(RO5541267) 
IMP (test product) 
Approved 
No a 
Nab-paclitaxel 
IMP (comparator) 
Approved 
No b 
Bevacizumab 
(RO4876646) 
IMP (test product) 
Approved 
No 
Gemcitabine 
IMP (comparator) 
Approved 
No c 
Fluorouracil 
IMP (comparator) 
Approved 
No d, e 
Oxaliplatin 
IMP (comparator) 
Approved 
No a, d 
Leucovorin 
IMP (comparator) 
Approved  
No d, f 
Tiragolumab 
(RO7092284) 
IMP (test product) 
Not approved 
Not applicable 
AB928 j 
IMP (test product) 
Not approved 
Not applicable 
Tocilizumab 
(RO4877533) 
IMP (test product) 
Approved 
No a 
Cobimetinib 
(RO5514041) g 
IMP (test product) 
Approved 
No a 
PEGPH20 g 
IMP (test product) 
Not approved 
Not applicable 
BL-8040 h 
IMP (test product) 
Not approved 
Not applicable 
Selicrelumab g 
IMP (test product) 
Not approved 
Not applicable 
Simlukafusp alfa  
(FAP-IL2v; 
RO6874281) g 
IMP (test product) 
Not approved 
Not applicable 
Emactuzumab i 
IMP (test product) 
Not approved 
Not applicable 
EEA   European Economic Area; IMP  investigational medicinal product. 
a Atezolizumab, oxaliplatin, tocilizumab, and cobimetinib are not approved in pancreatic cancer. 
b Nab-paclitaxel is approved in pancreatic cancer in combination with gemcitabine, but not in 
combination with atezolizumab, bevacizumab, AB928, tiragolumab, or tocilizumab. 
c Gemcitabine is approved in pancreatic cancer in combination with nab-paclitaxel, but not in 
combination with atezolizumab, bevacizumab, AB928, tiragolumab, or tocilizumab.   
d Component of mFOLFOX6:  fluorouracil, leucovorin, and oxaliplatin. 
e Fluorouracil is approved in pancreatic cancer in combination with leucovorin, but not in 
combination with oxaliplatin. 
f Leucovorin is approved in cytotoxic therapy in combination with fluorouracil, but not in 
combination with oxaliplatin. 
g Cobimetinib (RO5514041), PEGPH20, selicrelumab, and simlukafusp alfa (FAP-IL2v; 
RO6874281) were removed from Protocol WO39608, Version 11. 
h BL-8040 was removed from Protocol WO39608, Version 7. 
i Emactuzumab was removed from Protocol WO39608, Version 5. 
j AB928 was removed from Protocol WO39608, Version 16.  
 

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