A Phase III, Randomized, Double-Blind, Placebo-Controlled Study of Atezolizumab Plus Tiragolumab in Combination With Paclitaxel and Cisplatin Compared With Paclitaxel and Cisplatin as First-Line Treatment in Patients With Unresectable Locally Advanced, Unresectable Recurrent, or Metastatic Esophageal Squamous Cell Carcinoma
Phase: PHASE3
Conditions: Esophageal Cancer
Sponsor: Hoffmann-La Roche



CONFIDENTIAL 
This clinical study is being sponsored globally by F. Hoffmann-La Roche Ltd of Basel, Switzerland.  
However, it may be implemented in individual countries by Roche's local affiliates, including 
Genentech, Inc. in the United States.  The information contained in this document, especially any 
unpublished data, is the property of F. Hoffmann-La Roche Ltd (or under its control) and; therefore, is 
provided to you in confidence as an investigator, potential investigator, or consultant, for review by you, 
your staff, and an applicable Ethics Committee or Institutional Review Board.  It is understood that this 
information will not be disclosed to others without written authorization from Roche except to the extent 
necessary to obtain informed consent from persons to whom the drug may be administered. 
 
Atezolizumab and Tiragolumab—F. Hoffmann-La Roche Ltd 
Protocol YO42138, Version 7 
PROTOCOL 
TITLE: 
A PHASE III, RANDOMIZED, DOUBLE-BLIND, 
PLACEBO-CONTROLLED STUDY OF 
ATEZOLIZUMAB PLUS TIRAGOLUMAB IN 
COMBINATION WITH PACLITAXEL AND 
CISPLATIN COMPARED WITH PACLITAXEL AND 
CISPLATIN AS FIRST-LINE TREATMENT IN 
PATIENTS WITH UNRESECTABLE LOCALLY 
ADVANCED, UNRESECTABLE RECURRENT, OR 
METASTATIC ESOPHAGEAL SQUAMOUS CELL 
CARCINOMA 
PROTOCOL NUMBER: YO42138 
VERSION NUMBER: 
7 
EUDRACT NUMBER: 
Not applicable 
IND NUMBER: 
Not applicable 
NCT NUMBER: 
NCT04540211 
TEST PRODUCTS: 
Tiragolumab (RO7092284) 
Atezolizumab (RO5541267) 
SPONSOR: 
F. Hoffmann-La Roche Ltd 
APPROVAL: 
See electronic signature and date stamp on the final 
page of this document. 
 
 
 

Atezolizumab and Tiragolumab—F. Hoffmann-La Roche Ltd 
2/Protocol YO42138, Version 7 
PROTOCOL HISTORY 
Protocol 
Version 
Date Final 
7 
See electronic date stamp on the final page of this document. 
6 
8 December 2022 
5 
21 January 2022 
4 
20 October 2021 
3 
16 April 2021 
2 
15 December 2020 
1 
15 April 2020 

Atezolizumab and Tiragolumab—F. Hoffmann-La Roche Ltd 
3/Protocol YO42138, Version 7 
PROTOCOL AMENDMENT, VERSION 7: 
RATIONALE 
Protocol YO42138 has been amended primarily to provide additional clarity on the PK 
and ADA samples collection.  Changes to the protocol, along with a rationale for each 
change, are summarized below: 
 
 
 
 
 
The following changes have been made to align with the Atezolizumab Investigator's 
Brochure, Version 20: 
 
The list of approved indications for atezolizumab has been updated to include 
alveolar soft part sarcoma (Section 1.3). 
 
 
 
 
 
The adverse event management guidelines have been updated to align with the 
Atezolizumab Investigator’s Brochure, Version 20 (Appendix 10). 
The following additional changes and clarifications have been made: 
 
Personal identifiable information (i.e., name and telephone number) for the 
Medical Monitors has been removed from the protocol. Medical Monitor contact 
information has been replaced with a sentence indicating that this information 
will be provided separately to sites (Section 5.4.1). 
 
It has been made explicit that expedited safety reports are notified to 
EudraVigilance (Section 5.7). 
Additional minor changes have been made to improve clarity and consistency.  
Substantive new information appears in italics.  This amendment represents cumulative 
changes to the original protocol. 

Atezolizumab and Tiragolumab—F. Hoffmann-La Roche Ltd 
4/Protocol YO42138, Version 7 
 
TABLE OF CONTENTS 
PROTOCOL AMENDMENT ACCEPTANCE FORM .......................................... 11 
PROTOCOL SYNOPSIS .................................................................................... 12 
1. 
BACKGROUND ............................................................................ 21 
1.1 
Background on Esophageal Carcinoma .................................. 21 
1.2 
Treatment for Advanced Esophageal Squamous Cell 
Carcinoma ............................................................................... 21 
1.2.1 
Chemotherapy ......................................................................... 21 
1.2.2 
AntiPD-1 Therapy .................................................................. 22 
1.3 
Background on Atezolizumab .................................................. 22 
1.4 
Background on Tiragolumab .................................................... 23 
1.5 
Study Rationale and Benefit‑Risk Assessment ........................ 23 
2. 
OBJECTIVES AND ENDPOINTS ................................................. 27 
3. 
STUDY DESIGN ........................................................................... 29 
3.1 
Description of the Study ........................................................... 29 
3.2 
Independent Data Monitoring Committee ................................ 32 
3.3 
Independent Review Facility .................................................... 32 
3.4 
End of Study and Length of Study ........................................... 32 
3.5 
Rationale for Study Design ...................................................... 32 
 
 ...................... 32 
 
 ....................... 33 
3.5.3 
Rationale for Patient Population .............................................. 33 
3.5.4 
Rationale for Control Group ..................................................... 34 
3.5.5 
Rationale for Progression-Free Survival and Overall 
Survival as Co-Primary Endpoints ........................................... 34 
3.5.6 
Rationale for Study Treatment Beyond Initial Radiographic 
Progression.............................................................................. 34 
3.5.7 
Rationale for Pharmacokinetic Sampling Schedule ................. 35 
 
 ..................................... 35 
4. 
MATERIALS AND METHODS ...................................................... 35 
4.1 
Patients .................................................................................... 35 
4.1.1 
Inclusion Criteria ...................................................................... 35 

Atezolizumab and Tiragolumab—F. Hoffmann-La Roche Ltd 
5/Protocol YO42138, Version 7 
4.1.2 
Exclusion Criteria ..................................................................... 39 
4.2 
Method of Treatment Assignment and Blinding ....................... 43 
4.2.1 
Treatment Assignment ............................................................. 43 
4.2.2 
Blinding .................................................................................... 43 
4.3 
Study Treatment and Other Treatments Relevant to the 
Study Design ........................................................................... 44 
4.3.1 
Study Treatment Formulation and Packaging .......................... 45 
4.3.1.1 
Atezolizumab and Placebo ...................................................... 45 
4.3.1.2 
Tiragolumab and Placebo ........................................................ 45 
4.3.1.3 
Paclitaxel and Cisplatin ............................................................ 45 
4.3.2 
Study Treatment Dosage, Administration, and Compliance .... 45 
4.3.2.1 
Atezolizumab or Placebo ......................................................... 45 
4.3.2.2 
Tiragolumab or Placebo ........................................................... 46 
4.3.2.3 
Paclitaxel and Cisplatin ............................................................ 47 
4.3.3 
Investigational Medicinal Product Handling and 
Accountability ........................................................................... 48 
4.3.4 
Continued Access to Atezolizumab and Tiragolumab .............. 49 
4.4 
Concomitant Therapy .............................................................. 50 
4.4.1 
Permitted Therapy ................................................................... 50 
4.4.2 
Cautionary Therapy for Atezolizumab-Treated Patients .......... 51 
4.4.2.1 
Corticosteroids, Immunosuppressive Medications, and 
TNF- Inhibitors ....................................................................... 51 
4.4.2.2 
Herbal Therapies ..................................................................... 51 
4.4.3 
Prohibited Therapy .................................................................. 51 
4.5 
Study Assessments ................................................................. 52 
4.5.1 
Informed Consent Forms and Screening Log .......................... 52 
4.5.2 
Medical History, Baseline Conditions, Concomitant 
Medication, and Demographic Data ......................................... 52 
4.5.3 
Physical Examinations ............................................................. 53 
4.5.4 
Vital Signs ................................................................................ 53 
4.5.5 
Tumor and Response Evaluations ........................................... 53 
4.5.6 
Electrocardiograms .................................................................. 54 
4.5.7 
Clinical Outcome Assessments ............................................... 54 

Atezolizumab and Tiragolumab—F. Hoffmann-La Roche Ltd 
6/Protocol YO42138, Version 7 
4.5.7.1 
Data Collection Methods for Patient-Reported Outcome 
Assessments ........................................................................... 55 
4.5.7.2 
Description of Patient-Reported Outcome Instruments ............ 55 
4.5.8 
Laboratory, 
 and Other Biological Samples ............ 56 
4.5.9 
Optional Tumor Biopsies ......................................................... 59 
4.6 
Treatment, Patient, Study, and Site Discontinuation ................ 60 
4.6.1 
Study Treatment Discontinuation ............................................. 60 
4.6.2 
Patient Discontinuation from the Study .................................... 60 
4.6.3 
Study Discontinuation .............................................................. 61 
4.6.4 
Site Discontinuation ................................................................. 61 
5. 
ASSESSMENT OF SAFETY ......................................................... 62 
5.1 
Safety Plan .............................................................................. 62 
5.1.1 
Risks Associated with Atezolizumab ........................................ 62 
5.1.2 
Risks Associated with Tiragolumab ......................................... 63 
5.1.2.1 
Infusion-Related Reactions ...................................................... 63 
5.1.2.2 
 63 
5.1.2.3 
Immune-Mediated Adverse Events .......................................... 64 
5.1.2.4 
Lymphopenia ........................................................................... 64 
5.1.2.5 
Embryofetal Toxicity ................................................................ 64 
5.1.3 
Risks Associated with Paclitaxel .............................................. 65 
5.1.4 
Risks Associated with Cisplatin ............................................... 65 
5.1.5 
Risks Associated with Combination Use of Atezolizumab, 
Tiragolumab, Paclitaxel, and Cisplatin ..................................... 65 
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) ...................................................... 67 
5.3 
Methods and Timing for Capturing and Assessing 
Safety Parameters ................................................................... 68 
5.3.1 
Adverse Event Reporting Period .............................................. 69 
5.3.2 
Eliciting Adverse Event Information ......................................... 69 
5.3.3 
Assessment of Severity of Adverse Events ............................. 69 

Atezolizumab and Tiragolumab—F. Hoffmann-La Roche Ltd 
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5.3.4 
Assessment of Causality of Adverse Events............................ 71 
5.3.5 
Procedures for Recording Adverse Events .............................. 72 
5.3.5.1 
Infusion-Related Reactions and 
 
 ................................................................................ 72 
5.3.5.2 
Diagnosis Versus Signs and Symptoms .................................. 73 
5.3.5.3 
Adverse Events That Are Secondary to Other Events ............. 73 
5.3.5.4 
Persistent or Recurrent Adverse Events .................................. 74 
5.3.5.5 
Abnormal Laboratory Values ................................................... 74 
5.3.5.6 
Abnormal Vital Sign Values ..................................................... 75 
5.3.5.7 
Abnormal Liver Function Tests ................................................ 76 
5.3.5.8 
Deaths ..................................................................................... 76 
5.3.5.9 
Preexisting Medical Conditions ................................................ 76 
5.3.5.10 
Lack of Efficacy or Worsening of Esophageal Squamous 
Cell Carcinoma ........................................................................ 77 
5.3.5.11 
Hospitalization or Prolonged Hospitalization ............................ 77 
5.3.5.12 
Cases of Accidental Overdose or Medication Error ................. 78 
5.3.5.13 
Patient-Reported Outcome Data .............................................. 79 
5.4 
Immediate Reporting Requirements from Investigator to 
Sponsor ................................................................................... 79 
5.4.1 
Medical Monitors and Emergency Medical Contacts ............... 79 
5.4.2 
Reporting Requirements for Serious Adverse Events and 
Adverse Events of Special Interest .......................................... 80 
5.4.2.1 
Events That Occur Prior to Study Treatment Initiation ............. 80 
5.4.2.2 
Events That Occur After Study Treatment Initiation ................. 80 
5.4.3 
Reporting Requirements for Pregnancies ................................ 80 
5.4.3.1 
Pregnancies in Female Patients .............................................. 80 
5.4.3.2 
Pregnancies in Female Partners of Male Patients ................... 81 
5.4.3.3 
Abortions.................................................................................. 81 
5.4.3.4 
Congenital Anomalies/Birth Defects ........................................ 82 
5.5 
Follow-Up of Patients after Adverse Events............................. 82 
5.5.1 
Investigator Follow-Up ............................................................. 82 
5.5.2 
Sponsor Follow-Up .................................................................. 82 
5.6 
Adverse Events That Occur after the Adverse Event 
Reporting Period ...................................................................... 82 

Atezolizumab and Tiragolumab—F. Hoffmann-La Roche Ltd 
8/Protocol YO42138, Version 7 
5.7 
Expedited Reporting to Health Authorities, Investigators, 
Institutional Review Boards, and Ethics Committees ............... 83 
6. 
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN ......... 83 
6.1 
Determination of Sample Size ................................................. 83 
6.1.1 
Type I Error Control ................................................................. 84 
6.1.2 
Co-Primary Endpoint:  Overall Survival ................................... 84 
6.1.3 
Co-Primary Endpoint:  Progression-Free Survival ................... 85 
6.2 
Summaries of Conduct of Study .............................................. 85 
6.3 
Summaries of Treatment Group Comparability ........................ 85 
6.4 
Efficacy Analyses ..................................................................... 86 
6.4.1 
Co-Primary Efficacy Endpoints ................................................ 86 
6.4.1.1 
Overall Survival ........................................................................ 86 
6.4.1.2 
IRF-Assessed Progression-Free Survival ................................ 87 
6.4.2 
Secondary Efficacy Endpoints ................................................. 87 
6.4.2.1 
Investigator-Assessed Progression-Free Survival ................... 87 
6.4.2.2 
Objective Response Rate ........................................................ 87 
6.4.2.3 
Duration of Response .............................................................. 88 
6.4.2.4 
Time to Confirmed Deterioration .............................................. 88 
 
 ................................................ 89 
 
 ................................................................. 89 
 
 .................................................... 89 
6.5 
Safety Analyses ....................................................................... 89 
6.6 
Pharmacokinetic Analyses ....................................................... 90 
6.7 
Immunogenicity Analyses ........................................................ 90 
 
 ................................................................. 91 
6.9 
Health Status Utility Analyses .................................................. 91 
 
 ...................................................................... 91 
 
 ......................................................... 91 
 
 ......................................................... 92 
7. 
DATA COLLECTION AND MANAGEMENT ................................. 92 
7.1 
Data Quality Assurance ........................................................... 92 
7.2 
Electronic Case Report Forms ................................................. 93 
7.3 
Source Data Documentation .................................................... 93 

Atezolizumab and Tiragolumab—F. Hoffmann-La Roche Ltd 
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7.4 
Use of Computerized Systems ................................................ 94 
7.5 
Retention of Records ............................................................... 94 
8. 
ETHICAL CONSIDERATIONS ...................................................... 94 
8.1 
Compliance with Laws and Regulations .................................. 94 
8.2 
Informed Consent .................................................................... 95 
8.3 
Institutional Review Board or Ethics Committee ...................... 96 
8.4 
Confidentiality .......................................................................... 96 
8.5 
Financial Disclosure ................................................................. 97 
9. 
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION ....................................................................... 97 
9.1 
Study Documentation .............................................................. 97 
9.2 
Protocol Deviations .................................................................. 97 
9.3 
Management of Study Quality .................................................. 98 
9.4 
Site Inspections ....................................................................... 98 
9.5 
Administrative Structure ........................................................... 98 
9.6 
Dissemination of Data and Protection of Trade Secrets .......... 98 
9.7 
Protocol Amendments ............................................................. 99 
10. 
REFERENCES............................................................................ 100 
 
 
LIST OF TABLES 
Table 1 
Objectives and Corresponding Endpoints ................................... 27 
Table 2 
Treatment Regimens .................................................................. 30 
Table 3 
Administration of First and Subsequent Atezolizumab 
Infusions...................................................................................... 46 
Table 4 
Administration of First and Subsequent Tiragolumab 
Infusions...................................................................................... 47 
Table 5 
Adverse Event Severity Grading Scale for Events Not 
Specifically Listed in NCI CTCAE ............................................... 70 
 
 ............................................... 71 
Table 7 
Causal Attribution Guidance ....................................................... 72 
 
 ....... 91 
 
 
LIST OF FIGURES 
Figure 1 
Study Schema ............................................................................. 30 

Atezolizumab and Tiragolumab—F. Hoffmann-La Roche Ltd 
11/Protocol YO42138, Version 7 
PROTOCOL AMENDMENT ACCEPTANCE FORM 
TITLE: 
A PHASE III, RANDOMIZED, DOUBLE-BLIND, 
PLACEBO-CONTROLLED STUDY OF 
ATEZOLIZUMAB PLUS TIRAGOLUMAB IN 
COMBINATION WITH PACLITAXEL AND 
CISPLATIN COMPARED WITH PACLITAXEL AND 
CISPLATIN AS FIRST-LINE TREATMENT IN 
PATIENTS WITH UNRESECTABLE LOCALLY 
ADVANCED, UNRESECTABLE RECURRENT, OR 
METASTATIC ESOPHAGEAL SQUAMOUS CELL 
CARCINOMA 
PROTOCOL NUMBER: YO42138 
VERSION NUMBER: 
7 
EUDRACT NUMBER: 
Not applicable 
IND NUMBER: 
Not applicable 
NCT NUMBER: 
NCT04540211 
TEST PRODUCTS: 
Tiragolumab (RO7092284) 
Atezolizumab (RO5541267) 
SPONSOR: 
F. Hoffmann-La Roche Ltd 
I agree to conduct the study in accordance with the current protocol. 
 
 
 
Principal Investigator's Name  (print) 
 
 
 
 
 
Principal Investigator's Signature 
 
Date 
Please retain the signed original of this form for your study files.  Please return a copy of 
the signed form as instructed by your local study monitor. 
 

 
Atezolizumab and Tiragolumab—F. Hoffmann-La Roche Ltd 
12/Protocol YO42138, Version 7 
PROTOCOL SYNOPSIS 
TITLE: 
A PHASE III, RANDOMIZED, DOUBLE-BLIND, 
PLACEBO-CONTROLLED STUDY OF ATEZOLIZUMAB PLUS 
TIRAGOLUMAB IN COMBINATION WITH PACLITAXEL AND 
CISPLATIN COMPARED WITH PACLITAXEL AND CISPLATIN AS 
FIRST-LINE TREATMENT IN PATIENTS WITH UNRESECTABLE 
LOCALLY ADVANCED, UNRESECTABLE RECURRENT, OR 
METASTATIC ESOPHAGEAL SQUAMOUS CELL CARCINOMA 
PROTOCOL NUMBER: 
YO42138 
VERSION NUMBER: 
7 
EUDRACT NUMBER: 
Not Applicable 
IND NUMBER: 
Not Applicable 
NCT NUMBER: 
NCT04540211 
TEST PRODUCTS: 
Tiragolumab (RO7092284) 
Atezolizumab (RO5541267) 
PHASE: 
III 
INDICATION: 
Esophageal squamous cell carcinoma 
SPONSOR: 
F. Hoffmann-La Roche Ltd 
 
STUDY RATIONALE 
The purpose of this study is to evaluate the efficacy and safety of atezolizumab plus 
tiragolumab in combination with paclitaxel and cisplatin (Atezo  Tira  PC) compared with 
atezolizumab placebo plus tiragolumab placebo in combination with paclitaxel and cisplatin 
(Placebo  PC) as first-line treatment in patients with unresectable locally advanced, 
unresectable recurrent, or metastatic esophageal squamous cell carcinoma (ESCC). 
There is no consensus on the optimal regimen for first-line treatment of advanced esophageal 
cancer globally.  For ESCC in particular, there are no data from recent randomized controlled 
trials, and combination chemotherapy is typically given.  However, there continues to be a 
significant unmet medical need in patients with unresectable locally advanced, unresectable 
recurrent, or metastatic ESCC.

 
Atezolizumab and Tiragolumab—F. Hoffmann-La Roche Ltd 
13/Protocol YO42138, Version 7 
OBJECTIVES AND ENDPOINTS 
Primary Efficacy Objective 
Corresponding Endpoint  
 To evaluate the efficacy of 
Atezo  Tira  PC compared with 
Placebo  PC 
 OS, defined as the time from randomization to death 
from any cause 
 PFS, defined as the time from randomization to the 
first occurrence of disease progression or death from 
any cause (whichever occurs first), as determined by 
an IRF according to RECIST v1.1 
Secondary Efficacy Objectives 
Corresponding Endpoints  
 To evaluate the efficacy of 
Atezo  Tira  PC compared with 
Placebo  PC 
 PFS as determined by the investigator according to 
RECIST v1.1 
 Confirmed ORR, defined as the proportion of 
patients with a CR or PR on two consecutive 
occasions  4 weeks apart, as determined by an IRF 
according to RECIST v1.1 
 Confirmed ORR as determined by the investigator 
according to RECIST v1.1 
 DOR, defined as the time from the first occurrence of 
a confirmed objective response to the first 
occurrence of disease progression or death from any 
cause (whichever occurs first), as determined by an 
IRF according to RECIST v1.1 
 DOR as determined by the investigator according to 
RECIST v1.1 
 To evaluate the efficacy of 
Atezo  Tira  PC compared with 
Placebo  PC 
 TTCD in patient-reported physical functioning, role 
functioning, and GHS/QoL as measured by the 
respective scales of the EORTC QLQ C30 and 
defined as the time from randomization to first 
deterioration (decrease from baseline of   10 points) 
that is either maintained for two consecutive 
assessments or followed by death from any cause 
within 3 weeks 
 TTCD in patient-reported dysphagia as measured by 
the dysphagia scale of the EORTC QLQ OES18 and 
defined as the time from randomization to first 
deterioration (increase from baseline of   10 points) 
that is either maintained for two consecutive 
assessments or followed by death from any cause 
within 3 weeks 
Safety Objective 
Corresponding Endpoint 
 To evaluate the safety of 
Atezo  Tira  PC compared with 
Placebo  PC 
 Incidence and severity of adverse events 
Severity for all events will be graded 
according to NCI CTCAE v5.0,
 
 

 
Atezolizumab and Tiragolumab—F. Hoffmann-La Roche Ltd 
14/Protocol YO42138, Version 7 
OBJECTIVES AND ENDPOINTS (CONT.) 
Pharmacokinetic Objective 
Corresponding Endpoint 
 To characterize the PK profiles of  
tiragolumab and atezolizumab when 
given in combination with paclitaxel 
and cisplatin 
 Serum concentration of tiragolumab and 
atezolizumab at specified timepoints 
Immunogenicity Objective 
Corresponding Endpoint 
 To evaluate the immune response to 
tiragolumab and atezolizumab when 
given in combination with paclitaxel 
and cisplatin 
 Prevalence of ADAs to tiragolumab at baseline and 
incidence of ADAs to tiragolumab during the study 
 Prevalence of ADAs to atezolizumab at baseline and 
incidence of ADAs to atezolizumab during the study 
Health Status Utility Objectives 
Corresponding Endpoint 
 To evaluate health status utility scores 
of patients treated with 
Atezo  Tira  PC compared with 
Placebo  PC 
 Mean change from baseline in the index-based and 
VAS scores of the EuroQol EQ-5D-5L 
Atezo  Tira  PC  atezolizumab plus tiragolumab in combination with paclitaxel and cisplatin; 
CR  complete response;
DOR  duration of response; 
EORTC  European Organisation for Research and Treatment of Cancer; GHS/QoL  global 
health status and quality of life; IRF  independent review facility; NCI CTCAE v5.0  National 
Cancer Institute Common Terminology Criteria for Adverse Events, Version 5.0; ORR  objective 
response rate; OS  overall survival;
PFS  progression-free survival; PR  partial response; PK  pharmacokinetic; 
Placebo  PC  atezolizumab placebo plus tiragolumab placebo in combination with paclitaxel and 
cisplatin; RECIST v1.1  Response Evaluation Criteria in Solid Tumors, Version 1.1; 
TTCD  time to confirmed deterioration; VAS  Visual Analog Scale. 
 
OVERALL DESIGN AND STUDY POPULATION 
This Phase III, randomized, multicenter, double-blind study will evaluate the efficacy and safety 
of Atezo  Tira  PC compared with Placebo  PC as first-line treatment in patients with 
unresectable locally advanced, unresectable recurrent, or metastatic ESCC. 
Several key aspects of the study design and study population are summarized below. 
Phase: 
Phase III 
Population Type: 
Adult patients 

 
Atezolizumab and Tiragolumab—F. Hoffmann-La Roche Ltd 
16/Protocol YO42138, Version 7 
Cisplatin 
6080 mg/m2 
75% of previous dose 
75% of previous dose 
 
 
If further dose reduction is indicated for cisplatin and/or paclitaxel after 2 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.  Once the dose has been decreased, it should 
remain reduced for all subsequent administrations or further reduced if necessary.  There will be 
no dose escalations in this study.  All subsequent chemotherapy doses must be rescheduled 
according to the last chemotherapy dose administration date.  If any chemotherapy agent is 
held for more than 2 cycles (6 weeks) from the anticipated treatment date, or the dose level-2 is 
not tolerated, chemotherapy should be permanently discontinued. 
Cisplatin dose reductions for renal impairment are provided in the table below. 
Cisplatin Dose Reductions for Renal Impairment 
 
Action to Be Taken 
Creatinine Clearance (mL/min) 
 40 to  50 
 Continue atezolizumab, tiragolumab, and paclitaxel. 
 Withhold cisplatin. 
 If creatinine clearance recovers to baseline or better  6 weeks 
after event onset, resume cisplatin with dose reduced by one 
dose level. a  If not, permanently discontinue cisplatin. b 
 30 to  40 
 Continue atezolizumab, tiragolumab, and paclitaxel. 
 Withhold cisplatin. 
 If creatinine clearance recovers to baseline or better  6 weeks 
after event onset, resume cisplatin with dose reduced by 2 dose 
levels. a  If not, permanently discontinue cisplatin. b  
 30  
 Continue atezolizumab, tiragolumab, and paclitaxel. 
 Permanently discontinue cisplatin. b 
a The dose of paclitaxel and the dose of cisplatin may be reduced by up to 2 times, as outlined 
in Dose Reductions for Paclitaxel and Cisplatin. 
b Resumption of treatment may be considered if the investigator believes the patient is likely to 
derive clinical benefit.  The Medical Monitor is available to advise as needed. 
 
DURATION OF PARTICIPATION 
Patients will receive study 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 cancer immunotherapy, radiographic progression per 
Response Evaluation Criteria in Solid Tumors, Version 1.1 (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 study treatment 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 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 

 
Atezolizumab and Tiragolumab—F. Hoffmann-La Roche Ltd 
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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 5.0.  Laboratory safety assessments will include regular monitoring of 
hematology and blood chemistry. 
COMMITTEES 
Independent Committees: Independent Data Monitoring Committee, Independent Data 
Coordinating Center 
Other Committees: 
Not applicable 
 

 
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Abbreviation 
Definition 
iDCC 
independent Data Coordinating Center 
iDMC 
independent Data Monitoring Committee 
IFN 
interferon 
IL 
interleukin 
IMP 
investigational medicinal product 
IND 
Investigational New Drug (application) 
IRB 
Institutional Review Board 
IRF 
Independent Review Facility 
IRR 
infusion-related reaction 
IxRS 
interactive voice or Web-based response system 
 
 
MDD 
minimum detectable difference 
MRI 
magnetic resonance imaging 
NCCN 
National Comprehensive Cancer Network 
NCI CTCAE 
National Cancer Institute Common Terminology Criteria 
for Adverse Events 
NHCPRC 
National Health Commission of the People's Republic 
of China 
NK 
natural killer (cell) 
NSCLC 
nonsmall-cell lung cancer 
ORR 
objective response rate 
OS 
overall survival 
 
 
 
 
PFS 
progression-free survival 
PK 
pharmacokinetic 
Placebo  PC 
atezolizumab placebo plus tiragolumab placebo in 
combination with paclitaxel and cisplatin 
PR 
partial response 
PRO 
patient-reported outcome 
PVR 
poliovirus receptor 
 
 
RECIST v1.1 
Response Evaluation Criteria in Solid Tumors, 
Version 1.1 
SAP 
Statistical Analysis Plan 
SARS-CoV-2 
severe acute respiratory syndrome coronavirus 2 
SCC 
squamous cell carcinoma 
SITC 
Society for Immunotherapy for Cancer 

 
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Abbreviation 
Definition 
 
 
TNF- 
tumor necrosis factor- 
TTCD 
time to confirmed deterioration 
 
 
ULN 
upper limit of normal 
 
 
 

 
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1. 
BACKGROUND 
1.1 
BACKGROUND ON ESOPHAGEAL CARCINOMA 
Esophageal cancer is the seventh most common cancer and the sixth most common 
cause of death from cancer worldwide (Bray et al. 2018).  The incidence, prevalence, 
and histologic type of esophageal cancer varies between geographic regions, 
particularly between Western countries (United States and Europe) and an area 
commonly referred to as the "esophageal cancer belt" that stretches across 
central-eastern Asia from the Caspian region to northern China (Arnold et al. 2015).  
In 2018, 477,900 of the 572,034 new cases of esophageal cancer were estimated to 
occur in China.  While adenocarcinoma is the predominant histologic type in the 
United States, 90% of cases in China are squamous cell carcinoma (SCC) 
(Arnold et al. 2015; Chen et al. 2016).  Adenocarcinoma and SCC have differing biologic 
pathways and are, therefore, treated differently. 
Advanced esophageal cancer is a rapidly fatal disease.  More than two-thirds of patients 
diagnosed with esophageal cancer will have advanced or metastatic disease, with 
a median survival of 810 months and an expected 5-year survival rate of  5% 
(Drahos et al. 2013; Lin et al. 2016).  The impact of esophageal cancer on patients is 
multi-faceted.  Most affected individuals present with physical symptoms, primarily 
dysphagia (Daly et al. 2000), which can result in unintentional weight loss and loss of 
appetite; less common symptoms include chest pain, dyspnea, and gastrointestinal 
reflux.  However, patients also frequently report poor emotional well-being, and in 
particular high rates of anxiety and depression (Bergquist et al. 2007).  Each of these 
has a significant impact on patients’ quality of life.  These data, combined with the 
relative lack of highly effective treatments, are indicative of the large unmet medical 
need in patients diagnosed with advanced esophageal cancer. 
1.2 
TREATMENT FOR ADVANCED ESOPHAGEAL SQUAMOUS 
CELL CARCINOMA 
1.2.1 
Chemotherapy 
There is no consensus on the optimal regimen for first-line treatment of advanced 
esophageal cancer globally.  For esophageal squamous cell carcinoma (ESCC) in 
particular, there are no data from recent randomized controlled trials.  
However, combination chemotherapy is typically given.  Treatment regimens for ESCC 
commonly consist of cisplatin in combination with paclitaxel or 5-fluorouracil (5-FU) 
(Lordick and Janjigian 2016; Kitagawa et al. 2019; National Comprehensive Cancer 
Network [NCCN] 2019; National Health Commission of the People's Republic of China 
[NHCPRC] 2019); these regimens are associated with objective response rates (ORRs) 
ranging from 20%48%, 5-year survival rates of less than 10%, and significant toxicity 
rates (Grunberger et al. 2007).  There are regional preferences for the chemotherapy of 
choice, which may be based on the toxicity profile of each agent. 

 
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1.2.2 
AntiPD-1 Therapy 
Currently, antiPD-L1 therapy is not approved for first-line treatment of advanced 
esophageal cancer.  However, clinical outcome data are available from 2 Phase III 
studies evaluating antiPD-1 monotherapy (nivolumab and pembrolizumab) as 
second-line treatment in patients with advanced esophageal carcinoma. 
ATTRACTION-3 demonstrated the survival benefit of nivolumab versus 
investigator-selected chemotherapy (paclitaxel or docetaxel) in patients with ESCC 
(Kato et al. 2019).  In the intent-to-treat (ITT) population (n  419), overall survival (OS) 
was statistically significantly prolonged in the nivolumab arm compared with the 
chemotherapy arm (median OS: 10.9 vs. 8.4 months; hazard ratio [HR]: 0.77; 
95% CI: 0.62 to 0.96; p  0.019). 
In KEYNOTE-181, patients with advanced esophageal cancer after first-line 
chemotherapy were treated with pembrolizumab for up to 2 years or 
investigator-selected chemotherapy (paclitaxel, docetaxel, or irinotecan) for 
approximately 18 months.  Of the 628 patients who were randomized, 401 had ESCC 
and 222 had tumors that expressed PD-L1 (combined positive score [CPS]  10).  
Overall survival was statistically significantly prolonged in the pembrolizumab arm 
compared with the chemotherapy arm among patients with a CPS of  10 
(median OS: 9.3 vs. 6.7 months; HR: 0.69; 95% CI: 0.52 to 0.93; p  0.0074).  There was 
clinically meaningful improvement in OS with pembrolizumab versus chemotherapy 
among patients with ESCC, but this was not statistically significant per prespecified 
boundaries (median OS: 8.2 vs. 7.1 months; HR: 0.78; 95% CI: 0.63 to 0.96; p  0.0095). 
Overall, these data indicate that checkpoint inhibitors such as antiPD-1 demonstrate 
single-agent activity in esophageal cancer. 
1.3 
BACKGROUND ON ATEZOLIZUMAB 
Atezolizumab is a humanized IgG1 monoclonal antibody that targets PD-L1 and inhibits 
the interaction between PD-L1 and its receptors, PD-1 and B7-1 (also known as CD80), 
both of which function as inhibitory receptors expressed on T cells.  
Therapeutic blockade of PD-L1 binding by atezolizumab has been shown to enhance the 
magnitude and quality of tumor-specific T cell responses, resulting in improved 
anti-tumor activity (Fehrenbacher et al. 2016; Rosenberg et al. 2016).  Atezolizumab has 
minimal binding to fragment crystallizable (Fc) receptors, thus eliminating detectable 
Fc-effector function and associated antibody-mediated clearance of activated effector 
T cells. 
Atezolizumab shows anti-tumor activity in both nonclinical models and patients with 
cancer and is being investigated as a potential therapy in a wide variety of malignancies.  
Atezolizumab is being studied as a single agent in the advanced cancer and adjuvant 
therapy settings, as well as in combination with chemotherapy, targeted therapy, and 
cancer immunotherapy. 

 
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Atezolizumab is approved for the treatment of urothelial carcinoma, nonsmall-cell lung 
cancer (NSCLC), small-cell lung cancer, triple-negative breast cancer, hepatocellular 
carcinoma, melanoma and alveolar soft part sarcoma. 
Refer to the Atezolizumab Investigator's Brochure for details on nonclinical and clinical 
studies for atezolizumab. 
1.4 
BACKGROUND ON TIRAGOLUMAB 
Tiragolumab is a fully human IgG1/ monoclonal antibody that binds TIGIT, an immune 
inhibitory receptor that 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 poliovirus 
receptor [PVR]; Yu et al. 2009).  Genetic ablation of TIGIT in T cells in mice results in 
exacerbated T-cell responses, demonstrating the role of TIGIT in inhibiting T-cell 
responses (Joller et al. 2011; Johnston et al. 2014).  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 combined with other 
cancer immunotherapy and chemotherapy.  The available nonclinical and clinical data 
provide a strong rationale for evaluating the potential clinical benefit of tiragolumab in 
patients with cancer. 
Refer to the Tiragolumab Investigator’s Brochure for details on the nonclinical and 
clinical studies for tiragolumab. 
1.5 
STUDY RATIONALE AND BENEFIT‑RISK ASSESSMENT 
The purpose of this study is to assess the efficacy and safety of tiragolumab plus 
atezolizumab in combination with chemotherapy (paclitaxel and cisplatin) to address 
a significant unmet medical need in patients with unresectable locally advanced, 
unresectable recurrent, or metastatic ESCC. 
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).  
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).  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.  To date, these events have been manageable with treatment or interruption 
of atezolizumab treatment.  See Appendix 10 of the protocol and Section 6 of the 

 
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Atezolizumab Investigator's Brochure for details on the anticipated risks 
for atezolizumab. 
TIGIT is expressed on the surface of activated T-cell and NKcell subsets and interacts 
with high affinity with CD155 (also known as PVR; Yu et al. 2009), which is broadly 
expressed in solid tumors.  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).  TIGIT is, 
therefore, 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. 
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, levels of PVR 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). 
In a Phase I, dose-escalation and dose-expansion study (GO30103), tiragolumab was 
administered alone and in combination with atezolizumab to patients with locally 
advanced, recurrent, or metastatic incurable tumors, including esophageal cancer.  
 
 
  In a Phase II study (GO40290), 
tiragolumab plus atezolizumab was compared with placebo plus atezolizumab in patients 
with previously untreated, locally advanced unresectable or metastatic PD-L1positive 
(defined as tumor proportion score  1%) NSCLC.  As of the data cutoff date of 
30 June 2019, the confirmed ORR was higher in the tiragolumab plus atezolizumab arm 
(31.3%; n  67) than in the placebo plus atezolizumab arm (16.2%; n  68).  In addition, 
investigator-assessed progression-free survival (PFS) was improved in the tiragolumab 
plus atezolizumab arm compared with the placebo plus atezolizumab arm 
(stratified HR  0.57 [95% CI: 0.37 to 0.90]; median PFS, 5.4 vs. 3.6 months, 
respectively).  Detailed efficacy data for these studies are provided in the 
Tiragolumab Investigator's Brochure. 

 
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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.  In Study GO40290, serious and 
high-grade treatment-related adverse events have been balanced between the 
tiragolumab plus atezolizumab arm and the placebo plus atezolizumab arm, and 
immune-mediated adverse events have been balanced between the two treatment arms, 
with the exception of a higher frequency of 
 and rash 
reported in the tiragolumab plus atezolizumab arm. 
 
 
 
 
 
  Detailed safety data for these studies are 
provided in the Tiragolumab Investigator's Brochure.  Risk mitigation measures for this 
study are outlined in Section 5.1, and guidelines for managing adverse events 
associated with study treatment are provided in Appendix 9 and Appendix 10. 
Advanced ESCC is an incurable disease with a high unmet need for improved medical 
intervention.  Taking into account the preliminary efficacy and manageable safety 
profiles of tiragolumab plus atezolizumab and their potentially synergistic mechanisms of 
action, as well as the potential for improved outcomes when adding dual checkpoint 
inhibition to chemotherapy, treatment with atezolizumab, tiragolumab, and 
chemotherapy (paclitaxel and cisplatin) appears to have therapeutic potential in solid 
tumors such as ESCC. 
Neutropenia and lymphopenia associated with chemotherapy may increase the risk for 
developing an infection in patients receiving tiragolumab and atezolizumab in 
combination with chemotherapy. 
Given the mechanism of action for atezolizumab and tiragolumab, immune-mediated 
adverse events are potential overlapping toxicities associated with combination use of 
these two agents. 
In the setting of the coronavirus disease 2019 (COVID-19) pandemic, patients with 
comorbidities, including those with esophageal cancer, are considered a more 
vulnerable population, with the potential for more severe clinical outcomes from 
COVID-19.  However, it is unclear whether or how systemic cancer therapies, such as 
chemotherapy, targeted therapy, or immunotherapy, impact the incidence or severity 
of COVID-19. 
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; Schorer et al. 2020).  
In nonclinical models, PD-L1/PD-1 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 
COVID-19 is altered by cancer immunotherapy. 
Severe COVID-19 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 severe acute 
respiratory syndrome coronavirus 2 (SARS-CoV-2) infection while receiving 
atezolizumab and/or tiragolumab.  At this time, there is insufficient evidence for causal 
association between atezolizumab or tiragolumab and an increased risk of severe 
outcomes from COVID-19. 
There may be potential synergy or overlap in clinical and radiologic features for 
immune-mediated pulmonary toxicity with checkpoint inhibitors and clinical and 
radiologic features for COVID-19 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 cancer 
immunotherapy treatment and COVID-19 vaccination, and it is recognized that human 
immune responses are highly regulated and that immune-modifying therapies may 
positively or negatively impact the efficacy and safety of COVID-19 vaccination 
(Society for Immunotherapy for 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 cancer immunotherapy 
(SITC 2020).  For patients enrolling in this study and receiving atezolizumab and/or 
tiragolumab treatment, a decision to administer the vaccine to a patient should be made 
on an individual basis by the investigator in consultation with the patient. 
In alignment with clinical practice procedures, factors to consider when making the 
individualized decision for patients receiving atezolizumab and/or tiragolumab treatment 
to receive COVID-19 vaccination include the following:  the risk of SARS-CoV-2 infection 
and potential benefit from the vaccine, the general condition of the patient and potential 
complications associated with SARS-CoV-2 infection, underlying disease, and the 
severity of COVID-19 outbreak in a given area or region. 

 
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The SITC and NCCN recommendations along with institutional guidelines should be 
used by the investigator when deciding on administering COVID-19 vaccines.  
When administered, COVID-19 vaccines must be given in accordance with the approved 
or authorized vaccine label.  Receipt of the COVID-19 vaccine is considered a 
concomitant medication and should be documented as such (see Section 4.4.1). 
2. 
OBJECTIVES AND ENDPOINTS 
This study will evaluate the efficacy and safety of atezolizumab plus tiragolumab in 
combination with paclitaxel and cisplatin (Atezo  Tira  PC) compared with atezolizumab 
placebo plus tiragolumab placebo in combination with paclitaxel and cisplatin 
(Placebo  PC) as first-line treatment in patients with unresectable locally advanced, 
unresectable recurrent, or metastatic ESCC.  Specific objectives and corresponding 
endpoints for the study are outlined in Table 1. 
Table 1 
Objectives and Corresponding Endpoints 
Primary Efficacy Objective 
Corresponding Endpoints 
 To evaluate the efficacy of 
Atezo  Tira  PC compared with 
Placebo  PC 
 OS, defined as the time from randomization to death 
from any cause 
 PFS, defined as the time from randomization to the 
first occurrence of disease progression or death 
from any cause (whichever occurs first), as 
determined by an IRF according to RECIST v1.1 
Secondary Efficacy Objective 
Corresponding Endpoints 
 To evaluate the efficacy of 
Atezo  Tira  PC compared with 
Placebo  PC 
 PFS as determined by the investigator according to 
RECIST v1.1 
 Confirmed ORR, defined as the proportion of 
patients with a CR or PR on two consecutive 
occasions  4 weeks apart, as determined by an IRF 
according to RECIST v1.1 
 Confirmed ORR as determined by the investigator 
according to RECIST v1.1 
 DOR, defined as the time from the first occurrence 
of a confirmed objective response to the first 
occurrence of disease progression or death from 
any cause (whichever occurs first), as determined by 
an IRF according to RECIST v1.1 
 DOR as determined by the investigator according to 
RECIST v1.1 

 
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Table 1 
Objectives and Corresponding Endpoints (cont.) 
Health Status Utility Objectives 
Corresponding Endpoint 
 To evaluate health status utility scores 
of patients treated with 
Atezo  Tira  PC compared with 
Placebo  PC 
 Mean change from baseline in the index-based 
and VAS scores of the EuroQol EQ-5D-5L 
ADA  anti-drug antibody;
Atezo  Tira  PC  atezolizumab plus tiragolumab in combination with paclitaxel and cisplatin; 
CR  complete response;
DOR  duration of response; 
EORTC  European Organisation for Research and Treatment of Cancer; GHS/QoL  global 
health status and quality of life; IRF  Independent Review Facility; NCI CTCAE v5.0  National 
Cancer Institute Common Terminology Criteria for Adverse Events, Version 5.0; 
ORR  objective response rate; OS  overall survival;
PFS  progression-free survival; PR  partial response; PK  pharmacokinetic; 
Placebo  PC  atezolizumab placebo plus tiragolumab placebo in combination with paclitaxel 
and cisplatin; RECIST v1.1  Response Evaluation Criteria in Solid Tumors, Version 1.1; 
TTCD  time to confirmed deterioration;
VAS  Visual Analog Scale. 
 
3. 
STUDY DESIGN 
3.1 
DESCRIPTION OF THE STUDY 
This is a Phase III, randomized, multicenter, double-blind study designed to evaluate the 
efficacy and safety of Atezo  Tira  PC compared with Placebo  PC as first-line 
treatment in patients with unresectable locally advanced, unresectable recurrent, or 
metastatic ESCC. 
Patients who do not initially meet all eligibility criteria for participation in this study 
(screen failure) may qualify for 1 re-screening opportunity (for a total of 2 screenings per 
patient) at the discretion of the investigator, as described in Section 4.5.1.  
The Medical Monitor is available to advise as needed. 

 
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Patients will receive study 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 cancer immunotherapy, 
radiographic progression per Response Evaluation Criteria in Solid Tumors, Version 1.1 
(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 study treatment 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 ECOG Performance Status that can be attributed to 
disease progression 
 
Absence of tumor progression at critical anatomical sites (e.g., leptomeningeal 
disease) that cannot be managed by protocol-allowed medical interventions 
 
Patients 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 (NCI CTCAE), Version 5.0.  Laboratory safety assessments 
will include regular monitoring of hematology and blood chemistry. 
Patients will undergo tumor assessments every 69 weeks, as outlined in the schedule 
of activities (see Appendix 1).  Tumor assessment images will be reviewed by an 
Independent Review Facility (IRF) and by the investigator. 
Patients will undergo patient-reported outcome (PRO) assessments at specified 
timepoints during treatment and for up to 1 year after treatment discontinuation, as 
outlined in Appendix 1. 
Serum samples will be collected for pharmacokinetic (PK) and immunogenicity analyses.  
 
 
Following treatment discontinuation, information on survival follow-up and new 
anti-cancer therapy will be collected until death (unless the patient withdraws consent or 
the Sponsor terminates the study). 

 
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3.2 
INDEPENDENT DATA MONITORING COMMITTEE 
An independent Data Monitoring Committee (iDMC) will evaluate safety data during the 
study.  Sponsor affiliates will be excluded from iDMC membership.  The iDMC will follow 
a charter that outlines the iDMC roles and responsibilities. 
Unblinded safety data will be reviewed by the iDMC after a minimum of 16 patients have 
been enrolled and have received 2 cycles of study treatment.  Subsequently, the iDMC 
will review safety data approximately every 6 months until the study is unblinded or the 
study is terminated by the Sponsor.  All summaries and analyses for the iDMC review 
will be prepared by an independent Data Coordinating Center (iDCC). 
After reviewing the data, the iDMC will provide a recommendation to the Sponsor as 
described in the iDMC charter.  Final decisions will rest with the Sponsor. 
Any outcomes of these data reviews that affect study conduct will be communicated in 
a timely manner to the investigators for notification of their respective Institutional 
Review Boards (IRBs)/Ethics Committees (ECs). 
3.3 
INDEPENDENT REVIEW FACILITY 
An IRF will be used to enable centralized, independent reviews of tumor assessment 
images and other clinical data used for assessment of ESCC (e.g., histopathology, 
tumor markers).  Independent Review Facility reviews will be performed prior to the 
prespecified efficacy analyses.  Independent Review Facility membership and 
procedures will be detailed in an IRF charter. 
3.4 
END OF STUDY AND LENGTH OF STUDY 
The end of the study will occur when both of the following criteria have been met: 
 
Required number of deaths for the final OS analysis has been observed 
(see Section 6.10.1) 
 
Last patient, last visit has occurred 
 
In addition, the Sponsor may decide to terminate the study at any time. 
The total length of the study, from screening of the first patient to the end of the study, is 
expected to be approximately 
. 
3.5 
RATIONALE FOR STUDY DESIGN 
 
 
 
 
 
 

 
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3.5.3 
Rationale for Patient Population 
This study will enroll patients with unresectable locally advanced, unresectable 
recurrent, or metastatic ESCC, regardless of PD-L1 expression.  Because surgery is not 
an option for this patient population, first-line treatment commonly includes 
chemotherapy regimens consisting of cisplatin in combination with paclitaxel or 5-FU 
(NCCN 2019), which are associated with ORRs ranging from 20%48%, 5-year survival 
rates of less than 10%, and significant toxicity rates (Grunberger et al. 2007).  
Because the efficacy of platinum-containing chemotherapy has plateaued, the outcome 
of patients with a unresectable locally advanced, unresectable recurrent, or metastatic 
ESCC has not improved in the past two decades.  Thus, there is large unmet medical 
need in patients diagnosed with ESCC. 
Tumor-cell killing by cytotoxic chemotherapy may expose the immune system to high 
levels of tumor antigens.  Boosting tumor-specific T-cell immunity in this setting by 
blocking the PD-L1 pathway may result in deeper and more durable responses than 

 
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those observed with standard chemotherapy alone (Merritt et al. 2003; 
Apetoh et al. 2007), and this may reasonably occur in tumors regardless of 
PD-L1 expression. 
3.5.4 
Rationale for Control Group 
In general, a combined chemotherapy regimen can achieve a higher ORR than 
single-agent chemotherapy.  As described in Section 1.2.1, NCCN, European Society for 
Medical Oncology, Japanese, and Chinese Society of Clinical Oncology guidelines all 
recommend platinum-containing chemotherapy as a first-line treatment option for 
unresectable advanced recurrent or metastatic ESCC (Lordick and Janjigian 2016; 
Kitagawa et al. 2019; NCCN 2019; NHCPRC 2019).  The combination of paclitaxel and 
cisplatin is more widely used in China than the combination of cisplatin and 5-FU.  
Taking into consideration the toxicity of a three-drug chemotherapy regimen and the 
widespread use of a two-drug regimen in China, the control arm will receive combination 
chemotherapy consisting of paclitaxel and cisplatin. 
3.5.5 
Rationale for Progression-Free Survival and Overall Survival 
as Co-Primary Endpoints 
In this study, the co-primary efficacy endpoints will be IRF-assessed PFS and OS.  
This study will test the hypothesis that treatment with Atezo  Tira  PC will prolong PFS 
and OS compared with treatment with Placebo  PC. 
Progression-free survival as an endpoint can reflect tumor growth and can be assessed 
before the determination of a survival benefit; additionally, its determination is not 
generally confounded by subsequent therapies.  Whether an improvement in PFS 
represents a direct clinical benefit or a surrogate for clinical benefit depends on the 
magnitude of the effect and the benefitrisk profile of the new treatment compared with 
available therapies (FDA 2007; European Medicines Agency 2012). 
Improvement in OS is generally accepted as the best measure of clinical benefit for 
patients with advanced/unresectable or metastatic esophageal cancer.  Recent data also 
suggest that OS may be a more sensitive endpoint for cancer immunotherapy than PFS. 
3.5.6 
Rationale for Study Treatment Beyond Initial Radiographic 
Progression 
In studies of immunotherapeutic agents, CR, PR, 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 tumor-infiltrating immune cells and no viable cancer cells.  Because of 
the potential for a response after pseudoprogression, this study will allow all patients to 

 
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continue 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).  Patients should be discontinued for unacceptable toxicity or loss of clinical 
benefit as determined by the investigator after an integrated assessment of radiographic 
and biochemical data, local biopsy results (if available), and clinical status 
(see Section 3.1 for details). 
3.5.7 
Rationale for Pharmacokinetic Sampling Schedule 
Pharmacokinetic samples will be collected from all patients to characterize the 
pharmacokinetics of tiragolumab and atezolizumab when administered in combination.  
The exposures of tiragolumab and atezolizumab in this study will be compared with the 
exposure attained for each agent when administered as a single agent in previous 
studies, to evaluate whether exposures are altered when administered in combination or 
in this patient population. 
 
 
4. 
MATERIALS AND METHODS  
4.1 
PATIENTS 
Approximately 450 patients with unresectable locally advanced, unresectable recurrent, 
or metastatic ESCC will be enrolled in this study. 
4.1.1 
Inclusion Criteria 
Patients must meet the following criteria for study entry: 
 
Signed Informed Consent Form 

 
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 
Age  18 years at time of signing Informed Consent Form 
 
Ability to comply with the study protocol 
 
Histologically confirmed ESCC 
Patients with tumors of mixed histology (i.e., squamous and non-squamous) are 
eligible if the major histological component appears to be squamous, except if 
small-cell elements are present. 
 
Unresectable locally advanced, unresectable recurrent, or metastatic disease 
(i.e., advanced disease, not suitable for definitive treatment such as radiotherapy, 
chemoradiotherapy, and/or surgery) that meets the following criteria: 
– 
– 
 
Measurable disease per 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. 
 
Availability of a representative tumor specimen that is suitable for determination of 
PD-L1 expression, as assessed by a central laboratory through use of the 
 
 
A formalin-fixed, paraffin-embedded (FFPE) tumor specimen in a paraffin block 
(preferred) or 512 slides (12 slides preferred) containing unstained, freshly cut, 
serial sections (5 slides for determination of PD-L1 expression and 7 slides for 
 development) should be 
submitted along with an associated pathology report prior to enrollment.  
If archival tumor tissue is unavailable or is determined to be unsuitable for 
required testing, tumor tissue must be obtained from a biopsy performed at 
screening.  A biopsy may also be performed at screening if a patient's archival 
tissue test results do not meet eligibility criteria.  The number of slides provided 
may also be governed by local regulations (e.g., Human Genetic Resources 
Administration of China).  See Section 4.5.8 for additional information on tumor 
specimens collected at screening.  The remaining tissue samples collected for 
PD‑L1 assessment may be used for 
, when the 
tissue samples collected for 
 were insufficient. 
 
ECOG Performance Status of 0 or 1 
 
Body mass index  13 kg/m2 
 
Life expectancy  3 months 

 
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 
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 
 
 
 
 
 

 
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 
For women of childbearing potential:  agreement to remain abstinent (refrain from 
heterosexual intercourse) or use contraception, 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 90 days after the final dose 
of tiragolumab, for 5 months after the final dose of atezolizumab, and for 
6 months after the final dose of paclitaxel or cisplatin.  Women must refrain 
from donating eggs during this same period. 
A woman is considered to be of childbearing potential if she is postmenarchal, 
has not reached a postmenopausal state ( 12 continuous months of 
amenorrhea with no identified cause other than menopause), and is not 
permanently infertile due to surgery (i.e., removal of ovaries, fallopian tubes, 
and/or uterus) or another cause as determined by the investigator 
(e.g., Müllerian agenesis).  The definition of childbearing potential may be 
adapted for alignment with local guidelines or regulations. 
Examples of contraceptive methods with a failure rate of  1% per year include 
bilateral tubal ligation, male sterilization, hormonal contraceptives that inhibit 
ovulation, hormone-releasing intrauterine devices, and copper 
intrauterine devices. 
The reliability of sexual abstinence should be evaluated in relation to the 
duration of the clinical trial and the preferred and usual lifestyle of the patient.  
Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation 
methods) and withdrawal are not adequate methods of contraception.  
If required per local guidelines or regulations, locally recognized adequate 
methods of contraception and information about the reliability of abstinence will 
be described in the local Informed Consent Form. 
 
For men:  agreement to remain abstinent (refrain from heterosexual intercourse) or 
use contraceptive methods, and agreement to refrain from donating sperm, as 
defined below: 
With a female partner of childbearing potential who is not pregnant, 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 final dose of paclitaxel or cisplatin.  In the event of 
chemotherapy discontinuation, men who continue to receive tiragolumab for 
more than 6 months after the final chemotherapy dose must remain abstinent or 
use a condom until 90 days after the final dose of tiragolumab.  Men must 
refrain from donating sperm during this same period. 
With a pregnant female partner, men must remain abstinent or use a condom 
during the treatment period and for 90 days after the final dose of tiragolumab 
and 6 months after the final dose of paclitaxel or cisplatin to avoid exposing 
the embryo. 

 
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The reliability of sexual abstinence should be evaluated in relation to the 
duration of the clinical trial and the preferred and usual lifestyle of the patient.  
Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation 
methods) and withdrawal are not adequate methods of contraception.  
If required per local guidelines or regulations, locally recognized adequate 
methods of contraception and information about the reliability of abstinence will 
be described in the local Informed Consent Form. 
 
4.1.2 
Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from study entry: 
 
Palliative radiation treatment for ESCC within 4 weeks prior to initiation of 
study treatment 
 
Use of Chinese herbal medicine or Chinese patent medicines to control cancer 
within 7 days prior to initiation of study treatment 
 
Higher risk of bleeding or fistula caused by esophageal lesions invading adjacent 
organs (aorta or trachea) 
 
Evidence of complete esophageal obstruction not amenable to treatment 
 
Symptomatic, untreated, or actively progressing CNS metastases 
Asymptomatic patients with treated CNS lesions are eligible, provided that all of 
the following criteria are met: 
– 
– 
– 
– 
– 
– 
 
 

 
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 
Severe chronic or active 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.  
 
Active tuberculosis 
 
Major surgical procedure, other than for diagnosis, within 4 weeks prior to initiation 
of study treatment, or anticipation of need for a major surgical procedure during 
the study 
 
Any of the following cardiovascular risk factors: 
– 
– 
– 
– 
– 
– 
– 
– 
 
History of severe allergic anaphylactic reactions to chimeric or humanized 
antibodies or fusion proteins 
 
History of malignancy within 2 years prior to screening, with the exception of the 
cancer under investigation in this study and malignancies with a negligible risk of 
metastasis or death (e.g., 5-year OS rate  90%), such as adequately treated 
carcinoma in situ of the cervix, non-melanoma skin carcinoma, localized prostate 
cancer, ductal carcinoma in situ, or Stage I uterine cancer 
 
Grade  2 peripheral neuropathy at screening 
 
Uncontrolled diabetes or Grade  2 abnormalities in potassium, sodium, or corrected 
calcium despite standard medical management within 14 days prior to initiation of 
study treatment 

 
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 
Any other disease, medical condition, metabolic dysfunction, alcohol or drug abuse 
or dependence, physical examination finding, 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 
 
Poor peripheral venous access 
 
Prior treatment with CD137 agonists, T-cell co-stimulating, or immune checkpoint 
blockade therapies, including antiCTLA-4, antiPD-1, antiPD-L1, and antiTIGIT 
therapeutic antibodies  
 
Treatment with systemic immunostimulatory agents (including, but not limited to, 
IFN and IL-2) within 4 weeks or 5 drug-elimination half-lives (whichever is longer) 
prior to initiation of study treatment 
 
Treatment with investigational therapy within 28 days 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- [TNF-] agents) within 2 weeks prior to initiation of 
study treatment, or anticipation of need for systemic immunosuppressive medication 
during study treatment, with the following exceptions: 
– 
– 
 
Prior allogeneic stem cell or solid organ transplantation 
 
Treatment with a live, attenuated vaccine within 4 weeks prior to initiation of study 
treatment, or anticipation of need for such a vaccine during study treatment or within 
5 months after the final dose of study treatment 
 
Concurrent participation in another therapeutic clinical trial 
 
Known hypersensitivity to Chinese hamster ovary cell products or to any component 
of the atezolizumab formulation  
 
Known allergy or hypersensitivity to any component of the tiragolumab formulation 
 
Pregnant or breastfeeding 
Women of childbearing potential must have a negative serum pregnancy test 
result within 14 days prior to initiation of study treatment. 
 

 
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4.2 
METHOD OF TREATMENT ASSIGNMENT AND BLINDING  
4.2.1 
Treatment Assignment 
This is a randomized, double-blind study.  After written informed consent has been 
obtained, all screening procedures and assessments have been completed, and 
eligibility has been established for a patient, the study site will obtain the patient's 
identification number and treatment assignment from the interactive voice or Web-based 
response system (IxRS). 
Patients will be randomly assigned to one of two treatment arms:  Atezo  Tira  PC or 
Placebo  PC.  Randomization will occur in a 1:1 ratio through use of a permuted-block 
randomization method to ensure a balanced assignment to each treatment arm.  
Randomization will be stratified according to the following criteria: 
 
PD-L1 expression as assessed by a central laboratory through use of the 
 
Previous curative treatment (yes vs. no) 
 
ECOG Performance Status (0 vs. 1) 
 
4.2.2 
Blinding 
Study site personnel, patients, and the IRF will be blinded to treatment assignment 
during the study.  The Sponsor and its agents will also be blinded to treatment 
assignment, with the exception of individuals who require access to patient treatment 
assignments to fulfill their job roles during a clinical trial.  These roles include the 
unblinding group responsible, clinical supply chain managers, sample handling staff, 
operational assay group personnel, IxRS service provider, and iDMC members. 
While PK and immunogenicity samples must be collected from patients assigned to the 
comparator arm to maintain the blinding of treatment assignment, PK and ADA assay 
results for these patients are generally not needed for the safe conduct or proper 
interpretation of the study data.  Laboratories responsible for performing study drug PK 
and ADA assays will be unblinded to patient treatment assignments to identify 
appropriate samples for analysis.  Pharmacokinetic samples from patients assigned to 
the comparator arm will not be analyzed for study drug PK concentration except by 
request (e.g., to evaluate a possible error in dosing).  Baseline immunogenicity samples 
will be analyzed for all patients.  Postbaseline immunogenicity samples from patients 
assigned to the comparator arm will not be analyzed for ADAs except by request. 
The Sponsor will remain blinded to treatment assignment until the primary analysis of 
PFS has occurred.  Investigators and patients will remain blinded to treatment 
assignment until the final analysis of OS, except in cases where single-patient unblinding 
is necessary, as outlined below.  

 
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If unblinding is necessary for a medical emergency (e.g., in the case of a serious 
adverse event for which patient management might be affected by knowledge of 
treatment assignment), the investigator will be able to break the treatment code by 
contacting the IxRS.  The treatment code should not be broken except in emergency 
situations.  The investigator is not required to contact the Medical Monitor prior to 
breaking the treatment code.  However, the investigator should inform the 
Medical Monitor that the treatment code has been broken.  After emergency unblinding, 
medical- and study-related questions should be directed to the "Post-Unblinding Medical 
Monitor" (see Section 5.4.1). 
The "Post-Unblinding Medical Monitor" is a qualified medic/physician employed by the 
Sponsor who can support the investigator after single-subject unblinding and before the 
primary analysis of PFS occurs.  To avoid bias, the "Post-Unblinding Medical Monitor" 
will not work directly on the study and will have exclusive access to the unblinding 
mailbox for potentially receiving unblinded patient data.  Unblinded patient data or 
access to the unblinding mailbox will not be shared with blinded individuals on the study 
team, including, but not limited to the Roche Primary Medical Monitor, Roche Medical 
Monitor Back-up, or Roche Clinical Scientist. 
If the investigator wishes to know the identity of the study drug for any reason other than 
a medical emergency, he or she should contact the Medical Monitor directly.  
Unblinding may be permitted if an investigator is deciding whether a patient should 
withdraw from the study and initiate treatment with a proven therapy.  
However, unblinding will not be permitted if an investigator is deciding whether a patient 
should withdraw from the study and initiate treatment with an unproven therapy.  
The investigator should document and provide an explanation for any non-emergency 
unblinding.  If the Medical Monitor agrees to patient unblinding, the investigator will be 
able to break the treatment code by contacting the IxRS.  After unblinding, medical- and 
study-related questions should be directed to the "Post-Unblinding Medical Monitor" 
(see Section 5.4.1) to protect the integrity of the data. 
As per health authority reporting requirements, the Sponsor's Drug Safety representative 
will break the treatment code for all serious, unexpected suspected adverse reactions 
(see Section 5.7) that are considered by the investigator or Sponsor to be related to 
study drug.  The patient may continue to receive treatment, and the investigator, patient, 
and Sponsor personnel, with the exception of the Drug Safety representative and 
personnel who must have access to patient treatment assignments to fulfill their roles 
(as defined above), will remain blinded to treatment assignment. 
4.3 
STUDY TREATMENT AND OTHER TREATMENTS RELEVANT 
TO THE STUDY DESIGN 
The investigational medicinal products (IMPs) for this study are atezolizumab and 
tiragolumab and their matching placebos.  The non-IMPs for this study are paclitaxel and 
cisplatin. 

 
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4.3.1 
Study Treatment Formulation and Packaging 
4.3.1.1 
Atezolizumab and Placebo 
The atezolizumab and matching placebo drug product will be supplied by the Sponsor as 
a 
mL glass vial.  The vial contains approximately 
 mL 
of atezolizumab or placebo solution (1200 mg of atezolizumab in the active treatment 
vial).  For information on the atezolizumab formulation, see the pharmacy manual and 
the Atezolizumab Investigator's Brochure. 
4.3.1.2 
Tiragolumab and Placebo 
Tiragolumab and matching placebo will be supplied by the Sponsor as a 
 
mL glass vial.  The vial contains approximately 
 mL of tiragolumab or 
placebo solution (600 mg of tiragolumab in the active treatment vial).  For information 
on the tiragolumab formulation, see the pharmacy manual and the Tiragolumab 
Investigator's Brochure. 
4.3.1.3 
Paclitaxel and Cisplatin 
The commercially available formulations of paclitaxel and cisplatin will be administered 
in this study.  For information on the formulation and packaging of paclitaxel and 
cisplatin, refer to the local prescribing information for each drug. 
4.3.2 
Study Treatment Dosage, Administration, and Compliance 
The treatment regimens are summarized in Section 3.1 (see Table 2).  Patients will 
receive study 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 (see Section 3.1 
for details). 
Administration of study treatment 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 8.  
Refer to the pharmacy manual for detailed instructions on drug preparation, storage, and 
administration. 
Details on treatment administration (e.g., dose and timing) should be noted on the 
Study Drug Administration electronic Case Report Form (eCRF).  Cases of accidental 
overdose or medication error, along with any associated adverse events, should be 
reported as described in Section 5.3.5.12. 
Guidelines for dosage modification and treatment interruption or discontinuation for 
patients who experience adverse events are provided in Appendix 9 and Appendix 10. 
 
4.3.2.1 
Atezolizumab or Placebo 
Atezolizumab 1200 mg or matching placebo (referred to as "atezolizumab" hereafter) will 
be administered by IV infusion on Day 1 of each 21-day cycle.  Atezolizumab infusions 
will be administered per the instructions outlined in Table 3. 

 
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Table 3 
Administration of First and Subsequent Atezolizumab Infusions 
First Infusion 
Subsequent Infusions 
 
No premedication is permitted prior to the 
atezolizumab infusion. 
 
Vital signs (pulse rate, respiratory rate, 
blood pressure, and temperature) should 
be measured within 60 minutes prior to 
the infusion. 
 
Atezolizumab should be infused over 
60 ( 15) minutes. 
 
If clinically indicated, vital signs should be 
measured every 15 ( 5) minutes during 
the infusion. 
 
After the infusion of atezolizumab, patients 
should be observed for at least 60 minutes. 
 
Patient’s vital signs should be recorded at 
30 ( 10) minutes after the infusion 
of atezolizumab. 
 
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, anti-pyretic medications, 
and/or analgesics may be administered 
for subsequent doses at the discretion of 
the investigator. 
 
Vital signs should be measured within 
60 minutes prior to the infusion. 
 
Atezolizumab should be infused over 
30 ( 10) minutes if the previous infusion 
was tolerated without an infusion-related 
reaction, or 60 ( 15) minutes if the 
patient experienced an infusion-related 
reaction with the previous infusion. 
 
If clinically indicated, vital signs should be 
measured during the infusion. 
 
If the patient tolerated the previous 
infusion of atezolizumab well without an 
infusion-related reaction, the observation 
period may be reduced to at least 
30 minutes for subsequent infusions. 
 
If the patient experienced an 
infusion-related reaction in the previous 
infusion, the observation period should be 
at least 60 minutes. 
 
If clinically indicated, record the patient’s 
vital signs at 30 ( 10) minutes after 
the infusion. 
 
Guidelines for medical management of IRRs are provided in the Appendix 10. 
No dose modification for atezolizumab is allowed. 
4.3.2.2 
Tiragolumab or Placebo 
Tiragolumab 600 mg or matching placebo (referred to as "tiragolumab" hereafter) will be 
administered by IV infusion on Day 1 of each 21-day cycle.  On Day 1 of Cycle 1, 
tiragolumab will be administered at least 
 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 at least 
 minutes if 
the patient experienced an IRR with the previous atezolizumab infusion.  
Tiragolumab infusions will be administered per the instructions outlined in Table 4.

 
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Table 4 
Administration of First and Subsequent Tiragolumab Infusions 
 
Guidelines for medical management of IRRs for tiragolumab are provided in 
Appendix 10. 
No dose modification for tiragolumab is allowed. 
4.3.2.3 
Paclitaxel and Cisplatin 
On Day 1 of Cycles 16 (21-day cycles), patients will receive paclitaxel 175 mg/m2, 
administered by IV, followed by cisplatin 6080 mg/m2 (dose should be consistent with 
manufacturer and institutional standards), administered by IV. 
The amount of paclitaxel and cisplatin administered will be calculated based on 
a patient’s body surface area.  Weight and height should be recorded at baseline and 
weight should be recorded at every scheduled visit.  Height should be re-measured if the 
investigator thinks it is possible that the patient's height may have changed.  The amount 
paclitaxel and cisplatin to be administered must be recalculated if the patient’s body 
weight has increased or decreased by  10% from baseline. 
If the dose is recalculated because of a  10% change in weight from baseline, this 
weight will then be used as the new baseline to calculate the paclitaxel and cisplatin 
dose in subsequent cycles.  

 
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On Day 1 of Cycle 1, paclitaxel will be administered at least 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 at least 60 minutes if the patient experienced an 
IRR with the previous tiragolumab infusion. 
Patients should receive anti-emetics and IV hydration according to institutional standards 
and manufacturer's instructions for paclitaxel and cisplatin.  Because of the 
immunomodulatory effects of corticosteroids, premedication with corticosteroids should 
be minimized to the extent that is clinically feasible. 
Any treatment drug (atezolizumab, tiragolumab, paclitaxel, cisplatin, or placebo) that is 
administered will be counted in number of induction therapy cycles.  If one treatment is 
postponed due to an adverse event, administration for the rest of the treatments are 
allowed to be completed within 3 days from the first day of the treatment cycle. 
The dose of paclitaxel or cisplatin may be modified as outlined in Appendix 9. 
4.3.3 
Investigational Medicinal Product Handling and Accountability 
All IMPs required for completion of this study will be provided by the Sponsor.  The study 
site (i.e., investigator or other authorized personnel [e.g., pharmacist]) is responsible for 
maintaining records of IMP delivery to the site, IMP inventory at the site, IMP use by 
each patient, and disposition or return of unused IMP, thus enabling reconciliation of all 
IMP received, and for ensuring that patients are provided with doses specified by 
the protocol. 
The study site should follow all instructions included with each shipment of IMP.  
The study site will acknowledge receipt of IMPs supplied by the Sponsor, using the IxRS 
to confirm the shipment condition and content.  Any damaged shipments will be 
replaced.  The investigator or designee must confirm that appropriate temperature 
conditions have been maintained during transit, either by time monitoring 
(shipment arrival date and time) or temperature monitoring, for all IMPs received and 
that any discrepancies have been reported and resolved before use of the IMPs.  
All IMPs must be stored in a secure, environmentally controlled, and monitored 
(manual or automated) area in accordance with the labeled storage conditions, with 
access limited to the investigator and authorized staff. 
Only patients enrolled in the study may receive IMPs, and only authorized staff may 
supply or administer IMPs. 
Investigational medicinal products will either be disposed of at the study site according to 
the study site's institutional standard operating procedure or be returned to the Sponsor 
with the appropriate documentation.  The site's method of destroying Sponsor-supplied 
IMPs must be agreed to by the Sponsor.  The site must obtain written authorization from 

 
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the Sponsor before any Sponsor-supplied IMP is destroyed, and IMP destruction must 
be documented on the appropriate form. 
Accurate records of all IMPs received at, dispensed from, returned to, and disposed of by 
the study site should be recorded on the drug accountability log. 
Refer to the pharmacy manual and/or the applicable Investigator's Brochure or local 
prescribing information for information on IMP handling, including preparation and 
storage, and accountability. 
4.3.4 
Continued Access to Atezolizumab and Tiragolumab 
The Sponsor will offer continued access to Roche IMPs (atezolizumab and tiragolumab) 
free of charge to eligible patients in accordance with the Roche Global Policy on 
Continued Access to Investigational Medicinal Product, as outlined below. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
The Roche Global Policy on Continued Access to Investigational Medicinal Product is 
available at the following website: 
https://www.roche.com/policy_continued_access_to_investigational_medicines.pdf 
 

 
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4.4 
CONCOMITANT THERAPY 
Concomitant therapy consists of any medication (e.g., prescription drugs, 
over-the-counter drugs, vaccines, herbal or homeopathic remedies, nutritional 
supplements) used by a patient in addition to protocol-mandated treatment from 7 days 
prior to initiation of study drug to the treatment discontinuation visit.  All such 
medications should be reported to the investigator and recorded on the Concomitant 
Medications eCRF. 
4.4.1 
Permitted Therapy  
Patients are permitted to use the following therapies during the study: 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
In general, investigators should manage a patient's care (including preexisting 
conditions) with supportive therapies other than those defined as cautionary or 
prohibited therapies (see Sections 4.4.2 and 4.4.3) as clinically indicated, per local 
standard practice.  Patients who experience infusion-associated symptoms may be 
treated symptomatically with acetaminophen, ibuprofen, diphenhydramine, and/or 
H2-receptor antagonists (e.g., famotidine, cimetidine), or equivalent medications per local 
standard practice.  Serious infusion-associated events manifested by dyspnea, 
hypotension, wheezing, bronchospasm, tachycardia, reduced oxygen saturation, or 

 
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respiratory distress should be managed with supportive therapies as clinically indicated 
(e.g., supplemental oxygen and 2-adrenergic agonists; see Appendix 8). 
4.4.2 
Cautionary Therapy for Atezolizumab-Treated Patients 
4.4.2.1 
Corticosteroids, Immunosuppressive Medications, and TNF- 
Inhibitors 
Systemic corticosteroids, immunosuppressive medications, and TNF- inhibitors may 
attenuate potential beneficial immunologic effects of treatment with atezolizumab.  
Therefore, in situations in which systemic corticosteroids, immunosuppressive 
medications, or TNF- inhibitors would be routinely administered, alternatives, including 
antihistamines, should be considered.  If the alternatives are not feasible, systemic 
corticosteroids, immunosuppressive medications, and TNF- inhibitors may be 
administered at the discretion of the investigator. 
Systemic corticosteroids or immunosuppressive medications are recommended, at the 
discretion of the investigator, for the treatment of specific adverse events when 
associated with atezolizumab therapy (see Appendix 9 and Appendix 10 for details). 
4.4.2.2 
Herbal Therapies 
Concomitant use of herbal therapies is not recommended because their 
pharmacokinetics, safety profiles, and potential drugdrug interactions are generally 
unknown.  However, herbal therapies not intended for the treatment of cancer 
(see Section 4.4.3) may be used during the study at the discretion of the investigator. 
4.4.3 
Prohibited Therapy 
Use of the following concomitant therapies is prohibited as described below: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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4.5 
STUDY ASSESSMENTS 
The schedule of activities to be performed during the study is provided in Appendix 1.  
All activities should be performed and documented for each patient. 
Patients will be closely monitored for safety and tolerability throughout the study.  
Patients should be assessed for toxicity prior to each dose; dosing will occur only if the 
clinical assessment and local laboratory test values are acceptable. 
4.5.1 
Informed Consent Forms and Screening Log 
Written informed consent for participation in the study must be obtained before 
performing any study-related procedures (including screening evaluations).  
Informed Consent Forms for enrolled patients and for patients who are not subsequently 
enrolled will be maintained at the study site. 
All screening evaluations must be completed and reviewed to confirm that patients meet 
all eligibility criteria before randomization.  The investigator will maintain a screening log 
to record details of all patients screened and to confirm eligibility or record reasons for 
screening failure, as applicable.  The screening log form is not required if equivalent 
screening information is accessible via IxRS.  Patients who do not initially meet all 
eligibility criteria for participation in this study (screen failure) may qualify for 
1 re-screening opportunity (for a total of 2 screenings per patient) at the discretion of the 
investigator.  The Medical Monitor is available to advise as needed.  Patients must 
re-sign the Consent Form prior to re-screening.  For patients who are re-screened, all 
eligibility criteria must be re-evaluated and screening assessments should be repeated 
as applicable to meet the eligibility criteria outlined in Section 4.1. 
4.5.2 
Medical History, Baseline Conditions, Concomitant Medication, 
and Demographic Data 
Medical history, including clinically significant diseases, surgeries, cancer history 
(including prior cancer therapies and procedures), reproductive status, smoking 
history, and alcohol use, will be recorded at baseline.  In addition, all medications 
(e.g., prescription drugs, over-the-counter drugs, vaccines, herbal or homeopathic 
remedies, nutritional supplements) used by the patient within 7 days prior to initiation of 
study treatment will be recorded.  At the time of each follow-up physical examination, an 
interval medical history should be obtained and any changes in medications and 
allergies should be recorded. 
Demographic data will include age, sex, and self-reported race/ethnicity. 

 
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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, gastrointestinal, 
genitourinary, and neurologic systems.  Any abnormality identified at baseline should be 
recorded on the General Medical History and Baseline Conditions eCRF. 
Limited, symptom-directed physical examinations should be performed at specified 
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. 
As part of the tumor assessment, physical examinations should include evaluation of the 
presence and degree of enlarged lymph nodes, hepatomegaly, and splenomegaly. 
4.5.4 
Vital Signs 
Vital signs will include measurements of respiratory rate, pulse rate, systolic and 
diastolic blood pressure, and temperature.  Record abnormalities observed at baseline 
on the General Medical History and Baseline Conditions eCRF.  At subsequent visits, 
record new or worsened clinically significant abnormalities on the Adverse Event eCRF. 
4.5.5 
Tumor and Response Evaluations 
Patients will undergo tumor assessments at baseline, every 6 weeks ( 7 days) for the 
first 48 weeks following treatment initiation, and every 9 weeks ( 7 days) thereafter, 
regardless of dose delays, until radiographic disease progression per RECIST v1.1 as 
determined by the IRF.  Thus, tumor assessments are to continue according to schedule 
in patients who discontinue treatment for reasons other than disease progression or loss 
of clinical benefit, even if they start new anti-cancer therapy.  At the investigator's 
discretion, tumor assessments may be repeated at any time if progressive disease is 
suspected. 
All measurable and evaluable lesions should be assessed and documented at 
screening.  Tumor assessments performed as standard of care prior to obtaining 
informed consent and within 28 days prior to initiation of study treatment do not have to 
be repeated at screening. 
Screening assessments must include CT scans (with oral or IV contrast) or magnetic 
resonance imaging (MRI) scans of the chest, abdomen, pelvis, and head.  A spiral 
CT scan of the chest may be obtained but is not a requirement.  If a CT scan with 
contrast is contraindicated (e.g., in patients with impaired renal clearance), 
a non-contrast CT scan of the chest may be performed and MRI scans of the abdomen, 
pelvis, and head should be performed.  A CT scan with contrast or MRI scan of the head 
must be done at screening to evaluate CNS metastasis in all patients (MRI scan must be 
performed if CT scan is contraindicated).  An MRI scan of the head is required to confirm 

 
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or refute the diagnosis of CNS metastases at baseline in the event of an equivocal 
CT scan.  Bone scans and CT scans of the neck should also be performed if clinically 
indicated.  At the investigator's discretion, other methods of assessment of measurable 
disease as per RECIST v1.1 may be used.  Subsequent tumor assessments must 
include CT or MRI scans of the chest, abdomen and pelvis; head CT or MRI is not 
required except when clinically indicated. 
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 evaluable lesions identified at baseline should be re-assessed at 
each subsequent tumor evaluation.  The same radiographic procedures used to assess 
disease sites at screening should be used for subsequent tumor assessments 
(e.g., the same contrast protocol for CT scans). 
Objective response at a single timepoint will be determined by the investigator according 
to RECIST v1.1 (see Appendix 3).  Assessments should be performed by the same 
evaluator, if possible, to ensure internal consistency across visits.  In addition, scans will 
be submitted to an IRF for central review according to RECIST v1.1. 
4.5.6 
Electrocardiograms 
An ECG is required at screening and when clinically indicated.  Electrocardiograms for 
each patient should be obtained from the same machine wherever possible.  
Lead placement should be as consistent as possible.  Electrocardiogram recordings 
must be performed after the patient has been resting in a supine position for at least 
10 minutes. 
For safety monitoring purposes, the investigator must review, sign, and date all ECG 
reports.  Paper copies of ECG tracings will be kept as part of the patient's permanent 
study file at the site.  Any morphologic waveform changes or other ECG abnormalities 
must be documented on the eCRF. 
4.5.7 
Clinical Outcome Assessments 
To more fully characterize the clinical profile of tiragolumab and atezolizumab, clinical 
outcome assessment data will be obtained through use of the following PRO 
instruments:  European Organisation for Research and Treatment of Cancer (EORTC) 
QLQ-C30 and its esophageal cancerspecific module (QLQ-OES18) and the 
EuroQol EQ-5D-5L. 

 
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4.5.7.1 
Data Collection Methods for Patient-Reported Outcome 
Assessments 
Patient-reported outcome instruments will be completed at specified timepoints during 
the study (see schedule of activities in Appendix 1).  During the treatment period, PROs 
will be completed on paper at the clinic.  For patients who are unable to come into the 
clinic due to COVID-19 restrictions, PROs may be completed via telephone call; source 
documentation sufficient to pass an audit should be obtained which includes, among 
other information, that the questionnaires were administered via phone because of 
COVID-19.  During follow-up, PROs will be completed via telephone call or on paper at 
the clinic.  At the clinic, instruments will be self-administered before the patient receives 
any information on disease status, prior to the performance of non-PRO assessments, 
and prior to the administration of study treatment, unless otherwise specified. 
Patient-reported outcome instruments, translated into the local language as appropriate, 
will be provided by the Sponsor in pre-printed booklets to enable the appropriate 
instruments to be administered in the correct order at each specified timepoint. 
During clinic visits, PRO instruments should be administered as outlined below: 
 
Patients' health status should not be discussed prior to administration of the 
instruments 
 
Sites must administer the official version of each instrument, as provided by the 
Sponsor.  Instruments must not be copied from the protocol. 
 
Sites should allow sufficient time for patients to complete the instruments, estimated 
to be 20 minutes at each specified visit 
 
Sites should administer the instruments in a quiet area with minimal distractions and 
disruptions 
 
Patients should be instructed to answer questions to the best of their ability; there 
are no right or wrong answers 
 
Site staff should not interpret or explain questions, but may read questions verbatim 
upon request 
 
Patients should not obtain advice or help from others (e.g., family members or 
friends) when completing the instruments 
 
Site staff should review all completed instruments and should ask the patient to 
rectify any response that is not clearly marked in the appropriate location.  
If a response is missing, site staff should ask the patient to complete the item or 
confirm that the item was intentionally left blank. 
 
4.5.7.2 
Description of Patient-Reported Outcome Instruments 
 
EORTC QLQ-C30 
The QLQ-C30 is a validated, reliable self-report measure (Aaronson et al. 1993; 
Fitzsimmons et al. 1999; see Appendix 4).  It consists of 30 questions that assess 
five aspects of patient functioning (physical, emotional, role, cognitive, and social), 

 
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three symptom scales (fatigue, nausea and vomiting, and pain), global health status and 
quality of life (GHS/QoL), and six single items (dyspnea, insomnia, appetite loss, 
constipation, diarrhea, and financial difficulties) with a recall period of the previous week.  
Scale scores can be obtained for the multi-item scales.  The functioning and symptoms 
items are scored on a 4-point scale that ranges from "not at all" to "very much," and the 
GHS/QoL items are scored on a 7-point scale that ranges from "very poor" to "excellent."  
The EORTC QLQ-C30 module takes approximately 10 minutes to complete. 
EORTC QLQ-OES18 
The QLQ-OES18 is a modular supplement to the QLQ-C30, for use in patients with 
esophageal cancer (Blazeby et al. 2003; see Appendix 5).  This module incorporates 
four multi-item scales (dysphagia, eating, reflux, and pain) and six single items 
(trouble swallowing saliva, choking when swallowing, dry mouth, trouble with taste, 
trouble with coughing, and trouble talking) with a recall period of the previous week.  
The scoring approach is identical in principle to that for the symptom scales and single 
items of the QLQ-C30.  The QLQ-OES18 takes approximately 5 minutes to complete. 
EQ-5D-5L 
The EQ-5D-5L is a validated self-report health status questionnaire that is used to 
calculate a health status utility score for use in health economic analyses 
(EuroQol Group 1990; Brooks 1996; Herdman et al. 2011; Janssen et al. 2013; 
see  Appendix 6).  There are two components to the EQ-5D-5L:  a five-item health state 
profile that assesses mobility, self-care, usual activities, pain/discomfort, and 
anxiety/depression, as well as a visual analog scale that measures health state.  
The EQ-5D-5L is designed to capture the patient's current health status.  
Published weighting systems allow for creation of a single composite score of the 
patient's health status.  The EQ-5D-5L takes approximately 3 minutes to complete.  It will 
be used in this study for informing pharmacoeconomic evaluations. 
4.5.8 
Laboratory, 
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) 
 
Chemistry panel (serum or plasma):  bicarbonate or total carbon dioxide 
(if available), sodium, potassium, chloride, glucose, BUN or urea, creatinine, 
total protein, albumin, phosphate, calcium, total bilirubin, ALP, ALT, AST, and LDH 
 
Coagulation:  INR, and aPTT 
 
Thyroid function testing:  thyroid-stimulating hormone, T3 (or total T3 for sites where 
free T3 is not performed), and free thyroxine (also known as T4) 
 
Carcinoembryonic antigen 
 
Carbohydrate antigen 19-9 

 
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 
Pregnancy test 
All women of childbearing potential will have a serum pregnancy test at 
screening.  Urine pregnancy tests will be performed at specified subsequent 
visits.  If a urine pregnancy test is positive, it must be confirmed by a serum 
pregnancy test. 
A woman is considered to be of childbearing potential if she is postmenarchal, 
has not reached a postmenopausal state ( 12 continuous months of 
amenorrhea with no identified cause other than menopause), and is not 
permanently infertile due to surgery (i.e., removal of ovaries, fallopian tubes, 
and/or uterus) or another cause as determined by the investigator 
(e.g., Müllerian agenesis). 
 
Urinalysis (pH, specific gravity, glucose, protein, ketones, and blood); 
dipstick permitted  
 
Samples for the following laboratory tests will be sent to the study site's local laboratory 
or to a central laboratory for analysis: 
 
 
 
 
– 
– 
– 
 
 
 
 
 
 
 
C-reactive protein 
 
The following samples will be sent to one or several central laboratories or to the 
Sponsor or a designee for analysis: 
 
Serum samples for tiragolumab and atezolizumab PK analyses through use of 
validated assays 
All patients will undergo PK sample collection. 
 
Serum samples for assessment of ADAs to tiragolumab and atezolizumab through 
use of validated assays 
All patients will undergo ADA sample collection. 
 
 

 
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 
Archival or newly collected tumor tissue sample obtained at baseline for 
determination of PD-L1 expression through use of the 
 
 for patient stratification purposes (see Section 3.1) and 
for 
 development 
A representative FFPE tumor specimen in a paraffin block (preferred) or 
512 slides (12 slides preferred) containing unstained, freshly cut, serial 
sections (5 slides for determination of PD-L1 expression and 7 slides for 
 development) should be 
submitted along with an associated pathology report prior to enrollment.  
Tumor tissue should be of good quality based on total and viable tumor content.  
Samples should contain a minimum of 50 viable tumor cells that preserve 
cellular context and tissue architecture regardless of needle gauge or retrieval 
method.  Samples collected via resection, core-needle biopsy (at least 
three cores, embedded in a single paraffin block), or excisional, incisional, 
punch, or forceps biopsy are acceptable.  Fine-needle aspiration (defined as 
samples that do not preserve tissue architecture and yield cell suspension 
and/or smears), brushing, cell pellets from pleural effusion, and lavage samples 
are not acceptable.  Tumor tissue from bone metastases that have been 
decalcified is not acceptable. 
If archival tumor tissue is unavailable or is determined to be unsuitable for 
required testing, a pretreatment tumor biopsy is required.  A pretreatment tumor 
biopsy may also be performed if a patient's archival tissue test results do not 
meet eligibility criteria. 
 
 
 
  
 
For sampling procedures, storage conditions, and shipment instructions, see the 
laboratory manual. 
Biological samples will be destroyed no later than the time of completion of the final 
Clinical Study Report (CSR), with the following exceptions: 
 
Serum samples collected for PK or immunogenicity analysis may be needed for 
additional immunogenicity characterization and for PK or immunogenicity assay 
development and validation; therefore, these samples will be destroyed no later than 
5 years after the final CSR has been completed. 
 
 
 
For enrolled patients, remaining archival tissue blocks will be returned to the site 
upon request or no later than the time of final closure of the study database, 

 
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whichever occurs first.  For patients who are not enrolled, remaining archival tissue 
blocks will be returned to the site no later than 6 weeks after eligibility determination. 
 
Remaining tissue samples collected for PD-L1 assessment may be used for 
, when the tissue samples collected for 
 
 were insufficient. 
 
When a patient withdraws from the study, samples collected prior to the date of 
withdrawal may still be analyzed, unless the patient specifically requests that the 
samples be destroyed or local laws require destruction of the samples.  However, if 
samples have been tested prior to withdrawal, results from those tests will remain as 
part of the overall research data. 
Data arising from sample analysis will be subject to the confidentiality standards 
described in Section 8.4. 
Given the complexity and exploratory nature of 
 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. 
4.5.9 
Optional Tumor Biopsies 
Patients will be given the option of consenting to additional tumor biopsies.  Patients who 
consent to optional biopsies will undergo tumor biopsy sample collection at the time of 
disease progression per RECIST v1.1 or loss of clinical benefit as determined by the 
investigator (see Section 3.1 for details), if deemed clinically feasible by the investigator.  
In addition, patients who consent to optional biopsies may undergo additional 
on-treatment biopsies at any other time at the investigator’s discretion.  
Samples collected via resection, core-needle biopsy (at least three cores preferred), or 
excisional, incisional, punch, or forceps biopsy are preferred.  The samples may be sent 
to one or more laboratories for analysis. 
The Informed Consent Form will contain a separate section that addresses optional 
biopsies.  A separate, specific signature will be required to document a patient's 
agreement to undergo optional biopsies.  The investigator should document whether or 
not the patient has given consent to participate and (if applicable) the date(s) of consent, 
by completing the Optional Biopsy Sample Informed Consent eCRF. 
Samples may be used for 
 as described in Section 4.5.8.  
For sampling procedures, storage conditions, and shipment instructions, see the 
laboratory manual.  See Section 4.5.8 for details on duration of sample storage, use of 
samples after patient withdrawal, confidentiality standards for data, and availability of 
data from 
.  

 
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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 determination that treatment discontinuation is in the best 
interest of the patient 
 
Use of another non-protocol anti-cancer therapy 
 
Pregnancy 
 
Loss of clinical benefit as determined by the investigator after an integrated 
assessment of radiographic and biochemical data, local biopsy results (if available), 
and clinical status (e.g., symptomatic deterioration such as pain secondary to 
disease; see Section 3.1 for details) 
 
The primary reason for study treatment discontinuation should be documented on the 
appropriate eCRF.  Patients who discontinue study treatment prematurely will not be 
replaced. 
Patients will return to the clinic for a treatment discontinuation visit  30 days after the 
final dose of study treatment.  The visit at which response assessment shows 
progressive disease may be used as the treatment discontinuation visit.  Patients who 
discontinue study treatment for any reason other than progressive disease or loss of 
clinical benefit will continue to undergo tumor response assessments and PRO 
assessments as outlined in the schedule of activities (see Appendix 1). 
After treatment discontinuation, information on survival status and new anti-cancer 
therapy will be collected via telephone calls, patient medical records, and/or clinic visits 
approximately every 3 ( 1) months until death (unless the patient withdraws consent or 
the Sponsor terminates the study). 
4.6.2 
Patient Discontinuation from the Study 
Patients have the right to voluntarily withdraw from the study at any time for any reason.  
In addition, the investigator has the right to withdraw a patient from the study at any time. 

 
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Reasons for patient discontinuation from the study may include, but are not limited to, 
the following: 
 
Patient withdrawal of consent 
 
Study termination or site closure 
 
Adverse event 
 
Loss to follow-up 
 
Patient non-compliance, defined as failure to comply with protocol requirements as 
determined by the investigator or Sponsor 
 
Every effort should be made to obtain a reason for patient discontinuation from the 
study.  The primary reason for discontinuation from the study should be documented on 
the appropriate eCRF.  If a patient requests to be withdrawn from the study, this request 
must be documented in the source documents and signed by the investigator.  
Patients who withdraw from the study will not be replaced. 
If a patient withdraws from the study, the study staff may use a public information source 
(e.g., county records) to obtain information about survival status. 
4.6.3 
Study Discontinuation 
The Sponsor has the right to terminate this study at any time.  Reasons for terminating 
the study may include, but are not limited to, the following: 
 
The incidence or severity of adverse events in this or other studies indicates 
a potential health hazard to patients 
 
Patient enrollment is unsatisfactory 
 
If the Sponsor decides to terminate the study, patients who are still receiving study 
treatment or undergoing survival follow-up may be enrolled in an extension study.  
The Sponsor will notify the investigator if the Sponsor decides to discontinue the study. 
4.6.4 
Site Discontinuation 
The Sponsor has the right to close a site at any time.  Reasons for closing a site may 
include, but are not limited to, the following: 
 
Excessively slow recruitment 
 
Poor protocol adherence 
 
Inaccurate or incomplete data recording 
 
Non-compliance with the ICH guideline for Good Clinical Practice 
 
No study activity (i.e., all patients have completed the study and all obligations have 
been fulfilled) 
 

 
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5. 
ASSESSMENT OF SAFETY  
5.1 
SAFETY PLAN 
The safety plan for patients in this study is based on the prescribing information for 
paclitaxel and cisplatin and clinical experience with atezolizumab and tiragolumab in 
completed and ongoing studies.  The anticipated important safety risks are outlined 
below (see Sections 5.1.1, 5.1.2, 5.1.3, 5.1.4, and 5.1.5).  Refer to the Tiragolumab 
Investigator’s Brochure and the Atezolizumab Investigator’s Brochure for a complete 
summary of safety information for each respective study drug. 
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.  
Guidelines for managing patients, who experience anticipated adverse events, including 
criteria for dosage modification and treatment interruption or discontinuation, are 
provided in Appendix 9 and Appendix 10.  See Sections 5.25.6 for details on safety 
reporting (e.g., adverse events, pregnancies) for this study. 
Patients with active infection are excluded from study participation.  In the setting of 
a pandemic or epidemic, screening for active infections (including SARS-CoV-2) prior to 
and during study participation should be considered according to local or institutional 
guidelines or guidelines of applicable professional societies (e.g., American Society of 
Clinical Oncology or European Society for Medical Oncology). 
Severe COVID-19 appears to be associated with a CRS involving the inflammatory 
cytokines IL-6, IL-10, IL-2, and IFN- (Merad and Martin 2020).  If a patient develops 
suspected CRS during the study, a differential diagnosis should include COVID-19, 
which should be confirmed or refuted through assessment of exposure history, 
appropriate laboratory testing, and clinical or radiologic evaluations per investigator 
judgment.  If a diagnosis of COVID-19 is confirmed, the disease should be managed as 
per local or institutional guidelines.  An iDMC will periodically review safety data during 
the study (see Section 3.2). 
5.1.1 
Risks Associated with Atezolizumab 
Atezolizumab has been associated with risks such as the following:  IRRs and 
immune-mediated hepatitis, pneumonitis, colitis, pancreatitis, diabetes mellitus, 
hypothyroidism, hyperthyroidism, adrenal insufficiency, hypophysitis, Guillain-Barré 
syndrome, myasthenic syndrome or myasthenia gravis, facial paresis, myelitis, 
meningoencephalitis, myocarditis, pericardial disorders, nephritis, myositis, and severe 
cutaneous adverse reactions.  In addition, immune-mediated reactions may involve any 
organ system and lead to HLH.  See Appendix 10 of the protocol and Section 6 of the 

 
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Atezolizumab Investigator's Brochure for a detailed description of anticipated safety risks 
for atezolizumab. 
5.1.2 
Risks Associated with Tiragolumab 
Infusion-related reaction 
 identified risks for 
tiragolumab.  
 
 While clinical evaluation of tiragolumab is 
limited and not all risks are known, as an antagonist of TIGIT, tiragolumab is anticipated 
to enhance T-cell and NK-cell proliferation, survival, and function.  
Therefore, tiragolumab may increase the risk of autoimmune inflammation 
(also described as immune-mediated adverse events).  Refer to Section 6 of the 
Tiragolumab Investigator's Brochure for a detailed description of anticipated safety risks 
for tiragolumab. 
5.1.2.1 
Infusion-Related Reactions 
 
.  Clinical signs and symptoms of such reactions may include rigors, chills, 
wheezing, pruritus, flushing, rash, hypotension, hypoxemia, and fever.  Infusion-related 
reactions have been reported in patients treated with tiragolumab alone or in 
combination with atezolizumab.  The majority of events were mild to moderate and 
manageable. 
To minimize the risk and sequelae of IRRs, the initial dose of tiragolumab will be 
administered over 
 minutes followed by a 
-minute observation period.  
Subsequent infusions and observation times may be shortened if the preceding infusion 
was well-tolerated.  All infusions of tiragolumab will be administered in an appropriate 
medical setting. 
  
 
 
 

 
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5.1.2.3 
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 
encephalomyelitis (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). 
Clinical experience with therapeutics intended to enhance anti-tumor T-cell responses 
has demonstrated that development of autoimmune inflammatory conditions is a general 
risk and may; therefore, be considered a potential risk of tiragolumab.  
Such immune-mediated adverse events have been described for virtually all organ 
systems and include, but are not limited to, colitis, pneumonitis, endocrinopathy, ocular 
toxicity, pancreatic toxicity, neurologic toxicity, cardiac toxicity, nephritis, myositis, and 
severe cutaneous adverse reactions. 
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 
(see 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 5.2.3).  
5.1.2.4 
Lymphopenia 
 
 
  
 
 
 
 
 
 
5.1.2.5 
Embryofetal Toxicity 
  
 
 
 
 
 
 
  No reproductive or teratogenicity 
studies in animals have been conducted with tiragolumab.  There are no clinical studies 

 
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of tiragolumab in pregnant women.  Tiragolumab should not be administered to pregnant 
women. 
See Section 6 of the Tiragolumab Investigator’s Brochure for a detailed description of 
embryofetal toxicity. 
5.1.3 
Risks Associated with Paclitaxel 
Paclitaxel is known to cause bone marrow suppression (e.g., myelosuppression, 
anemia, thrombocytopenia), gastrointestinal symptoms (e.g., nausea, vomiting, 
diarrhea), hepatotoxicity, peripheral neuropathy, hypersensitivity reactions, alopecia, and 
cardiovascular effects such as hypotension, bradycardia, hypertension, arrhythmias, and 
other ECG abnormalities.  Patients will be monitored for paclitaxel-related adverse 
events.  For more details regarding the safety profile of paclitaxel, refer to the paclitaxel 
prescribing information. 
5.1.4 
Risks Associated with Cisplatin 
Cisplatin is known to cause bone marrow suppression (e.g., myelosuppression, anemia, 
thrombocytopenia), ototoxicity, and nephrotoxicity.  Cisplatin-based chemotherapy is 
considered to be moderately emetogenic.  Patients will be monitored for cisplatin-related 
adverse events.  For more details regarding the safety profile of cisplatin, refer to the 
cisplatin prescribing information. 
5.1.5 
Risks Associated with Combination Use of Atezolizumab, 
Tiragolumab, Paclitaxel, and Cisplatin 
Immune-mediated adverse events are potential overlapping toxicities associated with 
combination use of tiragolumab plus atezolizumab.  Because the expected 
pharmacologic activity of these two molecules is to increase adaptive T-cell immune 
responses, there is the possibility of heightened immune responses.  The risk of 
overlapping toxicities between the cancer immunotherapy agents (tiragolumab and 
atezolizumab) and the chemotherapy agents (paclitaxel and cisplatin) is thought to be 
minimal.  Nevertheless, the attribution and management of certain adverse events that 
have been associated with each agent separately (e.g., 
 
) may be ambiguous when the agents are administered together.  
It is theoretically possible that hypersensitivity reactions or inflammatory adverse events 
associated with paclitaxel and cisplatin (e.g., dermatitis, infusion-associated symptoms) 
could be exacerbated by the immunostimulatory activity of tiragolumab and/or 
atezolizumab. 
On the basis of clinical experience to date, it is anticipated that immune-mediated 
adverse events following treatment with tiragolumab and atezolizumab will be amenable 
to monitoring and manageable in the setting of this combination study.  The extensive 
experience with immune checkpoint inhibitors to date has been incorporated into the 
design and safety management plan to reduce the potential risks to participating 
patients.  Patients with a history of autoimmune disease will be excluded from this study, 

 
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with some exceptions (e.g., autoimmune hypothyroidism managed with 
thyroid-replacement hormone or Type 1 diabetes mellitus managed with insulin; 
see Section 4.1.2).  Patients previously treated with approved or experimental cancer 
immunotherapy will also be excluded from participation in this study. 
Owing to the risks of active viral infection and viral reactivation (see Section 1.5), 
patients with active infection (including, but not limited to, 
, or 
tuberculosis) and/or recent severe infections will be excluded from this study 
(see Sections 4.1.1 and 4.1.2).  
 
5.2 
SAFETY PARAMETERS AND DEFINITIONS 
Safety assessments will consist of monitoring and recording adverse events, including 
serious adverse events and adverse events of special interest, performing 
protocol-specified safety laboratory assessments, measuring protocol-specified vital 
signs, and conducting other protocol-specified tests that are deemed critical to the safety 
evaluation of the study. 
Certain types of events require immediate reporting to the Sponsor, as outlined in 
Section 5.4. 
5.2.1 
Adverse Events 
According to the ICH guideline for Good Clinical Practice, an adverse event is any 
untoward medical occurrence in a clinical investigation subject administered 
a pharmaceutical product, regardless of causal attribution.  An adverse event can; 
therefore, be any of the following: 
 
Any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal product, 
whether or not considered related to the medicinal product 
 
Any new disease or exacerbation of an existing disease (a worsening in the 
character, frequency, or severity of a known condition; see Sections 5.3.5.9 and 
5.3.5.10 for more information) 
 
Recurrence of an intermittent medical condition (e.g., headache) not present at 
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) 
 

 
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5.2.2 
Serious Adverse Events (Immediately Reportable to the 
Sponsor) 
A serious adverse event is any adverse event that meets any of the following criteria: 
 
Is fatal (i.e., the adverse event actually causes or leads to death) 
 
Is life-threatening (i.e., the adverse event, in the view of the investigator, places the 
patient at immediate risk of death) 
This does not include any adverse event that, had it occurred in a more severe 
form or was allowed to continue, might have caused death. 
 
Requires or prolongs inpatient hospitalization (see Section 5.3.5.11) 
 
Results in persistent or significant disability/incapacity (i.e., the adverse event 
results in substantial disruption of the patient's ability to conduct normal life 
functions) 
 
Is a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to 
study treatment 
 
Is a significant medical event in the investigator's judgment (e.g., may jeopardize the 
patient or may require medical/surgical intervention to prevent one of the outcomes 
listed above) 
 
The terms "severe" and "serious" are not synonymous.  Severity refers to the intensity of 
an adverse event (e.g., rated as mild, moderate, or severe, or according to NCI CTCAE; 
see Section 5.3.3); the event itself may be of relatively minor medical significance 
(such as severe headache without any further findings). 
Severity and seriousness need to be independently assessed for each adverse event 
recorded on the eCRF. 
Serious adverse events are required to be reported by the investigator to the Sponsor 
immediately (i.e., no more than 24 hours after learning of the event; see Section 5.4.2 for 
reporting instructions). 
5.2.3 
Adverse Events of Special Interest (Immediately Reportable to 
the Sponsor) 
Adverse events of special interest are required to be reported by the investigator to the 
Sponsor immediately (i.e., no more than 24 hours after learning of the event; 
see Section 5.4.2 for reporting instructions).  Adverse events of special interest for this 
study are as follows: 
 
 
 

 
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5.3 
METHODS AND TIMING FOR CAPTURING AND ASSESSING 
SAFETY PARAMETERS 
The investigator is responsible for ensuring that all adverse events (see Section 5.2.1 for 
definition) are recorded on the Adverse Event eCRF and reported to the Sponsor in 
accordance with instructions provided in this section and in Sections 5.45.6. 
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). 

 
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5.3.1 
Adverse Event Reporting Period 
Investigators will seek information on adverse events at each patient contact.  
All adverse events, whether reported by the patient or noted by study personnel, will be 
recorded in the patient's medical record and on the Adverse Event eCRF. 
After informed consent has been obtained but prior to initiation of study treatment, only 
serious adverse events caused by a protocol-mandated intervention 
(e.g., invasive procedures such as biopsies, discontinuation of medications) should be 
reported (see Section 5.4.2 for instructions for reporting serious adverse events). 
After initiation of study treatment, 
 
 
 
 
 
 
Instructions for reporting adverse events that occur after the adverse event reporting 
period are provided in Section 5.6. 
5.3.2 
Eliciting Adverse Event Information 
A consistent methodology of non-directive questioning should be adopted for eliciting 
adverse event information at all patient evaluation timepoints.  Examples of non-directive 
questions include the following: 
"How have you felt since your last clinic visit?" 
"Have you had any new or changed health problems since you were last here?"  
 
5.3.3 
Assessment of Severity of Adverse Events 
The adverse event severity grading scale for the NCI CTCAE (v5.0) will be used for 
assessing adverse event severity.  Table 5 will be used for assessing severity for 
adverse events that are not specifically listed in the NCI CTCAE. 

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

 
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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 7): 
 
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 

 
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 
Presence of risk factors in the patient or use of concomitant medications known to 
increase the occurrence of the event 
 
Presence of non-treatment-related factors that are known to be associated with the 
occurrence of the event 
 
Table 7 
Causal Attribution Guidance 
Is the adverse event suspected to be caused by study treatment on the basis of facts, 
evidence, science-based rationales, and clinical judgment? 
YES 
There is a plausible temporal relationship between the onset of the adverse event and 
administration of study treatment, and the adverse event cannot be readily explained by 
the patient's clinical state, intercurrent illness, or concomitant therapies; and/or the 
adverse event follows a known pattern of response to study treatment; and/or the 
adverse event abates or resolves upon discontinuation of study treatment or dose 
reduction and, if applicable, reappears upon re-challenge. 
NO 
An adverse event will be considered related, unless it fulfills the criteria specified below.   
Evidence exists that the adverse event has an etiology other than study treatment 
(e.g., preexisting medical condition, underlying disease, intercurrent illness, 
or concomitant medication); and/or the adverse event has no plausible temporal 
relationship to administration of study treatment (e.g., cancer diagnosed 2 days after 
first dose of study treatment). 
 
For patients receiving combination therapy, causality will be assessed individually for 
each protocol-mandated therapy. 
5.3.5 
Procedures for Recording Adverse Events 
Investigators should use correct medical terminology/concepts when recording adverse 
events on the Adverse Event eCRF.  Avoid colloquialisms and abbreviations. 
Only 1 adverse event term should be recorded in the event field on the 
Adverse Event eCRF. 
5.3.5.1 
Infusion-Related Reactions and 
 
There may be significant overlap in signs and symptoms of IRRs and CRS.  While IRRs 
occur during or within 24 hours after treatment administration, time to onset of CRS may 
vary.  Differential diagnosis should be applied, particularly for late-onset CRS 
(occurring more than 24 hours after treatment administration); to rule out other etiologies 
such as delayed hypersensitivity reactions, sepsis or infections, 
, tumor lysis 
syndrome, early disease progression, or other manifestations of systemic inflammation. 

 
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Adverse events that occur during or within 24 hours after study treatment administration 
and are judged to be related to study treatment infusion should be captured as 
a diagnosis (e.g., "infusion-related reaction" or 
) on the 
Adverse Event eCRF.  Avoid ambiguous terms such as "systemic reaction."  
 
 on the 
Adverse Event eCRF.  Associated signs and symptoms should be recorded on the 
dedicated Infusion-Related Reaction eCRF or 
, as 
appropriate. 
If a patient experiences both a local and systemic reaction to the same dose of study 
treatment, each reaction should be recorded separately on the Adverse Event eCRF, 
with signs and symptoms also recorded separately on the dedicated Infusion-Related 
Reaction eCRF or 
. 
 
 
 
 
 
 
 
Guidelines for medical management of IRRs and CRS are provided in Table A10-7 and 
Table A10-8, respectively, of Appendix 10. 
5.3.5.2 
Diagnosis Versus Signs and Symptoms 
A diagnosis (if known) should be recorded on the Adverse Event eCRF rather than 
individual signs and symptoms (e.g., record only liver failure or hepatitis rather than 
jaundice, asterixis, and elevated transaminases).  However, if a constellation of signs 
and/or symptoms cannot be medically characterized as a single diagnosis or syndrome 
at the time of reporting, each individual event should be recorded on the Adverse Event 
eCRF.  If a diagnosis is subsequently established, all previously reported adverse events 
based on signs and symptoms should be nullified and replaced by one adverse event 
report based on the single diagnosis, with a starting date that corresponds to the starting 
date of the first symptom of the eventual diagnosis. 
5.3.5.3 
Adverse Events That Are Secondary to Other Events 
In general, adverse events that are secondary to other events (e.g., cascade events or 
clinical sequelae) should be identified by their primary cause, with the exception of 
severe or serious secondary events.  A medically significant secondary adverse event 
that is separated in time from the initiating event should be recorded as an independent 
event on the Adverse Event eCRF.  For example: 
 
If vomiting results in mild dehydration with no additional treatment in a healthy adult, 
only vomiting should be reported on the eCRF 

 
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 
If vomiting results in severe dehydration, both events should be reported separately 
on the eCRF 
 
If a severe gastrointestinal hemorrhage leads to renal failure, both events should be 
reported separately on the eCRF 
 
If dizziness leads to a fall and consequent fracture, all 3 events should be reported 
separately on the eCRF 
 
If neutropenia is accompanied by an infection, both events should be reported 
separately on the eCRF 
 
All adverse events should be recorded separately on the Adverse Event eCRF if it is 
unclear as to whether the events are associated. 
5.3.5.4 
Persistent or Recurrent Adverse Events 
A persistent adverse event is one that extends continuously, without resolution, between 
patient evaluation timepoints.  Such events should only be recorded once on the 
Adverse Event eCRF.  The initial severity (intensity or grade) of the event will be 
recorded at the time the event is first reported.  If a persistent adverse event becomes 
more severe, the most extreme severity should also be recorded on the Adverse Event 
eCRF.  If the event becomes serious, it should be reported to the Sponsor immediately 
(i.e., no more than 24 hours after learning that the event became serious; 
see Section 5.4.2 for reporting instructions).  The Adverse Event eCRF should be 
updated by changing the event from "non-serious" to "serious," providing the date that 
the event became serious, and completing all data fields related to serious adverse 
events. 
A recurrent adverse event is one that resolves between patient evaluation timepoints 
and subsequently recurs.  Each recurrence of an adverse event should be recorded as 
a separate event on the Adverse Event eCRF. 
5.3.5.5 
Abnormal Laboratory Values 
Not every laboratory abnormality qualifies as an adverse event.  A laboratory test result 
must be reported as an adverse event if it meets any of the following criteria: 
 
Is accompanied by clinical symptoms 
 
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. 
 

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

 
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5.3.5.7 
Abnormal Liver Function Tests 
The finding of an elevated ALT or AST ( 3  baseline value) in combination with either 
an elevated total bilirubin ( 2  ULN) or clinical jaundice in the absence of cholestasis or 
other causes of hyperbilirubinemia is considered to be an indicator of severe liver injury 
(as defined by Hy's Law).  Therefore, investigators must report as an adverse event the 
occurrence of either of the following: 
 
Treatment-emergent ALT or AST  3  baseline value in combination with total 
bilirubin  2  ULN (of which   35% is direct bilirubin) 
 
Treatment-emergent ALT or AST  3  baseline value in combination with clinical 
jaundice 
 
The most appropriate diagnosis or (if a diagnosis cannot be established) the abnormal 
laboratory values should be recorded on the Adverse Event eCRF (see Section 5.3.5.2) 
and reported to the Sponsor immediately (i.e., no more than 24 hours after learning of 
the event), either as a serious adverse event or an adverse event of special interest 
(see Section 5.4.2). 
5.3.5.8 
Deaths 
For this protocol, mortality is an efficacy endpoint.  Deaths that occur during the 
protocol-specified adverse event reporting period (see Section 5.3.1) that are attributed 
by the investigator solely to progression of ESCC 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).  An independent monitoring committee will monitor the frequency of 
deaths from all causes. 
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. 

 
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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 Esophageal Squamous Cell 
Carcinoma 
Events that are clearly consistent with the expected pattern of progression of the 
underlying disease should not be recorded as adverse events.  These data will be 
captured as efficacy assessment data only.  In most cases, the expected pattern of 
progression will be based on RECIST v1.1.  In rare cases, the determination of clinical 
progression will be based on symptomatic deterioration.  However, every effort should 
be made to document progression through use of objective criteria.  If there is any 
uncertainty as to whether an event is due to disease progression, it should be reported 
as an adverse event. 
5.3.5.11 
Hospitalization or Prolonged Hospitalization 
Any adverse event that results in hospitalization (i.e., inpatient admission to a hospital) 
or prolonged hospitalization should be documented and reported as a serious adverse 
event (per the definition of serious adverse event in Section 5.2.2), except as outlined 
below. 
An event that leads to hospitalization under the following circumstances should not be 
reported as an adverse event or a serious adverse event: 
 
Hospitalization for respite care 
 
Planned hospitalization required by the protocol (e.g., for study treatment 
administration or performance of an efficacy measurement for the study) 
 
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 
 

 
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5.3.5.12 
Cases of Accidental Overdose or Medication Error 
Accidental overdose and medication error (hereafter collectively referred to as 
"special situations"), are defined as follows: 
 
Accidental overdose:  accidental administration of a drug in a quantity that is higher 
than the assigned dose 
 
Medication error: accidental deviation in the administration of a drug 
 
In some cases, a medication error may be intercepted prior to administration of the 
drug. 
 
Special situations are not in themselves adverse events, but may result in adverse 
events.  Each adverse event associated with a special situation should be recorded 
separately on the Adverse Event eCRF.  If the associated adverse event fulfills 
seriousness criteria or qualifies as an adverse event of special interest, the event should 
be reported to the Sponsor immediately (i.e., no more than 24 hours after learning of the 
event; see Section 5.4.2).  For atezolizumab or tiragolumab, adverse events associated 
with special situations should be recorded as described below for each situation: 
 
Accidental overdose:  Enter the adverse event term.  Check the 
"Accidental overdose" and "Medication error" boxes. 
 
Medication error that does not qualify as an overdose:  Enter the adverse event 
term.  Check the "Medication error" box. 
 
Medication error that qualifies as an overdose:  Enter the adverse event term.  
Check the "Accidental overdose" and "Medication error" boxes. 
 
In addition, all special situations associated with atezolizumab or tiragolumab, regardless 
of whether they result in an adverse event, should be recorded on the Adverse Event 
eCRF as described below: 
 
Accidental overdose:  Enter the drug name and "accidental overdose" as the event 
term.  Check the "Accidental overdose" and "Medication error" boxes. 
 
Medication error that does not qualify as an overdose:  Enter the name of the drug 
administered and a description of the error (e.g., wrong dose administered, wrong 
dosing schedule, incorrect route of administration, wrong drug, expired drug 
administered) as the event term.  Check the "Medication error" box. 
 
Medication error that qualifies as an overdose:  Enter the drug name and 
"accidental overdose" as the event term.  Check the "Accidental overdose" and 
"Medication error" boxes.  Enter a description of the error in the additional case 
details. 
 
Intercepted medication error:  Enter the drug name and "intercepted medication 
error" as the event term.  Check the "Medication error" box.  Enter a description of 
the error in the additional case details. 
 

 
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As an example, an accidental overdose that resulted in a headache would require 
2 entries on the Adverse Event eCRF, 1 entry to report the accidental overdose and 
1 entry to report the headache.  The "Accidental overdose" and "Medication error" boxes 
would need to be checked for both entries. 
5.3.5.13 
Patient-Reported Outcome Data 
Adverse event reports will not be derived from PRO data by the Sponsor.  Sites are not 
expected to review the PRO data for adverse events. 
5.4 
IMMEDIATE REPORTING REQUIREMENTS FROM 
INVESTIGATOR TO SPONSOR 
Certain events require immediate reporting to allow the Sponsor to take appropriate 
measures to address potential new risks in a clinical trial.  The investigator must report 
such events to the Sponsor immediately; under no circumstances should reporting take 
place more than 24 hours after the investigator learns of the event.  The following is a list 
of events that the investigator must report to the Sponsor within 24 hours after learning 
of the event, regardless of relationship to study treatment: 
 
Serious adverse events (defined in Section 5.2.2; see Section 5.4.2 for details on 
reporting requirements) 
 
Adverse events of special interest (defined in Section 5.2.3; see Section 5.4.2 for 
details on reporting requirements) 
 
Pregnancies (see Section 5.4.3 for details on reporting requirements) 
 
For serious adverse events and adverse events of special interest, the investigator must 
report new significant follow-up information to the Sponsor immediately (i.e., no more 
than 24 hours after becoming aware of the information).  New significant information 
includes the following: 
 
New signs or symptoms or a change in the diagnosis 
 
Significant new diagnostic test results 
 
Change in causality based on new information 
 
Change in the event's outcome, including recovery 
 
Additional narrative information on the clinical course of the event 
 
Investigators must also comply with local requirements for reporting serious adverse 
events to the local health authority and IRB/EC. 
5.4.1 
Medical Monitors and Emergency Medical Contacts 
 
Investigators will be provided with contact information for the Medical Monitor.  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 

 
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all calls.  Contact information, including toll-free numbers for the Emergency Medical 
Call Center, will be distributed to investigators.  
5.4.2 
Reporting Requirements for Serious Adverse Events and 
Adverse Events of Special Interest 
5.4.2.1 
Events That Occur Prior to Study Treatment Initiation 
After informed consent has been obtained but prior to initiation of study treatment, only 
serious adverse events caused by a protocol-mandated intervention should be reported.  
The paper Clinical Trial Adverse Event/ Special Situations Form provided to 
investigators should be completed and submitted to the Sponsor or its designee 
immediately (i.e., no more than 24 hours after learning of the event), either by faxing or 
by scanning and emailing the form using the fax number or e-mail address provided to 
investigators. 
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 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 e-mailing the form using the fax number or e-
mail address provided to investigators.  Once the EDC system is available, all 
information will need to be entered and submitted via the EDC system.   
Instructions for reporting serious adverse events that occur after the reporting period are 
provided in Section 5.6. 
5.4.3 
Reporting Requirements for Pregnancies 
5.4.3.1 
Pregnancies in Female Patients 
Female patients of childbearing potential will be instructed through the Informed Consent 
Form to immediately inform the investigator if they become pregnant during the study or 
within 90 days after the final dose of tiragolumab, 5 months after the final dose of 
atezolizumab, or 6 months after the final dose of paclitaxel or cisplatin.  A paper Clinical 
Trial Pregnancy Reporting Form should be completed and submitted to the Sponsor or 
its designee immediately (i.e., no more than 24 hours after learning of the pregnancy), 
either by faxing or by scanning and emailing the form using the fax number or e-mail 

 
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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. 
5.4.3.2 
Pregnancies in Female Partners of Male Patients 
Male patients will be instructed through the Informed Consent Form to immediately 
inform the investigator if their partner becomes pregnant while receiving chemotherapy 
or within 90 days after the final dose of tiragolumab or 6 months after the final dose of 
chemotherapy.  The investigator should report the pregnancy on the paper Clinical Trial 
Pregnancy Reporting Form and submit the form to the Sponsor or its designee 
immediately (i.e., no more than 24 hours after learning of the pregnancy), either by 
faxing or by scanning and emailing the form using the fax number or e-mail address 
provided to investigators.  Attempts should be made to collect and report details of the 
course and outcome of any pregnancy in the partner of a male patient exposed to study 
treatment.  When permitted by the site, the pregnant partner would need to sign an 
Authorization for Use and Disclosure of Pregnancy Health Information to allow for 
follow-up on her pregnancy.  If the authorization has been signed, the investigator 
should submit a Clinical Trial Pregnancy Reporting Form with additional information on 
the pregnant partner and the course and outcome of the pregnancy as it becomes 
available.  An investigator who is contacted by the male patient or his pregnant partner 
may provide information on the risks of the pregnancy and the possible effects on the 
fetus, to support an informed decision in cooperation with the treating physician 
and/or obstetrician. 
5.4.3.3 
Abortions 
A spontaneous abortion should be classified as a serious adverse event (as the Sponsor 
considers abortions to be medically significant), recorded on the Adverse Event eCRF, 
and reported to the Sponsor immediately (i.e., no more than 24 hours after learning of 
the event; see Section 5.4.2). 
If a therapeutic or elective abortion was performed because of an underlying maternal or 
embryofetal toxicity, the toxicity should be classified as a serious adverse event, 
recorded on the Adverse Event eCRF, and reported to the Sponsor immediately 
(i.e., no more than 24 hours after learning of the event; see Section 5.4.2).  A therapeutic 
or elective abortion performed for reasons other than an underlying maternal or 
embryofetal toxicity is not considered an adverse event. 

 
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All abortions should be reported as pregnancy outcomes on the paper Clinical Trial 
Pregnancy Reporting Form.  
5.4.3.4 
Congenital Anomalies/Birth Defects 
Any congenital anomaly/birth defect in a child born to a female patient exposed to study 
treatment or the female partner of a male patient exposed to study treatment should be 
classified as a serious adverse event, recorded on the Adverse Event eCRF, and 
reported to the Sponsor immediately (i.e., no more than 24 hours after learning of the 
event; see Section 5.4.2). 
5.5 
FOLLOW-UP OF PATIENTS AFTER ADVERSE EVENTS 
5.5.1 
Investigator Follow-Up 
The investigator should follow each adverse event until the event has resolved to baseline 
grade or better, 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, e-mail, and/or a monitoring visit 
to obtain additional case details and outcome information (e.g., from hospital discharge 
summaries, consultant reports, autopsy reports) in order to perform an independent 
medical assessment of the reported case. 
5.6 
ADVERSE EVENTS THAT OCCUR AFTER THE ADVERSE 
EVENT REPORTING PERIOD 
After the end of the reporting period for serious adverse events and adverse events of 
special interest (as defined in Section 5.3.1), all deaths, regardless of cause, should be 
reported through use of the Long-Term Survival Follow-Up eCRF. 
In addition, if the investigator becomes aware of a serious adverse event that is believed 
to be related to prior exposure to study treatment, the event should be reported through 
use of the Adverse Event eCRF.  However, if the EDC system is not available, the 
investigator should report these events directly to the Sponsor or its designee, either by 
faxing or by scanning and emailing the paper Clinical Trial Adverse Event/ Special 
Situations Form using the fax number or e-mail address provided to investigators. 

 
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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 the 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 through use of the reference safety 
information in the documents listed below: 
 
Drug 
Document 
Atezolizumab 
Atezolizumab Investigator's Brochure  
Tiragolumab 
Tiragolumab Investigator's Brochure  
 
The Sponsor will compare the severity of each event and the cumulative event 
frequency reported for the study with the severity and frequency reported in the 
applicable reference document. 
Reporting requirements will also be based on the investigator's assessment of causality 
and seriousness, with allowance for upgrading by the Sponsor as needed. 
6. 
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN 
This is a Phase III, randomized, multicenter, double-blind study designed to evaluate the 
efficacy and safety of Atezo  Tira  PC compared with Placebo  PC as first-line 
treatment in approximately 450 patients with unresectable locally advanced, 
unresectable recurrent, or metastatic ESCC. 
The statistical considerations and analysis plan are summarized below.  Further details 
on the statistical considerations and analysis plan will be provided in the Statistical 
Analysis Plan (SAP). 
6.1 
DETERMINATION OF SAMPLE SIZE 
The purpose of this study is to test the hypothesis that Atezo  Tira  PC prolongs the 
duration of OS and/or PFS relative to Placebo  PC in the full analysis set (FAS), defined 

 
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as all randomized patients regardless of whether they receive any study treatment.  
Approximately 450 patients in total will be randomized in a 1:1 ratio to the two arms. 
6.1.1 
Type I Error Control 
The type I error () for this study is 0.05 (two-sided) and will be controlled for the 
co-primary efficacy endpoints of OS and IRF-assessed PFS between treatment arms in 
the FAS. 
To control the overall type I error rate at 0.05, a group sequential weighted 
Holm procedure (Ye et al. 2013) will be used wherein the two-sided  of 0.04 and 0.01 
will be allocated to the primary endpoints of OS and PFS, respectively.  If OS in the FAS 
is statistically significant at the two-sided  of 0.04, the  of 0.04 will be recycled to PFS 
in the FAS, which will then be tested at a two-sided  of 0.05.  Additionally, if PFS in the 
FAS is statistically significant at the two-sided  of 0.01, the  of 0.01 will be recycled to 
OS in the FAS, which will then be tested at a two-sided  of 0.05.  The study will be 
considered positive if statistical significance is achieved for either of the two co-primary 
endpoints.  An overview of the type I error rate control strategy is shown in Figure 2. 
Figure 2 Overview of the Type I Error Control for Co-Primary Endpoints 
  
OS  overall survival; PFS  progression-free survival. 
 
6.1.2 
Co-Primary Endpoint:  Overall Survival 
The sample size of the study was determined on the basis of the number of deaths 
(OS events) required in the FAS to demonstrate efficacy in terms of OS.  To detect an 
improvement in OS through use of a log-rank test at a two-sided significance level of 
0.04, approximately 
 OS events (
 patients) will be required at the final OS 
analysis to achieve an overall 
 power, assuming a target HR of 
.  The minimum 
detectable difference (MDD) is an OS HR of 
 (median OS improvement of 
 months, from 
 months in the Placebo  PC arm to 
 months in the 
Atezo  Tira  PC arm).  The final analysis of OS is expected to occur at approximately 
 months after the first patient is randomized.  The calculation of sample size and 
estimates of the OS analysis timeline are based on the following assumptions: 
 
Patient randomization in a 
 ratio to the Atezo  Tira  PC arm or the 
Placebo  PC arm 
 
One-piece exponential distribution for OS in each arm 

 
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 
Median OS of 
 months in the Placebo  PC arm and 
 months in the 
Atezo  Tira  PC arm (increase of  months, corresponding to a target HR of 
) 
 
Annual dropout rate of 
 for OS in each arm 
 
 planned OS interim analysis at approximately 
 of the information fraction, 
using the O’BrienFleming stopping boundaries approximated by the LanDeMets 
-spending function 
 
Recruitment of 
 patients will take place over approximately 
 months 
 
6.1.3 
Co-Primary Endpoint:  Progression-Free Survival 
The primary analysis of IRF-assessed PFS will take place when approximately 
 PFS 
events (
 patients) or approximately 
 OS events (
 patients) 
have been observed in the FAS, whichever occurs later.  The 
 PFS events provides 
an overall 
 power to detect a target HR of 
 for PFS using a log-rank test at 
a two-sided significance level of 
.  The MDD based on 
 PFS events is a PFS HR 
of 
 (median PFS improvement of 
 months, from  months in the Placebo  PC 
arm to 
 months in the Atezo  Tira  PC arm).  The primary analysis of PFS is 
expected to occur at approximately 
 months after the first patient is randomized.  
The estimates are based on the following assumptions: 
 
Patient randomization in a 
 ratio to the Atezo  Tira  PC arm or the 
Placebo  PC arm 
 
One-piece exponential distribution for PFS in each arm 
 
Median PFS of  months in the Placebo  PC arm and 
 months in the 
Atezo  Tira  PC arm (increase of 
 months, corresponding to a target HR of 
) 
 
Annual dropout rate of 
 for PFS in each arm 
 
Recruitment of 
 patients will take place over approximately 
 months 
 
6.2 
SUMMARIES OF CONDUCT OF STUDY 
Enrollment, duration of survival follow-up, study drug administration, reasons for study 
drug discontinuation, and reasons for discontinuation from the study will be summarized 
by treatment arm.  Major protocol deviations, including major deviations with regard to 
the inclusion and exclusion criteria, will be summarized by treatment arm. 
6.3 
SUMMARIES OF TREATMENT GROUP COMPARABILITY 
Demographics (including age, sex, race) and baseline characteristics (e.g., PD-L1 
expression, previous curative treatment, and ECOG Performance Status) will be 
summarized overall and by treatment arm.  Descriptive statistics (mean, median, 
standard deviation, and range) will be presented for continuous data, and frequencies 
and percentages will be presented for categorical data, as appropriate. 
Baseline measurements are defined as the last available measurement obtained prior to 
the patient receiving the first dose of any component of study treatment, or prior to 
randomization for patients who were not treated, unless otherwise noted. 

 
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6.4 
EFFICACY ANALYSES 
Unless otherwise specified, efficacy analyses will be performed in the FAS.  Patients will 
be grouped according to the treatment assigned at randomization. 
6.4.1 
Co-Primary Efficacy Endpoints 
The co-primary efficacy endpoints for this study are OS and IRF-assessed PFS, as 
defined in Section 2. 
6.4.1.1 
Overall Survival 
Overall survival is defined as the time from randomization to death from any cause.  
Patients who are not reported as having died at the time of analysis will be censored at 
the last date they were known to be alive.  Patients with no postbaseline survival 
information will be censored at the date of randomization. 
The two-sided log-rank test, stratified by PD-L1 expression
see definition in Section 3.1), previous curative treatment (yes vs. no), 
and ECOG Performance Status (0 vs. 1), will be used as the primary analysis to 
compare OS between the two treatment arms.  The results from the unstratified log-rank 
test will also be provided as a sensitivity analysis to check the robustness of the results 
of the stratified log-rank test. 
The stratified Cox proportional-hazards model will be used to estimate the HR and its 
95% CI.  The stratification factors will be the same as those used for the primary 
stratified log-rank test.  The unstratified HR will also be provided. 
KaplanMeier methodology will be used to estimate the median OS for each treatment 
arm, and a KaplanMeier curve will be constructed to provide a visual description of the 
difference between treatment arms.  The BrookmeyerCrowley methodology will be 
used to construct the 95% CI for the median OS for each treatment arm. 
A group sequential design will be used for testing OS to account for the interim analysis.  
The type I error control plan is presented in Section 6.1.1, and the timing and stopping 
boundaries of the interim and final OS analyses are provided in Section 6.10.1.  On the 
basis of emerging external data, the testing strategy may be modified to improve the 
efficiency of the design.  Should this occur, modifications to the testing strategy will be 
made prior to any unblinding of the data. 
Sensitivity analyses may be conducted to assess the robustness of the analysis of the 
co-primary efficacy endpoint of OS.  For example, a sensitivity analysis may be 
conducted to evaluate the impact of non-protocol anti-cancer therapy on OS benefit, by 
applying the rank-preserving structural failure time model.  

 
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In order to assess the homogeneity of the treatment effect with respect to the co-primary 
efficacy endpoint of OS across important subgroups, forest plots (including the estimated 
HRs) will be provided. 
6.4.1.2 
IRF-Assessed Progression-Free Survival 
Independent Review Facility-assessed PFS is defined as the time from randomization to 
the first occurrence of disease progression or death from any cause (whichever occurs 
first), as determined by an IRF according to RECIST v1.1.  Patients who have not 
experienced disease progression or death at the time of analysis will be censored at the 
time of the last tumor assessment.  Patients with no postbaseline tumor assessment will 
be censored at the date of randomization. 
Methods for the IRF-assessed PFS analysis are similar to those described for OS.  
The type I error control plan and the analysis timing for PFS are presented in 
Section 6.1. 
6.4.2 
Secondary Efficacy Endpoints 
6.4.2.1 
Investigator-Assessed Progression-Free Survival 
Investigator-assessed PFS is defined as the time from randomization to the first 
occurrence of disease progression or death from any cause (whichever occurs first), as 
determined by the investigator according to RECIST v1.1.  Patients who have not 
experienced disease progression or death at the time of analysis will be censored at the 
time of the last tumor assessment.  Patients with no postbaseline tumor assessment will 
be censored at the date of randomization. 
Methods for the investigator-assessed PFS analysis will be similar to those described 
for OS. 
6.4.2.2 
Objective Response Rate 
IRF-Assessed Objective Response Rate 
An objective response per IRF is defined as a CR or PR as determined by an IRF 
according to RECIST v1.1.  Patients not meeting these criteria, including patients without 
any postbaseline tumor assessment, will be considered non-responders.  
Confirmed ORR is defined as the proportion of patients who achieved an objective 
response on two consecutive occasions  4 weeks apart.  Patients must have 
measurable disease at baseline to be included in the analysis. 
The two-sided CochranMantelHaenszel test, stratified by PD-L1 expression 
see definition in Section 3.1), previous curative 
treatment (yes vs. no), and ECOG Performance Status (0 vs. 1), will be used to compare 
ORR between the two treatment arms.  Objective response rate will be calculated for 
each treatment arm, and the difference in ORR between treatment arms will be 
computed.  The 95% CI for ORR for each arm will be derived through use of the 

 
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Wilson score method.  The 95% CI for difference in ORR will be computed using the 
Newcombe method. 
Investigator-Assessed Objective Response Rate 
Objective response rate analyses will be performed separately on the basis of 
investigator-assessed tumor response according to RECIST v1.1.  The analysis 
methods will be similar to those described for IRF-assessed ORR. 
6.4.2.3 
Duration of Response 
IRF-Assessed Duration of Response 
Duration of response (DOR) per IRF will be assessed in patients who achieved a 
confirmed objective response, as determined by an IRF according to RECIST v1.1.  
Duration of response is defined as the time from the first occurrence of a confirmed 
objective response (CR or PR, whichever status is recorded first) to the first occurrence 
of disease progression or death from any cause, whichever occurs first.  Patients who 
have not progressed and who have not died at the time of analysis will be censored at 
the date of the last tumor assessment.  The analysis of DOR is based on 
a non-randomized subset of patients (specifically, patients who achieved a confirmed 
objective response); therefore, comparisons between treatment arms will be made for 
descriptive purposes only. 
The analysis methods will be similar to those described for OS. 
Investigator-Assessed Duration of Response 
Duration of response analyses will be performed separately on the basis of 
investigator-assessed tumor response according to RECIST v1.1.  The analysis 
methods will be similar to those described for OS. 
6.4.2.4 
Time to Confirmed Deterioration 
Time to confirmed deterioration (TTCD) in patient-reported physical functioning, role 
functioning, and GHS/QoL, as measured by the respective scales of the QLQ-C30, will 
be defined as the time from randomization to first deterioration (decrease from baseline 
of  10 points) that is maintained for two consecutive assessments or followed by death 
from any cause within 3 weeks. 
Time to confirmed deterioration in patient-reported dysphagia, as measured by the 
dysphagia scale of the QLQ-OES18, will be defined as the time from randomization to 
first deterioration (increase from baseline of  10 points) that is maintained for 
two consecutive assessments or followed by death from any cause within 3 weeks. 
The analysis methods will be similar to those described for OS. 

 
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6.5 
SAFETY ANALYSES 
Safety analyses will be conducted in the safety-evaluable analysis set, which includes all 
randomized patients who receive any amount of study treatment, with patients grouped 
according to the actual treatment received.  Specifically, a patient will be included in the 
Atezo  Tira  PC arm in the safety analyses if the patient receives any amount of 
tiragolumab and/or atezolizumab, regardless of the initial treatment assignment 
at randomization. 
Study treatment exposure, including treatment duration, number of cycles, and dose 
intensity, will be summarized for each treatment arm with descriptive statistics. 

 
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Verbatim description of adverse events will be mapped to MedDRA thesaurus terms.  
Severity for all events will be graded by the investigator according to NCI CTCAE v5.0, 
and 
 
  All adverse events will be summarized by treatment arm and 
NCI CTCAE 
.  In addition, serious adverse events, adverse 
events of special interest, adverse events leading to study treatment discontinuation, 
and adverse events leading to study treatment interruption or dose modification will be 
summarized accordingly.  Multiple occurrences of the same event will be counted once 
at the maximum grade.  
All deaths and causes of deaths will be summarized by treatment arm. 
Laboratory data with values outside the normal ranges will be identified.  
Additionally, selected laboratory data will be graded according to NCI CTCAE v5.0 and 
will be summarized by treatment arm with shift tables from baseline to worst 
postbaseline value.  Changes in vital signs will be summarized.  
Additional analyses may be performed as indicated. 
6.6 
PHARMACOKINETIC ANALYSES 
Pharmacokinetic samples of tiragolumab and atezolizumab will be collected in this study 
as outlined in Appendix 2. 
Pharmacokinetic samples will be collected from all patients enrolled in the study.  
In these patients, tiragolumab and atezolizumab serum concentration data 
(minimum serum concentration [Cmin] and maximum serum concentration [Cmax]) will be 
tabulated and summarized.  Descriptive statistics will include mean, median, range, and 
standard deviation, as appropriate. 
Additional PK analyses will be conducted, as appropriate, based on the availability 
of data. 
6.7 
IMMUNOGENICITY ANALYSES 
The immunogenicity analyses will include patients with any ADA assessments, with 
patients grouped according to treatment received. 
The numbers and proportions of treatment-emergent ADA-positive patients and 
ADA-negative patients during both the treatment and follow-up periods for both 
tiragolumab and atezolizumab will be summarized by treatment arm. 
 
 

 
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6.9 
HEALTH STATUS UTILITY ANALYSES 
Health utility data from the EQ-5D-5L will be evaluated in pharmacoeconomic models.  
Results from health economic data analyses will be reported separately from the CSR. 
 
 
 
 

 
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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. 

 
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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. 
Electronic Case Report Forms and correction documentation will be maintained in the 
EDC system's audit trail.  System backups for data stored by the Sponsor and records 
retention for the study data will be consistent with the Sponsor's standard procedures. 
Patient-reported outcome data will be collected on paper questionnaires.  The data from 
the questionnaires will be entered into the EDC system by site staff. 
7.2 
ELECTRONIC CASE REPORT FORMS  
Electronic Case Report Forms are to be completed through use of a Sponsor-designated 
EDC system.  Sites will receive training and have access to a manual for appropriate 
eCRF completion.  Electronic Case Report Forms will be submitted electronically to the 
Sponsor and should be handled in accordance with instructions from the Sponsor. 
All eCRFs should be completed by designated, trained site staff.  Electronic Case Report 
Forms should be reviewed and electronically signed and dated by the investigator or a 
designee. 
At the end of the study, the investigator will receive patient data for his or her site in 
a readable format that must be kept with the study records.  Acknowledgement of receipt 
of the data is required. 
7.3 
SOURCE DATA DOCUMENTATION 
Study monitors will perform ongoing source data verification and review to confirm that 
critical protocol data (i.e., source data) entered into the eCRFs by authorized site 
personnel are accurate, complete, and verifiable from source documents.  
Source documents (paper or electronic) are those in which patient data are recorded 
and documented for the first time.  They include, but are not limited to, hospital records, 
clinical and office charts, laboratory notes, memoranda, PROs, evaluation checklists, 
pharmacy dispensing records, recorded data from automated instruments, copies of 
transcriptions that are certified after verification as being accurate and complete, 
microfiche, photographic negatives, microfilm or magnetic media, X-rays, patient files, 
and records kept at pharmacies, laboratories, and medico-technical departments 
involved in a clinical trial. 
Before study initiation, the types of source documents that are to be generated will be 
clearly defined in the Trial Monitoring Plan.  This includes any protocol data to be 
entered directly into the eCRFs (i.e., no prior written or electronic record of the data) and 
considered source data. 

 
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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 
as the source document if the system has been validated in accordance with health 
authority requirements pertaining to computerized systems used in clinical research.  
An acceptable computerized data collection system allows preservation of the original 
entry of data.  If original data are modified, the system should maintain a viewable audit 
trail that shows the original data as well as the reason for the change, name of the 
person making the change, and date of the change. 
7.5 
RETENTION OF RECORDS 
Records and documents pertaining to the conduct of this study and the distribution of 
IMP, including eCRFs, paper PRO data, Informed Consent Forms, laboratory test 
results, and medication inventory records, must be retained by the Principal Investigator 
for 15 years after completion or discontinuation of the study or for the length of time 
required by relevant national or local health authorities, whichever is longer.  After that 
period of time, the documents may be destroyed, subject to local regulations. 
No records may be disposed of without the written approval of the Sponsor.  
Written notification should be provided to the Sponsor prior to transferring any records to 
another party or moving them to another location.The Sponsor will retain study data for 
25 years after the final study results have been reported or for the length of time required 
by relevant national or local health authorities, whichever is longer. 
8. 
ETHICAL CONSIDERATIONS 
8.1 
COMPLIANCE WITH LAWS AND REGULATIONS 
This study will be conducted in full conformance with the ICH E6 guideline for 
Good Clinical Practice and the principles of the Declaration of Helsinki, or the applicable 
laws and regulations of the country in which the research is conducted, whichever 
affords the greater protection to the individual.  The study will comply with the 
requirements of the ICH E2A guideline (Clinical Safety Data Management:  
Definitions and Standards for Expedited Reporting).  Studies conducted in the 
United States or under a U.S. Investigational New Drug (IND) Application will comply 
with U.S. Food and Drug Administration regulations and applicable local, state, and 

 
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federal laws.  Studies conducted in the European Union or European Economic Area will 
comply with the E.U. Clinical Trials Directive (2001/20/EC) or Clinical Trials Regulation 
(536/2014) and applicable local, regional, and national laws. 
8.2 
INFORMED CONSENT 
The Sponsor's sample Informed Consent Form (and ancillary sample Informed Consent 
Forms such as an Assent Form or Mobile Nursing Informed Consent Form, if applicable) 
will be provided to each site.  If applicable, it will be provided in a certified translation of 
the local language.  The Sponsor or its designee must review and approve any proposed 
deviations from the Sponsor's sample Informed Consent Forms or any alternate 
Consent Forms proposed by the site (collectively, the "Consent Forms") before IRB/EC 
submission.  The final IRB/ECapproved Consent Forms must be provided to the 
Sponsor for health authority submission purposes according to local requirements. 
If applicable, the Informed Consent Form will contain separate sections for any optional 
procedures.  The investigator or authorized designee will explain to each patient the 
objectives, methods, and potential risks associated with each optional procedure.  
Patients will be told that they are free to refuse to participate and may withdraw their 
consent at any time for any reason.  A separate, specific signature will be required to 
document a patient's agreement to participate in optional procedures.  Patients who 
decline to participate will not provide a separate signature. 
The Consent Forms must be signed and dated by the patient or the patient's legally 
authorized representative before his or her participation in the study.  The case history or 
clinical records for each patient shall document the informed consent process and that 
written informed consent was obtained prior to participation in the study. 
The Consent Forms should be revised whenever there are changes to study procedures 
or when new information becomes available that may affect the willingness of the patient 
to participate.  The final revised IRB/EC-approved Consent Forms must be provided to 
the Sponsor for health authority submission purposes. 
If the Consent Forms are revised (through an amendment or an addendum) to 
communicate information that might affect a patient’s willingness to continue in the 
study, the patient or a legally authorized representative must re-consent by signing the 
most current version of the Consent Forms or the addendum, in accordance with 
applicable laws and IRB/EC policy.  For any updated or revised Consent Forms, the 
case history or clinical records for each patient shall document the informed consent 
process and that written informed consent was obtained using the updated/revised 
Consent Forms for continued participation in the study. 
A copy of each signed Consent Form must be provided to the patient or the patient's 
legally authorized representative.  All signed and dated Consent Forms must remain in 

 
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96/Protocol YO42138, Version 7 
each patient's study file or in the site file and must be available for verification by study 
monitors at any time. 
8.3 
INSTITUTIONAL REVIEW BOARD OR ETHICS COMMITTEE 
This protocol, the Informed Consent Forms, any information to be given to the patient, 
and relevant supporting information must be submitted to the IRB/EC by the 
Principal Investigator and reviewed and approved by the IRB/EC before the study is 
initiated.  In addition, any patient recruitment materials must be approved by the IRB/EC. 
The Principal Investigator is responsible for providing written summaries of the status of 
the study to the IRB/EC annually or more frequently in accordance with the 
requirements, policies, and procedures established by the IRB/EC.  Investigators are 
also responsible for promptly informing the IRB/EC of any protocol amendments 
(see Section 9.7). 
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 

 
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patients unless required by law.  The aggregate results of any conducted research will 
be available in accordance with the effective Sponsor policy on study data publication 
(see Section 9.6). 
Data generated by this study must be available for inspection upon request by 
representatives of national and local health authorities, Sponsor monitors, 
representatives, and collaborators, and the IRB/EC for each study site, as appropriate. 
Study data, which may include 
, may be submitted to 
government or other health research databases or shared with researchers, government 
agencies, companies, or other groups that are not participating in this study.  These data 
may be combined with or linked to other data and used for research purposes, to 
advance science and public health, or for analysis, development, and commercialization 
of products to treat and diagnose disease.  In addition, redacted CSRs and other 
summary reports will be provided upon request (see Section 9.6). 
8.5 
FINANCIAL DISCLOSURE 
Investigators will provide the Sponsor with sufficient, accurate financial information in 
accordance with local regulations to allow the Sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate health authorities.  
Investigators are responsible for providing information on financial interests during the 
course of the study and for 1 year after completion of the study (see definition of end of 
study in Section 3.4). 
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. 

 
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9.3 
MANAGEMENT OF STUDY QUALITY 
The Sponsor will implement a system to manage the quality of the study, focusing on 
processes and data that are essential to ensuring patient safety and data integrity.  
Prior to study initiation, the Sponsor will identify potential risks associated with critical 
trial processes and data and will implement plans for evaluating and controlling these 
risks.  Risk evaluation and control will include the selection of risk-based parameters 
(e.g., adverse event rate, protocol deviation rate) and the establishment of quality 
tolerance limits for these parameters prior to study initiation.  Detection of deviations 
from quality tolerance limits will trigger an evaluation to determine if action is needed.  
Details on the establishment and monitoring of quality tolerance limits will be provided in 
a Quality Tolerance Limit Management Plan. 
9.4 
SITE INSPECTIONS 
Site visits will be conducted by the Sponsor or an authorized representative for 
inspection of study data, patients' medical records, and eCRFs.  The investigator will 
permit national and local health authorities; Sponsor monitors, representatives, and 
collaborators; and the IRBs/ECs to inspect facilities and records relevant to this study. 
9.5 
ADMINISTRATIVE STRUCTURE 
This trial will be sponsored and managed by F. Hoffmann-La Roche Ltd.  The Sponsor 
will provide clinical operations management, data management, and medical monitoring. 
Approximately 40 sites globally will participate to randomize approximately 450 patients.  
Screening and enrollment will occur through an IxRS. 
Central facilities will be used for certain study assessments throughout the study 
(e.g., specified laboratory tests, 
), as specified in 
Sections 4.5.8 and 4.5.9.  Accredited local laboratories will be used for routine 
monitoring; local laboratory ranges will be collected. 
An iDMC will monitor and evaluate patient safety throughout the study.  All summaries 
and analyses for the iDMC review will be prepared by an iDCC. 
9.6 
DISSEMINATION OF DATA AND PROTECTION OF TRADE 
SECRETS 
Regardless of the outcome of a trial, the Sponsor is dedicated to openly providing 
information on the trial to healthcare professionals and to the public, at scientific 
congresses, in clinical trial registries, and in peer-reviewed journals.  The Sponsor will 
comply with all requirements for publication of study results.  Study data may be shared 
with others who are not participating in this study (see Section 8.4 for details), and 
redacted CSRs 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 

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

 
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10. 
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Appendix 1  
Schedule of Activities 
 
Screening a 
Induction  
(21-Day Cycles) 
Maintenance 
(21-Day Cycles) Treatment 
Discon. d 
Follow-Up f 
Cycle 1 
Cycles 26 b 
Cycles  7 b, c 
Days –28 
to –1 
Days –14 
to –1 
Day 1 e 
 
Day 8 
( 3 d) 
Day 1 
( 3 d) 
Day 8 
( 3 d) 
Day 1 
( 3 d) 
 30 Days 
after Final 
Dose 
Informed consent g 
x 
 
 
 
 
 
 
 
 
Baseline tumor tissue sample h 
x 
 
 
 
 
 
 
 
 
Demographic data 
x 
 
 
 
 
 
 
 
 
Medical history and baseline 
conditions 
x 
 
 
 
 
 
 
 
 
PRO assessments i 
 
 
x j 
 
x j 
 
Every other cycle 
(Cycles 7, 9, etc.) j 
x 
x k 
Complete physical examination l, m 
x 
 
 
 
 
 
 
x 
 
Limited physical examination m, n 
 
 
x j 
 
x j 
 
x j 
 
 
ECOG Performance Status 
x 
 
x j 
 
x j 
 
x j 
x 
 
Vital signs o 
x 
 
x 
x 
x 
x 
x 
x 
 
Weight 
x 
 
x 
 
x 
 
x 
x 
 
Height 
x 
 
 
 
 
 
 
 
 
12-lead ECG p 
x 
 
Perform as clinically indicated 
x 
 
Hematology s 
 
x 
x t 
x 
x t 
x 
x t 
x 
 
Chemistry u 
 
x 
x t 
x 
x t 
x 
x t 
x 
 
Coagulation (aPTT, INR)  
 
x 
x t 
 
x t 
 
x t 
x 
 

Appendix 1: Schedule of Activities 
  
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Screening a 
Induction  
(21-Day Cycles) 
Maintenance  
(21-Day Cycles) Treatment 
Discon. d 
Follow-Up f 
Cycle 1 
Cycles 26 b 
Cycles  7 b, c 
Days –28 
to –1 
Days –14 
to –1 
Day 1 e 
 
Day 8 
( 3 d) 
Day 1 
( 3 d) 
Day 8 
( 3 d) 
Day 1 
( 3 d) 
 30 Days 
after Final 
Dose 
TSH, free T3 (or total T3), 
free T4 v 
x 
 
x v 
x 
 
CA19-9 and CEA 
 
 
x j 
 
x j 
 
x j 
x 
 
C-reactive protein 
 
 
x j 
 
 
 
 
 
 
Pregnancy test w 
 
x 
x t 
 
x t 
 
x t 
x 
x w 
Urinalysis x 
x 
 
Perform as clinically indicated 
 
Tumor biopsy (optional) 
 
 
x y 
Tumor response assessments m 
x z 
 
x aa, bb 
Concomitant medications cc 
 
x cc 
x 
x 
x 
x 
x 
x 
 
Adverse events dd 
x dd 
x dd 
x dd 
x 
x 
x 
x 
x 
x dd 
Study treatment administration ee 
 
 
x ff 
 
x ff 
 
x gg 
 
 
Survival and anti-cancer therapy 
follow-up 
 
 
 
 
 
 
 
 
x 

Appendix 1: Schedule of Activities 
  
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i PRO instruments (EORTC QLQ-C30, EORTC QLQ-OES18, and EQ-5D-5L) will be completed before the patient receives any information 
on disease status, prior to the performance of non-PRO assessments, and prior to the administration of study treatment, unless otherwise 
specified.  In scenarios where laboratory assessments (e.g., blood draws) are done at a different location than the one providing treatment 
or when they are done on a different day than study treatment administration, laboratory assessments can be completed before the 
completion of PROs, as long as results have not been discussed with patients. PRO instruments are to be completed as outlined in 
Section 4.5.7. 
j PRO assessments, limited physical examination, CA19-9, CEA, C-reactive protein, and ECOG Performance Status may be performed 
within 96 hours prior to administration of study treatment. 
k During follow-up, patients will complete the PRO instruments at the clinic or via telephone call approximately every 3 months for 1 year. 
l A complete physical examination should include evaluation of the head, eyes, ears, nose, and throat, and the cardiovascular, dermatologic, 
musculoskeletal, respiratory, gastrointestinal, genitourinary, and neurologic systems. 
m As part of the tumor assessment, physical examinations should include evaluation of the presence and degree of enlarged lymph nodes, 
hepatomegaly, and splenomegaly. 
n Perform a limited, symptom-directed examination at specified timepoints and as clinically indicated. 
o Vital signs include respiratory rate, pulse rate, systolic and diastolic blood pressure, and temperature.  For the first infusion of 
atezolizumab/placebo, vital signs should be measured within 60 minutes prior to the infusion and, if clinically indicated, every 
15 ( 5) minutes during and at 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 at 
30 ( 10) minutes after the infusion.  For the first infusion of tiragolumab/placebo, vital signs should be measured within 
 minutes prior to 
the infusion and every
minutes during and at
minutes after the infusion; for subsequent infusions, 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 
at
minutes after the infusion. 
p Patients should be resting in a supine position for at least 10 minutes prior to ECG recording. 

Appendix 1: Schedule of Activities 
  
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108/Protocol YO42138, Version 7 
s Hematology includes WBC count, RBC count, hemoglobin, hematocrit, platelet count, and differential count (neutrophils, eosinophils, 
basophils, monocytes, lymphocytes). 
t If screening laboratory assessments were performed within 96 hours prior to Day 1 of Cycle 1, they do not have to be repeated.  During the 
study treatment period, test results of the assessments scheduled on the days of study treatment infusions should be reviewed prior to 
administration of study treatment unless otherwise noted. 
u Chemistry panel (serum or plasma) includes bicarbonate or total carbon dioxide (if available), sodium, potassium, chloride, glucose, BUN or 
urea, creatinine, total protein, albumin, phosphate, calcium, total bilirubin, ALP, ALT, AST, and LDH. 
v 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 4 cycles 
thereafter (i.e., Cycles 5, 9, 13, etc.).  If the screening test was performed within 96 hours prior to Day 1 of Cycle 1, it does not have to 
be repeated. 
w All women of childbearing potential will have a serum pregnancy test at screening, within 14 days prior to initiation of study treatment.  
Urine pregnancy tests will be performed at specified subsequent visits during treatment, at the treatment discontinuation visit, and at 
3 months and 6 months after the final dose of study treatment.  If a urine pregnancy test is positive, it must be confirmed by a serum 
pregnancy test. 
x Urinalysis includes pH, specific gravity, glucose, protein, ketones, and blood; dipstick permitted. 
y Patients who consent to optional biopsies will undergo tumor biopsy sample collection at the time of disease progression per RECIST v1.1 or 
loss of clinical benefit as determined by the investigator (see Section 3.1 for details), if deemed clinically feasible, and may undergo additional 
on-treatment biopsies at any time at the investigator's discretion. 
z All measurable and evaluable lesions should be assessed and documented at screening.  Tumor assessments performed as standard of 
care prior to obtaining informed consent and within 28 days prior to initiation of study treatment do not have to be repeated at screening.  
Screening assessments must include CT scans (with oral or IV contrast) or MRI scans of the chest, abdomen, pelvis, and head.  A spiral 
CT scan of the chest may be obtained but is not a requirement.  If a CT scan with contrast is contraindicated (e.g., in patients with impaired 
renal clearance), a non-contrast CT scan of the chest may be performed and MRI scans of the abdomen, pelvis, and head should be 
performed.  Bone scans and CT scans of the neck should also be performed if clinically indicated.  At the investigator's discretion, other 
methods of assessment of measurable disease as per RECIST v1.1 may be used.  

 
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Appendix 3  
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) since they 
are, by definition, simple cysts. 
 
Cystic lesions thought to represent cystic metastases can be considered 
measurable lesions if they meet the definition of measurability described above.  
However, if non-cystic lesions are present in the same patient, these are preferred 
for selection as target lesions. 
 
Lesions with Prior Local Treatment: 
 
Tumor lesions situated in a previously irradiated area or in an area subjected to 
other loco-regional therapy are usually not considered measurable unless there has 
been demonstrated progression in the lesion. 
 

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METHODS FOR ASSESSING LESIONS 
All measurements should be recorded in metric notation, using calipers if clinically 
assessed.  All baseline evaluations should be performed as close as possible to the 
treatment start and never more than 4 weeks before the beginning of the treatment. 
The same method of assessment and the same technique should be used to 
characterize each identified and reported lesion at baseline and during the study.  
Imaging-based evaluation should always be the preferred option. 
CLINICAL LESIONS 
Clinical lesions will only be considered measurable when they are superficial and 
 10 mm in diameter as assessed using calipers (e.g., skin nodules).  For the case of 
skin lesions, documentation by color photography, including a ruler to estimate the size 
of the lesion, is suggested. 
CHEST X-RAY 
Chest CT is preferred over chest X-ray, particularly when progression is an important 
endpoint, since CT is more sensitive than X-ray, particularly in identifying new lesions.  
However, lesions on chest X-ray may be considered measurable if they are clearly 
defined and surrounded by aerated lung. 
CT AND MRI SCANS 
Computed tomography is the best currently available and reproducible method to 
measure lesions selected for response assessment.  In this guideline, the definition of 
measurability of lesions on CT scan is based on the assumption that CT slice thickness 
is  5 mm.  When CT scans have slice thickness of  5 mm, the minimum size for a 
measurable lesion should be twice the slice thickness.  Magnetic resonance imaging is 
also acceptable.  
If prior to enrollment it is known that a patient is unable to undergo CT scans with IV 
contrast because of allergy or renal insufficiency, the decision as to whether a 
non-contrast CT or MRI (without IV contrast) will be used to evaluate the patient at 
baseline and during the study should be guided by the tumor type under investigation 
and the anatomic location of the disease.  For patients who develop contraindications to 
contrast after baseline contrast CT is done, the decision as to whether non-contrast CT 
or MRI (enhanced or non-enhanced) will be performed should also be based on the 
tumor type and the anatomic location of the disease, and should be optimized to allow 
for comparison with the prior studies if possible.  Each case should be discussed with 
the radiologist to determine if substitution of these other approaches is possible and, if 
not, the patient should be considered not evaluable from that point forward.  Care must 
be taken in measurement of target lesions and interpretation of non-target disease or 

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new lesions on a different modality, since the same lesion may appear to have a 
different size using a new modality. 
ENDOSCOPY, LAPAROSCOPY, ULTRASOUND, TUMOR MARKERS, 
CYTOLOGY, HISTOLOGY 
Endoscopy, laparoscopy, ultrasound, tumor markers, cytology, and histology cannot be 
used for objective tumor evaluation. 
ASSESSMENT OF TUMOR BURDEN 
To assess objective response or future progression, it is necessary to estimate the 
overall tumor burden at baseline and use this as a comparator for subsequent 
measurements. 
IDENTIFICATION OF TARGET AND NON-TARGET LESIONS 
When more than one measurable lesion is present at baseline, all lesions up to 
a maximum of five lesions total (and a maximum of two lesions per organ) representative 
of all involved organs should be identified as target lesions and will be recorded and 
measured at baseline.  This means that, for instances in which patients have only one or 
two organ sites involved, a maximum of two lesions (one site) and four lesions 
(two sites), respectively, will be recorded.  Other lesions (albeit measurable) in those 
organs will be considered non-target lesions. 
Target lesions should be selected on the basis of their size (lesions with the longest 
diameter) and should be representative of all involved organs, but in addition should lend 
themselves to reproducible repeated measurements.  It may be the case that, on 
occasion, the largest lesion does not lend itself to reproducible measurement, in which 
circumstance the next largest lesion that can be measured reproducibly should 
be selected. 
Lymph nodes merit special mention since they are normal anatomical structures that 
may be visible by imaging even if not involved by tumor.  As noted above, pathological 
nodes that are defined as measurable and may be identified as target lesions must meet 
the criterion of a short axis of  15 mm by CT scan.  Only the short axis of these nodes 
will contribute to the baseline sum.  The short axis of the node is the diameter normally 
used by radiologists to judge if a node is involved by solid tumor.  Lymph node size is 
normally reported as two dimensions in the plane in which the image is obtained (for CT, 
this is almost always the axial plane; for MRI, the plane of acquisition may be axial, 
sagittal, or coronal).  The smaller of these measures is the short axis.  For example, an 
abdominal node that is reported as being 20 mm  30 mm has a short axis of 20 mm and 
qualifies as a malignant, measurable node.  In this example, 20 mm should be recorded 
as the node measurement.  All other pathological nodes (those with short axis  10 mm 

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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 (CR) criteria are met, since a normal lymph node is defined as 
having a short axis of  10 mm. 
Measuring Lesions That Become Too Small to Measure 
During the study, all target lesions (lymph node and non-lymph node) recorded at 
baseline should have their actual measurements recorded at each subsequent 
evaluation, even when very small (e.g., 2 mm).  However, sometimes lesions or lymph 
nodes that are recorded as target lesions at baseline become so faint on CT scan that 
the radiologist may not feel comfortable assigning an exact measurement and may 
report them as being too small to measure.  When this occurs, it is important that a value 
be recorded on the CRF, as follows: 
 
If it is the opinion of the radiologist that the lesion has likely disappeared, the 
measurement should be recorded as 0 mm. 
 
If the lesion is believed to be present and is faintly seen but too small to measure, 
a default value of 5 mm should be assigned and "too small to measure" should be 
ticked.  (Note:  It is less likely that this rule will be used for lymph nodes since they 
usually have a definable size when normal and are frequently surrounded by fat 
such as in the retroperitoneum; however, if a lymph node is believed to be present 
and is faintly seen but too small to measure, a default value of 5 mm should be 
assigned in this circumstance as well and "too small to measure" should also be 
ticked). 

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To reiterate, however, if the radiologist is able to provide an actual measurement, that 
should be recorded, even if it is  5 mm, and in that case "too small to measure" should 
not be ticked. 
Measuring Lesions That Split or Coalesce on Treatment 
When nonlymph node lesions fragment, the longest diameters of the fragmented 
portions should be added together to calculate the sum of diameters.  Similarly, as 
lesions coalesce, a plane between them may be maintained that would aid in obtaining 
maximal diameter measurements of each individual lesion.  If the lesions have truly 
coalesced such that they are no longer separable, the vector of the longest diameter in 
this instance should be the maximum longest diameter for the coalesced lesion. 
EVALUATION OF NON-TARGET LESIONS 
Measurements are not required for non-target lesions, except that malignant lymph node 
non-target lesions should be monitored for reduction to  10 mm in short axis.  
Non-target lesions should be noted at baseline and should be identified as "present" or 
"absent" and (in rare cases) may be noted as "indicative of progression" at subsequent 
evaluations.  In addition, if a lymph node lesion shrinks to a non-malignant size 
(short axis  10 mm), this should be captured on the CRF as part of the assessment of 
non-target lesions. 
RESPONSE CRITERIA 
CRITERIA FOR TARGET LESIONS 
Definitions of the criteria used to determine objective tumor response for target lesions 
are provided below: 
 
Complete response (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:  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 progressive disease 
 

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CRITERIA FOR NON-TARGET LESIONS 
Definitions of the criteria used to determine the tumor response for the group of 
non-target lesions are provided below.  While some non-target lesions may actually be 
measurable, they need not be measured and instead should be assessed only 
qualitatively at the timepoints specified in the schedule of activities. 
 
CR:  Disappearance of all non-target lesions and (if applicable) normalization of 
tumor marker level 
All lymph nodes must be non-pathological in size ( 10 mm short axis). 
 
Non-CR/Non-progressive disease:  Persistence of one or more non-target lesions 
and/or (if applicable) maintenance of tumor marker level above the normal limits 
 
Progressive disease:  Unequivocal progression of existing non-target lesions 
 
SPECIAL NOTES ON ASSESSMENT OF PROGRESSION OF NON-TARGET 
LESIONS 
Patients with Measurable and Non-Measurable Disease 
For patients with both measurable and non-measurable disease to achieve unequivocal 
progression on the basis of the non-target lesions, there must be an overall level of 
substantial worsening in non-target lesions in a magnitude that, even in the presence of 
SD or PR in target lesions, the overall tumor burden has increased sufficiently to merit 
discontinuation of therapy.  A modest increase in the size of one or more non-target 
lesions is usually not sufficient to qualify for unequivocal progression status.  
The designation of overall progression solely on the basis of change in non-target 
lesions in the face of SD or PR in target lesions will; therefore, be extremely rare. 
NEW LESIONS 
The appearance of new malignant lesions denotes disease progression; therefore, some 
comments on detection of new lesions are important.  There are no specific criteria for 
the identification of new radiographic lesions; however, the finding of a new lesion 
should be unequivocal, that is, not attributable to differences in scanning technique, 
change in imaging modality, or findings thought to represent something other than tumor 
(e.g., 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 A3-1 provides a summary of the overall response status calculation at each 
response assessment timepoint for patients who have measurable disease at baseline. 
Table A3-1 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 progressive disease.  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 progressive disease 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 
"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 A3-1. 
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 4  
European Organisation for Research and 
Treatment of Cancer QLQ-C30 
Do not reproduce or distribute.  The Sponsor will provide sites with all instruments to 
be completed in this study. 
 
 

Appendix 4: European Organisation for Research and Treatment of Cancer QLQ-C30 
  
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Appendix 5  
European Organisation for Research and 
Treatment of Cancer QLQ-OES18 
Do not reproduce or distribute.  The Sponsor will provide sites with all instruments to 
be completed in this study. 
 
 

 
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Appendix 6  
EuroQol EQ-5D-5L 
Do not reproduce or distribute.  The Sponsor will provide sites with all instruments to 
be completed in this study. 
 
 

Appendix 6: EuroQol EQ-5D-5L 
  
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Appendix 7  
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. 

Appendix 6: EuroQol EQ-5D-5L 
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Appendix 8  
Anaphylaxis Precautions 
These guidelines are intended as a reference and should not supersede pertinent local 
or institutional standard operating procedures. 
REQUIRED EQUIPMENT AND MEDICATION 
The following equipment and medication are needed in the event of a suspected 
anaphylactic reaction during study treatment infusion: 
 
Monitoring devices:  ECG monitor, blood pressure monitor, oxygen saturation 
monitor, and thermometer 
 
Oxygen 
 
Epinephrine for subcutaneous, intramuscular, intravenous, and/or endotracheal 
administration in accordance with institutional guidelines 
 
Antihistamines 
 
Corticosteroids 
 
Intravenous infusion solutions, tubing, catheters, and tape 
 
PROCEDURES 
In the event of a suspected anaphylactic reaction during study treatment infusion, 
the following procedures should be performed: 
1. 
Stop the study treatment infusion. 
2. 
Call for additional medical assistance. 
3. 
Maintain an adequate airway. 
4. 
Ensure that appropriate monitoring is in place, with continuous ECG and pulse 
oximetry monitoring if possible. 
5. 
Administer antihistamines, epinephrine, or other medications and IV fluids as 
required by patient status and as directed by the physician in charge. 
6. 
Continue to observe the patient and document observations. 
 

 
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Appendix 9  
Overall Guidelines for Management of Patients Who Experience 
Adverse Events 
This appendix provides guidelines for management of patients who experience adverse 
events associated with atezolizumab or matching placebo (referred to as "atezolizumab" 
hereafter), tiragolumab or matching placebo (referred to as "tiragolumab" hereafter), 
paclitaxel, and cisplatin. 
DOSE MODIFICATIONS 
There will be no dose modifications for atezolizumab or tiragolumab in this study. 
For management of drug-related toxicities, the dose of paclitaxel and the dose of 
cisplatin may be reduced by up to 2 times, as outlined in Table A9-1 .  If the dose of one 
chemotherapy drug is reduced because of a toxicity considered to be solely related to 
that drug, there is no need to reduce the dose of the other chemotherapy drug. 
Table A9-1 Dose Reductions for Paclitaxel and Cisplatin 
 
Initial Dose 
First Dose Reduction 
Second Dose Reduction 
Paclitaxel 
175 mg/m2 
135 mg/m2 
90 mg/m2 
Cisplatin 
6080 mg/m2 
75% of previous dose 
75% of previous dose 
 
If further dose reduction is indicated for cisplatin and/or paclitaxel after 2 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.  Once the dose has 
been decreased, it should remain reduced for all subsequent administrations or further 
reduced if necessary.  There will be no dose escalations in this study.  All subsequent 
chemotherapy doses must be rescheduled according to the last chemotherapy dose 
administration date.  If any chemotherapy agent is held for more than 2 cycles (6 weeks) 
from the anticipated treatment date, or the dose level-2 is not tolerated, chemotherapy 
should be permanently discontinued. 

Appendix 9: Overall Guidelines for Management of Patients Who Experience 
Adverse Events 
  
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Cisplatin dose reductions for renal impairment are provided in Table A9-2 . 
Table A9-2  
Cisplatin Dose Reductions for Renal Impairment 
 
Action to Be Taken 
Creatinine Clearance (mL/min) 
 40 to  50 
 Continue atezolizumab, tiragolumab, and paclitaxel. 
 Withhold cisplatin. 
 If creatinine clearance recovers to baseline or better  6 weeks 
after event onset, resume cisplatin with dose reduced by one 
dose level. a  If not, permanently discontinue cisplatin. b 
 30 to  40 
 Continue atezolizumab, tiragolumab, and paclitaxel. 
 Withhold cisplatin. 
 If creatinine clearance recovers to baseline or better  6 weeks 
after event onset, resume cisplatin with dose reduced by 2 dose 
levels. a  If not, permanently discontinue cisplatin. b  
 30  
 Continue atezolizumab, tiragolumab, and paclitaxel. 
 Permanently discontinue cisplatin. b 
a The dose of paclitaxel and the dose of cisplatin may be reduced by up to 2 times, as outlined 
in Table A9-1. 
b Resumption of treatment may be considered if the investigator believes the patient is likely to 
derive clinical benefit.  The Medical Monitor is available to advise as needed. 
 

Appendix 9: Overall Guidelines for Management of Patients Who Experience 
Adverse Events 
  
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TREATMENT INTERRUPTION 
Atezolizumab and tiragolumab treatment may be temporarily suspended in patients 
experiencing toxicity considered to be related to study treatment.  
 
  Atezolizumab and 
tiragolumab treatment may be suspended for reasons other than toxicity (e.g., surgical 
procedures).  The acceptable length of treatment interruption must be based on the 
investigator's benefitrisk assessment and in alignment with the protocol requirements 
for the duration of treatment and documented by the investigator.  The Medical Monitor 
is available to advise as needed.  
 Paclitaxel and/or cisplatin treatment may be temporarily suspended in patients 
experiencing toxicity considered to be related to study treatment (see Table A9-3).  
If paclitaxel or cisplatin have been withheld for  6 weeks because of toxicity, the patient 
should be discontinued from both chemotherapy agents.  However, paclitaxel or cisplatin 
can be resumed after being withheld for  6 weeks if the patient is likely to derive clinical 
benefit as determined by the investigator.  The Medical Monitor is available to advise 
as needed. 
If one or more study treatments is interrupted, subsequent cycles should be restarted 
such that the study treatment infusions remain synchronized. 
 
 
MANAGEMENT GUIDELINES 
Guidelines for management of patients who experience specific adverse events are 
provided in Table A9-3.  If several toxicities of different severity grades occur at the 
same time, the patient should be managed according to guidelines for the most severe 

Appendix 9: Overall Guidelines for Management of Patients Who Experience 
Adverse Events 
  
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toxicity.  The investigator may use discretion in adhering to the guidelines 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. 
For adverse events associated with paclitaxel or cisplatin that are not listed in Table A9-
3, refer to guidelines in the applicable local prescribing information (if available) or 
Summary of Product Characteristics.  For cases in which management guidelines are 
not covered in the protocol or prescribing information, patients should be managed as 
deemed appropriate by the investigator according to best medical judgment.

 
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Appendix 9: Overall Guidelines for Management of Patients Who Experience 
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Appendix 9: Overall Guidelines for Management of Patients Who Experience 
Adverse Events 
 
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Appendix 9: Overall Guidelines for Management of Patients Who Experience 
Adverse Events 
 
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Appendix 9: Overall Guidelines for Management of Patients Who Experience 
Adverse Events 
 
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Appendix 9: Overall Guidelines for Management of Patients Who Experience 
Adverse Events 
 
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Appendix 9: Overall Guidelines for Management of Patients Who Experience 
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Appendix 9: Overall Guidelines for Management of Patients Who Experience 
Adverse Events 
 
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Appendix 9: Overall Guidelines for Management of Patients Who Experience 
Adverse Events 
 
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Appendix 9: Overall Guidelines for Management of Patients Who Experience 
Adverse Events 
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Appendix 9: Overall Guidelines for Management of Patients Who Experience 
Adverse Events 
 
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Appendix 9: Overall Guidelines for Management of Patients Who Experience 
Adverse Events 
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Appendix 9: Overall Guidelines for Management of Patients Who Experience 
Adverse Events 
 
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Appendix 10  
Risks Associated with Atezolizumab and/or Tiragolumab and 
Guidelines for Management of Adverse Events Associated with 
Atezolizumab and/or Tiragolumab 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 

Appendix 10: Risks Associated with Atezolizumab and/or Tiragolumab and Guidelines for 
Management of Adverse Events Associated with Atezolizumab and/or 
Tiragolumab 
  
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Appendix 10: Risks Associated with Atezolizumab and/or Tiragolumab and Guidelines for 
Management of Adverse Events Associated with Atezolizumab and/or 
Tiragolumab 
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Appendix 10: Risks Associated with Atezolizumab and/or Tiragolumab and Guidelines for 
Management of Adverse Events Associated with Atezolizumab and/or 
Tiragolumab 
  
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Appendix 10: Risks Associated with Atezolizumab and/or Tiragolumab and Guidelines for 
Management of Adverse Events Associated with Atezolizumab and/or 
Tiragolumab 
 
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Appendix 10: Risks Associated with Atezolizumab and/or Tiragolumab and Guidelines for 
Management of Adverse Events Associated with Atezolizumab and/or 
Tiragolumab 
 
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Appendix 10: Risks Associated with Atezolizumab and/or Tiragolumab and Guidelines for 
Management of Adverse Events Associated with Atezolizumab and/or 
Tiragolumab 
  
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Appendix 10: Risks Associated with Atezolizumab and/or Tiragolumab and Guidelines for 
Management of Adverse Events Associated with Atezolizumab and/or 
Tiragolumab 
  
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Appendix 10: Risks Associated with Atezolizumab and/or Tiragolumab and Guidelines for 
Management of Adverse Events Associated with Atezolizumab and/or 
Tiragolumab 
  
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Appendix 10: Risks Associated with Atezolizumab and/or Tiragolumab and Guidelines for 
Management of Adverse Events Associated with Atezolizumab and/or 
Tiragolumab 
  
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Appendix 10: Risks Associated with Atezolizumab and/or Tiragolumab and Guidelines for 
Management of Adverse Events Associated with Atezolizumab and/or 
Tiragolumab 
 
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Appendix 10: Risks Associated with Atezolizumab and/or Tiragolumab and Guidelines for 
Management of Adverse Events Associated with Atezolizumab and/or 
Tiragolumab 
 
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Appendix 10: Risks Associated with Atezolizumab and/or Tiragolumab and Guidelines for 
Management of Adverse Events Associated with Atezolizumab and/or 
Tiragolumab 
 
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Appendix 10: Risks Associated with Atezolizumab and/or Tiragolumab and Guidelines for 
Management of Adverse Events Associated with Atezolizumab and/or 
Tiragolumab 
  
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Appendix 10: Risks Associated with Atezolizumab and/or Tiragolumab and Guidelines for 
Management of Adverse Events Associated with Atezolizumab and/or 
Tiragolumab 
 
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Appendix 10: Risks Associated with Atezolizumab and/or Tiragolumab and Guidelines for 
Management of Adverse Events Associated with Atezolizumab and/or 
Tiragolumab 
 
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Appendix 10: Risks Associated with Atezolizumab and/or Tiragolumab and Guidelines for 
Management of Adverse Events Associated with Atezolizumab and/or 
Tiragolumab 
  
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13. 
 

Appendix 10: Risks Associated with Atezolizumab and/or Tiragolumab and Guidelines for 
Management of Adverse Events Associated with Atezolizumab and/or 
Tiragolumab 
  
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Appendix 10: Risks Associated with Atezolizumab and/or Tiragolumab and Guidelines for 
Management of Adverse Events Associated with Atezolizumab and/or 
Tiragolumab 
 
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Appendix 10: Risks Associated with Atezolizumab and/or Tiragolumab and Guidelines for 
Management of Adverse Events Associated with Atezolizumab and/or 
Tiragolumab 
  
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Appendix 10: Risks Associated with Atezolizumab and/or Tiragolumab and Guidelines for 
Management of Adverse Events Associated with Atezolizumab and/or 
Tiragolumab 
 
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Appendix 10: Risks Associated with Atezolizumab and/or Tiragolumab and Guidelines for 
Management of Adverse Events Associated with Atezolizumab and/or 
Tiragolumab 
 
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Appendix 10: Risks Associated with Atezolizumab and/or Tiragolumab and Guidelines for 
Management of Adverse Events Associated with Atezolizumab and/or 
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Tiragolumab 
 
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La Rosée P. Treatment of hemophagocytic lymphohistiocytosis in adults. Hematology 
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La Rosée P, Horne A, Hines M, et al. Recommendations for the management of 
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Lee DW, Santomasso BD, Locke FL, et al. ASTCT consensus grading for cytokine 
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McClain KL, Eckstein O. Clinical features and diagnosis of hemophagocytic 
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Merad M, Martin JC. Pathological inflammation in patients with COVID-19: a key role for 
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Riegler LL, Jones GP, Lee DW. Current approaches in the grading and management of 
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Rotz SJ, Leino D, Szabo S, et al. Severe cytokine release syndrome in a patient 
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