Clinical trial NCT04300647
Conditions: Cervical Cancer
Sponsor: Hoffmann-La Roche
Start date: 2020-06-30; Completion date: 2025-02-24
Enrollment: 172 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to evaluate the efficacy and safety of tiragolumab in combination with atezolizumab and atezolizumab monotherapy in patients with programmed death-ligand 1 (PD-L1)-positive cervical cancer (metastatic and/or recurrent).

Detailed description:

Arms: arm 1: Participants will receive tiragolumab and atezolizumab until unacceptable toxicity or loss of clinical benefit as determined by the investigator. arm 2: Participants will receive atezolizumab monotherapy until unacceptable toxicity or loss of clinical benefit as determined by the investigator.
Interventions: intervention 1: Tiragolumab intervention 2: Atezolizumab
Intervention descriptions: intervention 1: Tiragolumab at a fixed dose of 600 milligrams (mg) will be administered by intravenous (IV) infusion every 3 weeks (Q3W) on Day 1 of each 21-day cycle. intervention 2: Atezolizumab at a fixed dose of 1200 mg will be administered by IV infusion Q3W on Day 1 of each 21-day cycle.

Protocol documents:
Prot_000.pdf: 
 
Official Title: 
A Phase II, Safety, and Efficacy Study of Tiragolumab Plus 
Atezolizumab and Atezolizumab Monotherapy in Patients With 
Metastatic and/or Recurrent PD-L1-Positive Cervical Cancer 
NCT Number: 
NCT04300647 
Document Date: 
Protocol Amendment Version 8: 06-October-2023 
 
 
 


CONFIDENTIAL 
This clinical study is being sponsored globally by F. Hoffmann-La Roche Ltd of Basel, 
Switzerland.  However, it may be implemented in individual countries by Roche's local affiliates, 
including Genentech, Inc. in the United States.  The information contained in this document, especially 
any unpublished data, is the property of F. Hoffmann-La Roche Ltd (or under its control) and therefore 
is provided to you in confidence as an investigator, potential investigator, or consultant, for review by 
you, your staff, and an applicable Ethics Committee or Institutional Review Board.  It is understood that 
this information will not be disclosed to others without written authorization from Roche except to the 
extent necessary to obtain informed consent from persons to whom the drug may be administered. 
Tiragolumab and Atezolizumab—F. Hoffmann-La Roche Ltd 
Protocol WO42017, Version 8 
PROTOCOL 
TITLE: 
A PHASE II, SAFETY, AND EFFICACY STUDY 
OF TIRAGOLUMAB PLUS ATEZOLIZUMAB AND 
ATEZOLIZUMAB MONOTHERAPY IN PATIENTS 
WITH METASTATIC AND/OR RECURRENT 
PD-L1POSITIVE CERVICAL CANCER 
PROTOCOL NUMBER: 
WO42017 
VERSION NUMBER: 
8 
EUDRACT NUMBER: 
2019-004895-21 
IND NUMBER: 
147026 
NCT NUMBER: 
NCT04300647 
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. 


Tiragolumab and Atezolizumab—F. Hoffmann-La Roche Ltd 
2/Protocol WO42017, Version 8 
PROTOCOL HISTORY 
 
Protocol 
Associated Region-Specific Protocol 
Version 
Date Final 
Region 
Version 
Date Final 
8 
See electronic date stamp on the 
final page of this document. 
 
 
 
7 
11 Feb 2023 
 
 
 
6 
21 December 2022 
 
 
 
5 
16 February 2022 
 
 
 
4 
25 March 2021 
 
 
 
3 
8 January 2021 
 
 
 
2 
19 June 2020 
 
 
 
1 
23 December 2019 
VHP 
1 
12 May 2020 
VHP  Voluntary Harmonization Procedure. 


 
Tiragolumab and Atezolizumab—F. Hoffmann-La Roche Ltd 
3/Protocol WO42017, Version 8 
PROTOCOL AMENDMENT, VERSION 8: 
RATIONALE 
Protocol WO42017 Version 8 has been amended to extend the study timeline and 
recommend the removal of further assessment of imaging scans by Independent Review 
Committee (IRC).  Substantive changes to the protocol, along with a rationale for each 
change, are summarized below: 
• 
The synopsis has been simplified to align with current protocol guidelines. 
• 
The list of approved indications for atezolizumab has been updated to include 
alveolar soft part sarcoma (Section 1.7). 
• 
Language has been added to state that further imaging scans do not need to be 
assessed by the IRC because the Sponsor has decided no additional assessments 
are necessary (Sections 3.1.1, 4.5.6, 6.4.1, 6.4.2.1, 6.4.2.2, 6.4.2.4, and 9.5, 
Appendix 2). 
• 
The post-trial access language has been updated to state that, as the study is 
nearing closure and the patients will be transitioning to the continued access 
program, the timing of the end of the study and the length of the study has been 
extended to allow additional time for the last patient still on the study to transition 
into continued access program (Section 3.2). 
• 
The medical term “Wegener granulomatosis” has been replaced by the 
term “granulomatosis with polyangiitis” to align with the updated preferred term in 
MedDRA (Section 4.1.2). 
• 
Collection of information on long-term survival follow-up after treatment 
discontinuation has been removed as it will no longer be needed, in order to reduce 
site burden as the protocol analysis has been conducted (Section 4.6.1, 
Appendix 1). 
• 
The pharmacokinetic, immunogenicity, and biomarker sample collection schedule 
has been changed so that samples are no longer collected at treatment 
discontinuation visit or disease progression visit because the Sponsor has decided 
no additional sample collection is needed (Appendix 2). 
• 
The adverse event management guidelines have been updated to align with the 
Atezolizumab Investigator’s Brochure, Version 20 and Tiragolumab Investigator’s 
Brochure, Version 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. 
 
 


Tiragolumab and Atezolizumab—F. Hoffmann-La Roche Ltd 
4/Protocol WO42017, Version 8 
TABLE OF CONTENTS 
PROTOCOL AMENDMENT ACCEPTANCE FORM .......................................... 11 
PROTOCOL SYNOPSIS .................................................................................... 12 
1. 
BACKGROUND ............................................................................ 21 
1.1 
Background on Cervical Cancer .............................................. 21 
1.2 
TIGIT Pathway in Cancer as a Potential 
Anti-Cancer Therapy ................................................................ 22 
1.3 
PD-L1/PD-1 Pathway in Cancer .............................................. 22 
1.4 
PD-L1/PD-1 Inhibition in Viral-Associated Tumors .................. 23 
1.5 
Combined Inhibition of the Tigit and PD-L1/PD-1 Pathways 
as a Potential Anti-Cancer Therapy ......................................... 24 
1.6 
Background on Tiragolumab .................................................... 24 
1.6.1 
Preclinical Data with Tiragolumab ............................................ 25 
1.6.2 
Clinical Experience with Tiragolumab ...................................... 26 
1.6.2.1 
Ongoing Clinical Studies with Tiragolumab ............................. 26 
1.6.2.2 
Clinical Safety of Tiragolumab ................................................. 26 
1.6.2.3 
Clinical Pharmacokinetics and Immunogenicity of 
Tiragolumab and Atezolizumab ............................................... 28 
1.7 
Background on Atezolizumab .................................................. 29 
1.8 
Study Rationale and BenefitRisk Assessment ....................... 30 
2. 
OBJECTIVES AND ENDPOINTS ................................................. 32 
2.1 
Efficacy Objectives .................................................................. 32 
2.1.1 
Primary Efficacy Objective ....................................................... 32 
2.1.2 
Secondary Efficacy Objective .................................................. 32 
2.2 
Safety Objective ....................................................................... 33 
2.3 
Pharmacokinetic Objective ...................................................... 33 
2.4 
Immunogenicity Objectives ...................................................... 33 
............................................................... 33 
3. 
STUDY DESIGN ........................................................................... 34 
3.1 
Description of the Study ........................................................... 34 
3.1.1 
Overview of Study Design........................................................ 34 


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3.1.2 
Treatment after Disease Progression ...................................... 37 
3.1.3 
Safety Monitoring ..................................................................... 37 
3.1.4 
Internal Monitoring Committee ................................................. 37 
3.2 
End of Study and Length of Study ........................................... 38 
3.3 
Rationale for Study Design ...................................................... 38 
3.3.1 
Rationale for Atezolizumab Dose and Schedule ...................... 38 
....................... 38 
....... 39 
3.3.4 
Rationale for Open-Label Study ............................................... 39 
.................................... 39 
3.3.5.1 
Rationale for Collection of Mandatory Archival and/or 
Pretreatment Biopsy Tumor Specimens .................................. 40 
3.3.5.2 
Rationale for Collection of Blood Samples for 
Biomarker Analyses ................................................................. 41 
3.3.5.3 
Rationale for Next-Generation Sequencing, Whole 
Genome Sequencing, or Whole Exome Sequencing in 
Tumor and/or Blood Samples .................................................. 41 
3.3.6 
Rationale for Allowing Patients to Continue Study 
Treatment beyond Disease Progression per RECIST v1.1 ...... 42 
4. 
MATERIALS AND METHODS ...................................................... 42 
4.1 
Patients .................................................................................... 42 
4.1.1 
Inclusion Criteria ...................................................................... 42 
4.1.2 
Exclusion Criteria ..................................................................... 45 
4.2 
Method of Treatment Assignment ............................................ 47 
4.3 
Study Treatment and Other Treatments Relevant to the 
Study Design ........................................................................... 48 
4.3.1 
Study Treatment Formulation, Packaging, and Handling ......... 48 
4.3.1.1 
Tiragolumab ............................................................................. 48 
4.3.1.2 
Atezolizumab ........................................................................... 48 
4.3.2 
Study Treatment Dosage, Administration, and Compliance .... 48 
4.3.2.1 
Atezolizumab ........................................................................... 49 
4.3.2.2 
Tiragolumab and Atezolizumab ............................................... 50 
4.3.3 
Investigational Medicinal Product Accountability ..................... 51 
4.3.4 
Continued Access to Atezolizumab and/or Tiragolumab ......... 52 


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4.4 
Concomitant Therapy .............................................................. 53 
4.4.1 
Permitted Therapy ................................................................... 53 
4.4.2 
Cautionary Therapy for Atezolizumab-Treated Patients .......... 54 
4.4.2.1 
Corticosteroids, Immunosuppressive Medications, and 
TNF- Inhibitors ....................................................................... 54 
4.4.2.2 
Herbal Therapies ..................................................................... 54 
4.4.3 
Prohibited Therapy .................................................................. 54 
4.5 
Study Assessments ................................................................. 55 
4.5.1 
Informed Consent Forms and Screening Log .......................... 55 
4.5.2 
Medical History, Baseline Conditions, Concomitant 
Medication, and Demographic Data ......................................... 55 
4.5.3 
Physical Examinations ............................................................. 55 
4.5.4 
Vital Signs ................................................................................ 56 
4.5.5 
Performance Status ................................................................. 56 
4.5.6 
Tumor and Response Evaluations ........................................... 56 
4.5.7 
Laboratory, Biomarker, and Other Biological Samples ............ 58 
4.5.8 
Electrocardiograms .................................................................. 61 
4.6 
Treatment, Patient, Study, and Site Discontinuation ................ 61 
4.6.1 
Study Treatment Discontinuation ............................................. 61 
4.6.2 
Patient Discontinuation from the Study .................................... 62 
4.6.3 
Study Discontinuation .............................................................. 63 
4.6.4 
Site Discontinuation ................................................................. 63 
5. 
ASSESSMENT OF SAFETY ......................................................... 63 
5.1 
Safety Plan .............................................................................. 63 
5.1.1 
Risks Associated with Atezolizumab ........................................ 64 
5.1.2 
Risks Associated with Tiragolumab ......................................... 64 
5.1.2.1 
Infusion-Related Reactions ...................................................... 65 
.................................................... 65 
5.1.2.3 
Lymphopenia ........................................................................... 65 
5.1.2.4 
Immune-Mediated Adverse Events .......................................... 65 
.............................................................. 66 
5.1.3 
Risks Associated with Combination Use of Tiragolumab 
and Atezolizumab .................................................................... 66 
5.1.4 
Management of Adverse Events .............................................. 67 


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7/Protocol WO42017, Version 8 
5.1.4.1 
Dose Modifications .................................................................. 67 
5.1.4.2 
Treatment Interruption ............................................................. 67 
5.1.4.3 
Management Guidelines for Tiragolumab- and 
Atezolizumab-Specific Adverse Events ................................... 68 
5.2 
Safety Parameters and Definitions .......................................... 68 
5.2.1 
Adverse Events ........................................................................ 69 
5.2.2 
Serious Adverse Events (Immediately Reportable to 
the Sponsor) ............................................................................ 69 
5.2.3 
Adverse Events of Special Interest (Immediately 
Reportable to the Sponsor) ...................................................... 70 
5.3 
Methods and Timing for Capturing and Assessing 
Safety Parameters ................................................................... 71 
5.3.1 
Adverse Event Reporting Period .............................................. 71 
5.3.2 
Eliciting Adverse Event Information ......................................... 72 
5.3.3 
Assessment of Severity of Adverse Events ............................. 72 
5.3.4 
Assessment of Causality of Adverse Events............................ 73 
5.3.5 
Procedures for Recording Adverse Events .............................. 74 
5.3.5.1 
Infusion-Related Reactions and 
 
 ................................................................................ 74 
5.3.5.2 
Diagnosis versus Signs and Symptoms ................................... 75 
5.3.5.3 
Adverse Events That Are Secondary to Other Events ............. 75 
5.3.5.4 
Persistent or Recurrent Adverse Events .................................. 76 
5.3.5.5 
Abnormal Laboratory Values ................................................... 76 
5.3.5.6 
Abnormal Vital Sign Values ..................................................... 77 
5.3.5.7 
Abnormal Liver Function Tests ................................................ 77 
5.3.5.8 
Deaths ..................................................................................... 78 
5.3.5.9 
Preexisting Medical Conditions ................................................ 78 
5.3.5.10 
Lack of Efficacy or Worsening of Cervical Cancer ................... 79 
5.3.5.11 
Hospitalization or Prolonged Hospitalization ............................ 79 
5.3.5.12 
Cases of Accidental Overdose or Medication Error ................. 79 
5.3.5.13 
Safety Biomarker Data ............................................................. 81 
5.4 
Immediate Reporting Requirements from Investigator to 
Sponsor ................................................................................... 81 
5.4.1 
Emergency Medical Contacts .................................................. 81 


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5.4.2 
Reporting Requirements for Serious Adverse Events and 
Adverse Events of Special Interest .......................................... 82 
5.4.2.1 
Events That Occur prior to Study Treatment Initiation ............. 82 
5.4.2.2 
Events That Occur after Study Treatment Initiation ................. 82 
5.4.3 
Reporting Requirements for Pregnancies ................................ 82 
5.4.3.1 
Pregnancies in Female Patients .............................................. 82 
5.4.3.2 
Abortions.................................................................................. 83 
5.4.3.3 
Congenital Anomalies/Birth Defects ........................................ 83 
5.5 
Follow-Up of Patients after Adverse Events............................. 83 
5.5.1 
Investigator Follow-Up ............................................................. 83 
5.5.2 
Sponsor Follow-Up .................................................................. 84 
5.6 
Adverse Events That Occur after the Adverse Event 
Reporting Period ...................................................................... 84 
5.7 
Expedited Reporting to Health Authorities, Investigators, 
Institutional Review Boards, and Ethics Committees ............... 84 
6. 
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN ......... 85 
6.1 
Determination of Sample Size ................................................. 85 
............................................................... 86 
6.2 
Summaries of Conduct of Study .............................................. 87 
6.3 
Summaries of Demographic and Baseline Characteristics ...... 87 
6.4 
Efficacy Analyses ..................................................................... 87 
6.4.1 
Primary Efficacy Endpoint ........................................................ 87 
6.4.2 
Secondary Efficacy Endpoints ................................................. 88 
6.4.2.1 
Duration of Response .............................................................. 88 
6.4.2.2 
Disease Control Rate ............................................................... 88 
6.4.2.3 
Best Clinical Response ............................................................ 89 
6.4.2.4 
Progression-Free Survival, Including the 6-Month 
Progression-Free Survival Rate ............................................... 89 
6.4.2.5 
Overall Survival, Including the 6-Month and 12-Month 
Overall Survival Rate ............................................................... 89 
.............................................. 89 
6.4.4 
Analyses of Exposure, Adverse Event, Laboratory, and 
Vital Sign Data ......................................................................... 89 
6.5 
Safety Analyses ....................................................................... 90 


Tiragolumab and Atezolizumab—F. Hoffmann-La Roche Ltd 
9/Protocol WO42017, Version 8 
6.6 
Pharmacokinetic Analyses ....................................................... 90 
6.7 
Immunogenicity 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 
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 .................................................................... 94 
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 
 


Tiragolumab and Atezolizumab—F. Hoffmann-La Roche Ltd 
10/Protocol WO42017, Version 8 
LIST OF TABLES 
Table 1 
Administration of First and Subsequent Atezolizumab 
Monotherapy Infusions ................................................................ 49 
Table 2 
Administration of First and Subsequent Tiragolumab and 
Atezolizumab Infusions ............................................................... 50 
Table 3 
Adverse Event Severity Grading Scale for Events Not 
Specifically Listed in NCI CTCAE ............................................... 72 
...... 73 
Table 5 
Causal Attribution Guidance ....................................................... 74 
Table 6 
Overall Statistical Power in the Comparison of ORR in 
Tiragolumab in Combination with Atezolizumab Arm to a 
Reference Point of 14.6% ........................................................... 86 
Table 7 
Probability of Observed ORR in Atezolizumab Monotherapy 
Arm Greater than a Reference Point at the Final Analysis for 
ORR ............................................................................................ 86 
 
.... 87 
.... 92 
LIST OF FIGURES 
Figure 1 
Study Schema ............................................................................. 35 
LIST OF APPENDICES 
Appendix 1 
Schedule of Activities ................................................................ 104 
Appendix 2 
Schedule of Pharmacokinetic, Immunogenicity, and 
Biomarker Samples ................................................................... 109 
Appendix 3 
Response Evaluation Criteria in Solid Tumors, 
Version 1.1 (RECIST v1.1)........................................................ 110 
Appendix 4 
Eastern Cooperative Oncology Group Performance Status 
Scale ......................................................................................... 119 
Appendix 5 
Preexisting Autoimmune Diseases and Immune Deficiencies .. 120 
Appendix 6 
Anaphylaxis Precautions ........................................................... 121 
Appendix 7 
Risks Associated with Atezolizumab and Guidelines for 
Management of Adverse Events Associated with 
Tiragolumab and/or Atezolizumab ............................................ 122 


Tiragolumab and Atezolizumab—F. Hoffmann-La Roche Ltd 
11/Protocol WO42017, Version 8 
PROTOCOL AMENDMENT ACCEPTANCE FORM 
TITLE: 
A PHASE II, SAFETY, AND EFFICACY STUDY OF 
TIRAGOLUMAB PLUS ATEZOLIZUMAB AND 
ATEZOLIZUMAB MONOTHERAPY IN PATIENTS 
WITH METASTATIC AND/OR RECURRENT 
PD-L1POSITIVE CERVICAL CANCER 
PROTOCOL NUMBER: WO42017 
VERSION NUMBER: 
8 
EUDRACT NUMBER: 
2019-004895-21 
IND NUMBER: 
147026 
NCT NUMBER: 
NCT04300647 
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. 
 


Tiragolumab and Atezolizumab—F. Hoffmann-La Roche Ltd 
12/Protocol WO42017, Version 8 
PROTOCOL SYNOPSIS 
TITLE: 
A PHASE II, SAFETY, AND EFFICACY STUDY OF 
TIRAGOLUMAB PLUS ATEZOLIZUMAB AND ATEZOLIZUMAB 
MONOTHERAPY IN PATIENTS WITH METASTATIC AND/OR 
RECURRENT PD-L1POSITIVE CERVICAL CANCER 
PROTOCOL NUMBER: 
WO42017 
VERSION NUMBER: 
8 
EUDRACT NUMBER: 
2019-004895-21 
IND NUMBER: 
147026 
NCT NUMBER: 
NCT04300647 
TEST PRODUCTS: 
Atezolizumab (RO5541267) 
Tiragolumab (RO7092284) 
PHASE: 
Phase II 
INDICATION: 
Cervical cancer 
SPONSOR: 
F. Hoffmann-La Roche Ltd 
 
STUDY RATIONALE 
This Phase II study will evaluate the efficacy and safety of tiragolumab in combination with 
atezolizumab and atezolizumab monotherapy in patients with metastatic and/or recurrent 
programmed death -ligand 1 (PD-L1)-positive (tumor cells and tumor associated immune cells 
 cervical carcinoma. 
 
Primary Objective 
Corresponding Endpoint  
 To evaluate the efficacy of tiragolumab 
in combination with atezolizumab and 
of atezolizumab monotherapy 
 Objective response rate (ORR), defined as the 
proportion of patients with a complete response (CR) 
or a partial response (PR) on two consecutive 
occasions  4 weeks apart, as determined by an 
independent review committee (IRC) according to 
Response Evaluation Criteria in Solid Tumors, 
Version 1.1 (RECIST v1.1). Imaging scans do not 
need to be assessed by IRC. 


Tiragolumab and Atezolizumab—F. Hoffmann-La Roche Ltd 
13/Protocol WO42017, Version 8 
Secondary Objective 
Corresponding Endpoints  
 To evaluate the efficacy of tiragolumab 
in combination with atezolizumab and 
of atezolizumab 
 
Duration of response (DOR), defined as the time 
from the first occurrence of a documented 
objective response to disease progression or 
death from any cause (whichever occurs first), as 
determined by the IRC according to RECIST v1.1 
 
Disease control rate (DCR), defined as the 
proportion of patients with a CR, PR, or stable 
disease (SD), as determined by an IRC according 
to RECIST v1.1 
 
Best clinical response rate (BCR), defined as the 
proportion of patients with a CR, PR, or SD, and 
the DOR as clinically determined by the 
investigator 
 
Progression-free survival (PFS) after 
randomization, defined as the time from 
randomization to the first occurrence of disease 
progression, as determined by the IRC according 
to RECIST v1.1, or death from any cause, 
whichever occurs first 
 
Overall survival (OS) after randomization, defined 
as the time from randomization to death from 
any cause 
 
OS rate at 6 months and 12 months, defined as 
the proportion of patients who have not 
experienced death from any cause at 6 months 
and 12 months post-randomization, respectively 
– 
Imaging scans do not need to be assessed 
by IRC. 
Safety Objective 
Corresponding Endpoint 
 To evaluate the safety and tolerability 
of tiragolumab in combination with 
atezolizumab and of atezolizumab 
monotherapy 
 
Incidence and severity of adverse events, with 
severity determined according to National Cancer 
Institute (NCI) Common Terminology Criteria for 
Adverse Events, Version 5.0 (CTCAE v5.0) 
– 
 
 
 
 


Tiragolumab and Atezolizumab—F. Hoffmann-La Roche Ltd 
14/Protocol WO42017, Version 8 
Pharmacokinetic objective 
Corresponding Endpoints 
 To characterize the pharmacokinetics 
of tiragolumab and atezolizumab 
 
Serum concentrations of tiragolumab at specified 
timepoints 
 
Serum concentrations of atezolizumab at specified 
timepoints 
Immunogenicity objective 
Corresponding Endpoints 
 To evaluate the immune response to 
tiragolumab and atezolizumab 
 
Prevalence of anti-drug antibodies (ADAs) at 
baseline and incidence of ADAs to tiragolumab 
and to atezolizumab during the study 
 
 
 
 
OVERALL DESIGN AND STUDY POPULATION 
This Phase II, global, open-label, randomized study is designed to evaluate the efficacy and 
safety of tiragolumab in combination with atezolizumab and of atezolizumab monotherapy in 
patients with metastatic and/or recurrent PD-L1positive cervical cancer after progression or 
recurrence from at least one platinum-based but no more than two prior systemic therapies. 
Approximately 160 patients will be enrolled in the global enrollment phase of this study.  Women 
with Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1 who have 
metastatic and/or recurrent PD-L1positive cervical cancer are eligible. 
Additional patients may be subsequently randomized 
, 
 
 
 


Tiragolumab and Atezolizumab—F. Hoffmann-La Roche Ltd 
15/Protocol WO42017, Version 8 
 
Screening Period  
After providing informed consent, patients will undergo screening procedures as outlined in the 
schedule of activities.  Patients who do not meet the criteria for participation in this study 
(screen failure) may qualify for an additional two re-screening opportunities (for a total of three 
screenings per participant) at the investigator's discretion.  Patients are not required to re-sign 
the consent form if they are rescreened within 60 days after previously signing the consent 
form.  The investigator will record reasons for screen failure in the screening log. 
During screening, tumor specimens from each potentially eligible patient will be prospectively 
tested for PD-L1 expression, as assessed by a central laboratory, using the 
 
.  Only patients who are 
PD-L1positive with
will be enrolled. 
 
Treatment Period 
Eligible patients will be randomized in a 3:1 ratio to receive either tiragolumab in combination 
with atezolizumab or atezolizumab alone. 
Eligible patients will be stratified by ECOG Performance Status (0 versus 1), prior use of 
chemoradiotherapy or radiotherapy (yes versus no), and treatment history (persistent versus 
recurrent disease). 
In the doublet arm, patients will receive atezolizumab at a fixed dose of 1200 mg administered 
by IV infusion every 3 weeks (Q3W) on Day 1 of each 21-day cycle, followed by tiragolumab at 
a fixed dose of 600 mg administered by IV infusion Q3W also on Day 1 of each 21-day cycle. 
In the atezolizumab monotherapy arm, patients will receive atezolizumab at a fixed dose of 
1200 mg administered by IV infusion Q3W on Day 1 of each 21-day cycle. 
Treatment may be continued as long as patients are experiencing clinical benefit, as assessed 
by the investigator, in the absence of unacceptable toxicity or symptomatic deterioration 
attributed to disease progression after an integrated assessment of radiographic data, biopsy 
results (if available), and clinical status.  Patients who meet the criteria for equivocal disease 
progression per RECIST v1.1 will be permitted to continue treatment (tiragolumab in 
combination with atezolizumab or atezolizumab alone) if they meet all of the criteria specified. 
During the study, serum samples will be collected to monitor tiragolumab in combination with 
atezolizumab and atezolizumab pharmacokinetics and to detect the presence of antibodies to 
tiragolumab and atezolizumab.  Patient samples, including archival and fresh tumor tissue, 
serum, plasma, and blood samples, will also be collected for 
 
assessments. 
Patients will undergo tumor assessments at baseline and every 6 weeks (  7 days) for 
48 weeks following Day 1 of Cycle 1 regardless of treatment delays.  After the completion of the 
Week 48 tumor assessment, tumor assessments will be required every 9 weeks (  7 days) 
regardless of treatment delays until unequivocal radiographic disease progression per 
RECIST v1.1 (or loss of clinical benefit for patients who continue study treatment after disease 
progression per RECIST v1.1), withdrawal of consent, death, or study termination by the 
Sponsor, whichever occurs first.  Patients who are treated beyond disease progression per 
RECIST v1.1 will undergo tumor assessments at the frequency described above until study 
treatment is discontinued.  Patients who discontinue treatment for reasons other than 
radiographic disease progression per RECIST v1.1 (e.g., toxicity, symptomatic deterioration) will 
continue scheduled tumor assessments at the frequency described above until radiographic 
disease progression per RECIST v1.1, withdrawal of consent, death, or study termination by the 
Sponsor, whichever occurs first.  In the absence of radiographic disease progression per 
RECIST v1.1, tumor assessments should continue regardless of whether a patient starts a new 
anti-cancer therapy. 
Response will be assessed according to RECIST v1.1.  Objective response was previously 
determined at a single timepoint by the IRC according to RECIST v1.1.  Imaging scans do not 
need to be assessed by IRC. 
Crossover is allowed from the atezolizumab monotherapy arm to the tiragolumab plus 
atezolizumab arm after unequivocal progressive disease has been recorded during 
atezolizumab monotherapy, at the discretion of the investigator and after consultation with the 


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Medical Monitor.  For patients who crossover from atezolizumab monotherapy to tiragolumab 
plus atezolizumab, the tumor assessment just preceding crossover will serve as a rebaseline 
scan against which all subsequent scans will be compared. 
After initiation of study treatment, all adverse events will be reported according to the adverse 
event reporting period.  After this period, all deaths should continue to be reported.  In addition, 
the Sponsor should be notified if the investigators become aware of any serious adverse events 
or adverse events of special interest that are believed to be related to prior treatment with study 
drug(s).  These events should be reported using the Adverse Event electronic Case Report 
Form (eCRF).  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 protocol-related procedures until 
a final outcome can be reported. 
After study treatment discontinuation, survival follow -up information will no longer be collected. 
 
Treatment after Disease Progression 
During the study, patients who meet criteria for disease progression per RECIST v1.1 and show 
evidence of clinical benefit may continue study treatment at the investigator’s discretion 
provided that the patients meet all of the following criteria: 
 
Evidence of clinical benefit, as assessed by the investigator  
 
Absence of symptoms and signs (including worsening of laboratory values indicating 
unequivocal progression of disease)  
 
No 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.  
 
End of Study 
The end of this study is defined as the date when the “last patient last visit” occurs (i.e., when 
the last patient has recorded her last visit).  The end of study has been extended until all 
patients on active treatment in the study roll over to the continued access program. 
At study closure, patients will still receive study treatment through the continued access 
program. 
 
Several key aspects of the study design and study population are summarized below.  
Phase: 
Phase II 
Population Type: Adults 
Control Method: 
None 
Population 
Diagnosis or 
Condition: 
Histologically confirmed recurrent 
or persistent squamous cell 
carcinoma, adenosquamous 
carcinoma, or adenocarcinoma of 
the cervix (neuroendocrine, clear 
cell, and sarcoma histologies are 
not allowed) after progression  on 
or after 12 lines of prior systemic 
chemotherapy in the 
metastatic/recurrent setting that is 
not amenable to curative treatment 
with systemic chemotherapy, 
surgery, and/or radiotherapy 
– 
At least one prior line of 
platinum-based systemic 
chemotherapy 
– 
Radiosensitizing 
cisplatin given with 


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radiotherapy is not 
considered a line of 
systemic 
chemotherapy 
Interventional 
Model: 
Double group Population Age:  18 years 
Test Products: 
Atezolizumab 
Tiragolumab 
Site 
Distribution: 
Multi-site and multi-region 
Active 
Comparator: 
Not applicable Study Treatment 
Assignment 
Method: 
Not applicable 
Number of Arms: 
Two 
Number of 
Participants to 
Be Enrolled: 
160 
 
STUDY TREATMENT 
In the doublet arm, a fixed dose of 1200 mg atezolizumab will be administered by IV infusion 
every 3 weeks (Q3W) on Day 1 of each 21-day cycle, followed by tiragolumab at a fixed dose of 
600 mg administered by IV infusion Q3W also on Day 1 of each 21-day cycle. In the 
atezolizumab monotherapy arm, atezolizumab will be administered at a fixed dose of 1200 mg 
by IV infusion Q3W on Day 1 of each 21-day cycle. 
 
DURATION OF PARTICIPATION 
The total length of the study, from screening of the first patient to the end of the study, is 
expected to be approximately 
 months. 
 
COMMITTEES 
Independent Committees: Independent review committee (IRC) 
Other Committees: 
Internal Monitoring Committee (IMC) 
 
 
 


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Definition 
ADA 
anti-drug antibody 
ADCC 
antibody-dependent cell-mediated cytotoxicity 
ASTCT 
American Society for Transplantation and Cellular Therapy  
BCR 
best clinical response 
CE-IVD 
Conformité EuropéenneIn Vitro Diagnostic 
CIN 
cervical intraepithelial neoplasia 
CIT 
cancer immunotherapy  
COVID-19 
coronavirus disease 2019 
CPS 
combined positive score  
CR 
complete response 
CRS 
cytokine release syndrome 
CT 
computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
DCR 
disease control rate 
DLT 
dose-limiting toxicity 
DOR 
duration of response 
EAE 
experimental autoimmune encephalitis 
EC 
Ethics Committee 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic Case Report Form 
EDC 
electronic data capture 
EORTC 
European Organisation for Research and Treatment  
of Cancer 
Fc 
fragment crystallizable 
FDA 
(U.S.) Food and Drug Administration 
FFPE 
formalin-fixed, paraffin-embedded 
FIGO 
Fédération Internationale de Gynécologie et d’Obstétrique  
HIPAA 
Health Insurance Portability and Accountability Act 


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Abbreviation 
Definition 
HLH 
hemophagocytic lymphohistiocytosis 
HPV 
human papilloma virus 
IC 
immune cell 
ICH 
International Council for Harmonisation 
IFN 
Interferon 
IHC 
immunohistochemistry  
IL 
interleukin 
IMC 
Internal Monitoring Committee 
IMP 
investigational medicinal product 
IND 
Investigational New Drug (Application) 
IRB 
Institutional Review Board 
IRC 
independent review committee 
IRR 
infusion-related reaction 
IVD 
in vitro diagnostic 
IxRS 
interactive voice or web-based response system 
MAb 
monoclonal antibody 
MAS 
macrophage activation syndrome 
MRI 
magnetic resonance imaging 
MTD 
maximum tolerated dose 
NCCN 
National Comprehensive Cancer Network 
NCI 
National Cancer Institute 
NGS 
next-generation sequencing 
NK 
natural killer (cell) 
NSCLC 
nonsmall cell lung cancer 
ORR 
objective response rate 
OS 
overall survival 
PCR 
polymerase chain reaction 
PD-1 
programmed death1 
PD-L1 
programmed deathligand 1 
PET 
positron emission tomography 
PFS 
progression-free survival 
PK 
pharmacokinetic 
PR 
partial response 
PVR 
poliovirus receptor 
Q3W 
every 3 weeks 
RECIST v1.1 
Response Evaluation Criteria in Solid Tumors, Version 1.1 
SARS-CoV-2 
severe acute respiratory syndrome coronavirus 2 


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Abbreviation 
Definition 
SITC 
Society for Immunotherapy of Cancer 
SD 
stable disease 
T3 
triiodothyronine 
TC 
tumor cell 
TIC 
tumor cells and tumor-associated immune cells 
TIGIT 
T-cell immunoreceptor with Ig and ITIM domains  
TNF(-) 
tumor necrosis factor() 
TPS 
tumor proportion score 
TTE 
transthoracic echocardiogram 
ULN 
upper limit of normal 
VCA 
viral-capsid antigen 
VHP 
Voluntary Harmonization Procedure 
 
 


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1. 
BACKGROUND 
1.1 
BACKGROUND ON CERVICAL CANCER 
Cervical cancer is the fourth most frequently diagnosed cancer and the fourth leading 
cause of cancer-related death globally.  More than 569,847 women are diagnosed with 
cervical cancer annually worldwide, resulting in more than 311,365 deaths (Bray et al. 
2018).  Almost 90% of cervical cancer deaths occur in developing countries.  In the 
United States, there are 13,000 new cases of invasive cervical cancer and 
approximately 4000 cancer related deaths each year (American Cancer Society 2016).  
About a fifth of all global cervical cancer cases in 2018 occurred in China; approximately 
106,000 new cases and 48,000 deaths from the disease occurred in China (Arbyn et al. 
2020). 
Treatment for early stage (Fédération Internationale de Gynécologie et d’Obstétrique 
[FIGO] Stages IA1 to IB1) and locally advanced (FIGO Stages IB2 to IVA) cervical 
cancer consists of surgery and definitive chemoradiotherapy, respectively, and can be 
quite effective in eliciting a remission.  However, if cancer recurs or fails to resolve with 
primary treatment, prognosis is quite poor with 5-year survival rates of approximately 
15%, which is comparable to that of patients with de novo metastatic (Stage IVB) 
disease (American Cancer Society 2016).  With few exceptions, the standard of care for 
recurrent, persistent, or de novo metastatic disease is chemotherapy plus bevacizumab 
based on the Gynecology Oncology Group 240 trial, which showed that bevacizumab 
added to chemotherapy improved median overall survival (OS) compared with 
chemotherapy alone (17 vs. 13.3 months, respectively) (Tewari et al. 2014). 
Currently, no globally-accepted standard of care exists after recurrence or progression 
on chemotherapy plus bevacizumab.  As such, treatment options for these patients 
largely comprise various cytotoxic chemotherapy agents, administered as either a single 
agent or in combination.  However, given the historically low response rates of 
approximately 10%15%, increasing focus has been given to whether cytotoxic 
chemotherapies represent an acceptable standard of care over best supportive care 
given the impact and burden such agents can impart on patient quality of life. 
Cervical cancer has been identified to be a direct consequence of infections by specific 
high-risk genotypes of human papilloma virus (HPV), most commonly HPV16 and 
HPV18 (Clifford et al. 2003; Mayadev et al. 2019).  The notion that immune cells (ICs) 
can control HPV infections has been supported by results from studies showing 
spontaneous regression of HPV papillomas, and conversely other studies showing 
increased rates of HPV-related cancers among immunosuppressed and 
immune-deficient patients (Kadish et al. 2002; Lyford-Pike et al. 2013; Tong et al. 2015).  
The dynamic immune response to viral infections involves a balance of activating and 
deactivating signals with epitopes of viral peptides identified on antigen-presenting cells.  
Historically low efficacy rates of existing therapies, coupled with the engagement of the 


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immune response owing to HPV infection of the cervical epithelial cells, makes cervical 
cancer a particularly attractive opportunity for novel immunotherapy-based approaches. 
1.2 
TIGIT PATHWAY IN CANCER AS A POTENTIAL 
ANTI-CANCER THERAPY 
T-cell immunoreceptor with Ig and ITIM domains (TIGIT) is a novel immune inhibitory 
receptor that is a member of the immunoglobulin super family (Yu et al. 2009; 
Manieri et al. 2017).  TIGIT is expressed on the surface of activated T-cell and natural 
killer (NK)-cell subsets and interacts with high affinity with CD155 (also known as 
poliovirus receptor [PVR]) (Yu et al. 2009).  Genetic ablation of TIGIT in T cells in mice 
results in exacerbated T-cell responses in nonclinical models of autoimmune and viral 
infections, demonstrating the role of TIGIT in inhibiting T-cell responses (Joller et al. 
2011; Johnston et al. 2014).  TIGIT expression is elevated in the tumor 
microenvironment in many human tumors, is co-expressed with other checkpoint 
immune receptors such as programmed death1 (PD-1), and is associated with impaired 
T-cell function and anti-tumor immunity (Johnston et al. 2014).  Activation of TIGIT on 
T cells and NK cells limits cellular proliferation, effector cytokine production, and killing of 
target tumor cells (TCs) (Stanietsky et al. 2009; Yu et al. 2009; Johnston et al. 2014; 
Wang et al. 2015; Manieri et al. 2017). 
TIGIT is expressed in a wide variety of human tumors, including most solid tumors, such 
as nonsmall cell lung cancer (NSCLC), breast cancer, and melanoma, and is highly 
correlated with T-cell infiltration and programmed deathligand 1 (PD-1) expression 
(Johnston et al. 2014).  Fluorescence-activated cell sorting analysis of fresh tumor 
samples showed that TIGIT and PD-1 are also co-expressed on tumor-infiltrating T cells.  
TIGIT expression ranges from 30% to 80% and from 50% to 80% on tumor-infiltrating 
CD4 and CD8 T cells, respectively (Johnston et al. 2014).  High expression of 
TIGIT-positive ICs has also been reported in cervical cancer samples by both IHC and 
by RNA sequencing (Cattaruzza et al. 2017; Anderson et al. 2019).  High expression of 
TIGIT in immune-infiltrating cells in cervical cancer may have prognostic significance as 
well (Wang et al. 2019).  The TIGIT ligand PVR is also reported to be highly expressed 
in infiltrating NK cells in cervical cancer as compared to NK cells in normal cervical 
tissue (Textor et al. 2008). 
1.3 
PD-L1/PD-1 PATHWAY IN CANCER 
Programmed deathligand 1 (PD-L1) is a cell surface protein that is broadly expressed 
by TCs and tumor-infiltrating ICs in many human cancers, including cervical cancer.  
PD-L1 binds to PD-1 and B7.1, two known inhibitory receptors whose expression on 
activated T cells is sustained in states of chronic stimulation such as chronic infection or 
cancer (Blank et al. 2005; Keir et al. 2008).  Ligation of PD-L1 with PD-1 or B7.1 inhibits 
T-cell proliferation, cytokine production, and cytolytic activity, leading to a functional 
inactivation or inhibition of T cells.  Aberrant expression of PD-L1 on T cells has been 
reported to impede anti-tumor immunity, resulting in immune evasion (Blank and 


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Mackensen 2007).  Therefore, interruption of the PD-L1/PD-1 and PD-L1/B7.1 pathways 
represent an attractive strategy to reinvigorate tumor-specific T-cell immunity. 
Neoantigens, such as cancer antigens or viral antigen in HPV-related cancer, are 
recognized by T cells by means of antigen-presenting cells, leading to T-cell activation. 
Immunotolerance in the tumoral microenvironment includes PD-1 overexpression on 
tumoral-infiltrating lymphocytes and PD-L1 overexpression on TCs, leading to the 
inhibition of activated effector T cells, through inhibitory checkpoint signals.  By inhibiting 
the interaction between PD-1 and PD-L1, antiPD-1/PD-L1 antibodies block the 
inhibitory checkpoint signals and restore endogenous anti-tumor immunity. 
Therapeutic blockade of the PD-1/PD-L1 interaction has demonstrated modest, yet 
sustained disease control in cervical cancer.  Indeed, pembrolizumab monotherapy for 
patients with recurrent, metastatic cervical cancer produced a response rate of  15%, 
whereas nivolumab monotherapy also resulted in a comparable response rate of 
approximately 20% (Chung et al. 2019; Naumann et al. 2019).  While these response 
rates were modest, the totality of evidence, including disease control, duration of 
response (DOR), and safety profile, led to the U.S. Food and Drug Administration’s 
(FDA’s) accelerated approval of pembrolizumab for the treatment of metastatic/recurrent 
cervical cancer in 2018 (Keytruda U.S. Package Insert).  Despite this regulatory 
approval, the efficacy of this monotherapy approach leaves much room for improvement. 
Because of this, antagonists that target additional inhibitory receptors have the potential 
to enhance such anti-tumor T-cell responses.  One approach has been to combine 
antiPD-1 with anti-cytotoxic T lymphocyteassociated protein 4 (antiCTLA-4) 
(Naumann et al. 2019).  Although the observed improvement in response rate supported 
this immune doublet strategy, the tolerability of this particular immune doublet was 
challenging.  Refining and testing other co-inhibitory antagonists have emerged as 
attractive combination partners for antiPD-L1/PD-1 on the basis of their complementary 
mechanism of action. 
1.4 
PD-L1/PD-1 INHIBITION IN VIRAL-ASSOCIATED TUMORS 
There is a strong rationale for adopting an immunotherapeutic approach to treating 
cervical cancer given the prevalence of HPV tumorigenesis and associated viral antigen 
production.  A higher expression of PD-L1 has been described in virus-induced cancers, 
including cervical cancer (Chung et al. 2019), and an upregulation of PD-1 and PD-L1 
has been observed in high-risk HPV-related cervical intraepithelial neoplasia (Crafton 
and Salani 2016). 
The viral reactive T cells in patients with cervical cancer with chronic HPV are key, as 
anti-tumor immunity may be driven by these T cells, in addition to T cells that are specific 
to tumor-associated antigens.  Two important viral proteins, E6 and E7, are directly 
responsible for the development of HPV-induced tumorigenesis (Tomaic 2016).  
The presentation of viral antigens by APC activates naive T cells to proliferate and 


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differentiate into effector T cells and therefore initiates an HPV-specific immune 
response, recognizing and eliminating virus-infected cells. 
1.5 
COMBINED INHIBITION OF THE TIGIT AND PD-L1/PD-1 
PATHWAYS AS A POTENTIAL ANTI-CANCER THERAPY 
The inhibitory immunoreceptor TIGIT has been shown to limit the effector function of 
tumor-associated lymphocytes.  Activation of TIGIT on T cells and NK cells limits 
proliferation, effector cytokine production, and killing of target TCs.  Therefore, TIGIT 
acts to limit anti-tumor immune responses in the context of the tumor microenvironment.  
Interference with TIGITPVR interaction may enhance the magnitude and quality of the 
tumor-specific T-cell responses through increased expansion of T cells as well as 
improved T-cell priming and/or effector function.  Because TIGIT and PD-1 are 
coordinately expressed by infiltrating T cells in several human tumors, inhibition of the 
TIGIT/PVR pathways may complement and potentiate the anti-tumor activity of a PD-L1 
pathway inhibitor such as atezolizumab. 
In preclinical models, concomitant blockade of both TIGIT and PD-L1/PD-1 pathways 
demonstrated superior efficacy over the respective single-agent treatments.  In one such 
preclinical model, tumor-infiltrating T cells demonstrate increased interferon (IFN)- 
expression (a hallmark of activation and anti-tumor activity of T cells) only when both 
TIGIT and PD-1 are blocked concurrently and not when each individual pathway is 
blocked by the respective single-agent treatment.  Notably, co-inhibition of TIGIT and 
PD-L1 in this syngeneic tumor model was not associated with loss of body weight or any 
other observable adverse responses. 
On the basis of these preclinical studies, this study hypothesizes that the combination of 
anti-TIGIT antibody with antiPD-L1/PD-1 therapy may result in activation of anti-tumor 
immune responses, leading to enhanced killing of TCs and improved clinical responses 
in patients with metastatic cervical cancer than with either agent alone. 
1.6 
BACKGROUND ON TIRAGOLUMAB  
Tiragolumab is a fully human IgG1/monoclonal antibody (MAb) that binds TIGIT and 
prevents its interaction with PVR.  The recombinant antibody is produced in Chinese 
hamster ovary cells and consists of two heavy chains (456 amino acid residues each) 
and two light chains (220 amino acid residues each).  There are two N-linked 
glycosylation sites (Asn306) in the fragment crystallizable (Fc) domain.  The predicted 
molecular weight of tiragolumab is 148,409 Da (peptide chains only, without heavy chain 
C-terminal lysine residue). 
Tiragolumab is being investigated in clinical studies as a potential therapy against 
various tumor types.  Refer to the Tiragolumab Investigator’s Brochure for additional 
details on the preclinical and clinical studies for tiragolumab. 


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1.6.1 
Preclinical Data with Tiragolumab 
The preclinical strategy for tiragolumab was to demonstrate in vitro and in vivo 
pharmacology, to evaluate the pharmacokinetic (PK) profile, to demonstrate an 
acceptable safety profile, and to identify a Phase Ia and Phase Ib starting dose for 
tiragolumab.  Comprehensive pharmacology, PK, and toxicology evaluations were thus 
undertaken with tiragolumab. 
The completed preclinical pharmacology studies demonstrate that tiragolumab binds to 
TIGIT and prevents TIGITPVR interactions.  Tiragolumab is a human IgG1 MAb and 
therefore binds to Fc receptors and is capable of mediating antibody-dependent 
cell-mediated cytotoxicity (ADCC).  However, neither complement-dependent cytotoxicity 
nor increased cytokine release were detected in the nonclinical models following 
tiragolumab treatment compared with the control-treated models.  In the CT26 syngeneic 
colon tumor model, co-inhibition of the TIGIT/PVR and PD-L1/PD-1 pathways improves 
anti-tumor activity compared with inhibition of only one pathway with either monotherapy 
in the absence of loss of body weight or any other observable adverse responses.  
Taken together, the data provide a rationale for evaluating the combination of anti-TIGIT 
with antiPD-L1 agents in clinical studies. 
Because tiragolumab does not cross-react with rodent TIGIT, the pharmacokinetics and 
toxicokinetics of tiragolumab were investigated in cynomolgus monkeys.  Overall, the 
preclinical PK behavior observed for tiragolumab is consistent with that expected for 
a receptor targeting human IgG1 MAb.  The pivotal repeat-dose toxicity study 
demonstrated that weekly IV administration of tiragolumab 
 
 was well tolerated in cynomolgus 
monkeys, and no findings were directly attributed to tiragolumab administration.  On the 
basis of the proposed mechanism of action of tiragolumab, possible safety risks to 
patients following TIGIT/PVR pathway inhibition include heightened immune responses 
and the potential to increase the frequency and/or the severity of immune-associated 
inflammatory lesions.  These potential effects are considered to be monitorable and are 
expected to be manageable (see Section 5 for the safety plan). 
Overall, the preclinical pharmacokinetics and toxicokinetics observed for tiragolumab 
supported entry into clinical studies, including providing adequate safety factors for the 
proposed Phase I starting doses.  The results of the toxicology program were consistent 
with the anticipated pharmacologic activity of downmodulating the PD-L1/PD-1 pathway 
and supported entry into clinical studies. 
Refer to the Tiragolumab Investigator’s Brochure for additional details on 
preclinical studies. 


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1.6.2 
Clinical Experience with Tiragolumab 
1.6.2.1 
Ongoing Clinical Studies with Tiragolumab 
Tiragolumab has been tested in Study GO30103, a first-in-human, combined 
Phase Ia/Phase Ib, open-label, dose-escalation, multicenter study.  The study evaluated 
the safety, tolerability, immunogenicity, pharmacokinetics, exploratory 
pharmacodynamics, and preliminary evidence of biologic activity of tiragolumab 
administered as a single agent by IV infusion every 21 days (Phase Ia portion of the 
study) or in combination with 1200 mg atezolizumab administered by IV infusion every 
21 days (Phase Ib) to patients with locally advanced or metastatic malignancies.  
The most common cancer types of patients enrolled in the study include NSCLC, head 
and neck squamous cell carcinoma, urinary bladder cancer, and renal cell cancer. 
The combination of tiragolumab plus atezolizumab was further evaluated in patients with 
NSCLC in Study GO40290, an ongoing, Phase II, global randomized, double-blind, 
placebo-controlled study. 
Available safety data and preliminary efficacy data for single-agent tiragolumab from 
Phase I study GO30103 and safety and efficacy data for the combination of tiragolumab 
and atezolizumab from Phase II Study GO40290 are summarized below. 
1.6.2.2 
Clinical Safety of Tiragolumab 
Currently, no maximum tolerated dose (MTD), no dose-limiting toxicities (DLTs), and no 
clear dose-related trends in the incidence or severity of adverse events in Phase Ia or 
Phase Ib portion of the study have been determined. 
The safety profile of tiragolumab administered to patients as a single agent and in 
combination with atezolizumab in Study GO30103 is observed to be consistent across 
the different tumor indications. 
Refer to the Tiragolumab Investigator’s Brochure for further details and the most current 
information on the adverse events observed in patients treated with single-agent 
tiragolumab or tiragolumab in combination with atezolizumab in Study GO30103. 
Clinical and Safety of Tiragolumab Plus Atezolizumab in Patients with 
NonSmall Cell Lung Cancer:  Study GO40290 
Study GO40290 is an ongoing, global Phase II, randomized, double-blinded, 
placebo-controlled study in first-line setting of NSCLC.  The co-primary endpoints were 
confirmed objective response rate (ORR) and investigator-assessed progression-free 
survival (PFS) per Response Evaluation Criteria in Solid Tumors, Version 1.1 


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(RECIST v1.1).  Secondary endpoints included DOR, OS, safety, pharmacokinetics, and 
immunogenicity. 
Eligible patients were stratified by the PD-L1 immunohistochemistry (IHC) 22C3 
pharmDx assay result (tumor proportion score [TPS] 1%49% vs. TPS  50%), tumor 
histology (non-squamous vs. squamous), and history of tobacco use (yes vs. no). 
As of the primary clinical cutoff date of 30 June 2019, a total of 135 patients with 
a PD-L1 TPS  1% were included in the intent-to-treat (ITT) population and were 
randomly assigned to receive tiragolumab plus atezolizumab (n  67) or placebo plus 
atezolizumab (n  68).  Of the enrolled patients, 43.0% of patients had a TPS  50% 
relative to 57.0% of patients with a TPS 1%49%, 59.3% had non-squamous histology 
compared with 40.7% of patients who had squamous histology, and 10.4% of patients 
were never smokers versus 89.6% who had smoked. 
In all randomized patients with TPS  1%, the confirmed ORR was higher in the 
tiragolumab plus atezolizumab arm (31.3%) than in the placebo plus atezolizumab arm 
(16.2%); investigator-assessed 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). 
The improvement in ORR and PFS observed with the combination of tiragolumab plus 
atezolizumab compared with placebo plus atezolizumab appears to be driven by the 
subgroup of patients with high PD-L1 expression (TPS  50%).  In the subgroup of 
patients with TPS  50%, the confirmed ORR was higher in the tiragolumab plus 
atezolizumab arm (n  29; 55.2% [95% CI: 35.4% to 75.0%]) than in the placebo plus 
atezolizumab arm (n  29; 17.2% [95% CI: 1.8% to 32.7%]).  Investigator-assessed PFS 
was improved in the tiragolumab plus atezolizumab arm relative to the placebo plus 
atezolizumab arm (unstratified HR  0.33; 95% CI: 0.15 to 0.72; median PFS: not 
reached vs. 3.9 months, respectively). 
The safety profile was comparable between the tiragolumab plus atezolizumab arm and 
the placebo plus atezolizumab arm for all grade adverse events (98.5% vs. 95.6%, 
respectively), Grade  3 adverse events (41.8% vs. 44.1%), Grade 5 adverse events 
(3.0% vs. 7.4%), serious adverse events (34.3% vs. 35.3%), and adverse events leading 
to study treatment withdrawal (7.5% vs. 10.3%).  Study treatmentrelated adverse 
events occurred at a higher frequency in the tiragolumab plus atezolizumab arm (80.6%) 
compared with that in the placebo plus atezolizumab arm (72.1%). 
Grade   3 adverse events (with a  2% difference between arms) that occurred at 
a higher frequency in the tiragolumab plus atezolizumab arm were pneumonia 
(9.0% vs. 4.4%), pleural effusion (6.0% vs.1.5%), increased lipase (6.0% vs. 2.9%), and 
hypokalemia (3.0% vs. 0%).  Grade  3 adverse events that occurred at a higher 
frequency in the placebo plus atezolizumab arm were pulmonary embolism 


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(0% vs. 2.9%), increased amylase (0% vs. 2.9%), and asthenia (0% vs. 2.9%).  
Grade 5 adverse events that occurred in the tiragolumab plus atezolizumab arm were 
 infection and pyrexia (reported for 1 patient each), and 
Grade 5 adverse events in the placebo plus atezolizumab arm were cardiorespiratory 
arrest, cerebrovascular accident, multiple organ dysfunction syndrome, pneumonia, and 
pulmonary embolism (reported for 1 patient each). 
Using a comprehensive medical concepts strategy, immune-mediated adverse events 
were reported with a higher frequency in the tiragolumab plus atezolizumab arm (65.7%) 
compared with the placebo plus atezolizumab arm (47.1%).  The difference ( 10% 
difference between arms) was predominantly attributed to events of immune-mediated 
rash (preferred terms of rash, maculopapular rash, dermatitis, pruritic rash, eczema, 
erythema, and folliculitis) (38.8% vs. 14.7%) and infusion-related reactions (IRRs) 
(preferred term of infusion-related reaction) (28.4% vs. 10.3%).  One Grade 3 adverse 
event of rash was observed in the tiragolumab plus atezolizumab arm.  All other events 
of rash and IRRs were of Grade 1 or 2 severity.  No events of rash or IRR led to 
tiragolumab or atezolizumab discontinuation. 
1.6.2.3 
Clinical Pharmacokinetics and Immunogenicity of Tiragolumab 
and Atezolizumab 
Clinical Pharmacokinetics and Immunogenicity of Tiragolumab 
 
 
 
 
As of December 2019 in the Phase Ia portion of Study GO30103,
 
 
 
 
As of October 2019 in Study GO40290, 
 


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Refer to the Tiragolumab Investigator’s Brochure for further details on the clinical 
pharmacokinetics and immunogenicity of tiragolumab. 
Clinical Pharmacokinetics and Immunogenicity of Atezolizumab 
Overall, atezolizumab exposures increased dose proportionally over the dose range of 
, including the fixed dose of 1200 mg administered Q3W.  
The clearance and terminal half-life of atezolizumab was estimated to be 0.2 L/day and 
27 days, respectively, based on a Phase I population-PK analysis that included 
472 patients from Studies PCD4989g and JO28944.  ADAs to atezolizumab have been 
observed in some patients at all dosing levels, but the presence of ADAs did not appear 
to have a clinically relevant impact on pharmacokinetics, safety, or efficacy of 
atezolizumab at the 1200-mg dose. 
Refer to the Atezolizumab Investigator’s Brochure for details on the clinical 
pharmacokinetics and immunogenicity of atezolizumab. 
1.7 
BACKGROUND ON ATEZOLIZUMAB 
Atezolizumab is a humanized IgG1 monoclonal antibody that targets PD-L1 and inhibits 
the interaction between PD-L1 and its receptors, PD-1 and B7-1 (also known as CD80), 
both of which function as inhibitory receptors expressed on T cells.  Therapeutic 
blockade of PD-L1 binding by atezolizumab has been shown to enhance the magnitude 
and quality of tumor-specific T-cell responses, resulting in improved anti-tumor activity 
(Fehrenbacher et al. 2016; Rosenberg et al. 2016).  Atezolizumab has minimal binding 
to Fc receptors, thus eliminating detectable fragment crystallizable (Fc)-effector function 
and associated antibody-mediated clearance of activated effector T cells. 
Atezolizumab shows anti-tumor activity in both preclinical models and cancer patients 
and is being investigated as a potential therapy in a wide variety of malignancies as 
a single agent in the advanced cancer and adjuvant therapy settings, as well as in 
combination with chemotherapy, targeted therapy, and other cancer immunotherapies 
(CITs). 
Atezolizumab is currently being explored in cervical cancer as part of various treatment 
regimens, including with radiotherapy (NCT03614949 and NCT03738228) and 
chemotherapy with bevacizumab (NCT03556839).  While efficacy data for atezolizumab 
in these combinations are not available, early safety evaluation did not identify unique 
disease-specific safety signals.  A pilot study (NCT02921269) of atezolizumab in 
conjunction with bevacizumab in 11 biomarker-agnostic patients with cervical cancer 
showed no confirmed responders, despite achieving disease stabilization in 4 patients.  


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This lack of initial efficacy precluded activation of the expansion cohort; however, 
no safety signals were identified (Friedman et al. 2019). 
Atezolizumab is currently approved for the treatment of urothelial carcinoma, 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 preclinical and 
clinical studies. 
1.8 
STUDY RATIONALE AND BENEFITRISK ASSESSMENT 
This study will enroll patients with metastatic and/or recurrent PD-L1positive cervical 
cancer after progression or recurrence from systemic therapy to receive either 
tiragolumab in combination with atezolizumab or atezolizumab monotherapy.  Based on 
results from the Phase II GO40290 study, the combination of tiragolumab plus 
atezolizumab in the experimental arm may represent a potentially efficacious treatment 
option for patients with PD-L1positive cervical cancer and can offer a reasonable 
benefitrisk balance for patients in this study.  Atezolizumab monotherapy has been 
extensively studied in a wide number of tumor types.  Atezolizumab is well tolerated, and 
adverse events have been broadly consistent across tumor types. 
Tumors may use more than one mechanism to evade the immune system.  Therefore, 
using more than one method to activate the immune response may show synergistic 
effects.  Based on the above data, the combination of tiragolumab plus atezolizumab is 
expected to have enhanced efficacy and safety profiles similar to atezolizumab 
monotherapy. 
In the setting of the coronavirus disease 2019 (COVID-19) pandemic, patients with 
comorbidities, including those with cervical cancer, are considered a more vulnerable 
population, with the potential for more severe clinical outcomes from severe acute 
respiratory syndrome coronavirus 2 (SARS-CoV-2) infection.  However, it is unclear 
whether or how systemic cancer therapies such as chemotherapy, targeted therapy, or 
immunotherapy, impact the incidence or severity of SARS-CoV-2 injection. 
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 
dysregulated immune system defenses.  In nonclinical models, PD-1/PD-L1 blockade 
appears to be associated with serious exacerbation of inflammation in the setting of 
acute (as opposed to chronic) viral infection with lymphocytic choriomeningitis virus 
(Clone 13) (Frebel et al. 2012).  However, there are insufficient and inconsistent clinical 
data to assess if outcome from SARS-CoV-2 infection is altered by cancer 
immunotherapy. 


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Severe SARS-CoV-2 infection appears to be associated with a cytokine-release 
syndrome (CRS) involving the inflammatory cytokines interleukin (IL)-6, IL-10, IL-2, and 
IFN- (Merad and Martin 2020).  While it is not known, there may be a potential for an 
increased risk of an enhanced inflammatory response if a patient develops acute 
SARS CoV-2 infection while receiving atezolizumab 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 SARS-CoV-2 infection. 
There may be potential synergy or overlap in clinical and radiologic features for immune 
mediated pulmonary toxicity with immune checkpoint inhibitors and clinical and 
radiologic features for SARS-CoV-2related interstitial pneumonia.  Thus, investigators 
should use their clinical judgment when evaluating and managing patients with 
pulmonary symptoms. 
There are limited data concerning the possible interactions between cancer 
immunotherapy treatment and COVID-19 vaccination, and it is recognized that human 
immune responses are highly regulated and that immune-modifying therapies may 
positively or negatively impact the efficacy and safety of COVID-19 vaccination (Society 
for Immunotherapy of Cancer [SITC] 2020). 
Per recommendations of the National Comprehensive Cancer Network (NCCN) 
COVID-19 Vaccination Advisory Committee, COVID-19 vaccination is recommended for 
all patients with cancer receiving active therapy (including immune checkpoint inhibitors), 
with the understanding that there are limited safety and efficacy data in such patients 
(NCCN 2021).  Given the lack of clinical data, currently no recommendations can be 
made regarding the optimal sequence of COVID-19 vaccination in patients who are 
receiving cancer immunotherapy (SITC 2020).  For patients enrolling in this study and 
receiving atezolizumab treatment, a decision to administer the vaccine to a patient 
should be made on an individual basis by the investigator in consultation with the 
patient. 
In alignment with clinical practice procedures, factors to consider when making the 
individualized decision for patients receiving tiragolumab and/or atezolizumab treatment 
to receive COVID-19 vaccination include the following:  the risk of SARS-CoV-2 infection 
and potential benefit from the vaccine, the general condition of the patient and potential 
complications associated with SARS-CoV-2 infection, underlying disease, and the 
severity of COVID-19 outbreak in a given area or region. 
SITC and NCCN recommendations along with institutional guidelines should be used by 
the investigator when deciding on administering COVID-19 vaccines.  
When administered, COVID-19 vaccines must be given in accordance with the approved 
or authorized vaccine label.  Receipt of the COVID-19 vaccine is considered a 
concomitant medication and should be documented as such (see Section 4.4.1). 


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2. 
OBJECTIVES AND ENDPOINTS 
This Phase II study will evaluate the efficacy and safety of tiragolumab in combination 
with atezolizumab and atezolizumab monotherapy in patients with metastatic and/or 
recurrent PDL1positive (tumor cells and tumor-associated immune cells [
) 
cervical carcinoma.  Specific objectives and corresponding endpoints for the study are 
outlined in the following sections. 
 
2.1 
EFFICACY OBJECTIVES 
2.1.1 
Primary Efficacy Objective 
The primary efficacy objective for this study is to evaluate the efficacy of tiragolumab in 
combination with atezolizumab and of atezolizumab monotherapy on the basis of the 
following endpoint: 
 
ORR, defined as the proportion of patients with a complete response (CR) or 
a partial response (PR) on two consecutive occasions  4 weeks apart, as 
determined by an independent review committee (IRC) according to RECIST v1.1 
 
2.1.2 
Secondary Efficacy Objective 
The secondary efficacy objective for this study is to evaluate the efficacy of tiragolumab 
in combination with atezolizumab and of atezolizumab monotherapy on the basis of the 
following endpoints: 
 
DOR, defined as the time from the first occurrence of a documented objective 
response to disease progression or death from any cause (whichever occurs first), 
as determined by the IRC according to RECIST v1.1 
 
Disease control rate (DCR), defined as the proportion of patients with a CR, PR, or 
stable disease (SD), as determined by an IRC according to RECIST v1.1 
 
Best clinical response (BCR) rate, defined as the proportion of patients with a CR, 
PR, or SD, and the DOR as clinically determined by the investigator  
 
PFS after randomization, defined as the time from randomization to the first 
occurrence of disease progression, as determined by the IRC according to 
RECIST v1.1, or death from any cause, whichever occurs first  
 
PFS rate at 6 months, defined as the proportion of patients who have not 
experienced disease progression, as determined by the IRC according to 
RECIST v1.1, or death from any cause at 6 months post-randomization 
 
OS after randomization, defined as the time from randomization to death from 
any cause 
 
OS rate at 6 months and 12 months, defined as the proportion of patients who have 
not experienced death from any cause at 6 months and 12 months 
postrandomization, respectively 
 


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2.2 
SAFETY OBJECTIVE 
The safety objective for this study is to evaluate the safety and tolerability of tiragolumab 
in combination with atezolizumab and of atezolizumab monotherapy on the basis of the 
following endpoint: 
 
Incidence and severity of adverse events, with severity determined according to 
National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events, 
Version 5.0 (CTCAE v5.0) 
 
 
 
. 
2.3 
PHARMACOKINETIC OBJECTIVE 
The PK objective for this study is to characterize the pharmacokinetics of tiragolumab 
and atezolizumab on the basis of the following endpoints: 
 
Serum concentrations of tiragolumab at specified timepoints 
 
Serum concentrations of atezolizumab at specified timepoints 
 
2.4 
IMMUNOGENICITY OBJECTIVES 
The immunogenicity objective for this study is to evaluate the immune response to 
tiragolumab and atezolizumab on the basis of the following endpoint: 
 
Prevalence of ADAs at baseline and incidence of ADAs to tiragolumab and to 
atezolizumab during the study 


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3. 
STUDY DESIGN 
3.1 
DESCRIPTION OF THE STUDY 
3.1.1 
Overview of Study Design  
This Phase II, global, open-label, randomized study is designed to evaluate the efficacy 
and safety of tiragolumab in combination with atezolizumab and of atezolizumab 
monotherapy in patients with metastatic and/or recurrent PD-L1positive cervical cancer 
after progression or recurrence from at least one platinum-based but no more than two 
prior systemic therapies. 
Approximately 160 patients will be enrolled in the global enrollment phase of this study.  
Women with Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 
1 who have metastatic and/or recurrent PD-L1positive cervical cancer are eligible 
(for the complete list of eligibility criteria, refer to Sections 4.1.1 and 4.1.2). 
Additional patients may be subsequently randomized in a 
 
 
 
 
 
 
 
After providing informed consent, patients will undergo screening procedures as outlined 
in the schedule of activities in Appendix 1.  Patients who do not meet the criteria for 
participation in this study (screen failure) may qualify for an additional two re-screening 
opportunities (for a total of three screenings per participant) at the investigator's 
discretion.  Patients are not required to re-sign the consent form if they are rescreened 
within 60 days after previously signing the consent form.  The investigator will maintain 
a record of reasons for screen failure. 
During screening, tumor specimens from each potentially eligible patient will be 
prospectively tested for PD-L1 expression, as assessed by a central laboratory, using 
the 
.  
Only patients who are PD-L1positive with 
 will be enrolled. 
Eligible patients will be randomized in a 3:1 ratio to receive either tiragolumab in 
combination with atezolizumab or atezolizumab alone. 
Eligible patients will be stratified by ECOG Performance Status (0 versus 1), prior use of 
chemoradiotherapy or radiotherapy (yes versus no), and treatment history (persistent 
versus recurrent disease). 


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In the doublet arm, patients will receive atezolizumab at a fixed dose of 1200 mg 
administered by IV infusion Q3W on Day 1 of each 21-day cycle, followed by 
tiragolumab at a fixed dose of 600 mg administered by IV infusion Q3W also on Day 1 of 
each 21-day cycle. 
In the atezolizumab monotherapy arm, patients will receive atezolizumab at a fixed dose 
of 1200 mg administered by IV infusion Q3W on Day 1 of each 21-day cycle. 
Treatment may be continued as long as patients are experiencing clinical benefit, as 
assessed by the investigator, in the absence of unacceptable toxicity or symptomatic 
deterioration attributed to disease progression after an integrated assessment of 
radiographic data, biopsy results (if available), and clinical status.  Patients who meet the 
criteria for equivocal disease progression per RECIST v1.1 will be permitted to continue 
treatment (tiragolumab in combination with atezolizumab or atezolizumab alone) if they 
meet all of the criteria specified. 
Figure 1 presents an overview of the study design.  The schedule of activities is provided 
in Appendix 1. 
Figure 1 Study Schema 
 
1L  first line;
 ECOG  Eastern Cooperative Oncology Group; 
PD-L1  programmed deathligand 1; Q3W  every 3 weeks; R  randomization; s/p   status-post. 
Note:  Crossover is allowed from the atezolizumab monotherapy arm to the tiragolumab plus 
atezolizumab arm after unequivocal progressive disease has been recorded during atezolizumab 
monotherapy, at the discretion of the investigator and after consultation with the Medical Monitor. 
 
During the study, serum samples will be collected to monitor tiragolumab in combination 
with atezolizumab and atezolizumab pharmacokinetics and to detect the presence of 
Metastatic, recurrent, 
or persistent cervical 
carcinoma 
Progression or 
recurrence s/p 1L 
systemic therapy 
Measurable disease 
ECOG Performance 
Status 0 or 1 
PD-L1 positivity, as 
determined according to 
 
Regimen A (n  ~120) 
Tiragolumab 600 mg IV Q3W  
+ 
Atezolizumab 1200 mg IV Q3W  
Regimen B (n  ~40) 
Atezolizumab 1200 mg IV Q3W 
Treat until 
disease 
progression 
or loss of 
clinical 
benefit 
Stratification factors: 
ECOG Performance Status (0 vs. 1)  
Prior use of chemoradiotherapy or radiotherapy (yes vs. no)  
Treatment history (persistent vs. recurrent disease) 
 
R 
3:1 
Ratio 


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antibodies to tiragolumab and atezolizumab (see Appendix 2 for the sampling schedule).  
Patient samples, including archival and fresh tumor tissue, serum, plasma, and blood 
samples, will also be collected for 
 assessments. 
Patients will undergo tumor assessments at baseline and every 6 weeks ( 7 days) for 
48 weeks following Day 1 of Cycle 1 regardless of treatment delays.  After the 
completion of the Week 48 tumor assessment, tumor assessments will be required every 
9 weeks ( 7 days) regardless of treatment delays until unequivocal radiographic 
disease progression per RECIST v1.1 (or loss of clinical benefit for patients who 
continue study treatment after disease progression per RECIST v1.1), withdrawal of 
consent, death, or study termination by the Sponsor, whichever occurs first.  Patients 
who are treated beyond disease progression per RECIST v1.1 will undergo tumor 
assessments at the frequency described above until study treatment is discontinued.  
Patients who discontinue treatment for reasons other than radiographic disease 
progression per RECIST v1.1 (e.g., toxicity, symptomatic deterioration) will continue 
scheduled tumor assessments at the frequency described above until radiographic 
disease progression per RECIST v1.1, withdrawal of consent, death, or study 
termination by the Sponsor, whichever occurs first.  In the absence of radiographic 
disease progression per RECIST v1.1, tumor assessments should continue regardless 
of whether a patient starts a new anti-cancer therapy. 
Response will be assessed according to RECIST v1.1 (see Appendix 3).  Objective 
response will be determined at a single timepoint by the IRC according to RECIST v1.1.  
As of protocol amendment version 8, imaging scans no longer need to be sent to or 
assessed by IRC. 
Crossover is allowed from the atezolizumab monotherapy arm to the tiragolumab plus 
atezolizumab arm after unequivocal progressive disease has been recorded during 
atezolizumab monotherapy, at the discretion of the investigator and after consultation 
with the Medical Monitor.  For patients who crossover from atezolizumab monotherapy 
to tiragolumab plus atezolizumab, the tumor assessment just preceding crossover will 
serve as a rebaseline scan against which all subsequent scans will be compared. 
After initiation of study treatment, all adverse events will be reported according to the 
adverse event reporting period (see Section 5.3.1).  After this period, all deaths should 
continue to be reported.  In addition, the Sponsor should be notified if the investigators 
become aware of any serious adverse events or adverse events of special interest that 
are believed to be related to prior treatment with study drug(s).  These events should be 
reported using the Adverse Event electronic Case Report Form (eCRF).  
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 
protocol-related procedures until a final outcome can be reported. 


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After study treatment discontinuation, survival follow-up information will be collected by 
means of telephone calls, patient medical records, and/or clinic visits approximately 
every 3 months until death, loss to follow-up, or study termination by the Sponsor, 
whichever occurs first.  All patients will be periodically contacted for survival and new 
anti-cancer therapy information unless the patient requests to be withdrawn from 
follow-up (this request must be documented in the source documents and signed by the 
investigator).  If the patient withdraws from the study, study staff may use a public 
information source (e.g., county records) when permissible to obtain information about 
survival status only. 
3.1.2 
Treatment after Disease Progression 
During the study, patients who meet criteria for disease progression per RECIST v1.1 
and show evidence of clinical benefit may continue study treatment at the investigator’s 
discretion provided that the patients meet all of the following criteria:  
 
Evidence of clinical benefit, as assessed by the investigator 
 
Absence of symptoms and signs (including worsening of laboratory values indicating 
unequivocal progression of disease) 
 
No 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 
 
3.1.3 
Safety Monitoring 
The Sponsor will monitor patient safety throughout the study.  In addition to the ongoing 
assessment of the incidence, nature, and severity of adverse events; deaths; vital signs; 
and laboratory abnormalities, the Sponsor will review all cumulative data at regular 
intervals during the study. 
3.1.4 
Internal Monitoring Committee 
An Internal Monitoring Committee (IMC) composed of representatives from safety 
science, clinical science, and statistics, who are independent from the study team, will 
be established.  Representatives from other functions may be added on an ad hoc basis 
depending on the nature of the findings.  The primary responsibility of the IMC is to 
evaluate the safety, not efficacy, of treatment arms being evaluated.  The IMC will share 
responsibility with the study team for the monitoring of patient safety. 
The IMC may meet during the course of the study.  The IMC may conduct an ad hoc 
meeting should an unexpected safety concern arise, as specified in the IMC Charter.  
At the time of each review of cumulative data, the IMC may make recommendations in 
consideration of the totality of the available data.  Specific operational details such as the 
committee's composition, timing of meetings, and members' roles and responsibilities 
will be detailed in an IMC Charter. 


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3.2 
END OF STUDY AND LENGTH OF STUDY 
The end of this study is defined as the date when the “last patient last visit” occurs 
(i.e., when the last patient has recorded her last visit).  The end of study has been 
extended until all patients on active treatment in the study roll over to the continued 
access program. 
3.3 
RATIONALE FOR STUDY DESIGN 
This Phase II study design is based on the hypothesis that the combination of 
tiragolumab plus atezolizumab and atezolizumab monotherapy may elicit more 
responses (either a CR or a PR) and prolong the durability of such responses in patients 
with metastatic and/or recurrent PD-L1positive cervical carcinoma. 
3.3.1 
Rationale for Atezolizumab Dose and Schedule 
Atezolizumab will be administered at a fixed dose of 1200 mg Q3W (1200 mg on Day 1 
of each 21-day cycle), which is an approved dosage for atezolizumab, as outlined in the 
Tecentriq prescribing information.  Anti-tumor activity has been observed across doses 
ranging from 1 mg/kg to 20 mg/kg Q3W.  In Study PCD4989g, the MTD of atezolizumab 
was not reached and no DLTs were observed at any dose.  The fixed dose of 1200 mg 
atezolizumab Q3W (equivalent to an average body weightbased dose of 15 mg/kg 
Q3W) was selected on the basis of both nonclinical studies (Deng et al. 2016) and 
available clinical PK, efficacy, and safety data (refer to the Atezolizumab Investigator's 
Brochure for details). 


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For further details, refer to the Tiragolumab Investigator’s Brochure. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
3.3.4 
Rationale for Open-Label Study  
Given that this study is designed to generate efficacy and safety data in this cervical 
cancer population, an open-label study design was chosen to enable rapid assessment 
and shared decision-making between physicians and patients in the study. 
To ensure the objectivity of tumor-response data collected in an open-label study, the 
primary efficacy endpoint is IRC-determined ORR per RECIST v1.1.  In addition, the 
strategy and timing for interim and final analysis of the primary endpoint have been 
prespecified in the protocol to ensure adequate duration of surveillance in the study. 


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. 
3.3.5.1 
Rationale for Collection of Mandatory Archival and/or 
Pretreatment Biopsy Tumor Specimens 
In this Phase II study, archival and/or fresh tumor specimens from patients will be tested 
for PD-L1 expression by a central laboratory and only patients with PD-L1positive 
tumors (defined by expression of PD-L1 detected with the 
 
 at
by central laboratory assessment) will be 
enrolled.  The efficacy endpoints will be analyzed in all randomized patients who receive 
at least one dose of study treatment.  In addition, as part of an 
 
efficacy analysis, investigator-assessed PFS and OS will also be analyzed in PD-L1 
subgroups. 
In addition, archival and/or pretreatment biopsy tumor specimens obtained from patients 
 


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immunobiology, mechanisms of resistance, or tumor types or subtypes, and tumor 
mutational burden.  The evaluation of biomarkers may help to identify which patients 
may potentially benefit most from tiragolumab plus atezolizumab and may help to guide 
future development of novel therapeutic and diagnostic options.  DNA and/or RNA 
extraction and analysis may be performed to enable next-generation sequencing (NGS) 
and to evaluate expression of genes to assess their association with efficacy and/or to 
identify selected somatic mutations and disease pathways to increase the understanding 
of cervical cancer pathobiology. 
3.3.5.2 
Rationale for Collection of Blood Samples for 
Biomarker Analyses 
Blood samples will be collected at screening and/or at baseline, during therapy, and at 
first evidence of radiographic progression or loss of clinical benefit.  
 
 
 
 
 
3.3.5.3 
Rationale for Next-Generation Sequencing, Whole 
Genome Sequencing, or Whole Exome Sequencing in 
Tumor and/or Blood Samples 
Tumor tissue and blood samples collected in this study may be used for DNA and RNA 
extraction to enable analysis by means of NGS techniques to identify mutations (somatic 
and possibly germline) and gene expression profiles that may be predictive of response 
or of resistance to tiragolumab plus atezolizumab.  These analyses may also help 
identify susceptibility to developing adverse events, understand the mechanisms of 
response or resistance to treatment, and increase the knowledge and understanding of 
the biology of cervical cancer. 
 
 
 
 
 
 
Genomics is increasingly informing researchers’ understanding of disease pathobiology.  
 provide a comprehensive characterization of the genome and exome, 
respectively, and, along with clinical data collected in this study, may increase the 
opportunity for developing new therapeutic approaches or new methods for monitoring 


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3.3.6 
Rationale for Allowing Patients to Continue Study Treatment 
beyond Disease Progression per RECIST v1.1 
Conventional response criteria may not adequately assess the activity of 
immunotherapeutic agents because progressive disease (by initial radiographic 
evaluation) may not necessarily reflect therapeutic failure.  Because of the potential for 
pseudoprogression and/or tumor immune infiltration, this study will allow patients 
randomized to continue to receive study treatment after apparent radiographic 
progression, provided the benefitrisk ratio is judged to be favorable.  Patients should be 
discontinued for unacceptable toxicity or symptomatic deterioration attributed to disease 
progression as determined by the investigator after an integrated assessment of 
radiographic data, biopsy results (if available), and clinical status (see Section 3.1.2). 
4. 
MATERIALS AND METHODS  
4.1 
PATIENTS 
Approximately 160 patients with metastatic and/or recurrent PD-L1positive cervical 
cancer will be enrolled in the global enrollment phase.  
 
 
 
 
4.1.1 
Inclusion Criteria 
Patients must meet the following criteria for study entry: 
 
Signed Informed Consent Form 
 
Age  18 years at time of signing Informed Consent Form 
 
Life expectancy  12 weeks 
 
Ability to comply with the study protocol 
 
ECOG Performance Status of 0 or 1 (see Appendix 4) 
 
Histologically confirmed recurrent or persistent squamous cell carcinoma, 
adenosquamous carcinoma, or adenocarcinoma of the cervix (neuroendocrine, 
clear cell, and sarcoma histologies are not allowed) after progression on or after 
12 lines of prior systemic chemotherapy in the metastatic/recurrent setting that is 
not amenable to curative treatment with systemic chemotherapy, surgery, and/or 
radiotherapy 
At least one prior line of platinum-based systemic chemotherapy. 


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Radiosensitizing cisplatin given with radiotherapy is not considered a line of 
systemic chemotherapy. 
 
Measurable disease, defined as: 
– 
At least one lesion that can be accurately and reliably measured in at least one 
dimension using computed tomography (CT) or magnetic resonance imaging 
(MRI) scan.  Positron emission tomography (PET-CT) may be used if the CT 
portion is of diagnostic quality. 
– 
Tumors within a previously irradiated field cannot serve as a “target lesion”; 
however, they may serve as a “non-target lesion.” 
 
Formalin-fixed, paraffin-embedded (FFPE) cervical cancer tissue specimen (archival 
or tissue obtained from biopsy at screening) that is PD-L1 positive, as determined 
by the 
, with positivity defined 
as 
 as determined by a central laboratory. 
 
Adequate hematologic and end-organ function, defined by the following laboratory 
test results, obtained within 14 days prior to randomization:  
– 
– 
– 
– 
– 
– 
– 
– 
– 
– 
 
 
 
 


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 
 
  
– 
– 
 
 
Recovery from the effects of surgery, radiotherapy, or chemoradiotherapy   
At least 6 weeks must have elapsed from the last administration of 
chemoradiotherapy, and at least 3 weeks must have elapsed from the last 
administration of radiotherapy alone. 
 
For women of childbearing potential:  agreement to remain abstinent (refrain from 
heterosexual intercourse) or use contraception as defined below: 
Women must remain abstinent or use contraceptive methods with a failure rate 
of  1% per year during the treatment period, for 90 days after the final dose of 
tiragolumab, and for 5 months after the final dose of atezolizumab. 
A woman is considered to be of childbearing potential if she is postmenarcheal, 
has not reached a postmenopausal state ( 12 continuous months of 
amenorrhea with no identified cause other than menopause), and is not 
permanently infertile due to surgery (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. 
 


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4.1.2 
Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from study entry: 
 
FFPE cervical cancer tissue specimens  (archival or tissue obtained from biopsy at 
screening) that is PD-L1 negative, as determined by the 
 
, with negativity defined as
, as determined by 
a central laboratory 
 
Pregnant or breastfeeding, or intending to become pregnant during study treatment, 
within 90 days after the final dose of tiragolumab, or within 5 months after the final 
dose of atezolizumab  
Women of childbearing potential must have a negative pregnancy test result 
within 14 days prior to Cycle 1, Day 1. 
 
Treatment with investigational therapy with therapeutic intent within 28 days prior to 
randomization 
 
Planned surgery during the study 
 
Current treatment with anti-viral therapy for 
 
 
Substance abuse within 12 months prior to screening, in the investigator's judgment 
 
Any serious medical condition or abnormality in clinical laboratory tests that, in the 
investigator's judgment, precludes the patient's safe participation in and completion 
of the study 
 
Bilateral hydronephrosis that cannot be alleviated by ureteral stents or 
percutaneous drainage 
 
History of other malignancy within 5 years prior to screening, except for those with 
an expected negligible risk for metastases or death (e.g., 5-year OS  90%) after 
curative treatment 
Examples include appropriately treated basal or squamous cell skin carcinoma, 
FIGO Stage I Grade 1 uterine cancer or ductal carcinoma in situ of the breast. 
 
Active or untreated CNS or brain metastases 
 
Spinal cord compression not definitively treated with surgery and/or radiation, or 
previously diagnosed and treated spinal cord compression without evidence that 
disease has been clinically stable for  1 week prior to randomization 
 
Leptomeningeal disease 
 
Uncontrolled or symptomatic hypercalcemia (ionized calcium  1.5 mmol/L, total 
serum calcium  12 mg/dL, or corrected serum calcium greater than ULN) 
 
Known, clinically significant liver disease, including active viral, alcoholic, or other 
hepatitis, cirrhosis, and inherited liver disease, or current alcohol abuse 


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 
Active or history of autoimmune disease or immune deficiency, 
 
 
 
 
 
  
 
Active tuberculosis 
 
Severe infection per investigator judgment at the time of randomization, including, 
but not limited to, use of systemic antibiotics, hospitalization for complications of 
infection, bacteremia, or severe pneumonia, or any active infection that, in the 
opinion of the investigator, could impact patient safety  
 
Significant cardiovascular disease, such as cardiac disease New York Heart 
Association Class II or greater, myocardial infarction, or cerebrovascular accident 
within 3 months prior to randomization, unstable arrhythmias, or unstable angina 
Patients with known coronary artery disease, congestive heart failure not meeting 
the above criterion or with a left ventricular ejection fraction  50% must be on 
a stable medical regimen that is optimized in the opinion of the treating physician, 
in consultation with a cardiologist if appropriate.  
 
Major surgical procedure other than for diagnosis within 28 days prior to 
randomization or anticipation of need for a major surgical procedure during 
the study 


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 
Prior allogeneic bone marrow transplantation or solid organ transplant  
 
Any other diseases, metabolic dysfunction, physical examination finding, or clinical 
laboratory finding giving reasonable suspicion of a disease or condition that 
contraindicates the use of an investigational drug or that may affect the 
interpretation of the results or renders the patient at high risk for treatment 
complications 
 
Illnesses or conditions that interfere with the patient’s capacity to understand, follow, 
and/or comply with study procedures 
 
Administration of a live, attenuated vaccine within 4 weeks before randomization or 
anticipation that such a live attenuated vaccine will be required during the study 
Patients must not receive live, attenuated influenza vaccines (e.g., FluMist®) 
within 4 weeks prior to randomization, during treatment, for 90 days following the 
last dose of tiragolumab, and for 5 months following the last dose of 
atezolizumab. 
 
Prior treatment with CD137 agonists or immune checkpoint blockade therapies, 
antiCTLA-4, anti-TIGIT, antiPD-1, and antiPD-L1 therapeutic antibodies  
 
Treatment with systemic immunostimulatory agents (including, but not limited to, 
interferon and IL-2) within 4 weeks or 5 drug-elimination half-lives (whichever is 
longer) prior to randomization 
 
Treatment with systemic immunosuppressive medications (including, but not limited 
to, corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide, and 
antitumor necrosis factor [anti-TNF] agents) within 1 week prior to randomization or 
anticipation of need for systemic immunosuppressive medication during study 
treatment, with the following exceptions: 
– 
 
 
 
  
– 
 
 
 
 
History of severe allergic anaphylactic reactions to chimeric, fully humanized, or 
humanized antibodies or fusion proteins  
 
Known hypersensitivity to Chinese hamster ovary cell products or to any component 
of the tiragolumab or atezolizumab formulations 
 
4.2 
METHOD OF TREATMENT ASSIGNMENT  
This is a randomized, open-label 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 


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identification number and treatment assignment from the web-based response system 
(IxRS). 
Patients will be randomly assigned to one of two treatment arms of tiragolumab in 
combination with atezolizumab or atezolizumab monotherapy.  Randomization will occur 
in a 3:1 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: 
 
ECOG Performance Status (0 vs. 1) 
 
Prior use of chemoradiotherapy or radiotherapy (yes vs. no) 
 
Treatment history (persistent vs. recurrent disease) 
 
4.3 
STUDY TREATMENT AND OTHER TREATMENTS RELEVANT 
TO THE STUDY DESIGN 
The investigational medicinal product (IMPs) for this study are tiragolumab and 
atezolizumab. 
4.3.1 
Study Treatment Formulation, Packaging, and Handling 
4.3.1.1 
Tiragolumab 
Tiragolumab will be supplied by the Sponsor as a sterile liquid in a 
, 
 
.  The vial contains approximately 
 of tiragolumab. 
For further information on the formulation and handling of tiragolumab, please see the 
pharmacy manual and/or the Tiragolumab Investigator’s Brochure. 
4.3.1.2 
Atezolizumab  
Atezolizumab will be supplied by the Sponsor as a 
 
.  The vial contains approximately 
 of atezolizumab solution. 
For information on the formulation and handling of atezolizumab, see the pharmacy 
manual and the Atezolizumab Investigator's Brochure. 
4.3.2 
Study Treatment Dosage, Administration, and Compliance 
The treatment regimens are summarized in Section 3.1.1. 
All patients will receive 1200 mg atezolizumab administered by IV infusion on Day 1 of 
each 21-day cycle.  The atezolizumab dose is fixed and is not dependent on body 
weight. 
After the atezolizumab infusion, patients in the atezolizumab in combination with 
tiragolumab cohort will receive 600 mg tiragolumab administered by IV infusion on Day 1 
of each 21-day cycle.  The tiragolumab and atezolizumab doses are fixed and are not 
dependent on body weight. 


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Administration of tiragolumab and atezolizumab will be performed in a monitored setting 
where there is immediate access to trained personnel and adequate equipment and 
medicine to manage potentially serious reactions. 
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 eCRF.  Cases of accidental overdose or medication error, 
along with any associated adverse events, should be reported as described in 
Section 5.3.5.12. 
Guidelines for treatment interruption or discontinuation for patients who experience 
adverse events are provided in Section 5.1.2.3 and Appendix 7. 
4.3.2.1 
Atezolizumab  
Atezolizumab will be administered by IV infusion at a fixed dose of 1200 mg on Day 1 of 
each 21-day cycle until unacceptable toxicity or loss of clinical benefit as determined by 
the investigator after an integrated assessment of radiographic and biochemical data, 
local biopsy results (if available), and clinical status (see Section 3.1.1 for details). 
For anaphylaxis precautions, Appendix 6.  Atezolizumab infusions will be administered 
per the instructions outlined in Table 1. 
Table 1 
Administration of First and Subsequent Atezolizumab 
Monotherapy 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 ( 10) minutes. 
 
If clinically indicated, vital signs should be 
measured every 15 ( 5) minutes during the 
infusion and at 30 ( 10) minutes after the 
infusion. 
 
Patients should be informed about the 
possibility of delayed post-infusion 
symptoms and instructed to contact their 
study physician if they develop such 
symptoms. 
 
If the patient experienced an IRR with any 
previous infusion, premedication with 
antihistamines, antipyretics, and/or 
analgesics may be administered for 
subsequent doses at the discretion of the 
investigator. 
 
Vital signs should be measured within 
60 minutes prior to the infusion. 
 
Atezolizumab should be infused over 
30 ( 10) minutes if the previous infusion 
was tolerated without an IRR, or 
60 ( 15) minutes if the patient experienced 
an IRR with the previous infusion. 
 
If the patient experienced an IRR with the 
previous infusion or if clinically indicated, 
vital signs should be measured during the 
infusion and at 30 ( 10) minutes after the 
infusion. 
IRR  infusion-related reaction. 
 


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Guidelines for medical management of IRRs are provided in the Appendix 7. 
No dose modification for atezolizumab is allowed. 
4.3.2.2 
Tiragolumab and Atezolizumab 
In the doublet arm, patients will receive atezolizumab at a fixed dose of 1200 mg 
administered by IV infusion Q3W on Day 1 of each 21-day cycle, followed by 
tiragolumab at a fixed dose of 600 mg administered by IV infusion Q3W also on Day 1 of 
each 21-day cycle (see Section 3.1.1).  The tiragolumab and atezolizumab dose are 
fixed and are not dependent on body weight.   
For anaphylaxis precautions, refer to Appendix 6.  Tiragolumab and atezolizumab 
infusions will be administered per the instructions outlined in Table 2. 
Table 2 
Administration of First and Subsequent Tiragolumab and 
Atezolizumab Infusions 
 
First Infusion 
Subsequent Infusions 
Atezolizumab 
infusion 
 No premedication is permitted 
for the first atezolizumab 
infusion. 
 Vital signs (pulse rate, 
respiratory rate, blood pressure, 
and temperature) should be 
recorded within 60 minutes prior 
to the infusion. 
 Atezolizumab should be infused 
over 60 ( 10) minutes. 
 If clinically indicated, vital signs 
should be measured every 
15 ( 5) minutes during the 
infusion. 
 If the patient experienced an IRR during 
any previous infusion of atezolizumab, 
premedication with antihistamines, 
antipyretics, and/or analgesics may be 
administered for subsequent doses at the 
discretion of the investigator. 
 Vital signs should be recorded within 
60 minutes prior to the infusion. 
 Atezolizumab should be infused over 
30 ( 10) minutes if the previous infusion 
was tolerated without an IRR or 
60 ( 15) minutes if the patient 
experienced an IRR with the previous 
infusion.  If the patient experienced an 
IRR with the previous infusion, or if 
clinically indicated, vital signs should be 
recorded during the infusion. 
Observation 
period after 
infusion of 
atezolizumab 
 After the infusion of 
atezolizumab, the patient begins 
a 60-minute observation period. 
 Vital signs should be recorded at 
30 ( 10) minutes after the 
infusion of atezolizumab. 
 Patients will be informed about 
the possibility of delayed 
post-infusion symptoms and 
instructed to contact their study 
physician if they develop such 
symptoms. 
 If the patient tolerated the previous 
atezolizumab infusion well without 
infusion-associated adverse events, the 
observation period after the next and 
following infusions may be reduced to 
30 minutes. 
 If the patient experienced 
infusion-associated adverse events in the 
previous infusion, the observation period 
should be 60 minutes. 
 If clinically indicated, vital signs should be 
recorded at 30 ( 10) minutes after the 
infusion of atezolizumab. 
IRR  infusion-related reaction. 
 


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Table 2 
Administration of First and Subsequent Tiragolumab and 
Atezolizumab Infusions (cont.)  
 
First Infusion 
Subsequent Infusions 
Infusion of 
tiragolumab 
Observation 
period after 
infusion of 
tiragolumab 
IRR  infusion-related reaction. 
4.3.3 
Investigational Medicinal Product Accountability 
All IMPs required for completion of this study will be provided by the Sponsor.  The study 
site will acknowledge receipt of IMPs supplied by the Sponsor, using the IxRS to confirm 
the shipment condition and content.  Any damaged shipments will be replaced. 
IMPs will either be disposed of at the study site according to the study site's institutional 
standard operating procedure or be returned to the Sponsor (if supplied by the Sponsor) 
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IMPs must be agreed to by the Sponsor.  The site must obtain written authorization from 
the Sponsor before any Sponsor-supplied IMP is destroyed, and IMP destruction must 
be documented on the appropriate form. 
Accurate records of all IMPs received at, dispensed from, returned to, and disposed of by 
the study site should be recorded on the Drug Inventory Log. 
4.3.4 
Continued Access to Atezolizumab and/or Tiragolumab 
The Sponsor will offer continued access to Roche IMPs (tiragolumab and/or 
atezolizumab) free of charge to eligible patients in accordance with the Roche Global 
Policy on Continued Access to Investigational Medicinal Product, as outlined below. 
A patient will be eligible to receive Roche IMPs (tiragolumab and/or atezolizumab) after 
completing the study if all of the following conditions are met: 
 
The patient has a life-threatening or severe medical condition and requires 
continued Roche IMP treatment for his or her well-being. 
 
There are no appropriate alternative treatments available to the patient. 
 
The patient and his or her doctor comply with and satisfy any legal or regulatory 
requirements that apply to them. 
 
A patient will not be eligible to receive Roche IMPs (tiragolumab and/or atezolizumab) 
after completing the study if any of the following conditions are met: 
 
The Roche IMP is commercially marketed in the patient's country and is reasonably 
accessible to the patient (e.g., is covered by the patient's insurance or wouldn't 
otherwise create a financial hardship for the patient). 
 
The Sponsor has discontinued development of the IMP or data suggest that the IMP 
is not effective for cervical cancer. 
 
The Sponsor has reasonable safety concerns regarding the IMP as treatment for 
cervical cancer. 
 
Provision of the Roche IMP is not permitted under the laws and regulations of the 
patient's country. 
 
The Roche Global Policy on Continued Access to Investigational Medicinal Product is 
available at the following website: 
http://www.roche.com/policy_continued_access_to_investigational_medicines.pdf 
Patients may be eligible to receive tiragolumab and/or atezolizumab as part of an 
extension study, as described in Section 3.2. 


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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: 
 
 
 
 
 
Premedication with antihistamines, antipyretics, and/or analgesics may be administered 
for the second and subsequent study treatment infusions only, at the discretion of the 
investigator. 
In general, investigators should manage a patient's care (including preexisting 
conditions) with supportive therapies other than those defined as cautionary or 
prohibited therapies (see Sections 4.4.1 and 4.4.2) 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, 
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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 7). 
4.4.2 
Cautionary Therapy for Atezolizumab-Treated Patients 
4.4.2.1 
Corticosteroids, Immunosuppressive Medications, and TNF- 
Inhibitors 
Systemic corticosteroids, immunosuppressive medications, and TNF- inhibitors may 
attenuate potential beneficial immunologic effects of treatment with atezolizumab.  
Therefore, in situations in which systemic corticosteroids, immunosuppressive 
medications, or TNF- inhibitors would be routinely administered, alternatives, including 
antihistamines, should be considered.  If the alternatives are not feasible, systemic 
corticosteroids, immunosuppressive medications, and TNF- inhibitors may be 
administered at the discretion of the investigator. 
Systemic corticosteroids or immunosuppressive medications are recommended, at the 
discretion of the investigator, for the treatment of specific adverse events when 
associated with atezolizumab therapy (refer to Appendix 7 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 4.4.2.2) 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 undergo tumor assessments as described in Section 4.5.6. 
Patients will be closely monitored for safety and tolerability throughout the study.  
Patients should be assessed for toxicity prior to each dose; dosing will occur only if the 
clinical assessment and local laboratory test values are acceptable. 
4.5.1 
Informed Consent Forms and Screening Log 
Written informed consent for participation in the study must be obtained before 
performing any study-related procedures (including screening evaluations).  Informed 
Consent Forms for enrolled patients and for patients who are not subsequently enrolled 
will be maintained at the study site. 
All screening evaluations must be completed and reviewed to confirm that patients meet 
all eligibility criteria before enrollment.  The investigator will maintain a detailed record of 
all patients screened and to document eligibility or record reasons for screening failure, 
as applicable. 
Patients who do not meet the criteria for participation in this study (screen failure) may 
qualify for an additional re-screening opportunities as described in Section 3.1.1. 
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), and reproductive status, 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. 
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, pelvic exam, and neurologic systems.  Any abnormality identified at 
baseline should be recorded on the General Medical History and Baseline 
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Limited, symptom-directed physical examinations should be performed at specified 
postbaseline visits and as clinically indicated.  Changes from baseline abnormalities 
should be recorded in patient notes.  New or worsened clinically significant abnormalities 
should be recorded as adverse events on the Adverse Event eCRF. 
4.5.4 
Vital Signs 
Vital signs will include measurements of respiratory rate, pulse rate, 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. 
See Table 1 and Table 2 for details on the measurements of vital signs during study 
treatment. 
4.5.5 
Performance Status 
Performance status will be measured using the ECOG Performance Status and will be 
assessed at regular intervals throughout the study as specified in the schedule of 
activities (see Appendix 1).  For further details, see Appendix 4. 
4.5.6 
Tumor and Response Evaluations 
Screening and subsequent tumor assessments must include CT scans (with oral and/or 
IV contrast, unless contraindicated) or MRI scans of the chest-abdomen-pelvis.  
MRI scans with contrast of the chest, abdomen, and pelvis may be used in patients for 
whom CT scans with contrast are contraindicated (i.e., patients with contrast allergy or 
impaired renal clearance).  A non-contrast CT scan of the chest may be used in lieu of 
an MRI of the chest. 
In all patients with clinical evidence suspicious for CNS involvement, a CT scan with 
contrast or MRI scan with contrast (if CT contrast is contraindicated) of the brain must be 
performed at screening to evaluate CNS metastasis.  If a CT scan with contrast is 
performed and the presence of brain metastases is considered equivocal, an MRI scan 
of the brain is required to confirm or refute the diagnosis of CNS metastases at baseline.  
Patients with active or untreated CNS metastases are not eligible for the study (see 
Section 4.1.2). 
If a CT scan for tumor assessment is performed in a positron emission tomography 
(PET)/CT scanner, the CT acquisition must be consistent with the standards for a full 
contrast diagnostic CT scan. 
Further investigations such as 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 according to RECIST v1.1 may be used. 


Tumor assessments performed as standard of care prior to obtaining informed consent 
and within 28 days of Day 1 of Cycle 1 may be used rather than repeating tests.  
All known sites of disease, including measurable and/or non-measurable disease, must 
be documented at screening and re-assessed at each subsequent tumor evaluation.  At 
subsequent (post-screening) tumor assessments, patients with a history of irradiated 
brain metastases at screening are not required to undergo brain scans unless clinically 
indicated (e.g., in patients with neurologic symptoms).  The same radiographic 
procedure used to assess disease sites at screening should be used throughout the 
study (e.g., the same contrast protocol for CT scans). 
Patients will undergo tumor assessments at baseline and at every 6 weeks ( ± 7 days) for 
48 weeks following Day 1 of Cycle 1, regardless of treatment delays.  After the 
completion of the Week 48 tumor assessment, tumor assessment will be required every 
9 weeks ( ± 7 days) regardless of treatment delays, until unequivocal radiographic 
disease progression per RECIST v1.1 (or loss of clinical benefit for patients who 
continue study treatment after disease progression per RECIST v1.1), withdrawal of 
consent, death, or study termination by the Sponsor, whichever occurs first 
(see Appendix 1).  At the investigator’s discretion, scans may be performed at any time if 
progressive disease or loss of clinical benefit is suspected. 
Response was previously assessed by the IRC on the imaging modalities detailed above, 
using RECIST v1.1 (see Appendix 3).  As of protocol amendment version 8, imaging scans no 
longer need to be sent to or assessed by IRC.  The investigator’s assessment of overall 
tumor response at all timepoints should only be based on RECIST v1.1.  Assessments 
should be performed by the same evaluator if possible to ensure internal consistency 
across visits.  Results must be reviewed by the investigator before dosing at the next 
cycle. 
Study treatment may be continued as long as patients are experiencing clinical benefit 
as assessed by the investigator in the absence of unacceptable toxicity or symptomatic 
deterioration attributed to disease progression after an integrated assessment of 
radiographic data, biopsy results (if available), and clinical status.  Patients who meet 
criteria for disease progression per RECIST v1.1 will be permitted to continue treatment 
(tiragolumab plus atezolizumab or atezolizumab monotherapy) if they meet all of the 
criteria specified in Section 3.1.2. 
Patients who are treated beyond disease progression per RECIST v1.1 will undergo 
tumor assessments at the frequency described above until study treatment is 
discontinued.  Patients who discontinue treatment for reasons other than radiographic 
disease progression per RECIST v1.1 (e.g., toxicity, symptomatic deterioration) will 
continue scheduled tumor assessments at the frequency described above until 
radiographic disease progression per RECIST v1.1, withdrawal of consent, death, or 
study termination by Sponsor, whichever occurs first at the discretion of the investigator. 
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Investigator assessment of overall tumor response at all timepoints will be only based on 
RECIST v1.1 (see Appendix 3).  This includes continued measurement of target lesions, 
evaluation of non-target lesions (including monitoring for further worsening of any 
non-target lesions that have shown unequivocal progression), and evaluation of any 
newly identified lesions (including measurements, if lesions are measurable; 
see Appendix 3) at all subsequent assessments. 
4.5.7 
Laboratory, Biomarker, and Other Biological Samples 
Samples for the following laboratory tests will be sent to the study site's local laboratory 
for analysis: 
 
Hematology:  WBC count, hemoglobin, platelet count, and differential count 
(neutrophils, eosinophils, basophils, monocytes, and lymphocytes) 
 
Chemistry panel (serum or plasma):  sodium, potassium, glucose, BUN or urea, 
creatinine, albumin, total calcium, total and direct bilirubin, ALP, ALT, AST, and LDH 
 
Coagulation:  PT (or INR) and aPTT (or PTT) 
 
Thyroid-function testing:  thyroid-stimulating hormone, free triiodothyronine (T3) 
(or total T3 for sites where free T3 is not performed), and free thyroxine (also known 
as T4) 
 
Pregnancy test 
All women of childbearing potential will have a urine or serum pregnancy test 
14 days prior to Cycle 1, Day 1.  Urine pregnancy tests will be performed at 
specified subsequent visits.  A positive urine pregnancy test must be confirmed 
by a quantitative serum pregnancy test and an ultrasound confirming 
intrauterine pregnancy. 
 
Urinalysis (glucose, protein, ketones, blood, leukocyte esterase, nitrites, WBC, 
bacteria, and epithelial cells); dipstick permitted  
 


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The following samples will be sent to one or several central laboratories or to the 
Sponsor or a designee for analysis.  Instruction manual and supply kits will be provided 
for these central assessments.  Refer to the laboratory manual for additional details on 
sample handling. 
Assessments Performed on Blood Samples 
The following assessments will be performed on the blood samples: 
 
PK assays 
Serum samples will be obtained for measurement of tiragolumab or atezolizumab 
concentrations using validated immunoassays. 
 
ADA assays 
Serum samples will be obtained for measurement of ADAs to tiragolumab or to 
atezolizumab using validated assays. 
Blood will be obtained for DNA extraction and used as a control to support the 
identification of somatic mutations in tissue and plasma circulating tumor DNA. 
 
Auto-antibody assays 
Serum samples collected for the assessment of PK, ADAs, or biomarkers at 
baseline on Day 1 of Cycle 1 prior to the first dose of study treatment may be 
used for auto-antibody testing if an immune-mediated adverse event develops in 
a patient that would warrant such an assessment. 
 
Assessments Performed on Tissue Samples 
The following assessments will be performed on tumor tissue samples: 
 
Archival or newly collected tumor tissue sample obtained at baseline for 
determination of PD-L1 and for 
 
 


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Biosamples, including those screening tumor tissues collected from patients who do not 
enroll in the study, may be used for future research and/or development of 
disease-related tests or tools. 
For sampling procedures, storage conditions, and shipment instructions, see the 
laboratory manual. 
Biological samples will be destroyed no later than the time of completion of the final 
Clinical Study Report, with the following exceptions: 
 
Serum samples collected for PK or immunogenicity analysis may be needed for 
additional immunogenicity characterization and for PK or immunogenicity assay 
development and validation; therefore, these samples will be destroyed no later than 
5 years after the final Clinical Study Report has been completed. 
 
Blood, plasma, serum and tumor tissue samples collected for biomarker research 
and/or biomarker assay development will be destroyed no later than 15 years after 
the final Clinical Study Report has been completed.  However, the storage period 
will be in accordance with the IRB/EC-approved Informed Consent Form and 
applicable laws (e.g., health authority requirements). 
 
For enrolled patients, remaining archival tissue blocks will be returned to the site 
upon request or no later than 18 months after the final closure of the study 


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database, 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, if requested. 
 
When a patient withdraws from the study, samples collected prior to the date of 
withdrawal may still be analyzed, unless the patient specifically requests that the 
samples be destroyed or local laws require destruction of the samples.  However, if 
samples have been tested prior to withdrawal, results from those tests will remain as 
part of the overall research data. 
Data arising from sample analysis, including data on genomic variants, will be subject to 
the confidentiality standards described in Section 8.4. 
Given the complexity and 
, data 
derived from these analyses will generally not be provided to study investigators or 
patients unless required by law.  The aggregate results of any conducted research will 
be available in accordance with the effective Sponsor policy on study data publication. 
4.5.8 
Electrocardiograms 
An ECG is required at screening and when clinically indicated.  ECGs for each patient 
should be obtained from the same machine wherever possible.  Lead placement should 
be as consistent as possible.  ECG recordings must be performed after the patient has 
been resting in a supine position for at least 10 minutes. 
For safety monitoring purposes, the investigator must review, sign, and date all ECG 
tracings.  ECG tracings will be kept as part of the patient's permanent study file at the 
site as paper copies or per institutional standard.  Any morphologic waveform changes 
or other ECG abnormalities must be documented on the eCRF. 
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 she continues study 
treatment 
 
Investigator or Sponsor determination that treatment discontinuation is in the best 
interest of the patient 
 
Use of another nonprotocol-specified anti-cancer therapy 
 
Pregnancy 


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 
Loss of clinical benefit as determined by the investigator after an integrated 
assessment of radiographic and biochemical data, local biopsy results (if available), 
and clinical status (e.g., symptomatic deterioration such as pain secondary to 
disease) (see Section 3.1.2 for details) 
 
The primary reason for study treatment discontinuation should be documented on the 
appropriate eCRF.  Patients who discontinue study treatment prematurely will not be 
replaced. 
Patients will return to the clinic for a treatment discontinuation visit  30 days after the 
final dose of study treatment.  The visit at which response assessment shows 
progressive disease may be used as the treatment discontinuation visit.  Patients who 
discontinue study treatment for any reason other than progressive disease or loss of 
clinical benefit will continue to undergo tumor response assessments as outlined in the 
schedule of activities (see Appendix 1). 
After treatment discontinuation, no further information on survival follow-up will be 
collected as of protocol version 8. 
4.6.2 
Patient Discontinuation from the Study 
Patients have the right to voluntarily withdraw from the study at any time for any reason.  
In addition, the investigator has the right to withdraw a patient from the study at any time. 
Reasons for patient discontinuation from the study may include, but are not limited to, 
the following: 
 
Patient withdrawal of consent 
 
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. 


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4.6.3 
Study Discontinuation 
The Sponsor has the right to terminate this study at any time.  Reasons for terminating 
the study may include, but are not limited to, the following: 
 
The incidence or severity of adverse events in this or other studies indicates 
a potential health hazard to patients 
 
Patient enrollment is unsatisfactory 
 
The Sponsor will notify the investigator if the Sponsor decides to discontinue the study. 
4.6.4 
Site Discontinuation 
The Sponsor has the right to close a site at any time.  Reasons for closing a site may 
include, but are not limited to, the following: 
 
Excessively slow recruitment 
 
Poor protocol adherence 
 
Inaccurate or incomplete data recording 
 
Non-compliance with the International Council for Harmonisation (ICH) guideline for 
Good Clinical Practice 
 
No study activity (i.e., all patients have completed the study and all obligations have 
been fulfilled) 
 
5. 
ASSESSMENT OF SAFETY  
5.1 
SAFETY PLAN 
The safety plan for patients in this study is based on anticipated mechanism of action, 
results from nonclinical studies, published data on similar molecules, clinical experience 
with tiragolumab alone and in combination with atezolizumab in Phase I and II studies, 
and the clinical safety profile of atezolizumab as a single agent.  The anticipated 
important safety risks for tiragolumab, atezolizumab, and tiragolumab in combination 
with atezolizumab are outlined below (see Sections 5.1.2, 5.1.1, and 5.1.3, respectively).  
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 tiragolumab and atezolizumab will be 
performed in a monitored setting in which there is immediate access to trained personnel 
and adequate equipment and medicine to manage potentially serious reactions.  
Guidelines for managing patients who experience anticipated adverse events, including 
criteria for treatment interruption or discontinuation, are provided in Appendix 7.  


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All patients will be closely monitored for adverse events throughout the study, and 
adverse events will be graded according to the NCI CTCAE v5.0. 
Safety assessments will include the incidence, nature, and severity of adverse events, 
protocol-mandated vital signs, laboratory abnormalities, and other protocol-specified 
tests that are deemed critical to the safety evaluation of the study.  Adverse events will 
be graded according to the NCI CTCAE v5.0.  Refer to Sections 5.45.6 for details on 
safety reporting (e.g., adverse events, pregnancies) for this study. 
Patients with active infection are excluded from study participation.  In the setting of 
a pandemic or epidemic, screening for active infections (including SARS-CoV-2) prior to 
and during study participation should be considered according to local or institutional 
guidelines or guidelines of applicable professional societies (e.g., American Society of 
Clinical Oncology or European Society for Medical Oncology). 
Severe SARS-CoV-2 infection appears to be associated with a CRS involving the 
inflammatory cytokines IL-6, IL-10, IL-2, and IFN- (Merad and Martin 2020).  If a patient 
develops suspected CRS during the study, a differential diagnosis should include 
SARS-CoV-2 infection, which should be confirmed or refuted through assessment of 
exposure history, appropriate laboratory testing, and clinical or radiologic evaluations per 
investigator judgment.  If a diagnosis of SARS-CoV-2 infection is confirmed, the disease 
should be managed as per local or institutional guidelines. 
5.1.1 
Risks Associated with Atezolizumab 
Atezolizumab has been associated with risks such as the following:  IRRs and 
immunemediated hepatitis, pneumonitis, colitis, pancreatitis, diabetes mellitus, 
hypothyroidism, hyperthyroidism, adrenal insufficiency, hypophysitis-, Guillain-Barré 
syndrome, myasthenic syndrome or myasthenia gravis, facial paresis, myelitis, 
meningoencephalitis, myocarditis, pericardial disorders, nephritis, myositis, and severe 
cutaneous adverse reactions.  In addition, immune-mediated reactions may involve any 
organ system and lead to hemophagocytic lymphohistiocytosis (HLH).  Refer to 
Appendix 7 and Section 6 of the Atezolizumab Investigator's Brochure for a detailed 
description of anticipated safety risks for atezolizumab. 
5.1.2 
Risks Associated with Tiragolumab 
 
 
 
 
 
 
 
 


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5.1.2.1 
Infusion-Related Reactions 
Because tiragolumab is a therapeutic MAb and targets immune cells, IRRs associated 
with hypersensitivity reactions and/or target-mediated cytokine release may occur.  
Clinical signs and symptoms of such reactions may include rigors, chills, wheezing, 
pruritus, flushing, rash, hypotension, hypoxemia, and fever. 
 
 
 
 
 
Refer to Section 4.3.2 for detailed guidance on administration of atezolizumab as well as 
tiragolumab in this study.  Refer to Appendix 6 for guidance on anaphylaxis precautions, 
and Appendix 7 for guidance on management of IRRs. 
 
 
 
 
Refer to Appendix 7 for guidance on the management of immune-mediated hepatitis. 
5.1.2.3 
Lymphopenia 
The IgG1 backbone of tiragolumab with the intact Fc-effector function may lead to 
ADCC-mediated reduction in lymphocyte count.  
 
 
  
Patients with a lymphocyte count  500 cells/mL will be excluded from this study (see 
Section 4.1.2), and CBCs will be monitored regularly during the study (see Appendix 7). 
5.1.2.4 
Immune-Mediated Adverse Events 
Nonclinical models have suggested a role of TIGIT signaling interruption in 
autoimmunity.  In a knockout model (TIGIT/), loss of TIGIT signaling resulted in 
hyperproliferative T-cell responses and exacerbation of experimental autoimmune 
encephalitis (EAE).  TIGIT/and wild-type B6 mice were immunized with myelin 
oligodendrocyte glycoprotein peptide in an EAE using suboptimal doses.  In contrast to 
the wild-type B6 mice, the majority of the TIGIT/mice developed severe EAE 
(Joller et al. 2011). 


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Patients with a history of autoimmune disease will be excluded from this study 
(see Section 4.1.2). 
Management guidelines for individual suspected immune-mediated adverse events are 
provided in Appendix 7. 
 
 
5.1.3 
Risks Associated with Combination Use of Tiragolumab 
and Atezolizumab 
Based on results from clinical data with tiragolumab and atezolizumab, there are known 
and potential for overlapping toxicities in patients treated with 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. 
Refer to Section 6 of the Tiragolumab Investigator's Brochure for a list of identified risks 
associated with tiragolumab in combination with atezolizumab.  Based on the 
mechanism of action of tiragolumab and atezolizumab, additional immune-mediated 
adverse events are potential overlapping toxicities associated with combination use of 
tiragolumab plus atezolizumab. 
Based on clinical experience to date, it is anticipated that immune-mediated adverse 
events following treatment with tiragolumab and atezolizumab will be amenable to 


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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 (see Section 5.1) in order to reduce the potential 
risks to participating patients.  Patients with a history of autoimmune disease will be 
excluded from this study (see Section 4.1.2).  Patients previously treated with approved 
or experimental CIT will also be excluded from participation in this study.  
 
 
 
 
 (see Section 4.1.2). 
5.1.4 
Management of Adverse Events 
5.1.4.1 
Dose Modifications 
 
 
5.1.4.2 
Treatment Interruption 
Study treatment may be temporarily suspended as appropriate for management of 
toxicity.  On the basis of the available characterization of mechanism of action, 
tiragolumab may cause adverse events similar to but independent of atezolizumab, may 
exacerbate the frequency or severity of atezolizumab-related adverse events, or may 
have non-overlapping toxicities with atezolizumab.  Because these scenarios may not be 
distinguished from one another in the clinical setting, immune-mediated adverse events 
should generally be attributed to both study drugs, and dose interruptions or treatment 
discontinuation in response to immune-mediated adverse events should be applied to 
both tiragolumab and atezolizumab. 
 
 
 
 
 
 
 
 


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Dose interruptions for reason(s) other than toxicity, such as surgical procedures, may be 
allowed.  The Medical Monitor is available to advise as needed.  
After both tiragolumab and atezolizumab have been permanently discontinued, the 
patient will be monitored for safety and efficacy as defined in Section 4.6.1. 
5.1.4.3 
Management Guidelines for Tiragolumab- and 
Atezolizumab-Specific Adverse Events 
General guidelines for management of patients who experience adverse events, 
including HLH and macrophage activation syndrome (MAS), are presented in 
Appendix 7. 
Guidelines for management of patients who experience adverse events associated with 
tiragolumab and/or atezolizumab, including immune-mediated adverse events, are 
provided in Appendix 7. 
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 
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5.2.1 
Adverse Events 
According to the ICH guideline for Good Clinical Practice, an adverse event is any 
untoward medical occurrence in a clinical investigation subject administered a 
pharmaceutical product, regardless of causal attribution.  An adverse event can 
therefore be any of the following: 
 
Any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal product, 
whether or not considered related to the medicinal product 
 
Any new disease or exacerbation of an existing disease (a worsening in the 
character, frequency, or severity of a known condition) (see 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) 
 
5.2.2 
Serious Adverse Events (Immediately Reportable to 
the Sponsor) 
A serious adverse event is any adverse event that meets any of the following criteria: 
 
Is fatal (i.e., the adverse event actually causes or leads to death) 
 
Is life threatening (i.e., the adverse event, in the view of the investigator, places the 
patient at immediate risk of death) 
This does not include any adverse event that, had it occurred in a more severe 
form or was allowed to continue, might have caused death. 
 
Requires or prolongs inpatient hospitalization (see Section 5.3.5.11) 
 
Results in persistent or significant disability/incapacity (i.e., the adverse event 
results in substantial disruption of the patient's ability to conduct normal life 
functions) 
 
Is a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to 
study treatment 
 
Is a significant medical event in the investigator's judgment (e.g., may jeopardize the 
patient or may require medical/surgical intervention to prevent one of the outcomes 
listed above) 
 
The terms "severe" and "serious" are not synonymous.  Severity refers to the intensity of 
an adverse event (e.g., rated as mild, moderate, or severe, or according to NCI CTCAE; 


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see Section 5.3.3); the event itself may be of relatively minor medical significance (such 
as severe headache without any further findings). 
Severity and seriousness need to be independently assessed for each adverse event 
recorded on the eCRF. 
Serious adverse events are required to be reported by the investigator to the Sponsor 
immediately (i.e., no more than 24 hours after learning of the event; see Section 5.4.2 for 
reporting instructions). 
5.2.3 
Adverse Events of Special Interest (Immediately Reportable to 
the Sponsor) 
Adverse events of special interest are required to be reported by the investigator to the 
Sponsor immediately (i.e., no more than 24 hours after learning of the event; see 
Section 5.4.2 for reporting instructions).  Adverse events of special interest for this study 
are as follows: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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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). 
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. 


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


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5.3.4 
Assessment of Causality of Adverse Events 
Investigators should use their knowledge of the patient, the circumstances surrounding 
the event, and an evaluation of any potential alternative causes to determine whether an 
adverse event is considered to be related to study treatment, indicating "yes" or "no" 
accordingly.  The following guidance should be taken into consideration (see also 
Table 5). 
 
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 5 
Causal Attribution Guidance 
Is the adverse event suspected to be caused by study treatment on the basis of facts, 
evidence, science-based rationales, and clinical judgment? 
YES 
There is a plausible temporal relationship between the onset of the adverse event and 
administration of study treatment, and the adverse event cannot be readily explained by 
the patient's clinical state, intercurrent illness, or concomitant therapies; and/or the 
adverse event follows a known pattern of response to study treatment; and/or the 
adverse event abates or resolves upon discontinuation of study treatment or dose 
reduction and, if applicable, reappears upon re-challenge. 
NO 
An adverse event will be considered related, unless it fulfills the criteria specified below.   
Evidence exists that the adverse event has an etiology other than study treatment 
(e.g., preexisting medical condition, underlying disease, intercurrent illness, 
or concomitant medication); and/or the adverse event has no plausible temporal 
relationship to administration of study treatment (e.g., cancer diagnosed 2 days after 
first dose of study treatment). 
  
For patients receiving combination therapy, causality will be assessed individually for 
each protocol-mandated therapy. 
5.3.5 
Procedures for Recording Adverse Events 
Investigators should use correct medical terminology/concepts when recording adverse 
events on the Adverse Event eCRF.  Avoid colloquialisms and abbreviations. 
Only one adverse event term should be recorded in the event field on the Adverse 
Event eCRF. 
5.3.5.1 
Infusion-Related Reactions and 
 
There may be significant overlap in signs and symptoms of IRRs and 
.  Whereas 
IRRs occur during or within 24 hours after treatment administration, time to onset of 
 
may vary.  Differential diagnosis should be applied, particularly for
 
(occurring more than 24 hours after treatment administration), to rule out other etiologies 
such as delayed hypersensitivity reactions, sepsis or infections, 
, tumor lysis 
syndrome, early disease progression, or other manifestations of systemic inflammation. 
Adverse events that occur during or within 24 hours after study treatment administration 
and are judged to be related to study treatment infusion 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 


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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 
. 
NCI CTCAE v5.0 and 
 
should be used when reporting severity of 
 on the Adverse Event eCRF.  
NCI CTCAE v5.0 should be used when reporting severity of organ toxicities associated 
with 
on the dedicated 
.  Organ toxicities 
associated with 
 should not influence overall CRS grading. 
Guidelines for medical management of IRRs and 
 are provided in Appendix 7, 
Table 7, and Table 8, respectively. 
Severe SARS-CoV-2 infection appears to be associated with a CRS involving the 
inflammatory cytokines IL-6, IL-10, IL-2, and IFN- (Merad and Martin 2020).  If a patient 
develops suspected CRS during the study, a differential diagnosis should include 
SARS-CoV-2 infection, which should be confirmed or refuted through assessment of 
exposure history, appropriate laboratory testing, and clinical or radiologic evaluations per 
investigator judgment.  If a diagnosis of SARS-CoV-2 infection is confirmed, the disease 
should be managed as per local or institutional guidelines. 
5.3.5.2 
Diagnosis versus Signs and Symptoms 
A diagnosis (if known) should be recorded on the Adverse Event eCRF rather than 
individual signs and symptoms (e.g., record only liver failure or hepatitis rather than 
jaundice, asterixis, and elevated transaminases).  However, if a constellation of signs 
and/or symptoms cannot be medically characterized as a single diagnosis or syndrome 
at the time of reporting, each individual event should be recorded on the Adverse Event 
eCRF.  If a diagnosis is subsequently established, all previously reported adverse events 
based on signs and symptoms should be nullified and replaced by one adverse event 
report based on the single diagnosis, with a starting date that corresponds to the starting 
date of the first symptom of the eventual diagnosis. 
5.3.5.3 
Adverse Events That Are Secondary to Other Events 
In general, adverse events that are secondary to other events (e.g., cascade events or 
clinical sequelae) should be identified by their primary cause, with the exception of 
severe or serious secondary events.  A medically significant secondary adverse event 
that is separated in time from the initiating event should be recorded as an independent 
event on the Adverse Event eCRF.  For example: 
 
If vomiting results in mild dehydration with no additional treatment in a healthy adult, 
only vomiting should be reported on the eCRF. 
 
If vomiting results in severe dehydration, both events should be reported separately 
on the eCRF. 


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 
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 three events should be 
reported separately on the eCRF. 
 
If neutropenia is accompanied by an infection, both events should be reported 
separately on the eCRF. 
 
All adverse events should be recorded separately on the Adverse Event eCRF if it is 
unclear as to whether the events are associated. 
5.3.5.4 
Persistent or Recurrent Adverse Events 
A persistent adverse event is one that extends continuously, without resolution, between 
patient evaluation timepoints.  Such events should only be recorded once on the 
Adverse Event eCRF.  The initial severity (intensity or grade) of the event will be 
recorded at the time the event is first reported.  If a persistent adverse event becomes 
more severe, the most extreme severity should also be recorded on the Adverse Event 
eCRF.  If the event becomes serious, it should be reported to the Sponsor immediately 
(i.e., no more than 24 hours after learning that the event became serious; 
see Section 5.4.2 for reporting instructions).  The Adverse Event eCRF should be 
updated by changing the event from "non-serious" to "serious," providing the date 
that the event became serious, and completing all data fields related to serious 
adverse events. 
A recurrent adverse event is one that resolves between patient evaluation timepoints 
and subsequently recurs.  Each recurrence of an adverse event should be recorded as 
a separate event on the Adverse Event eCRF. 
5.3.5.5 
Abnormal Laboratory Values 
Not every laboratory abnormality qualifies as an adverse event.  A laboratory test result 
must be reported as an adverse event if it meets any of the following criteria: 
 
Is accompanied by clinical symptoms 
 
Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation) 
 
Results in a medical intervention (e.g., potassium supplementation for hypokalemia) 
or a change in concomitant therapy 
 
Is clinically significant in the investigator's judgment  
Note:  For oncology trials, certain abnormal values may not qualify as adverse 
events. 
 
It is the investigator's responsibility to review all laboratory findings.  Medical and 
scientific judgment should be exercised in deciding whether an isolated laboratory 
abnormality should be classified as an adverse event. 


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If a clinically significant laboratory abnormality is a sign of a disease or syndrome 
(e.g., ALP and bilirubin 5  ULN associated with cholestasis), only the diagnosis 
(i.e., cholestasis) should be recorded on the Adverse Event eCRF. 
If a clinically significant laboratory abnormality is not a sign of a disease or syndrome, 
the abnormality itself should be recorded on the Adverse Event eCRF, along with 
a descriptor indicating whether the test result is above or below the normal range 
(e.g., "elevated potassium," as opposed to "abnormal potassium").  If the laboratory 
abnormality can be characterized by a precise clinical term per standard definitions, the 
clinical term should be recorded as the adverse event.  For example, an elevated serum 
potassium level of 7.0 mEq/L should be recorded as "hyperkalemia." 
Observations of the same clinically significant laboratory abnormality from visit to visit 
should only be recorded once on the Adverse Event eCRF (see Section 5.3.5.4 for 
details on recording persistent adverse events). 
5.3.5.6 
Abnormal Vital Sign Values 
Not every vital sign abnormality qualifies as an adverse event.  A vital sign result must 
be reported as an adverse event if it meets any of the following criteria: 
 
Is accompanied by clinical symptoms 
 
Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation) 
 
Results in a medical intervention or a change in concomitant therapy 
 
Is clinically significant in the investigator's judgment  
 
It is the investigator's responsibility to review all vital sign findings.  Medical and scientific 
judgment should be exercised in deciding whether an isolated vital sign abnormality 
should be classified as an adverse event. 
If a clinically significant vital sign abnormality is a sign of a disease or syndrome 
(e.g., high blood pressure), only the diagnosis (i.e., hypertension) should be recorded on 
the Adverse Event eCRF. 
Observations of the same clinically significant vital sign abnormality from visit to visit 
should only be recorded once on the Adverse Event eCRF (see Section 5.3.5.4 for 
details on recording persistent adverse events). 
5.3.5.7 
Abnormal Liver Function Tests 
The finding of an elevated ALT or AST ( 3  ULN) in combination with either an elevated 
total bilirubin ( 2  ULN) or clinical jaundice in the absence of cholestasis or other 
causes of hyperbilirubinemia is considered to be an indicator of severe liver injury 


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(as defined by Hy's Law).  Therefore, investigators must report as an adverse event the 
occurrence of either of the following: 
 
Treatment-emergent ALT or AST  3  ULN in combination with total bilirubin 
 2  ULN 
 
Treatment-emergent ALT or AST  3  ULN in combination with clinical jaundice 
 
The most appropriate diagnosis or (if a diagnosis cannot be established) the abnormal 
laboratory values should be recorded on the Adverse Event eCRF (see Section 5.3.5.2) 
and reported to the Sponsor immediately (i.e., no more than 24 hours after learning of 
the event), either as a serious adverse event or an adverse event of special interest 
(see Section 5.4.2). 
5.3.5.8 
Deaths 
For this protocol, mortality is an efficacy endpoint.  Deaths that occur during the 
protocol-specified adverse event reporting period (see Section 5.3.1) that are attributed 
by the investigator solely to progression of cervical cancer should be recorded on the 
Death Attributed to Progressive Disease eCRF.  All other deaths that occur during the 
adverse event reporting period, regardless of relationship to study treatment, must be 
recorded on the Adverse Event eCRF and immediately reported to the Sponsor 
(see Section 5.4.2). 
Death should be considered an outcome and not a distinct event.  The event or condition 
that caused or contributed to the fatal outcome should be recorded as the single medical 
concept on the Adverse Event eCRF.  Generally, only one such event should be 
reported.  If the cause of death is unknown and cannot be ascertained at the time of 
reporting, "unexplained death" should be recorded on the Adverse Event eCRF.  If the 
cause of death later becomes available (e.g., after autopsy), "unexplained death" should 
be replaced by the established cause of death.  The term "sudden death" should not be 
used unless combined with the presumed cause of death (e.g., "sudden cardiac death"). 
Deaths that occur after the adverse event reporting period should be reported as 
described in Section 5.6. 
5.3.5.9 
Preexisting Medical Conditions 
A preexisting medical condition is one that is present at the screening visit for this study.  
Such conditions should be recorded on the General Medical History and Baseline 
Conditions eCRF. 
A preexisting medical condition should be recorded as an adverse event only if the 
frequency, severity, or character of the condition worsens during the study.  
When recording such events on the Adverse Event eCRF, it is important to convey the 
concept that the preexisting condition has changed by including applicable descriptors 
(e.g., "more frequent headaches"). 


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5.3.5.10 
Lack of Efficacy or Worsening of Cervical Cancer 
Events that are clearly consistent with the expected pattern of progression of the 
underlying disease should not be recorded as adverse events.  These data will be 
captured as efficacy assessment data only.  In most cases, the expected pattern of 
progression will be based on RECIST v1.1.  In rare cases, the determination of clinical 
progression will be based on symptomatic deterioration.  However, every effort should 
be made to document progression through use of objective criteria.  If there is any 
uncertainty as to whether an event is due to disease progression, it should be reported 
as an adverse event. 
5.3.5.11 
Hospitalization or Prolonged Hospitalization 
Any adverse event that results in hospitalization (i.e., inpatient admission to a hospital) 
or prolonged hospitalization should be documented and reported as a serious adverse 
event (per the definition of serious adverse event in Section 5.2.2), except as 
outlined below. 
An event that leads to hospitalization under the following circumstances should not be 
reported as an adverse event or a serious adverse event: 
 
Hospitalization for respite care 
 
Planned hospitalization required by the protocol (e.g., for study treatment 
administration or performance of an efficacy measurement for the study) 
 
Hospitalization for a preexisting condition, provided that all of the following criteria 
are met: 
The hospitalization was planned prior to the study or was scheduled during the 
study when elective surgery became necessary because of the expected 
normal progression of the disease 
The patient has not experienced an adverse event 
 
Hospitalization due solely to progression of the underlying cancer 
 
An event that leads to hospitalization under the following circumstances is not 
considered to be a serious adverse event, but should be reported as an adverse 
event instead: 
 
Hospitalization that was necessary because of patient requirement for outpatient 
care outside of normal outpatient clinic operating hours. 
 
5.3.5.12 
Cases of Accidental Overdose or Medication Error  
Accidental overdose and medication error (hereafter collectively referred to as "special 
situations"), are defined as follows: 
 
Accidental overdose:  accidental administration of a drug in a quantity that is higher 
than the assigned dose. 


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 
Medication error:  accidental deviation in the administration of a drug  
In some cases, a medication error may be intercepted prior to administration of 
the drug. 
 
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 tiragolumab and atezolizumab, 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 tiragolumab and atezolizumab, 
regardless of whether they result in an adverse event, should be recorded on the 
Adverse Event eCRF as described below: 
 
Accidental overdose:  Enter the drug name and "accidental overdose" as the event 
term.  Check the "Accidental overdose" and "Medication error" boxes. 
 
Medication error that does not qualify as an overdose:  Enter the name of the drug 
administered and a description of the error (e.g., wrong dose administered, wrong 
dosing schedule, incorrect route of administration, wrong drug, expired drug 
administered) as the event term.  Check the "Medication error" box. 
 
Medication error that qualifies as an overdose:  Enter the drug name and "accidental 
overdose" as the event term.  Check the "Accidental overdose" and "Medication 
error" boxes.  Enter a description of the error in the additional case details. 
 
Intercepted medication error:  Enter the drug name and "intercepted medication 
error" as the event term.  Check the "Medication error" box.  Enter a description of 
the error in the additional case details. 
 
As an example, an accidental overdose that resulted in a headache would require two 
entries on the Adverse Event eCRF, one entry to report the accidental overdose and one 
entry to report the headache.  The "Accidental overdose" and "Medication error" boxes 
would need to be checked for both entries. 


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5.3.5.13 
Safety Biomarker Data  
Adverse event reports will not be derived from safety biomarker data by the Sponsor, 
and safety biomarker data will not be included in the formal safety analyses for this 
study.  In addition, safety biomarker data will not inform decisions on patient 
management. 
5.4 
IMMEDIATE REPORTING REQUIREMENTS FROM 
INVESTIGATOR TO SPONSOR 
Certain events require immediate reporting to allow the Sponsor to take appropriate 
measures to address potential new risks in a clinical trial.  The investigator must report 
such events to the Sponsor immediately; under no circumstances should reporting take 
place more than 24 hours after the investigator learns of the event.  The following is a list 
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 
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 
all calls.  Contact information, including toll-free numbers for the Emergency Medical 
Call Center, will be distributed to investigators. 


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5.4.2 
Reporting Requirements for Serious Adverse Events and 
Adverse Events of Special Interest 
5.4.2.1 
Events That Occur prior to Study Treatment Initiation 
After informed consent has been obtained but prior to initiation of study treatment, only 
serious adverse events caused by a protocol-mandated intervention should be reported.  
The paper Clinical Trial Adverse Event/Special Situations Form provided to investigators 
should be completed and submitted to the Sponsor or its designee immediately (i.e., no 
more than 24 hours after learning of the event), either by faxing or by scanning and 
emailing the form using the fax number or email address provided to investigators. 
5.4.2.2 
Events That Occur after Study Treatment Initiation 
After initiation of study treatment, serious adverse events and adverse events of special 
interest will be reported for the period defined in Section 5.3.1.  Investigators should 
record all case details that can be gathered immediately (i.e., within 24 hours after 
learning of the event) on the Adverse Event eCRF and submit the report via the 
electronic data capture (EDC) system.  A report will be generated and sent to Roche 
Safety Risk Management by the EDC system. 
In the event that the EDC system is unavailable, the paper Clinical Trial Adverse 
Event/Special Situations Form provided to investigators should be completed and 
submitted to the Sponsor or its designee immediately (i.e., no more than 24 hours after 
learning of the event), either by faxing or by scanning and emailing the form using the 
fax number or email address provided to investigators.  Once the EDC system is 
available, all information will need to be entered and submitted via the EDC system. 
Instructions for reporting serious adverse events that occur after the reporting period are 
provided in Section 5.6. 
5.4.3 
Reporting Requirements for Pregnancies 
5.4.3.1 
Pregnancies in Female Patients 
Female patients of childbearing potential will be instructed through the Informed Consent 
Form to immediately inform the investigator if they become pregnant during the study 
treatment, within 90 days after the final dose of tiragolumab, or within 5 months after the 
final dose of atezolizumab.  A paper Clinical Trial Pregnancy Reporting Form should be 
completed and submitted to the Sponsor or its designee immediately (i.e., no more than 
24 hours after learning of the pregnancy), either by faxing or by scanning and emailing 
the form using the fax number or email address provided to investigators.  Pregnancy 
should not be recorded on the Adverse Event eCRF.  The investigator should 
discontinue study treatment and counsel the patient, discussing the risks of the 
pregnancy and the possible effects on the fetus.  Monitoring of the patient should 
continue until conclusion of the pregnancy.  Any serious adverse events associated with 
the pregnancy (e.g., an event in the fetus, an event in the mother during or after the 
pregnancy, or a congenital anomaly/birth defect in the child) should be reported on the 
Adverse Event eCRF.  In addition, the investigator will submit a Clinical Trial Pregnancy 


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Reporting Form when updated information on the course and outcome of the pregnancy 
becomes available. 
5.4.3.2 
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 
embryofetal 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 
embryofetal toxicity is not considered an adverse event. 
All abortions should be reported as pregnancy outcomes on the paper Clinical Trial 
Pregnancy Reporting Form. 
5.4.3.3 
Congenital Anomalies/Birth Defects 
Any congenital anomaly/birth defect in a child born to a female 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. 


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5.5.2 
Sponsor Follow-Up 
For serious adverse events, adverse events of special interest, and pregnancies, the 
Sponsor or a designee may follow up by telephone, fax, email, and/or a monitoring visit 
to obtain additional case details and outcome information (e.g., from hospital discharge 
summaries, consultant reports, autopsy reports) in order to perform an independent 
medical assessment of the reported case. 
5.6 
ADVERSE EVENTS THAT OCCUR AFTER THE 
ADVERSE EVENT REPORTING PERIOD 
After the end of the reporting period for serious adverse events and adverse events of 
special interest (see 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 email address provided to investigators. 
5.7 
EXPEDITED REPORTING TO HEALTH AUTHORITIES, 
INVESTIGATORS, INSTITUTIONAL REVIEW BOARDS, 
AND ETHICS COMMITTEES 
The Sponsor will promptly evaluate all serious adverse events and adverse events of 
special interest against cumulative product experience to identify and expeditiously 
communicate possible new safety findings to investigators, IRBs, ECs, and applicable 
health authorities based on applicable legislation. 
The Sponsor has a legal responsibility to notify regulatory authorities about the safety 
of a study treatment under clinical investigation.  The Sponsor will comply with 
regulatory requirements for expedited safety reporting to regulatory authorities (which 
includes the use of applicable systems, such as EudraVigilance), IRBs, ECs, and 
investigators. 
To determine reporting requirements for single adverse event cases, the Sponsor will 
assess the expectedness of these events through use of the reference safety 
information in the documents listed below:  
Drug 
Document 
Tiragolumab 
Tiragolumab Investigator's Brochure 
Atezolizumab 
Atezolizumab Investigator’s Brochure 
 


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The Sponsor will compare the severity of each event and the cumulative event 
frequency reported for the study with the severity and frequency reported in the 
applicable reference document. 
Reporting requirements will also be based on the investigator's assessment of causality 
and seriousness, with allowance for upgrading by the Sponsor as needed. 
6. 
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN 
This is a Phase II, global, open-label, randomized study designed to evaluate the 
efficacy and safety of tiragolumab in combination with atezolizumab and of atezolizumab 
monotherapy in approximately 160 patients with metastatic and/or recurrent 
PD-L1positive cervical cancer after progression or recurrence from systemic therapy. 
Efficacy analyses will be conducted in all randomized patients who receive at least one 
dose of study treatment.  Patients will be grouped according to treatment received, 
excluding treatment received during a potential crossover period. 
Safety analyses will be conducted in all randomized patients who receive at least one 
dose of tiragolumab or atezolizumab.  Safety analyses will be performed by treatment 
arm and will be based on actual treatment received.  Specifically, a patient will be 
included in the tiragolumab plus atezolizumab arm in the safety analyses if the patient 
receives any amount of tiragolumab, regardless of the initial treatment assignment at 
randomization.  
The global population will include all patients enrolled during the global enrollment 
phase, and the 
 
  Separate analyses will be performed for the global 
population and the 
 
. 
More details of analyses are provided in the Statistical Analysis Plan (SAP). 
6.1 
DETERMINATION OF SAMPLE SIZE 
A total of 160 patients will be enrolled in this study and randomized in a 3:1 ratio 
(tiragolumab in combination with atezolizumab and atezolizumab monotherapy).  
The overall statistical power for several assumptions of the true underlying ORR in 
tiragolumab in combination with atezolizumab arm is given in Table 6 and takes the 
following considerations into account: 
 
Primary statistical test is a 
 at a one-sided 
 significance level, 
and the doublet arm will be compared to a historical reference of 14.6% 
(Chung et al. 2019). 
 


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No type-I error control is applied for descriptive comparisons, including that of the 
atezolizumab monotherapy ORR to the historical reference.  The probability of the 
observed ORR in the atezolizumab monotherapy arm being greater than a reference 
point at the time of final ORR analysis is also shown in Table 7. 
Table 6 
Overall Statistical Power in the Comparison of ORR in 
Tiragolumab in Combination with Atezolizumab Arm to a 
Reference Point of 14.6% 
Reference ORR 
True Underlying ORR in Tiragolumab in Combination with Atezolizumab 
14.6% a 
(MDO b  
) 
MDO  minimum detectable observation; ORR  overall response rate. 
a Source:  Chung et al. 2019. 
b MDO is defined as the smallest observed ORR leading to statistical significance at final 
analysis. 
  
Table 7 
Probability of Observed ORR in Atezolizumab Monotherapy Arm 
Greater than a Reference Point at the Final Analysis for ORR 
Reference ORR 
True Underlying ORR in Atezolizumab Monotherapy 
14.6% a  
ORR  overall response rate. 
a Source:  Chung et al. 2019. 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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6.2 
SUMMARIES OF CONDUCT OF STUDY 
Enrollment, study drug administration, and discontinuation from the study will be 
summarized by treatment arm.  The reasons for study drug discontinuation will also be 
tabulated.  Major protocol deviations, including major deviations with regard to the 
inclusion and exclusion criteria, will be summarized by treatment arm. 
6.3 
SUMMARIES OF DEMOGRAPHIC AND BASELINE 
CHARACTERISTICS 
Demographic and baseline characteristics (including age, sex, race/ethnicity) will be 
summarized using means, standard deviations, medians, and ranges for continuous 
variables and proportions for categorical variables, as appropriate.  Summaries will be 
presented overall and by treatment group. 
6.4 
EFFICACY ANALYSES 
The analysis population for the efficacy analyses will consist of all randomized patients 
who receive at least one dose of study treatment.  Patients will be grouped according to 
treatment received, excluding treatment received during a potential crossover period.  
6.4.1 
Primary Efficacy Endpoint 
The primary efficacy objective for this study is to evaluate the efficacy of tiragolumab in 
combination with atezolizumab and of atezolizumab monotherapy on the basis of the 
following endpoint: 
 
ORR, defined as the proportion of patients with a CR or PR on two consecutive 
occasions  4 weeks apart, as determined by the IRC according to RECIST v1.1.  
As of protocol amendment version 8, imaging scans no longer need to be sent to or 
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The primary efficacy analysis population will consist of all randomized patients who 
receive at least one dose of study treatment, with patients grouped according to 
treatment received.  
The primary efficacy analysis will take place once all patients have been enrolled and a 
minimum follow-up of approximately 6 months after the second tumor assessment, or 
approximately 9 months after randomization, has been achieved among the patients 
who remain in follow-up for ORR assessment, whichever is earlier. 
In the primary analysis, patients whose ORR assessment was missing will be counted 
as not achieving a response.  A one-sample z-test for proportion will be used for 
comparing the ORR of the tiragolumab in combination with atezolizumab arm to the 
historical reference.  An estimate of the ORR and its 95% CI (Clopper-Pearson; Clopper 
and Pearson 1934) will be calculated for each treatment arm. 
A sensitivity analysis will be performed for the primary endpoint of confirmed ORR on the 
ITT population (all randomized patients). 
6.4.2 
Secondary Efficacy Endpoints 
The secondary efficacy objective for this study is to evaluate the efficacy of tiragolumab 
in combination with atezolizumab and of atezolizumab monotherapy on the basis of the 
following endpoints as described below. 
6.4.2.1 
Duration of Response 
DOR is defined for patients who had an objective response as the time from the first 
occurrence of a documented objective response (CR or PR) to the date of disease 
progression or death from any cause (whichever occurs first), as determined by the IRC 
according to RECIST v1.1.  As of protocol amendment version 8, imaging scans no 
longer need to be sent to or assessed by IRC.  Data for patients who have not 
experienced disease progression or death will be censored at the last tumor assessment 
date.  If no tumor assessments were performed after the date of the first occurrence of 
CR or PR, data for DOR will be censored at the date of the first occurrence of CR or PR 
plus1 day. 
The analysis of DOR is based on a non-randomized subset of patients (those who 
achieve an objective response); therefore, formal hypothesis testing will not be 
performed for this endpoint.  Comparisons between treatment arms will be made for 
descriptive purposes only.  In particular, Kaplan-Meier methodology will be used to 
estimate the median DOR for each treatment arm, and Kaplan-Meier curves will be 
produced.  The Brookmeyer-Crowley methodology will be used to construct the 95% CI 
for the median DOR for each treatment arm (Brookmeyer and Crowley 1982). 
6.4.2.2 
Disease Control Rate 
DCR is defined as the proportion of patients with a CR, PR, or SD, as determined by the 
IRC according to RECIST v1.1.  As of protocol amendment version 8, imaging scans no 


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longer need to be sent to or assessed by IRC.  The methodologies described for the 
analysis of ORR will be the same as used for the analysis of DCR. 
6.4.2.3 
Best Clinical Response 
BCR is defined as the proportion of patients with a CR, PR, or SD, as determined by the 
investigator.  The methodologies described for the analysis of ORR will be the same as 
used for the analysis of BCR.  DOR determined by the investigator will also be provided, 
and the methodology will be the same as used for the analysis of the IRC DOR. 
6.4.2.4 
Progression-Free Survival, Including the 6-Month 
Progression-Free Survival Rate 
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 IRC 
according to RECIST v1.1.  As of protocol amendment version 8, imaging scans no 
longer need to be sent to or assessed by IRC. 
Kaplan-Meier methodology will be used to estimate the median PFS for each treatment 
arm, and Kaplan-Meier curves will be produced.  The Brookmeyer-Crowley methodology 
will be used to construct the 95% CI for the median PFS for each treatment arm 
(Brookmeyer and Crowley 1982).  The Kaplan-Meier approach will also be used to 
estimate 6-month PFS rate in each arm. 
6.4.2.5 
Overall Survival, Including the 6-Month and 12-Month Overall 
Survival Rate 
OS is defined as the time from randomization to death from any cause. 
The methodologies described for the analysis of PFS will be the same as used for the 
analysis of OS. 
6.4.4 
Analyses of Exposure, Adverse Event, Laboratory, and 
Vital Sign Data 
The safety analyses will include all randomized patients who receive at least one dose of 
study drug, with patients grouped according to treatment received.  Safety will be 
assessed through summaries of adverse events, changes in laboratory test results, 
changes in vital signs, and study treatment exposures and will be presented by 
treatment arm.  Verbatim descriptions of adverse events will be summarized by mapped 
term, appropriate thesaurus level, and toxicity grade.  For each patient, if multiple 
incidences of the same adverse events occur, the maximum severity reported will be 
used in the summaries.  The following treatment-emergent adverse events will be 
summarized separately:  adverse events leading to withdrawal of study drug, adverse 


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events leading to dose reduction or interruption, Grade 3 adverse events, adverse 
events leading to death, serious adverse events, and adverse events of special interest 
(see Section 5.2.3).  Relevant laboratory values will be summarized by time, with 
NCI CTCAE v5.0 Grade 3 and Grade 4 values identified, where appropriate.  Changes in 
NCI CTCAE grade will be tabulated by treatment arm. 
6.5 
SAFETY ANALYSES 
Safety analyses will be conducted in all randomized patients who receive at least one 
dose of tiragolumab or atezolizumab.  Safety analyses will be performed by treatment 
arm and will be based on actual treatment received.  Specifically, a patient will be 
included in the tiragolumab plus atezolizumab arm in the safety analyses if the patient 
receives any amount of tiragolumab, regardless of the initial treatment assignment at 
randomization. 
Safety assessments will include the incidence, nature, and severity of adverse events, 
protocol-mandated vital signs, laboratory abnormalities, and other protocol-specified 
tests that are deemed critical to the safety evaluation of the study. 
Safety will be assessed through summaries of adverse events, changes in laboratory 
test results, changes in vital signs, study treatment exposures, and immunogenicity as 
measured by ADAs and will be presented by treatment arm. 
Verbatim descriptions of adverse events will be mapped to MedDRA 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.  For each 
patient, if multiple incidences of the same adverse events occur, the maximum severity 
reported will be used in the summaries. 
The following treatment-emergent adverse events will be summarized separately: 
adverse events leading to withdrawal of study drug, adverse events leading to dose 
reduction or interruption, Grade  3 adverse events, Grade 5 adverse events, serious 
adverse events, and adverse events of special interest. 
All deaths and causes of death will be summarized. 
Relevant laboratory values will be summarized by treatment arm, with NCI CTCAE 
Grade 3 and Grade 4 values identified, where appropriate. 
6.6 
PHARMACOKINETIC ANALYSES 
PK samples of tiragolumab and atezolizumab will be collected in this study as outlined in 
Appendix 2.  Tiragolumab and atezolizumab serum concentration data (minimum serum 
concentration and maximum serum concentration) will be tabulated and summarized.  


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Descriptive statistics will include means, medians, ranges, and standard deviations, 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 number and proportion of treatment-emergent ADA-positive patients and 
ADA-negative patients during both the treatment and follow-up periods will be 
summarized by treatment arm. 
 
 
 
 
 
 
  
 
 
 
 
 
 
 


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7. 
DATA COLLECTION AND MANAGEMENT 
7.1 
DATA QUALITY ASSURANCE 
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. 
The Sponsor will be responsible for data management of this study, including quality 
checking of the data.  Data entered manually will be collected via EDC through use of 
eCRFs.  Sites will be responsible for data entry into the EDC system.  In the event of 
discrepant data, the Sponsor will request data clarification from the sites, which the sites 
will resolve electronically in the EDC system. 
The Sponsor will produce an EDC Study Specification document that describes the 
quality checking to be performed on the data.  Central laboratory data will be sent 
directly to the Sponsor, using the Sponsor's standard procedures to handle and process 
the electronic transfer of these data. 


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


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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, 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. 
Roche will retain study data for 25 years after the final study results have been reported 
or for the length of time required by relevant national or local health authorities, 
whichever is longer. 
8. 
ETHICAL CONSIDERATIONS 
8.1 
COMPLIANCE WITH LAWS AND REGULATIONS 
This study will be conducted in full conformance with the ICH E6 guideline for Good 
Clinical Practice and the principles of the Declaration of Helsinki, or the applicable laws 
and regulations of the country in which the research is conducted, whichever affords the 
greater protection to the individual.  The study will comply with the requirements of the 
ICH E2A guideline (Clinical Safety Data Management:  Definitions and Standards for 
Expedited Reporting).  Studies conducted in the United States or under a U.S. 
Investigational New Drug (IND) Application will comply with U.S. FDA regulations and 
applicable local, state, and federal laws.  Studies conducted in the European Union or 
European Economic Area will comply with the E.U. Clinical Trials Directive (2001/20/EC) 
or Clinical Trials Regulation (536/2014) and applicable local, regional, and national laws. 
8.2 
INFORMED CONSENT 
The Sponsor's sample Informed Consent Form (and ancillary sample Informed Consent 
Forms such as an Assent Form or Mobile Nursing Informed Consent Form, if applicable) 
will be provided to each site.  If applicable, it will be provided in a certified translation of 


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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 her participation in the study.  The case history or 
clinical records for each patient shall document the informed consent process and that 
written informed consent was obtained prior to participation in the study. 
The Consent Forms should be revised whenever there are changes to study procedures 
or when new information becomes available that may affect the willingness of the patient 
to participate.  The final revised IRB/EC-approved Consent Forms must be provided to 
the Sponsor for health authority submission purposes. 
If the Consent Forms are revised (through an amendment or an addendum) while 
a patient is participating in the study, the patient or a legally authorized representative 
must re-consent by signing the most current version of the Consent Forms or the 
addendum, in accordance with applicable laws and IRB/EC policy.  For any updated or 
revised Consent Forms, the case history or clinical records for each patient shall 
document the informed consent process and that written informed consent was obtained 
using the updated/revised Consent Forms for continued participation in the study. 
A copy of each signed Consent Form must be provided to the patient or the patient's 
legally authorized representative.  All signed and dated Consent Forms must remain in 
each patient's study file or in the site file and must be available for verification by study 
monitors at any time. 
For sites in the United States, each Consent Form may also include patient authorization 
to allow use and disclosure of personal health information in compliance with the U.S. 
Health Insurance Portability and Accountability Act (HIPAA) of 1996.  If the site utilizes 
a separate Authorization Form for patient authorization for use and disclosure of 
personal health information under the HIPAA regulations, the review, approval, 
and other processes outlined above apply except that IRB review and approval may not 
be required per study site policies. 


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


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Data generated by this study must be available for inspection upon request by 
representatives of national and local health authorities, Sponsor monitors, 
representatives, and collaborators, and the IRB/EC for each study site, as appropriate. 
Study data may be submitted to government or other health research databases or 
shared with researchers, government agencies, companies, or other groups that are not 
participating in this study.  These data may be combined with or linked to other data and 
used for research purposes, to advance science and public health, or for analysis, 
development, and commercialization of products to treat and diagnose disease.  In 
addition, redacted Clinical Study Reports and other summary reports will be provided 
upon request (see Section 9.6). 
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 3.2). 
9. 
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION 
9.1 
STUDY DOCUMENTATION 
The investigator must maintain adequate and accurate records to enable the conduct of 
the study to be fully documented, including, but not limited to, the protocol, protocol 
amendments, Informed Consent Forms, and documentation of IRB/EC and 
governmental approval.  In addition, at the end of the study, the investigator will receive 
the patient data, including an audit trail containing a complete record of all changes 
to data. 
9.2 
PROTOCOL DEVIATIONS 
The investigator should document and explain any protocol deviations.  The investigator 
should promptly report any deviations that might have an impact on patient safety and 
data integrity to the Sponsor and to the IRB/EC in accordance with established IRB/EC 
policies and procedures.  The Sponsor will review all protocol deviations and assess 
whether any represent a serious breach of Good Clinical Practice guidelines and require 
reporting to health authorities.  As per the Sponsor's standard operating procedures, 
prospective requests to deviate from the protocol, including requests to waive protocol 
eligibility criteria, are not allowed. 


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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 study will be sponsored and managed by F. Hoffmann-La Roche Ltd.  The Sponsor 
will provide clinical operations management, data management, and medical monitoring. 
Approximately 100 sites globally will participate to randomize approximately 
160 patients.  Screening and enrollment will occur through an IxRS. 
Central facilities will be used for certain study assessments throughout the study 
(e.g., specified laboratory tests, biomarker analyses, and PK analyses), as specified in 
Section 4.5.7.  Accredited local laboratories will be used for routine monitoring; local 
laboratory ranges will be collected. 
Tumor response and progression will be evaluated by an IRC.  As of protocol 
amendment version 8, imaging scans no longer need to be sent to or assessed by IRC. 
An IMC will be employed to monitor and evaluate patient safety throughout the study. 
9.6 
DISSEMINATION OF DATA AND PROTECTION OF 
TRADE SECRETS 
Regardless of the outcome of a trial, the Sponsor is dedicated to openly providing 
information on the trial to healthcare professionals and to the public, at scientific 
congresses, in clinical trial registries, and in peer-reviewed journals.  The Sponsor will 
comply with all requirements for publication of study results.  Study data may be shared 
with others who are not participating in this study (see Section 8.4 for details), and 
redacted Clinical Study Reports and/or summaries of clinical study results may be 
available in health authority databases for public access, as required by local regulation, 


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and reports will be made available upon request.  For more information, refer to the 
Roche Global Policy on Sharing of Clinical Study Information at the following website: 
https://www.roche.com/innovation/process/clinical-trials/data-sharing/ 
The results of this study may be published or presented at scientific congresses.  For all 
clinical trials in patients involving an IMP for which a marketing authorization application 
has been filed or approved in any country, the Sponsor aims to submit a journal 
manuscript reporting primary clinical trial results within 6 months after the availability of 
the respective Clinical Study Report.  In addition, for all clinical trials in patients involving 
an IMP for which a marketing authorization application has been filed or approved in any 
country, the Sponsor aims to publish results from analyses of additional endpoints and 
exploratory data that are clinically meaningful and statistically sound. 
The investigator must agree to submit all manuscripts or abstracts to the Sponsor prior 
to submission for publication or presentation.  This allows the Sponsor to protect 
proprietary information and to provide comments based on information from other 
studies that may not yet be available to the investigator. 
In accordance with standard editorial and ethical practice, the Sponsor will generally 
support publication of multicenter trials only in their entirety and not as individual center 
data.  In this case, a coordinating investigator will be designated by mutual agreement. 
Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements.  Any formal publication 
of the study in which contribution of Sponsor personnel exceeded that of conventional 
monitoring will be considered as a joint publication by the investigator and the 
appropriate Sponsor personnel. 
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. 


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Lyford-Pike S, Peng S, Young GD, et al. Evidence for a role of the PD-1:PD-L1 pathway 
in immune resistance of HPV-associated head and neck squamous cell carcinoma. 
Cancer Res 2013;73:173341. 


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Manieri NA, Chiang EY, Grogan JN. TIGIT: a key inhibitor of the cancer immunity cycle. 
Trends Immunol 2017;38:208. 
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curative-intent treatment of patients with node-positive cervical cancer. JAMA 
Oncol 27 November 2019. (Epub ahead of print.) 
doi://https://doi.org/10.1001/jamaoncol.2019.3857. 
Merad M, Martin JC. Pathological inflammation in patients with COVID-19: a key role for 
monocytes and macrophages. Nat Rev Immunol 2020;20:35562. 
Naumann RW, Hollebecque A, Meyer T, et al. Safety and efficacy of nivoluman 
monotherapy in recurrent or metastatic cervical, vaginal, or vulvar carcinoma: 
results from the phase I/II CheckMate 358 trial. J Clin Oncol 2019;37:282534. 
[NCCN] National Comprehensive Cancer Network. Recommendations of the NCCN 
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Powell RM, Lissauer D, Tamblyn J, et al. Decidual T cells exhibit a highly differentiated 
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Appendix 1  
Schedule of Activities 
Assessment/Procedure (Window) 
Screening  
All Treatment 
Cycles a 
Treatment 
Discontinuation 
Long-Term  
Survival Follow-Up d 
Days 
–28 to –1 b 
Every 21 days  
( 3 Days) c 
 30 Days after  
Final Dose 
Approximately Every  
3 Months after  
Disease Progression or  
Loss of Clinical Benefit d 
Informed consent 
x  
 
 
 
Archival or fresh tumor tissue specimen for PD-L1 
testing (20 FFPE slides required; blocks preferred) e, f 
x 
 
 
 
Demographics (age, sex, and self-reported 
ethnicity/race) 
x 
 
 
 
Medical and cervical cancer history, and baseline 
conditions 
x 
 
 
 
Vital signs g 
x 
x 
x 
 
Weight 
x 
x 
x 
 
Height 
x 
 
 
 
Complete physical examination h 
x 
 
 
 
Limited physical examination h 
 
x 
 
 
ECOG Performance Status 
x 
x 
x 
 
ECG i 
x 
 
 
 
Hematology j 
x 
x 
x 
 
Chemistry k 
x 
x 
x 
 
Coagulation test (PT [or INR] and aPTT [or PTT]) 
x 
 
x 
 


Appendix 1: Schedule of Activities 
  
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Assessment/Procedure (Window) 
Screening 
All Treatment 
Cycles a 
Treatment 
Discontinuation 
Long-Term  
Survival Follow-Up d 
Days 
–28 to –1b 
Every 21 days  
( 3 Days) c 
 30 Days after  
Final Dose 
Approximately Every  
3 Months after  
Disease Progression or  
Loss of Clinical Benefit d 
Pregnancy test l 
x l 
x 
x 
 
TSH, free T3, and free T4 m 
x 
x 
x 
 
Urinalysis o 
x 
 
 
 
Arm A:  atezolizumab plus tiragolumab administration p 
 
x 
 
 
Arm B:  atezolizumab administration p 
 
x 
 
 
Tumor response assessment q 
x 
x r 
 
x s 
Concomitant medications t 
x 
x 
x 
 
Adverse events u 
 
x 
x 
x u 
Survival and anti-cancer follow-up v 
 
 
 
x 
 


Appendix 1: Schedule of Activities 
  
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ADA  anti-drug antibody; CT  computed tomography;
 ECOG  Eastern Cooperative Oncology Group; eCRF  electronic 
Case Report Form; FFPE  formalin-fixed, paraffin-embedded;
 
 
; MRI  magnetic resonance imaging; NA  not applicable; PCR  polymerase chain reaction; PD-L1  programmed deathligand 1; 
PK  pharmacokinetic; RECIST v1.1  Response Evaluation Criteria in Solid Tumors, Version 1.1; T3  triiodothyronine; T4  thyroxine; 
TSH  thyroid-stimulating hormone. 
a Assessments should be performed before study drug infusion unless otherwise noted. 
b Adequate hematologic and end-organ function, defined by laboratory test results, must be obtained within 14 days prior to randomization. 
c Cycle 1 must be performed within 5 days after the patient is randomized.  Screening assessments performed  4 days prior to Cycle 1, Day 1 are 
not required to be repeated for the Cycle 1, Day 1 infusion. 
d This visit was previously conducted by telephone.  Approximately every 3 months as defined as every 84 days  7 days.  Long-term survival 
follow-up is no longer needed as of protocol version 8. 
e 
 
 
 
 
 
 
 
 
 
 
f Biomarker samples should not be collected for patients enrolling from 
.  Samples collected should match 
the number of slides allowed per 
. 
g Vital signs include respiratory rate, pulse rate, systolic and diastolic blood pressure, and temperature.  Vital signs should be recorded as 
described in Section 4.5.4. 
h Complete physical examination must include pelvic examination.  Limited physical examination will be a symptom-directed physical examination, 
as clinically indicated; see Section 4.5.3 for details. 
i ECGs for each patient should be obtained from the same machine wherever possible.  Lead placement should be as consistent as possible.  
ECG recordings must be performed after the patient has been resting in a supine position for at least 10 minutes. 


Appendix 1: Schedule of Activities 
  
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j Hematology consists of WBC count, hemoglobin, platelet count, and differential count (neutrophils, eosinophils, basophils, monocytes, and 
lymphocytes). 
k Chemistry panel (serum or plasma) includes sodium, potassium, glucose, BUN or urea, creatinine, albumin, total calcium, total and direct 
bilirubin, ALP, ALT, AST, and LDH. 
l Pregnancy test should be performed for women of childbearing-potential only.  Pregnancy test (serum or urine) must be performed 14 days 
prior to Cycle 1, Day 1.  A positive urine pregnancy test must be confirmed by a quantitative serum pregnancy test and an ultrasound confirming 
intrauterine pregnancy. 
m TSH, free T3 (or total T3 for sites where free T3 is not performed), and free T4 will be assessed on Day 1 of Cycles 1, 5, 9, and 13, and every 
fourth cycle thereafter.  The thyroid-function test in Cycle 1 does not need to be performed if the previous test was performed within the 
screening window. 
n 
 
 
 
 
 
o Urinalysis is required at screening and can be by dipstick (glucose, protein, ketones, blood, leukocyte esterase, nitrites, WBC, bacteria, and 
epithelial cells). 
p The initial cycle of atezolizumab plus tiragolumab or atezolizumab monotherapy should be administered over
minutes for each agent.  
Subsequent infusions of each agent should be infused over
 minutes if the previous infusion was tolerated without an infusion-related 
reaction, or
minutes if patient experienced an infusion-related reaction with the previous infusion (see Section 4.3.2).  For the 
tiragolumab and atezolizumab doublet, the tiragolumab must be administered after the atezolizumab. 
q At screening and subsequent visits, CT scans (with oral and/or IV contrast, unless contraindicated) or MRI scans of the chest-abdomen-pelvis 
will be performed.  A CT (with contrast) or MRI scan of the brain must be done at screening to evaluate CNS metastases in symptomatic 
patients, as clinically indicated.  The same radiographic procedure used to assess disease sites at screening should be used throughout the 
study (e.g., the same contrast protocol for CT scans).  Refer to Section 4.5.6. 
r Perform every 6 weeks (7 days) for 48 weeks following Day 1 of Cycle 1, regardless of treatment delays.  After completing the Week 48 tumor 
assessment, tumor assessments will be required every 9 weeks (7 days) regardless of treatment delays, until unequivocal radiographic disease 
progression per RECIST v1.1 (or loss of clinical benefit for patients who continue study treatment after RECIST v1.1defined disease 
progression), withdrawal of consent, death, or study termination by the Sponsor, whichever occurs first. 


Appendix 1: Schedule of Activities 
  
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s If a patient discontinues study treatment for any reason other than radiographic RECIST v1.1defined disease progression (e.g., toxicity, 
symptomatic deterioration), tumor assessments will continue at the same frequency as would have been followed if the patient had remained on 
study treatment (i.e., every 6 weeks [7 days]) for 48 weeks following Day 1 of Cycle 1, and then every 9 weeks [7 days] thereafter) until 
unequivocal radiographic disease progression per RECIST v1.1, withdrawal of consent, death, or study termination by the Sponsor, whichever 
occurs, first, even if the patient starts another anti-cancer therapy after discontinuing study treatment.  See Section 4.6.1 for details. 
t From 7 days prior to initiation of study drug until the treatment discontinuation visit.  All such medications should be reported to the investigator 
and recorded on the Concomitant Medications eCRF.  
u 
 
 
  After this period, all deaths should continue to 
be reported.  In addition, the Sponsor should be notified if the investigator becomes aware of any serious adverse event or adverse event of 
special interest that is believed to be related to prior exposure to study treatment (see Section 5.6).  These events should be reported on the 
Adverse Event eCRF. 
v As of protocol version 8, survival follow-up information will no longer be collected.  The study will no longer contact the patients for survival 
and new anti-cancer therapy information.  


 
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Appendix 2  
Schedule of Pharmacokinetic, Immunogenicity, and 
Biomarker Samples 


 
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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"). 
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 
                                            
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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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.  
 
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. 


Appendix 3: Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST v1.1) 
  
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CLINICAL LESIONS 
Clinical lesions will only be considered measurable when they are superficial and 
 10 mm in diameter as assessed using calipers (e.g., skin nodules).  For the case of 
skin lesions, documentation by color photography, including a ruler to estimate the size 
of the lesion, is suggested. 
CHEST X-RAY 
Chest CT is preferred over chest X-ray, particularly when progression is an important 
endpoint, since CT is more sensitive than X-ray, particularly in identifying new lesions.  
However, lesions on chest X-ray may be considered measurable if they are clearly 
defined and surrounded by aerated lung. 
CT AND MRI SCANS 
CT is the best currently available and reproducible method to measure lesions selected 
for response assessment.  In this guideline, the definition of measurability of lesions on 
CT scan is based on the assumption that CT slice thickness is  5 mm.  When CT scans 
have slice thickness of  5 mm, the minimum size for a measurable lesion should be 
twice the slice thickness.  MRI is also acceptable.  
If prior to enrollment it is known that a patient is unable to undergo CT scans with 
intravenous (IV) contrast because of allergy or renal insufficiency, the decision as to 
whether a non-contrast CT or MRI (without IV contrast) will be used to evaluate the 
patient at baseline and during the study should be guided by the tumor type under 
investigation and the anatomic location of the disease.  For patients who develop 
contraindications to contrast after baseline contrast CT is done, the decision as to 
whether non-contrast CT or MRI (enhanced or non-enhanced) will be performed should 
also be based on the tumor type and the anatomic location of the disease, and should 
be optimized to allow for comparison with the prior studies if possible.  Each case should 
be discussed with the radiologist to determine if substitution of these other approaches is 
possible and, if not, the patient should be considered not evaluable from that point 
forward.  Care must be taken in measurement of target lesions and interpretation of 
non-target disease or new lesions on a different modality, since the same lesion may 
appear to have a different size using a new modality. 
ENDOSCOPY, LAPAROSCOPY, ULTRASOUND, TUMOR MARKERS, 
CYTOLOGY, HISTOLOGY 
Endoscopy, laparoscopy, ultrasound, tumor markers, cytology, and histology cannot be 
used for objective tumor evaluation. 


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


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on the Case Report Form (CRF) (e.g., "multiple enlarged pelvic lymph nodes" or 
"multiple liver metastases"). 
CALCULATION OF SUM OF DIAMETERS 
A sum of the diameters (longest diameter for nonlymph node lesions, short axis for 
lymph node lesions) will be calculated for all target lesions at baseline and at each 
subsequent tumor assessment as a measure of tumor burden. 
Measuring Lymph Nodes 
Lymph nodes identified as target lesions should always have the actual short axis 
measurement recorded (measured in the same anatomical plane as the baseline 
examination), even if the node regresses to  10 mm during the study.  Thus, when 
lymph nodes are included as target lesions, the sum of diameters may not be zero even 
if complete response criteria are met, since a normal lymph node is defined as having 
a short axis of  10 mm. 
Measuring Lesions That Become Too Small to Measure 
During the study, all target lesions (lymph node and nonlymph node) recorded at 
baseline should have their actual measurements recorded at each subsequent 
evaluation, even when very small (e.g., 2 mm).  However, sometimes lesions or lymph 
nodes that are recorded as target lesions at baseline become so faint on CT scan that 
the radiologist may not feel comfortable assigning an exact measurement and may 
report them as being too small to measure.  When this occurs, it is important that a value 
be recorded on the CRF, as follows: 
 
If it is the opinion of the radiologist that the lesion has likely disappeared, the 
measurement should be recorded as 0 mm. 
 
If the lesion is believed to be present and is faintly seen but too small to measure, 
a default value of 5 mm should be assigned and "too small to measure" should be 
ticked.  (Note:  It is less likely that this rule will be used for lymph nodes since they 
usually have a definable size when normal and are frequently surrounded by fat 
such as in the retroperitoneum; however, if a lymph node is believed to be present 
and is faintly seen but too small to measure, a default value of 5 mm should be 
assigned in this circumstance as well and "too small to measure" should also be 
ticked). 
 
To reiterate, however, if the radiologist is able to provide an actual measurement, that 
should be recorded, even if it is  5 mm, and in that case "too small to measure" should 
not be ticked. 


Appendix 3: Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST v1.1) 
  
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Measuring Lesions That Split or Coalesce on Treatment 
When nonlymph node lesions fragment, the longest diameters of the fragmented 
portions should be added together to calculate the sum of diameters.  Similarly, as 
lesions coalesce, a plane between them may be maintained that would aid in obtaining 
maximal diameter measurements of each individual lesion.  If the lesions have truly 
coalesced such that they are no longer separable, the vector of the longest diameter in 
this instance should be the maximum longest diameter for the coalesced lesion. 
EVALUATION OF NON-TARGET LESIONS 
Measurements are not required for non-target lesions, except that malignant lymph node 
non-target lesions should be monitored for reduction to  10 mm in short axis.  
Non-target lesions should be noted at baseline and should be identified as "present" or 
"absent" and (in rare cases) may be noted as "indicative of progression" at subsequent 
evaluations.  In addition, if a lymph node lesion shrinks to a non-malignant size (short 
axis  10 mm), this should be captured on the CRF as part of the assessment of 
non-target lesions. 
RESPONSE CRITERIA 
CRITERIA FOR TARGET LESIONS 
Definitions of the criteria used to determine objective tumor response for target lesions 
are provided below: 
 
Complete response (CR):  Disappearance of all target lesions 
Any pathological lymph nodes must have reduction in short axis to  10 mm. 
 
Partial response (PR):  At least a 30% decrease in the sum of diameters of all target 
lesions, taking as reference the baseline sum of diameters, in the absence of CR 
 
Progressive disease (PD):  At least a 20% increase in the sum of diameters of target 
lesions, taking as reference the smallest sum of diameters at prior timepoints 
(including baseline)  
In addition to the relative increase of 20%, the sum of diameters must also 
demonstrate an absolute increase of  5 mm. 
 
Stable disease (SD):  Neither sufficient shrinkage to qualify for CR or PR nor 
sufficient increase to qualify for PD 
 


Appendix 3: Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST v1.1) 
  
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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-PD:  Persistence of one or more non-target lesions and/or 
(if applicable) maintenance of tumor marker level above the normal limits 
 
PD:  Unequivocal progression of existing non-target lesions 
 
SPECIAL NOTES ON ASSESSMENT OF PROGRESSION OF NON-TARGET 
LESIONS 
Patients with Measurable and Non-Measurable Disease 
For patients with both measurable and non-measurable disease to achieve unequivocal 
progression on the basis of the non-target lesions, there must be an overall level of 
substantial worsening in non-target lesions in a magnitude that, even in the presence of 
SD or PR in target lesions, the overall tumor burden has increased sufficiently to merit 
discontinuation of therapy.  A modest increase in the size of one or more non-target 
lesions is usually not sufficient to qualify for unequivocal progression status.  The 
designation of overall progression solely on the basis of change in non-target lesions in 
the face of SD or PR in target lesions will therefore be extremely rare. 
Patients with Non-Measurable Disease Only  
For patients with non-measurable disease only, the same general concepts apply as 
noted above.  However, in this instance there is no measurable disease assessment to 
factor into the interpretation of an increase in non-measurable disease burden.  Because 
worsening in non-measurable disease cannot be easily quantified (by definition, if all 
lesions are truly non-measurable), a useful test that can be applied when assessing 
patients for unequivocal progression is to consider if the increase in overall disease 
burden based on the change in non-measurable disease is comparable in magnitude to 
the increase that would be required to declare PD for measurable disease, that is, an 
increase in tumor burden representing an additional 73% increase in volume (which is 
equivalent to a 20% increase in diameter in a measurable lesion).  Examples include an 
increase in a pleural effusion from "trace" to "large" or an increase in lymphangitic 
disease from localized to widespread.  If unequivocal progression is seen, the patient 
should be considered to have had overall PD at that point.  While it would be ideal to 
have objective criteria to apply to non-measurable disease, the very nature of that 
disease makes it impossible to do so; therefore, the increase must be substantial. 


Appendix 3: Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST v1.1) 
  
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NEW LESIONS 
The appearance of new malignant lesions denotes disease progression; therefore, some 
comments on detection of new lesions are important.  There are no specific criteria for 
the identification of new radiographic lesions; however, the finding of a new lesion 
should be unequivocal, that is, not attributable to differences in scanning technique, 
change in imaging modality, or findings thought to represent something other than tumor 
(for example, some "new" bone lesions may be simply healing or flare of preexisting 
lesions).  This is particularly important when the patient's baseline lesions show PR or 
CR.  For example, necrosis of a liver lesion may be reported on a CT scan report as 
a "new" cystic lesion, which it is not. 
A lesion identified during the study in an anatomical location that was not scanned at 
baseline is considered a new lesion and will indicate disease progression. 
If a new lesion is equivocal, for example because of its small size, continued therapy and 
follow-up evaluation will clarify if it represents truly new disease.  If repeat scans confirm 
there is definitely a new lesion, progression should be declared using the date of the 
initial scan. 
CRITERIA FOR OVERALL RESPONSE AT A SINGLE TIMEPOINT 
Table 1 provides a summary of the overall response status calculation at each response 
assessment timepoint for patients who have measurable disease at baseline. 
Table 1 
Criteria for Overall Response at a Single Timepoint:  Patients 
with Target Lesions (with or without Non-Target Lesions) 
Target Lesions 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
CR 
No 
CR 
CR 
Non-CR/non-PD 
No 
PR 
CR 
Not all evaluated 
No 
PR 
PR 
Non-PD or not all 
evaluated 
No 
PR 
SD 
Non-PD or not all 
evaluated 
No 
SD 
Not all evaluated 
Non-PD 
No 
NE 
PD 
Any 
Yes or no 
PD 
Any 
PD 
Yes or no 
PD 
Any 
Any 
Yes 
PD 
CR  complete response; NE  not evaluable; PD  progressive disease; PR  partial response; 
SD  stable disease. 
 


Appendix 3: Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST v1.1) 
  
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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 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  
Eastern Cooperative Oncology Group Performance Status Scale 
Grade 
Description 
0 
Fully active; able to carry on all pre-disease performance without 
restriction. 
1 
Restricted in physically strenuous activity but ambulatory and able to carry 
out work of a light or sedentary nature (e.g., light housework or office 
work). 
2 
Ambulatory and capable of all self-care but unable to carry out any work 
activities.  Up and about  50% of waking hours. 
3 
Capable of only limited self-care; confined to a bed or chair  50% of 
waking hours. 
4 
Completely disabled.  Cannot carry on any self-care.  Totally confined to 
bed or chair. 
5 
Dead. 
 


 
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Appendix 5  
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 reaction or pericardial disorder while receiving another immunostimulatory 
anticancer agent.  The Medical Monitor is available to advise on any uncertainty over 
autoimmune exclusions. 
Autoimmune Diseases and Immune Deficiencies 


 
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Appendix 6  
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 7  
Risks Associated with Atezolizumab and Guidelines 
for Management of Adverse Events Associated with 
Tiragolumab and/or Atezolizumab 
Toxicities associated or possibly associated with tiragolumab and/or atezolizumab 
treatment should be managed according to standard medical practice.  Additional tests, 
such as autoimmune serology or biopsies, should be used to evaluate for a possible 
immunogenic etiology. 
Although most immune-mediated adverse events observed with immunomodulatory 
agents have been mild and self-limiting, such events should be recognized early and 
treated promptly to avoid potential major complications.  Discontinuation of tiragolumab 
and/or atezolizumab may not have an immediate therapeutic effect, and in severe cases, 
immune-mediated toxicities may require acute management with topical corticosteroids, 
systemic corticosteroids, or other immunosuppressive agents.  
Patients and family caregivers should receive timely and up-to-date information about 
immunotherapies, their mechanism of action, and the clinical profile of possible 
immune−related adverse events prior to initiating therapy and throughout treatment and 
survival follow-up.  There should be a high level of suspicion that new symptoms are 
treatment related. 
• 
The following are general recommendations for management of any other adverse 
events that may occur and are not specifically listed in subsequent subsections. 
• 
• 
• 
• 
• 


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 
 
 
 
 
 
DOSE MODIFICATIONS  
 
TREATMENT INTERRUPTION 
Tiragolumab and atezolizumab treatment may be temporarily suspended in patients 
experiencing toxicity considered to be related to study treatment.
 
MANAGEMENT GUIDELINES 
PULMONARY EVENTS 
Pulmonary events may present as new or worsening cough, chest pain, fever, dyspnea, 
fatigue, hypoxia, pneumonitis, and pulmonary infiltrates.  Patients will be assessed for 
pulmonary signs and symptoms throughout the study. 
All pulmonary events should be thoroughly evaluated for other commonly reported 
etiologies such as pneumonia or other infection, lymphangitic carcinomatosis, pulmonary 
embolism, heart failure, chronic obstructive pulmonary disease, or pulmonary 
hypertension.  COVID-19 evaluation should be performed per institutional guidelines 


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where relevant.  Management guidelines for pulmonary events are provided in Table 1.
Table 1 
Management Guidelines for Pulmonary Events, Including 
Pneumonitis 
Event 
Management 


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


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


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Table 3 
Management Guidelines for Gastrointestinal Events  
(Diarrhea or Colitis) 
Event 
Management 


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


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Table 4 
Management Guidelines for Endocrine Events 
Event 
Management 


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Table 4 
Management Guidelines for Endocrine Events 
Event 
Management 


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Table 4 
Management Guidelines for Endocrine Events 
Event 
Management 
OCULAR EVENTS 
An ophthalmologist should evaluate visual complaints (e.g., uveitis, retinal events).  
Management guidelines for ocular events are provided in Table 5. 
Table 5 
Management Guidelines for Ocular Events 
Event 
Management 


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Table 5 
Management Guidelines for Ocular Events 
Event 
Management 
IMMUNE-MEDIATED CARDIAC EVENTS 
In high-risk patients (including those with abnormal baseline cardiac troponin levels, 
when available), transthoracic echocardiogram (TTE) monitoring should be considered, 
as clinically indicated, and based on local clinical practice.  Management guidelines for 
cardiac events are provided in Table 6. 
IMMUNE-MEDIATED MYOCARDITIS 
Immune-mediated myocarditis should be suspected in any patient presenting with signs 
or symptoms suggestive of myocarditis, including, but not limited to, laboratory (e.g., 
troponin, B-type natriuretic peptide) or cardiac imaging abnormalities, dyspnea, chest 
pain, palpitations, fatigue, decreased exercise tolerance, or syncope.  Myocarditis may 
also be a clinical manifestation of myositis or associated with pericarditis (see section on 
immune-mediated pericardial disorders below) and should be managed accordingly.  
Immune-mediated myocarditis needs to be distinguished from myocarditis resulting from 
infection (commonly viral, e.g., in a patient who reports a recent history of 
gastrointestinal illness), ischemic events, underlying arrhythmias, exacerbation of 
preexisting cardiac conditions, or progression of malignancy. 


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


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Table 6 
Management Guidelines for Immune-Mediated Cardiac Events 
INFUSION-RELATED REACTIONS 
No premedication is indicated for the administration of Cycle 1 of tiragolumab or 
atezolizumab.  However, patients who experience an infusion-related reaction (IRR) with 
Cycle 1 of tiragolumab or atezolizumab may receive premedication with antihistamines, 
antipyretic medications, and/or analgesics (e.g., acetaminophen) for subsequent 
infusions.  Metamizole (dipyrone) is prohibited in treating atezolizumab-associated IRRs 
because of its potential for causing agranulocytosis. 
IRRs are known to occur with the administration of monoclonal antibodies and have 
been reported with tiragolumab and atezolizumab.  These reactions, which are thought 
to be due to release of cytokines and/or other chemical mediators, occur within 24 hours 
of atezolizumab or tiragolumab administration and are generally mild to moderate in 
severity. 
Guidelines for medical management of IRRs during Cycle 1 are provided in Table 7.  
For subsequent cycles, IRRs should be managed according to institutional guidelines. 
Table 7 
Management Guidelines for Infusion-Related Reactions 
Event 
Management 


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Table 7 
Management Guidelines for Infusion-Related Reactions 
CYTOKINE-RELEASE SYNDROME 
No premedication is indicated for the administration of Cycle 1 of tiragolumab or 
atezolizumab.  However, patients who experience cytokine-release syndrome (CRS) 
with tiragolumab or atezolizumab may receive premedication with antihistamines, 
antipyretic medications, and/or analgesics (e.g., acetaminophen) for subsequent 
infusions. 
CRS is defined as a supraphysiologic response following administration of any immune 
therapy that results in activation or engagement of endogenous or infused T cells and/or 
other immune effector cells.  Symptoms can be progressive, always include fever at the 
onset, and may include hypotension, capillary leak (hypoxia), and end-organ dysfunction 
(Lee et al. 2019).  CRS has been well documented with chimeric antigen receptor T-cell 
therapies and bispecific T-cell engager antibody therapies but has also been reported 
with immunotherapies that target PD-1 or PD-L1 (Rotz et al. 2017; Adashek and 
Feldman 2019), including atezolizumab. 
Severe SARS-CoV-2 infection appears to be associated with a CRS involving the 
inflammatory cytokines interleukin (IL)-6, IL-10, IL-2, and interferon- (Merad and Martin 
2020).  If a patient develops suspected CRS during the study, a differential diagnosis 


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should include SARS-CoV-2 infection, which should be confirmed or refuted through 
assessment of exposure history, appropriate laboratory testing, and clinical or radiologic 
evaluations per investigator’s judgment.  If a diagnosis of SARS‑CoV‑2 infection is 
confirmed, the disease should be managed as per local or institutional guidelines. 
Guidelines for medical management of CRS are provided in Table 8. 
Table 8 
Management Guidelines for Cytokine-Release Syndrome 
Event 
Management 


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Table 8 
Management Guidelines for Cytokine-Release Syndrome 


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Table 8 
Management Guidelines for Cytokine-Release Syndrome 
 


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PANCREATIC EVENTS 
The differential diagnosis of acute abdominal pain should include pancreatitis.  
Appropriate workup should include an evaluation for ductal obstruction, as well as serum 
amylase and lipase tests.  Management guidelines for pancreatic events, including 
pancreatitis, are provided in Table 9. 
Table 9 
Management Guidelines for Pancreatic Events, Including 
Pancreatitis 
Event 
Management 


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Table 9 
Management Guidelines for Pancreatic Events, Including 
Pancreatitis 
Event 
Management 
DERMATOLOGIC EVENTS 
The majority of cases of rash reported with the use of atezolizumab and/or tiragolumab 
were mild in severity and self-limiting, with or without pruritus.  Although uncommon, 


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cases of severe cutaneous adverse reactions such as Stevens-Johnson syndrome and 
toxic epidermal necrolysis have been reported with atezolizumab.  A dermatologist 
should evaluate persistent and/or severe rash or pruritus.  A biopsy should be 
considered unless contraindicated.  Management guidelines for dermatologic events are 
provided in Table 10.
Table 10 Management Guidelines for Dermatologic Events 
Event 
Management 


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Table 10 Management Guidelines for Dermatologic Events 
NEUROLOGIC DISORDERS 
Patients may present with signs and symptoms of sensory and/or motor neuropathy.  
Diagnostic workup is essential for an accurate characterization to differentiate between 
alternative etiologies.  Myasthenia may be associated with myositis (see section on 
immune-mediated myositis) and patients should be managed accordingly.  Management 
guidelines for neurologic disorders are provided in Table 11, with specific guidelines for 
myelitis provided in Table 12. 
Table 11 Management Guidelines for Neurologic Disorders 
Event 
Management 


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Table 11 Management Guidelines for Neurologic Disorders 
 


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Table 11 Management Guidelines for Neurologic Disorders 
Table 12 Management Guidelines for Immune-Mediated Myelitis 
Event 
Management 
IMMUNE-MEDIATED MENINGOENCEPHALITIS 
Immune-mediated meningoencephalitis should be suspected in any patient presenting 
with signs or symptoms suggestive of meningitis or encephalitis, including, but not 


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limited to, headache, neck pain, confusion, seizure, motor or sensory dysfunction, and 
altered or depressed level of consciousness.  Encephalopathy from metabolic or 
electrolyte imbalances needs to be distinguished from potential meningoencephalitis 
resulting from infection (bacterial, viral, or fungal) or progression of malignancy, or 
secondary to a paraneoplastic process. 
All patients being considered for meningoencephalitis should be urgently evaluated with 
a CT scan and/or MRI scan of the brain to evaluate for metastasis, inflammation, or 
edema.  If deemed safe by the treating physician, a lumbar puncture should be 
performed, and a neurologist should be consulted. 
Patients with signs and symptoms of meningoencephalitis, in the absence of an 
identified alternate etiology, should be treated according to the guidelines in Table 13. 
Table 13 Management Guidelines for Immune-Mediated 
Meningoencephalitis 
Event 
Management 
 
RENAL EVENTS 
Eligible patients must have adequate renal function.  Renal function, including serum 
creatinine, should be monitored throughout study treatment.  Patients with abnormal 
renal function should be evaluated and treated for other more common etiologies 
(including prerenal and postrenal causes, and concomitant medications such as 
non-steroidal anti-inflammatory drugs).  Refer the patient to a renal specialist if clinically 
indicated.  A renal biopsy may be required to enable a definitive diagnosis and 
appropriate treatment. 
Patients with signs and symptoms of nephritis, in the absence of an identified alternate 
etiology, should be treated according to the guidelines in Table 14. 


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Table 14 Management Guidelines for Renal Events 
Event 
Management 
IMMUNE-MEDIATED MYOSITIS 
Myositis or inflammatory myopathies are a group of disorders sharing the common 
feature of inflammatory muscle injury; dermatomyositis and polymyositis are among the 
most common disorders.  Initial diagnosis is based on clinical (muscle weakness, muscle 


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pain, skin rash in dermatomyositis), biochemical (serum creatine kinase/creatine 
phosphokinase increase), and imaging (electromyography/MRI) features, and is 
confirmed with a muscle biopsy.  Patients may initially present with low grade 
nondescript symptoms including mild pain and weakness; thus, there should be a low 
threshold for suspicion of myositis.  Patients with possible myositis should be referred to 
a rheumatologist or neurologist.  Patients with possible myositis should be monitored for 
signs of myocarditis (see section on immune-mediated myocarditis) and myasthenia 
gravis (bulbar symptoms such as dysphagia, dysphonia, and dyspnea; see section on 
neurologic disorders). 
Patients with signs and symptoms of myositis, in the absence of an identified alternate 
etiology, should be treated according to the guidelines in Table 15
Table 15 Management Guidelines for Immune-Mediated Myositis 
Event 
Management 


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Table 15 Management Guidelines for Immune-Mediated Myositis 
Event 
Management 
 
HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS 
Immune-mediated reactions may involve any organ system and may lead to 
hemophagocytic lymphohistiocytosis (HLH). 


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Clinical and laboratory features of severe CRS overlap with HLH, and HLH should be 
considered when CRS presentation is atypical or prolonged. 
Patients with suspected HLH should be diagnosed according to published criteria by 
McClain and Eckstein (2014).  A patient should be classified as having HLH if five of the 
following eight criteria are met: 
 
Fever  38.5°C 
 
Splenomegaly 
 
Peripheral blood cytopenia consisting of at least two of the following: 
– 
Hemoglobin  90 g/L (9 g/dL) ( 100 g/L [10 g/dL] for infants  4 weeks old) 
– 
Platelet count  100  109/L (100,000/L) 
– 
ANC  1.0  109/L (1000/L) 
 
Fasting triglycerides  2.992 mmol/L (265 mg/dL) and/or fibrinogen  1.5 g/L 
(150 mg/dL) 
 
Hemophagocytosis in bone marrow, spleen, lymph node, or liver 
 
Low or absent natural killer cell activity 
 
Ferritin  500 mg/L (500 ng/mL) 
 
Soluble interleukin 2 (IL2) receptor (soluble CD25) elevated  2 standard deviations 
above age-adjusted laboratory-specific norms 
 
Patients with suspected HLH should be treated according to the guidelines in Table 16. 
Table 16 Management Guidelines for Suspected Hemophagocytic 
Lymphohistiocytosis 
Event 
Management 
HLH  hemophagocytic lymphohistiocytosis 


Appendix 7: Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Tiragolumab and Atezolizumab 
  
Tiragolumab and Atezolizumab—F. Hoffmann-La Roche Ltd 
150/Protocol WO42017, Version 8 
REFERENCES 
Adashek ML, Feldman M. Cytokine release syndrome resulting from antiprogrammed 
death-1 antibody: raising awareness among community oncologist. J Oncol 
Practice 2019;15:5024. 
La Rosée P. Treatment of hemophagocytic lymphohistiocytosis in adults. Hematology 
Am Soc Hematol Educ Protram 2015;1:1906. 
La Rosée P, Horne A, Hines M, et al. Recommendations for the management of 
hemophagocytic lymphohistiocytosis in adults. Blood 2019;133:246577. 
Lee DW, Santomasso BD, Locke FL, et al. ASTCT consensus grading for cytokine 
release syndrome and neurologic toxicity associated with immune effector cells. 
Biol Blood Marrow Transplant 2019;25:62538. 
McClain KL, Eckstein O. Clinical features and diagnosis of hemophagocytic 
lymphohistiocytosis. Up to Date [resource on the Internet]. 2014 [updated: 
29 October 2018; cited: 17 May 2019]. Available from: 
https://www.uptodate.com/contents/clinical-features-and-diagnosis-of-
hemophagocytic-lymphohistiocytosis. 
Merad M, Martin JC. Pathological inflammation in patients with COVID-19: a key role for 
monocytes and macrophages. Nat Rev Immunol 2020;20:35562. 
Riegler LL, Jones GP, Lee DW. Current approaches in the grading and management of 
cytokine release syndrome after chimeric antigen receptor T-cell therapy. Ther Clin 
Risk Manag 2019;15:32335. 
Rotz SJ, Leino D, Szabo S, et al. Severe cytokine release syndrome in a patient 
receiving PD-1-directed therapy. Pediatr Blood Cancer 2017;64:e26642. 
Schram AM, Berliner N. How I treat hemophagocytic lymphohistiocytosis in the adult 
patient. Blood 2015;125:290814. 


Signature Page for Protocol - WO42017 - TIRAGOLUMAB - v8 - Global/Core- Publishe
System identifier: RIM-CLIN-504844
Approval Task
Company Signatory
06-Oct-2023 02:41:08 GMT+0000

SAP_001.pdf: 
 
Official Title: 
A Phase II, Safety, and Efficacy Study of Tiragolumab Plus 
Atezolizumab and Atezolizumab Monotherapy in Patients with 
Metastatic and/or Recurrent PD-L1-Positive Cervical Cancer 
NCT Number: 
NCT04300647 
Document Date: 
SAP Version 2: 17-June-2021 
 
 
 


STATISTICAL ANALYSIS PLAN APPROVAL
CONFIDENTIAL
This is an F. Hoffmann-La Roche Ltd document that contains confidential information.  Nothing 
herein is to be disclosed without written consent from F. Hoffmann-La Roche Ltd.
Tiragolumab and Atezolizumab—F. Hoffmann-La Roche Ltd
Statistical Analysis Plan WO42017
STATISTICAL ANALYSIS PLAN
TITLE:
A PHASE II, SAFETY, AND EFFICACY STUDY OF
TIRAGOLUMAB PLUS ATEZOLIZUMAB AND
ATEZOLIZUMAB MONOTHERAPY IN PATIENTS
WITH METASTATIC AND/OR RECURRENT
PD-L1-POSITIVE CERVICAL CANCER
PROTOCOL NUMBER:
WO42017
STUDY DRUG:
Tiragolumab and Atezolizumab
VERSION NUMBER:
2
IND NUMBER:
147026
EUDRACT NUMBER:
2019-004895-21
SPONSOR:
F. Hoffmann-La Roche Ltd
PLAN PREPARED BY:
DATE FINAL:
See electronic date stamp below
Date and Time(UTC)        Reason for Signing                              Name
Company Signatory
17-Jun-2021 16:05:04


Tiragolumab and Atezolizumab—F. Hoffmann-La Roche Ltd
Statistical Analysis Plan WO42017
STATISTICAL ANALYSIS PLAN VERSION HISTORY
SAP Version
Approval Date
Based on Protocol 
(Version, Approval Date)
2
See electronic date stamp 
on title page
V 4, 25 March 2021
1
16 December 2020
V 2, 19 June 2020


Tiragolumab and Atezolizumab—F. Hoffmann-La Roche Ltd
Statistical Analysis Plan WO42017
STATISTICAL ANALYSIS PLAN AMENDMENT RATIONALE
Key changes to the SAP, along with the rationale(s) for each change, are summarized 
below.
Section
Description of Change
Rationale for Change
4.4.1, 4.1.3, 4.2, 
4.3, 4.4
Change of population for efficacy 
analysis to only randomized 
patients who receive at least one 
dose of study treatment. Patients 
grouped by treatment received.
This change enables 
evaluation of the efficacy 
of tiragolumab in 
combination with 
atezolizumab and 
atezolizumab monotherapy 
in the context of currently 
available therapy, in line 
with the use of a pre-
specified reference for the 
primary statistical test.
2.3.1
Change of primary analysis timing 
to enable at least 6 months of 
follow-up from the onset of 
response for the majority of patients
This change enables 
sufficient follow-up of the 
responders and to assess 
the durability of the 
response
2.2.3, 4.4.7
Addition of a potential 
 
This change enables 
evaluation of consistency 
with the efficacy and safety
observed in the global 
population
Additional minor changes have been made throughout to improve clarity and 
consistency.




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5/Statistical Analysis Plan WO42017
4.4.2.2
Disease Control Rate ............................................................ 15
4.4.2.3
Best Clinical Response.......................................................... 16
4.4.2.4
Progression-Free Survival ..................................................... 16
4.4.2.5
Overall Survival ..................................................................... 16
4.4.3
Exploratory Efficacy Endpoints.............................................. 17
4.4.3.1
......................................... 17
4.4.3.2
Investigator-assessed Objective Response Rate 
(confirmation required)........................................................... 17
4.4.3.3
Assessment of Tumor Burden ............................................... 17
4.4.3.4
Best change from baseline in tumor burden (% 
SLD) ...................................................................................... 17
............................................................ 18
4.4.4
Crossover Analyses............................................................... 18
4.4.4.1
Confirmed Objective Response Rate after 
Crossover .............................................................................. 18
4.4.4.2
Analysis of Overall Survival Accounting for 
Crossover .............................................................................. 18
4.4.5
Sensitivity Analyses............................................................... 18
4.4.6
Subgroup Analyses ............................................................... 19
...................................................... 19
4.5
Pharmacokinetic and Pharmacodynamic 
Analyses................................................................................ 19
4.6
Safety Analyses..................................................................... 19
4.6.1
Exposure to Study Medication............................................... 20
4.6.2
Adverse Events ..................................................................... 20
4.6.3
Laboratory Data..................................................................... 21
4.6.4
Vital Signs.............................................................................. 21
4.6.5
Anti-Drug Antibody ................................................................ 21
4.7
Missing Data.......................................................................... 22
5.
REFERENCES ........................................................................................... 22




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7/Statistical Analysis Plan WO42017
1.
BACKGROUND
This Statistical Analysis Plan (SAP) provides details of the planned analyses and 
statistical methods for Study WO42017, “A Phase II, Safety, and Efficacy Study of 
Tiragolumab plus Atezolizumab and Atezolizumab Monotherapy in Patients with 
Metastatic and/or Recurrent PD-L1positive Cervical Cancer”. The background for the 
study can be found in the study Protocol.
2.
STUDY DESIGN
Study WO42017 is a randomized, Phase II, global, multicenter, open-label study 
designed to evaluate the efficacy and safety of tiragolumab plus atezolizumab and 
atezolizumab monotherapy in patients with metastatic and/or recurrent PD-L1positive 
cervical cancer after progression or recurrence from at least one platinum-based but no 
more than two prior systemic therapies.
Approximately 160 patients will be randomized in this study global enrollment phase in a 
3:1 ratio.  Additional patients may be subsequently randomized in a 
 
 
. Women with Eastern Cooperative Oncology Group (ECOG) Performance Status 
of 0 or 1 who have metastatic and/or recurrent PD-L1positive cervical cancer are 
eligible (refer to protocol synopsis in Appendix 1 for complete eligibility criterion).
In the doublet arm, patients will receive atezolizumab at a fixed dose of 1200 mg 
administered by IV infusion Q3W on Day 1 of each 21-day cycle, followed by 
tiragolumab at a fixed dose of 600 mg administered by IV infusion Q3W also on Day 1 of 
each 21-day cycle.
In the atezolizumab monotherapy arm, patients will receive atezolizumab at a fixed dose 
of 1200 mg administered by IV infusion Q3W on Day 1 of each 21-day cycle.
Treatment may be continued as long as patients are experiencing clinical benefit, as 
assessed by the investigator, in the absence of unacceptable toxicity or symptomatic 
deterioration attributed to disease progression after an integrated assessment of 
radiographic data, biopsy results (if available), and clinical status.  Patients who meet the 
criteria for equivocal disease progression per RECIST v1.1 will be permitted to continue 
treatment (tiragolumab in combination with atezolizumab or atezolizumab alone) if they 
meet all of the following criteria:

Evidence of clinical benefit, as assessed by the investigator

Absence of symptoms and signs (including worsening of laboratory values indicating
unequivocal progression of disease)

No decline in ECOG Performance Status that can be attributed to disease
progression




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9/Statistical Analysis Plan WO42017
2.2
DETERMINATION OF SAMPLE SIZE
Approximately 160 patients are planned for enrollment in the global enrollment phase. 
After completion of the global enrollment, additional patients may be subsequently 
randomized
 
2.2.1
Type I Error Control
Type I error for the study is 
 (one-sided).
The primary endpoint is confirmed ORR, defined as the proportion of patients with a 
complete response (CR) or a partial response (PR) on two consecutive occasions ≥4 
weeks apart, as determined by an independent review committee (IRC) according to 
RECIST v1.1. 
Primary statistical test is a 
 at a one-sided 
 significance level, and 
the ORR of the doublet arm will be compared to a historical reference of 14.6% (Chung 
et al. 2019). This is the only comparison with a statistical hypothesis testing.
No type I error control is applied for descriptive comparisons, including that of the 
atezolizumab monotherapy ORR to the historical reference.
 
2.2.2
Primary Endpoint: Confirmed ORR
The overall statistical power under several assumptions of the true underlying ORR in 
the tiragolumab in combination with atezolizumab arm is given in Table 1, with the 
following considerations taken into account:

, historical reference of 14.6% (Chung et al. 2019)

alpha = 
, one-sided

3:1 randomization ratio

True underlying ORR in tiragolumab in combination with atezolizumab arm between 



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10/Statistical Analysis Plan WO42017
Table 1
Overall Statistical Power in the Comparison of ORR in the 
Tiragolumab in Combination with Atezolizumab Arm to a 
Reference Point of 14.6%
Reference ORR
14.6% a (MDO b
)
True Underlying ORR in Tiragolumab in Combination with Atezolizumab
Power
MDOminimum detectable observation; ORRoverall response rate.
a Source:  Chung et al. 2019.
b MDO is defined as the smallest observed ORR leading to statistical significance at final 
analysis.
The ORR in the atezolizumab monotherapy arm will only be compared with the historical 
reference and with tiragolumab in combination with atezolizumab as a descriptive 
comparison, with no type I error control. The probability of the observed ORR in the 
atezolizumab monotherapy arm being greater than a reference point at the time of final 
ORR analysis is also shown in Table 2.
Table 2
Probability of Observed ORR in the Atezolizumab Monotherapy 
Arm Greater than a Reference Point at the Final Analysis for ORR
Reference ORR
14.6% a
True Underlying ORR in Atezolizumab Monotherapy
P(ORRAM > ref ORR)
ORRoverall response rate.
a Source:  Chung et al. 2019.
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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2.3
INTERIM AND PRIMARY ANALYSIS TIMING
2.3.1
Primary Analysis Timing
The primary analysis of confirmed ORR will be performed once all patients have been 
enrolled and a minimum follow-up of approximately 6 months after the second tumor 
assessment, or approximately 9 months after randomization, has been achieved among 
the patients, who remain in follow-up for ORR assessment, whichever is earlier.
The analysis of confirmed ORR for 
 will be conducted after all 
enrolled Chinese patients 
 have had a minimum 
follow-up of approximately 6 months after the second tumor assessment, or 
approximately 9 months after randomization, has been achieved among the patients, 
who remain in follow-up for ORR assessment, whichever is earlier.
 
 
 
 
 
 
 
 
 


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12/Statistical Analysis Plan WO42017
 
3.
STUDY CONDUCT
3.1
RANDOMIZATION ISSUES
Eligible patients will be randomized in a 3:1 ratio to receive either atezolizumab plus 
tiragolumab or atezolizumab monotherapy with the use of a stratified permuted-block 
randomization. The randomization will be stratified for the following factors:

ECOG Performance Status (0 vs. 1)

Prior use of chemoradiotherapy or radiotherapy (yes vs. no)

Treatment history (persistent vs. recurrent disease)
 
3.2
INDEPENDENT REVIEW COMMITEE
An Independent Review Committee (IRC) will be used to conduct a blinded radiology 
review of the imaging data and will provide an independent assessment of tumor 
response and progression for all patients according to a separate IRC Charter. The IRC 
will follow the Response Evaluation Criteria in Solid Tumor, Version 1.1 (RECIST 1.1).
3.3
DATA MONITORING
The Sponsor will monitor patient safety throughout the study.  In addition to the ongoing 
assessment of the incidence, nature, and severity of adverse events; deaths; vital signs; 
and laboratory abnormalities, the Sponsor will review all cumulative data at regular 
intervals during the study.
An Internal Monitoring Committee (IMC) composed of representatives from safety 
science, clinical science, and statistics, who are independent from the study team, will 
also be established.  Representatives from other functions may be added on an ad hoc 


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13/Statistical Analysis Plan WO42017
basis depending on the nature of the findings.  The primary responsibility of the IMC is to 
evaluate the safety, not efficacy, of treatment arms being evaluated.  The IMC will share 
responsibility with the study team for the monitoring of patient safety.
The IMC may meet during the course of the study.  The IMC may conduct an ad hoc 
meeting should an unexpected safety concern arise, as specified in the IMC Charter.  At 
the time of each review of cumulative data, the IMC may make recommendations in 
consideration of the totality of the available data.  Specific operational details such as the 
committee's composition, timing of meetings, and members' roles and responsibilities 
will be detailed in an IMC Charter.
4.
STATISTICAL METHODS
The analyses described in this SAP will supersede those specified in Protocol WO42017
for the purposes of a regulatory filing.
4.1
ANALYSIS POPULATIONS
4.1.1
Treated Patients Population
The Treated Patients Population is defined as all randomized patients that have received 
at least any dose of study treatment. Patients will be grouped according to the actual 
treatment received. The Treated Patients Population will be used at primary analysis for 
the efficacy analysis.
4.1.2
ITT Population
The ITT population is defined as all randomized patients, irrespective of whether or not 
the patient received the assigned treatment. Patients will be grouped according to the 
treatment assigned at randomization. The ITT Population will be used for efficacy 
sensitivity analysis.
4.1.3
IA Treated Patients Population
The IA Treated Patients Population is defined as all patients randomized at least 5 
months prior to the interim analysis CCOD that have received at least any dose of study 
treatment. Analysis by treatment arm performed on the IA Treated Patients Population 
will be grouped according to the actual treatment received. The IA Treated Patients 
Population will be used at interim analysis for the efficacy analysis.
4.1.4
Crossover Population
The Crossover Patients, Treated Patients Population or Safety Population is defined as 
all patients randomized to the atezolizumab monotherapy arm that crossed-over to the 
tiragolumab in combination with atezolizumab arm, and received at least any dose of 
tiragolumab after cross-over but not prior to cross-over.


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4.1.5
Pharmacokinetic-Evaluable Population 
The Pharmacokinetic-Evaluable Population is defined as all patients who received any 
dose of study treatment and who have at least one post-baseline PK sample available. 
4.1.6
Safety Population
The safety population is defined as patients who received at least one dose of 
tiragolumab or atezolizumab. The Safety Population is identical to the Treated Patients 
Population (see Section 4.1.1) and will be used for the safety analysis.
4.2
ANALYSIS OF STUDY CONDUCT
Enrollment, major protocol deviations including major deviations of inclusion/exclusion 
criteria, and reasons for discontinuation from the study will be summarized by treatment 
arm for the ITT Population.  Study treatment administration and reasons for 
discontinuation from study treatment will be summarized for the Safety Population.
4.3
ANALYSIS OF TREATMENT GROUP COMPARABILITY
Demographic characteristics (age, race/ethnicity, geographic region), baseline disease 
characteristics (histology, initial diagnosis stage, target lesions size, disease location, 
PD-L1 expression, number of prior lines of systemic anti-cancer therapy, prior 
bevacizumab use) and stratification factors (ECOG performance status, prior use of 
(chemo) radiotherapy, treatment history) will be summarized by treatment arm for the 
Treated Patients Population and for the IA Treated Patients Population at interim 
analysis.
Baseline values are the last available data obtained prior to the patient receiving the first 
dose of any component of study treatment on Cycle 1, Day 1 (or at screening, for 
patients who were not treated), unless otherwise noted. Descriptive statistics (mean, 
median, standard deviation, minimum, maximum) will be presented for continuous 
variables, and frequencies and percentages will be presented for categorical variables.
4.4
EFFICACY ANALYSIS
4.4.1
Primary Efficacy Endpoint
4.4.1.1
Objective Response Rate (confirmation required)
The primary efficacy endpoint is confirmed objective response rate (ORR), defined as 
the proportion of patients with a confirmed objective response, either complete response 
(CR) or partial response (PR), observed on two consecutive assessments ≥ 4 weeks
apart with the use of RECIST v1.1, based on IRC assessment.  
In the primary efficacy analysis, patients without any post-baseline tumor assessments 
will be considered non-responders. Confirmed ORR will be analyzed for the Treated 
Patients Population at primary analysis. Confirmed ORR will be analyzed for the IA 
Treated Patients Population at interim analysis.


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15/Statistical Analysis Plan WO42017
A one-sample z-test for proportion will be used to compare the confirmed ORR of the 
tiragolumab in combination with atezolizumab arm to the historical reference (see 
Section 2.2.2). No formal treatment comparison will be performed between the two arms 
or between the atezolizumab monotherapy arm and the historical reference.
An estimate of the confirmed ORR and its 95% CI will be calculated for each treatment 
arm using the Clopper-Pearson method.  
In order to characterize responders, descriptive statistics (e.g. median, range) will be 
provided for time from randomization to response (TTR) for patients with an objective 
response.
4.4.2
Secondary Efficacy Endpoint
4.4.2.1
Duration of Response 
A secondary endpoint is duration of response (DOR), defined for patients with a 
confirmed objective response, as the time from the first documented objective response 
to documented disease progression with the use of RECIST v1.1, as determined by the 
IRC, or death from any cause, whichever occurs first. 
Data for patients who are alive and who have not experienced disease progression at 
the time of analysis will be censored at the date of the last tumor assessment at which 
they were known to be progression-free.  DOR will be analyzed in a subset of patients 
(those who achieve an objective response) from the Treated Patients Population at 
primary analysis and from the IA Treated Patients Population at interim analysis.
The analysis of DOR is based on a non-randomized subset of patients (those who
achieve an objective response); therefore, comparisons between treatment arms will be 
made for descriptive purposes only.  In particular, Kaplan-Meier methodology will be 
used to estimate the median DOR for each treatment arm, and Kaplan-Meier curves will 
be produced.  The Brookmeyer-Crowley methodology will be used to construct the 
95% CI for the median DOR for each treatment arm (Brookmeyer and Crowley 1982).
The Kaplan-Meier approach will also be used to estimate 6-month DOR rate in each 
arm.
4.4.2.2
Disease Control Rate
A secondary endpoint is 
 
  
 
The methodologies described for the analysis of confirmed ORR will be used for the 
analysis of DCR (except the formal treatment comparison with the historical reference
that will not be performed on DCR).


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4.4.2.3
Best Clinical Response
A secondary endpoint is best clinical response (BCR), defined as the proportion of 
patients with a CR, PR, or SD, as clinically determined by the investigator.
 
The methodologies described for the analysis of confirmed ORR will be used for the 
analysis of BCR (except the formal treatment comparison with the historical reference
that will not be performed on BCR). DOR as clinically determined by the investigator will 
also be provided, and the methodology will be the same as used for the analysis of the 
IRC DOR.
4.4.2.4
Progression-Free Survival 
A secondary efficacy endpoint is progression-free survival (PFS), defined as the time 
from randomization to the first documented disease progression as determined by the 
IRC with the use of RECIST v1.1, or death from any cause, whichever occurs first. 
Data for patients who are alive and have not experienced disease progression at the 
time of analysis will be censored at the date of the last tumor assessment at which they 
were known to be progression-free with radiographic evidence. Data for patients with no 
post-baseline tumor assessment will be censored at the date of randomization. PFS will 
be analyzed in the Treated Patients Population and in the IA Treated Patients Population 
at interim analysis
Kaplan-Meier methodology will be used to construct survival curves for each treatment 
arm and to estimate median PFS for each treatment arm.  The Brookmeyer-Crowley 
methodology will be used to construct the 95% CI for the median PFS for each treatment 
arm (Brookmeyer and Crowley 1982).
The Kaplan-Meier approach will also be used to estimate 6-month PFS rate in each arm.
4.4.2.5
Overall Survival
A secondary efficacy endpoint is overall survival (OS).  OS is defined as the time from 
randomization to death from any cause.
Data for patients who are not reported as having died at the time of analysis will be 
censored at the date last known to be alive.  Data for patients who do not have post-
baseline information will be censored at the date of randomization.  OS will be analyzed 
for the Treated Patients Population and in the IA Treated Patients Population at interim 
analysis.
Kaplan-Meier methodology will be used to construct survival curves for each treatment 
arm and to estimate median OS for each treatment arm.  The Brookmeyer-Crowley 


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17/Statistical Analysis Plan WO42017
methodology will be used to construct the 95% CI for the median OS for each treatment 
arm (Brookmeyer and Crowley 1982).
The Kaplan-Meier approach will also be used to estimate 6-month OS rate in each arm,
along with 95% CI calculated using Greenwood’s formula. 12-month OS rate in each 
arm will also be provided as appropriate.
Duration of survival follow-up will be summarized for all patients in the analysis using 
descriptive statistics (median, range).  Duration of survival follow-up is defined as the 
survival time for all patients in the analysis (whether a patient is alive or has died).
4.4.3
Exploratory Efficacy Endpoints
4.4.3.1
Disease Control Rate
Disease control rate is defined as the proportion of patients with either confirmed 
objective response (CR or PR observed on 
 
. The methodologies described for the analysis 
of confirmed ORR will be used for the analysis of DCR
(except the formal 
treatment comparison with the historical reference that will not be performed on DCR
).
4.4.3.2
Investigator-assessed Objective Response Rate (confirmation 
required)
Investigator-assessed ORR, is defined as the proportion of patients with a confirmed 
objective response, either CR or PR, observed on two consecutive assessments ≥ 4 
weeks apart with the use of RECIST v1.1, based on the investigator assessment. The 
methodologies described for the analysis of confirmed ORR will be used for the analysis 
of investigator-assessed ORR (except the formal treatment comparison with the 
historical reference that will not be performed on investigator-assessed ORR).
4.4.3.3
Assessment of Tumor Burden
Changes over time in the sum of longest diameters (SLD) for target lesions identified by
the IRC will be plotted for each patient by visit for each treatment arm.
4.4.3.4
Best change from baseline in tumor burden (% SLD)
A summary of the best percent change from baseline, defined as the smallest percent 
change observed post-baseline, in the sum of longest diameters (SLD) for target lesions, 
according to the IRC, will be presented by treatment arm.
A waterfall plot or vertical bar chart of observed best percent change from baseline 
ordered from highest (i.e., largest increase) to lowest (i.e., largest decrease) by patient 
will be presented for each treatment arm.


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4.4.4
Crossover Analyses
4.4.4.1
Confirmed Objective Response Rate after Crossover
Confirmed ORR after crossover is defined as the proportion of patients with a confirmed 
objective response during the post crossover period, either complete response (CR) or 
partial response (PR), observed on two consecutive assessments ≥ 4 weeks apart with 
the use of RECIST v1.1, based on IRC assessment.
The tumor assessment just preceding crossover will serve as a re-baseline scan against 
which all subsequent scans will be compared. Confirmed ORR after crossover will be 
analyzed for the Crossover Patients, Treated Patients Population.
The methodologies described for the analysis of confirmed ORR will be used for the 
analysis of confirmed ORR after crossover (except the formal treatment comparison with 
the historical reference that will not be performed on confirmed ORR after crossover).
Duration of response will also be provided and the methodology will be the same as 
used for the analysis of the IRC DOR.
4.4.4.2
Analysis of Overall Survival Accounting for Crossover
The impact of subsequent crossover for patients in the atezolizumab arm on OS will be 
assessed depending on the number of patients who crossover to atezolizumab plus 
tiragolumab.  If more than 10% of patients in the atezolizumab arm crossover, the 
following analyses may be performed:

OS will be discounted according to a range of possible effects on OS of subsequent 
crossover (e.g. 10%, 20%, 30%, 40%, 50%).

Additional sensitivity analyses may be conducted if deemed necessary.
4.4.5
Sensitivity Analyses
Sensitivity analyses will also be performed for the primary endpoint of confirmed ORR to 
check the robustness of the primary results.
Confirmed ORR will be estimated for each treatment arm among all treated patients 
without major exclusion/inclusion criterion protocol deviation (also excluding patients 
without measurable disease at study entry, according to the IRC) and that are PD-L1 


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19/Statistical Analysis Plan WO42017
positive per
according to glass reads only of the 
. Confirmed 
ORR will also be estimated among the ITT Population.
Furthermore, at interim analysis, confirmed ORR will be analyzed for the IA Treated 
Patients Population (see Section 4.4.1.1).
 
 
4.4.6
Subgroup Analyses
The consistency of confirmed ORR results in subgroups defined by demographics (age,
race/ethnicity, geographic regions), baseline disease characteristics (histology, prior 
bevacizumab use, maximal extent of disease, PD-L1 expression level) and stratification 
factors (ECOG performance status, prior use of (chemo) radiotherapy, treatment history) 
will be examined.  Summaries of confirmed ORR by subgroup will be provided.
Kaplan-Meier plots of PFS and OS will also be produced for selected subgroups.
 
 
 
 
 
  
4.5
PHARMACOKINETIC AND PHARMACODYNAMIC ANALYSES
PK samples of tiragolumab and atezolizumab will be collected in this study.
Tiragolumab and atezolizumab serum concentration data (minimum serum concentration 
and maximum serum concentration) will be tabulated and summarized.
Descriptive statistics will include means, medians, ranges, and standard deviations, as
appropriate.
Additional PK analyses will be conducted, as appropriate, based on the availability of
data. These additional analyses may not be included in the CSR for this study.
4.6
SAFETY ANALYSES
Unless specified otherwise, safety analyses described below will be conducted for the 
Safety Population (see Section 4.1.3).


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Patients will be grouped into two categories:

atezolizumab monotherapy
o
Patients that received at least one dose of atezolizumab and never received 
any dose of tiragolumab.
o
Information from patients originally randomized to atezolizumab monotherapy;
that received at least one dose of atezolizumab prior to crossover and received 
a dose of tiragolumab after crossover; safety information up until the first dose 
of tiragolumab treatment will be included.

tiragolumab in combination with atezolizumab
o
Patients originally randomized to tiragolumab in combination with atezolizumab 
that received at least one dose of tiragolumab.
o
Patients randomized to atezolizumab monotherapy that received a dose of 
tiragolumab (due to a medication error) prior to an eventual crossover. 
Information after the start of tiragolumab, for patients randomized to atezolizumab that 
received a dose of tiragolumab after crossover, will be reported in separate safety 
analysis. Only selected safety analysis will be performed on this Crossover Patients, 
Safety Population.
4.6.1
Exposure to Study Medication
Study drug exposure, including treatment duration, number of cycles, and dose intensity, 
will be summarized for each treatment arm for atezolizumab and for tiragolumab with 
descriptive statistics.
4.6.2
Adverse Events
Verbatim description of adverse events will be mapped to Medical Dictionary for 
Regulatory Activities (MedDRA) thesaurus terms.  Adverse events will be graded by the 
investigator according to the NCI CTCAE v5.0.  Treatment-emergent adverse events will 
be summarized by mapped term, appropriate thesaurus level, NCI CTCAE grade and 
treatment arm.  Multiple occurrences of the same event will be counted once at the 
maximum grade.  All reported AEs, SAEs, Grade 5 AEs, treatment-related AEs (as 
assessed by the investigator), severe AEs (Grade ≥ 3), immune-mediated AEs (imAEs),  
imAEs requiring the use of systemic corticosteroids, AEs leading to study drug 
discontinuation, and AEs leading to interruption or reduction will be summarized.
Listings of AEs will include all treatment-emergent AEs.
 


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Deaths and cause of death will be summarized by treatment arm overall, as well as,
during the study treatment period, and those reported during the follow-up period after 
treatment discontinuation.
4.6.3
Laboratory Data
Laboratory data will be summarized by treatment arm.  Laboratory data will be graded 
according to NCI CTCAE v5.0 and will be summarized descriptively with shift tables from 
baseline to worst value post-baseline.
Potential Hy’s law patients will be listed. Potential Hy’s law cases are defined as 
elevated ALT or AST (3 ULN) with concomitant elevated total bilirubin (2 ULN).
4.6.4
Vital Signs
Changes from baseline in selected vital signs will be summarized by treatment arm.  
ECOG performance status will also be summarized over time.
4.6.5
Anti-Drug Antibody
Incidence of anti-drug antibodies (ADAs) against atezolizumab and tiragolumab will be 
summarized.  
The immunogenicity analyses will include patients with any ADA assessments, with 
patients grouped according to treatment received.
Patients will be classified as treatment-emergent ADA-positive if they were ADA 
negative at baseline or missing data but developed an ADA response following study 
drug administration (treatment-induced ADA response) or if they were ADA-positive at 
baseline and the titre of one or more post-baseline samples was 
 greater 
(
) than the titre of the baseline sample (treatment-enhanced ADA 
response).
Patients will be classified as post-baseline ADA negative if they were ADA negative or 
missing data at baseline and all post-baseline samples were negative or if they were 
ADA-positive at baseline but did not have any post-baseline samples with a titre that was 
 greater than the titre of the baseline sample (treatment unaffected).
The number and proportion of treatment-emergent ADA-positive patients and ADA 
negative patients during both the treatment and follow-up periods will be summarized by 
treatment arm.
 


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4.7
MISSING DATA
Sections 4.4.1.1, 4.4.2.4, and 4.4.2.5 describe methods for handling missing data for the 
primary and secondary efficacy endpoints.
5.
REFERENCES
Brookmeyer R, Crowley J. A confidence interval for the median survival time. Biometrics 
1982;38:29-41.
Chung HC, Ros W, Delord J-P, et al. Efficacy and safety of pembrolizumab in previously 
treated advanced cervical cancer: results from the phase II KEYNOTE-158 study. 
J Clin Oncol 2019;37:14708.
Clopper CJ, Pearson ES. The use of confidence or fiducial limits illustrated in the case of 
the binomial. Biometrika 1934;26:40413.
DeMets D, Lan KKG. Interim analysis: the alpha spending function approach. Stat Med 
1994;13:1341−52.


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Appendix 1 Protocol Synopsis


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PROTOCOL SYNOPSIS
TITLE:
A PHASE II, SAFETY, AND EFFICACY STUDY OF 
TIRAGOLUMAB PLUS ATEZOLIZUMAB AND ATEZOLIZUMAB 
MONOTHERAPY IN PATIENTS WITH METASTATIC AND/OR 
RECURRENT PD-L1POSITIVE CERVICAL CANCER
PROTOCOL NUMBER:
WO42017
VERSION NUMBER:
4
EUDRACT NUMBER:
2019-004895-21
IND NUMBER:
147026
NCT NUMBER:
NCT04300647
TEST PRODUCTS:
Atezolizumab (RO5541267)
Tiragolumab (RO7092284)
PHASE:
Phase II
INDICATION:
Cervical cancer
SPONSOR:
F. Hoffmann-La Roche Ltd
Objectives and Endpoints
This Phase II study will evaluate the efficacy and safety of tiragolumab in combination with 
atezolizumab and atezolizumab monotherapy in patients with metastatic and/or recurrent 
programmed death-ligand 1 (PD-L1)-positive (tumor cells and tumor associated immune cells 
[
) cervical carcinoma.  Specific objectives and corresponding endpoints for the study 
are outlined in the following sections.
Efficacy Objectives
Primary Efficacy Objective
The primary efficacy objective for this study is to evaluate the efficacy of tiragolumab in 
combination with atezolizumab and of atezolizumab monotherapy on the basis of the following 
endpoint:

Objective response rate (ORR), defined as the proportion of patients with a complete 
response (CR) or a partial response (PR) on two consecutive occasions 4 weeks apart, as 
determined by an independent review committee (IRC) according to Response Evaluation 
Criteria in Solid Tumors, Version 1.1 (RECIST v1.1)
Secondary Efficacy Objective
The secondary efficacy objective for this study is to evaluate the efficacy of tiragolumab in 
combination with atezolizumab and of atezolizumab on the basis of the following endpoints:

Duration of response (DOR), defined as the time from the first occurrence of a documented 
objective response to disease progression or death from any cause (whichever occurs first), 
as determined by the IRC according to RECIST v1.1

Disease control rate (DCR), defined as the proportion of patients with a CR, PR, or stable 
disease (SD), as determined by an IRC according to RECIST v1.1

Best clinical response rate (BCR), defined as the proportion of patients with a CR, PR, or 
SD, and the DOR as clinically determined by the investigator 






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treatment is discontinued.  Patients who discontinue treatment for reasons other than 
radiographic disease progression per RECIST v1.1 (e.g., toxicity, symptomatic deterioration) will 
continue scheduled tumor assessments at the frequency described above until radiographic 
disease progression per RECIST v1.1, withdrawal of consent, death, or study termination by the 
Sponsor, whichever occurs first. In the absence of radiographic disease progression per 
RECIST v1.1, tumor assessments should continue regardless of whether a patient starts a new 
anti-cancer therapy.
Response will be assessed according to RECIST v1.1.  Objective response will be determined 
at a single timepoint by the IRC according to RECIST v1.1.
Crossover is allowed from the atezolizumab monotherapy arm to the tiragolumab plus 
atezolizumab arm after unequivocal progressive disease has been recorded during 
atezolizumab monotherapy, at the discretion of the investigator and after consultation with the 
Medical Monitor.  For patients who crossover from atezolizumab monotherapy to tiragolumab 
plus atezolizumab, the tumor assessment just preceding crossover will serve as a rebaseline 
scan against which all subsequent scans will be compared.
After initiation of study treatment, all adverse events will be reported according to the adverse 
event reporting period.  After this period, all deaths should continue to be reported.  In addition, 
the Sponsor should be notified if the investigators become aware of any serious adverse events 
or adverse events of special interest that are believed to be related to prior treatment with study 
drug(s).  These events should be reported using the Adverse Event electronic Case Report 
Form (eCRF).  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 protocol-related procedures until 
a final outcome can be reported.
After study treatment discontinuation, survival follow-up information will be collected by means 
of telephone calls, patient medical records, and/or clinic visits approximately every 3 months 
until death, loss to follow-up, or study termination by the Sponsor, whichever occurs first.  All 
patients will be periodically contacted for survival and new anti-cancer therapy information 
unless the patient requests to be withdrawn from follow up (this request must be documented in 
the source documents and signed by the investigator).  If the patient withdraws from the study, 
study staff may use a public information source (e.g., county records) when permissible to 
obtain information about survival status only.
Treatment after Disease Progression
During the study, patients who meet criteria for disease progression per RECIST v1.1 and show 
evidence of clinical benefit may continue study treatment at the investigator’s discretion 
provided that the patients meet all of the following criteria:

Evidence of clinical benefit, as assessed by the investigator 

Absence of symptoms and signs (including worsening of laboratory values indicating 
unequivocal progression of disease) 

No 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 
Safety Monitoring
The Sponsor will monitor patient safety throughout the study.  In addition to the ongoing 
assessment of the incidence, nature, and severity of adverse events; deaths; vital signs; and 
laboratory abnormalities, the Sponsor will review all cumulative data at regular intervals during 
the study.
Internal Monitoring Committee
An Internal Monitoring Committee (IMC) composed of representatives from safety science, 
clinical science, and statistics, who are independent from the study team, will be established.  
Representatives from other functions may be added on an ad hoc basis depending on the 
nature of the findings.  The primary responsibility of the IMC is to evaluate the safety, not 










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End of Study
The end of this study is defined as the date when the “last patient last visit” occurs (i.e., when 
the last patient has recorded her last visit).  The end of the study is expected to occur 
approximately 
months after the last patient is enrolled.
In addition, the Sponsor may decide to terminate the study at any time.  If the Sponsor decided 
to terminate the study, patients who are still receiving study treatment or undergoing survival 
follow-up may be enrolled in an extension study.
Length of Study
The total length of the study, from screening of the first patient to the end of the study, is 
expected to be approximately 36 months.
Investigational Medicinal Products
Test Products (Investigational Drugs)
Atezolizumab 
In the atezolizumab monotherapy arm, patients will receive atezolizumab at a fixed dose of 
1200 mg administered by IV infusion Q3W on Day 1 of each 21-day cycle.
Treatment may be continued as long as patients are experiencing clinical benefit, as assessed 
by the investigator, in the absence of unacceptable toxicity or symptomatic deterioration 
attributed to disease progression after an integrated assessment of radiographic data, biopsy 
results (if available), and clinical status.
Tiragolumab and Atezolizumab
In the doublet arm, patients will receive atezolizumab at a fixed dose of 1200 mg administered 
by IV infusion Q3W on Day 1 of each 21-day cycle, followed by tiragolumab at a fixed dose of 
600 mg administered by IV infusion Q3W also on Day 1 of each 21-day cycle.  The tiragolumab 
and atezolizumab doses are fixed and are not dependent on body weight. 
Administration of tiragolumab and atezolizumab will be performed in a monitored setting where 
there is immediate access to trained personnel and adequate equipment and medicine to 
manage potentially serious reactions.
Statistical Methods
Primary Analysis
The primary efficacy objective for this study is to evaluate the efficacy of tiragolumab in 
combination with atezolizumab and of atezolizumab monotherapy on the basis of the following 
endpoint:

ORR, defined as the proportion of patients with a CR or PR on two consecutive occasions
4 weeks apart, as determined by the IRC according to RECIST v1.1
The primary efficacy analysis population will consist of all randomized patients who receive at 
least one dose of study treatment, with patients grouped according to treatment received.
The primary efficacy analysis will take place once all patients have been enrolled and a 
minimum follow-up of approximately 6 months after the second tumor assessment, or 
approximately 9 months after randomization, has been achieved among those patients, who 
remain in follow-up for ORR assessment, whichever is earlier.
In the primary analysis, patients whose ORR assessment was missing will be counted as not 
achieving a response.  A one-sample z-test for proportion will be used for comparing the ORR 
of the tiragolumab in combination with atezolizumab arm to the historical reference.  An 
estimate of the ORR and its 95% CI will be calculated for each treatment arm.
Determination of Sample Size  
A total of 160 patients will be enrolled in this study and randomized in a 3:1 ratio (tiragolumab in 
combination with atezolizumab and atezolizumab monotherapy).  The overall statistical power 
for several assumptions of the true underlying ORR in tiragolumab in combination with 
atezolizumab arm takes the following considerations into account:

Primary statistical test is a 
 at a one-sided 
 significance level, and 
the doublet arm will be compared to a historical reference of 14.6%.




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Appendix 2
Schedule of Activities
Assessment/Procedure (Window)
Screening
All Treatment 
Cycles a
Treatment 
Discontinuation
Long-Term 
Survival Follow-Up
Days
–28 to –1 b
Every 21 days 
(3 Days) c
30 Days after
Final Dose
Approximately Every 
3 Months after 
Disease Progression or 
Loss of Clinical Benefit d
Informed consent
x
Archival or fresh tumor tissue specimen for PD-L1 
testing (20 FFPE slides required; blocks preferred) e, f
x
Demographics (age, sex, and self-reported 
ethnicity/race)
x
Medical and cervical cancer history, and baseline 
conditions
x
Vital signs g
x
x
x
Weight
x
x
x
Height
x
Complete physical examination h
x
Limited physical examination h
x
ECOG Performance Status
x
x
x
ECG i
x
Hematology j
x
x
x
Chemistry k
x
x
x
Coagulation test (PT [or INR] and aPTT [or PTT])
x
x


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Assessment/Procedure (Window)
Screening
All Treatment 
Cycles a
Treatment 
Discontinuation
Long-Term 
Survival Follow-Up
Days
–28 to –1b
Every 21 days 
(3 Days) c
30 Days after 
Final Dose
Approximately Every 
3 Months after 
Disease Progression or 
Loss of Clinical Benefit d
Pregnancy test l
x l
x
x
TSH, free T3, and free T4 m
x
x
x
Urinalysis o
x
Arm A:  atezolizumab plus tiragolumab administration p
x
Arm B:  atezolizumab administration p
x
Tumor response assessment q
x
x r
x s
Concomitant medications t
x
x
x
Adverse events u
x
x
x u
Survival and anti-cancer follow-up v
x