Conditions: Ovarian Cancer Fallopian Tube Cancer Peritoneal Neoplasms
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 1301
Healthy volunteers: no

Brief summary:
This is a Phase III, global, double-blind, 2-arm randomized study designed to compare the efficacy and safety of atezolizumab + paclitaxel + carboplatin + bevacizumab versus placebo + paclitaxel + carboplatin + bevacizumab. Study participants will have Stage 3 or 4 ovarian cancer (OC), fallopian tube cancer (FTC), or primary peritoneal cancer (PPC) with macroscopic residual disease postoperatively (i.e., after primary tumor reductive surgery) or who will undergo neoadjuvant therapy followed by interval surgery.

Detailed description:

Arms:
arm 1: Participants in the primary tumor-reductive surgery group will receive paclitaxel, carboplatin, atezolizumab intravenous (IV) infusion on Day 1 of each 21-day cycle for a total of 6 cycles, and bevacizumab IV infusion starting with Cycle 2 for a total of 5 cycles, followed by maintenance therapy bevacizumab with atezolizumab for a total of 22 cycles of atezolizumab and 21 cycles of bevacizumab. Participants in the neoadjuvant therapy group will receive paclitaxel, carboplatin and atezolizumab for 6 cycles and bevacizumab for 4 cycles. Interval surgery will occur between cycles 3 and 4. Each cycle is 21 days long. After 6 cycles, participants will start maintenance therapy of bevacizumab and atezolizumab for additional 16 cycles. arm 2: Participants in the primary tumor-reductive surgery group will receive paclitaxel, carboplatin, atezolizumab placebo IV infusion on Day 1 of each 21-day cycle for a total of 6 cycles, and bevacizumab IV infusion starting with Cycle 2 for a total of 5 cycles, followed by maintenance therapy bevacizumab with atezolizumab placebo for a total of 22 cycles of atezolizumab placebo and 21 cycles of bevacizumab. Participants in the neoadjuvant therapy group will receive paclitaxel, carboplatin and placebo for 6 cycles and bevacizumab for 4 cycles. Interval surgery will occur between cycles 3 and 4. Each cycle is 21 days long. After 6 cycles, participants will start maintenance therapy of bevacizumab and placebo for additional 16 cycles.

Interventions: intervention 1: Paclitaxel intervention 2: Carboplatin intervention 3: Atezolizumab intervention 4: Bevacizumab intervention 5: Atezolizumab Placebo
Intervention descriptions: intervention 1: Paclitaxel 175 milligrams per square meter (mg/m\^2) IV infusion on Day 1 of each 21-day cycle intervention 2: Carboplatin at a dose to achieve a target area under the curve (AUC) of 6 milligrams per milliliter\*minute (mg/mL\*min) on Day 1 of each 21-day cycle for a total of 6 cycles intervention 3: Atezolizumab 1200 mg IV infusion on Day 1 of each 21-day cycle intervention 4: Bevacizumab 15 milligrams per kilogram (mg/kg) IV infusion as per the schedule specified in respective arms intervention 5: Placebo matching to atezolizumab on Day 1 of each 21-day cycle

Protocol document:
Prot_000.pdf: 
PROTOCOL AMENDMENT APPROVAL
CONFIDENTIAL
This clinical study is being sponsored globally by F. Hoffmann-La Roche Ltd of Basel, 
Switzerland. However, it may be implemented in individual countries by Roche’s local affiliates, including 
Genentech, Inc. in the United States.  The information contained in this document, especially any 
unpublished data, is the property of F. Hoffmann-La Roche Ltd (or under its control) and therefore is 
provided to you in confidence as an investigator, potential investigator, or consultant, for review by you, your 
staff, and an applicable Ethics Committee or Institutional Review Board.  It is understood that this 
information will not be disclosed to others without written authorization from Roche except to the extent 
necessary to obtain informed consent from persons to whom the drug may be administered.
Atezolizumab—F. Hoffmann-La Roche Ltd
Protocol YO39523, Version 8
  
  
PROTOCOL
TITLE:
A PHASE III, MULTICENTER, RANDOMIZED, STUDY OF 
ATEZOLIZUMAB VERSUS PLACEBO ADMINISTERED IN 
COMBINATION WITH PACLITAXEL, CARBOPLATIN, AND 
BEVACIZUMAB TO PATIENTS WITH NEWLY-DIAGNOSED 
STAGE III OR STAGE IV OVARIAN, FALLOPIAN TUBE, OR 
PRIMARY PERITONEAL CANCER
PROTOCOL NUMBER:
Roche YO39523
GOG3015
ENGOTov39
VERSION NUMBER:
8
EUDRACT NUMBER:
2016-003472-52
IND NUMBER:
130,637
NCT NUMBER:
03038100
TEST PRODUCT:
Atezolizumab (RO5541267)
MEDICAL MONITOR:
, M.D., M.S.
SPONSOR:
F. Hoffmann-La Roche Ltd
APPROVAL DATE:
See electronic date stamp below
 
Company Signatory
Approver's Name
Title
Date and Time (UTC)
22-Nov-2021 06:57:16


Atezolizumab—F. Hoffmann-La Roche Ltd
2/Protocol YO39523, Version 8
PROTOCOL HISTORY
Protocol
Version
Date Final
8
See electronic date stamp on title 
page
7
24 February 2021
6
29 January 2020
5
3 November 2018
4
22 May 2018
3
6 October 2017
2
15 March 2017
1
12 September 2016


 
Atezolizumab—F. Hoffmann-La Roche Ltd 
3/Protocol YO39523, Version 8 
PROTOCOL AMENDMENT, VERSION 8: 
RATIONALE 
Protocol YO39523 has been amended to implement changes to align with Atezolizumab 
Investigator’s Brochure.  The changes to the protocol, along with a rationale for each 
change, are summarized below: 
• 
Benefit-risk assessment and guidance on concomitant administration of COVID-19 
vaccines with atezolizumab has been added (Sections 1.3, 4.4.1). 
• 
Language has been added to clarify that the Sponsor may close the study if futility is 
observed (Section 3.2). 
• 
The responsibilities of the Principal Investigator and the role of the Medical Monitor 
in determining patient eligibility during study conduct have been clarified (Sections 
4.1.2, 4.2.3, 5.1.5, Appendix 7, Appendix 9). 
• 
For clarity, language has been modified regarding a one-time pulse dose of 
systemic immunosuppressant medication in the exclusion criteria (Section 4.1.2). 
• 
The medical term “primary biliary cirrhosis” has been replaced by the term “primary 
biliary cholangitis” to align with the updated preferred term in MedDRA (Appendix 7). 
• 
The adverse event management guidelines have been updated to align with the 
Atezolizumab Investigator’s Brochure, Version 18 (Appendix 9). 
 
Additional minor changes have been made to improve readability, clarity, and 
consistency.  Substantive new information appears in italics.  This amendment 
represents cumulative changes to the original protocol. 


Atezolizumab—F. Hoffmann-La Roche Ltd
4/Protocol YO39523, Version 8
TABLE OF CONTENTS
PROTOCOL ACCEPTANCE FORM .................................................................. 12
PROTOCOL SYNOPSIS .................................................................................... 13
1.
BACKGROUND .......................................................................................... 29
1.1
Background on Ovarian, Fallopian Tube, and 
Primary Peritoneal Cancers................................................... 29
1.2
Background on Atezolizumab................................................ 32
1.3
Study Rationale and Benefit-Risk Assessment...................... 32
1.3.1
COVID-19 Benefit-Risk Assessment ..................................... 35
2.
OBJECTIVES AND ENDPOINTS ............................................................... 36
3.
STUDY DESIGN......................................................................................... 40
3.1
Description of the Study......................................................... 40
3.1.1
Overview of Study Design ..................................................... 40
3.1.2
Independent Data Monitoring Committee .............................. 43
3.2
End of Study and Length of Study......................................... 43
3.3
Rationale for Study Design.................................................... 44
3.3.1
Rationale for Atezolizumab Dose and Schedule.................... 44
3.3.2
Rationale for Patient Population ............................................ 45
3.3.3
Rationale for Control Group................................................... 46
3.3.4
Rationale for Progression-Free Survival and 
Overall Survival as Co-Primary Endpoints............................. 47
3.3.5
Rationale for Biomarker Assessments................................... 48
3.3.6
Rationale for Patient-Reported Outcome 
Assessments ......................................................................... 49
4.
MATERIALS AND METHODS .................................................................... 50
4.1
Patients.................................................................................. 50
4.1.1
Inclusion Criteria.................................................................... 51
4.1.2
Exclusion Criteria................................................................... 54
4.2
Method of Treatment Assignment and Blinding..................... 58
4.2.1
Treatment Assignment........................................................... 58
4.2.2
Blinding the Treatment Assignment....................................... 59
4.2.3
Unblinding the Treatment Assignment................................... 59


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4.3
Study Treatment.................................................................... 60
4.3.1
Formulation, Packaging, and Handling.................................. 60
4.3.1.1
Atezolizumab and Placebo .................................................... 60
4.3.1.2
Paclitaxel, Carboplatin, and Bevacizumab............................. 60
4.3.2
Dosage, Administration, and Compliance.............................. 61
4.3.2.1
Timing and Sequence of Treatment 
Administration........................................................................ 61
4.3.2.2
Atezolizumab and Placebo .................................................... 64
4.3.2.3
Bevacizumab, Paclitaxel, and Carboplatin............................. 65
4.3.3
Additional Required Medication............................................. 67
4.3.3.1
Prophylactic Measures for Carboplatin.................................. 67
4.3.3.2
Premedication for Paclitaxel .................................................. 68
4.3.4
Investigational Medicinal Product Accountability ................... 68
4.3.5
Post-Study Access to Atezolizumab ...................................... 69
4.4
Concomitant Therapy ............................................................ 69
4.4.1
Permitted Therapy................................................................. 69
4.4.2
Cautionary Therapy for Atezolizumab-Treated 
Patients.................................................................................. 70
4.4.2.1
Corticosteroids, Immunosuppressive 
Medications, and TNF-Alpha Inhibitors.................................. 70
4.4.2.2
Herbal Therapies................................................................... 70
4.4.3
Prohibited Therapy ................................................................ 71
4.5
Study Assessments............................................................... 71
4.5.1
Informed Consent Forms and Screening Log........................ 72
4.5.2
Medical History and Demographic Data ................................ 72
4.5.3
Physical Examinations........................................................... 72
4.5.4
Vital Signs.............................................................................. 72
4.5.5
Tumor and Response Evaluations......................................... 72
4.5.6
Laboratory, Biomarker, and Other Biological 
Samples................................................................................. 74
4.5.7
Electrocardiograms................................................................ 77
4.5.8
Patient-Reported Outcomes .................................................. 78
4.5.8.1
EORTC QLQ-C30 and EORTC QLQ-OV28 .......................... 79
4.5.8.2
FACT-G Single Item GP5 ...................................................... 79


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4.5.8.3
EQ-5D-5L .............................................................................. 79
4.5.9
Eastern Cooperative Oncology Group 
Performance Status............................................................... 80
4.5.10
Mandatory Samples for Whole Genome 
Sequencing............................................................................ 80
4.5.11
Samples for Research Biosample Repository ....................... 80
4.5.11.1
Overview of the Research Biosample Repository.................. 80
4.5.11.2
Approval by the Institutional Review Board or 
Ethics Committee .................................................................. 81
4.5.11.3
Sample Collection.................................................................. 81
4.5.11.4
Confidentiality........................................................................ 82
4.5.11.5
Consent to Participate in the Research 
Biosample Repository............................................................ 83
4.5.11.6
Withdrawal from the Research Biosample 
Repository ............................................................................. 83
4.5.11.7
Monitoring and Oversight....................................................... 83
4.6
Treatment, Patient, Study, and Site 
Discontinuation...................................................................... 84
4.6.1
Study Treatment Discontinuation........................................... 84
4.6.2
Patient Discontinuation from Study........................................ 85
4.6.3
Participants Lost to Follow-Up............................................... 85
4.6.4
Study Discontinuation............................................................ 86
4.6.5
Site Discontinuation............................................................... 86
5.
ASSESSMENT OF SAFETY....................................................................... 86
5.1
Safety Plan ............................................................................ 86
5.1.1
Risks Associated with Atezolizumab ..................................... 87
5.1.2
Risks Associated with Paclitaxel............................................ 87
5.1.3
Risks Associated with Carboplatin......................................... 87
5.1.4
Risks Associated with Bevacizumab ..................................... 88
5.1.5
Bevacizumab Dose Modification and 
Management of Specific Adverse Events .............................. 88
5.1.6
Carboplatin and Paclitaxel Dose Modification and 
Management of Specific Adverse Events .............................. 88
5.1.6.1
Carboplatin ............................................................................ 89
5.1.6.2
Paclitaxel ............................................................................... 89


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5.1.7
Potential Overlapping Toxicities ............................................ 89
5.2
Safety Parameters and Definitions ........................................ 89
5.2.1
Adverse Events ..................................................................... 90
5.2.2
Serious Adverse Events (Immediately Reportable 
to the Sponsor)...................................................................... 90
5.2.3
Adverse Events of Special Interest (Immediately 
Reportable to the Sponsor).................................................... 91
5.2.3.1
General Adverse Events of Special Interest .......................... 91
5.2.3.2
Adverse Events of Special Interest for 
Atezolizumab......................................................................... 91
5.2.3.3
Adverse Events of Special Interest for 
Bevacizumab......................................................................... 92
5.3
Methods and Timing to Capture and Assess 
Safety Parameters................................................................. 92
5.3.1
Adverse Event Reporting Period ........................................... 93
5.3.2
Eliciting of Adverse Event Information ................................... 93
5.3.3
Assessment of Severity of Adverse Events ........................... 93
5.3.4
Assessment of Causality of Adverse Events ......................... 94
5.3.5
Procedures to Record Adverse Events.................................. 95
5.3.5.1
Infusion-Related Reactions and Cytokine-
Release Syndrome................................................................ 95
5.3.5.2
Diagnosis versus Signs and Symptoms................................. 95
5.3.5.3
Adverse Events That Are Secondary to Other 
Events.................................................................................... 96
5.3.5.4
Persistent or Recurrent Adverse Events................................ 96
5.3.5.5
Abnormal Laboratory Test Result Values .............................. 96
5.3.5.6
Abnormal Vital Sign Values ................................................... 97
5.3.5.7
Abnormal Liver Function Test Results................................... 98
5.3.5.8
Deaths ................................................................................... 98
5.3.5.9
Preexisting Medical Conditions.............................................. 98
5.3.5.10
Lack of Efficacy or Deterioration of Ovarian, 
Fallopian Tube, or Primary Peritoneal Cancer....................... 99
5.3.5.11
Hospitalization or Prolonged Hospitalization.......................... 99
5.3.5.12
Reporting Requirements for Cases of Accidental 
Overdose or Medication Error.............................................. 100
5.3.5.13
Patient-Reported Outcome Data ......................................... 101


Atezolizumab—F. Hoffmann-La Roche Ltd
8/Protocol YO39523, Version 8
5.4
Immediate Reporting Requirements from 
Investigator to Sponsor........................................................ 101
5.4.1
Medical Monitors and Emergency Medical 
Contacts .............................................................................. 101
5.4.2
Reporting Requirements for Serious Adverse 
Events and Adverse Events of Special Interest................... 102
5.4.2.1
Events That Occur prior to the Initiation of the 
Study Treatment.................................................................. 102
5.4.2.2
Events That Occur after the Initiation of the Study 
Treatment ............................................................................ 102
5.4.3
Reporting Requirements for Pregnancies............................ 103
5.4.3.1
Pregnancies in Female Patients.......................................... 103
5.4.3.2
Abortions ............................................................................. 103
5.4.3.3
Congenital Anomalies and/or Birth Defects ......................... 104
5.5
Follow-Up of Patients after Adverse Events ........................ 104
5.5.1
Investigator Follow-Up......................................................... 104
5.5.2
Sponsor Follow-Up .............................................................. 104
5.6
Adverse Events that occur after the adverse 
event Reporting Period........................................................ 104
5.7
Expedited Reporting to Health Authorities, 
Investigators, Institutional Review Boards, and 
Ethics Committees............................................................... 105
6.
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN..................... 105
6.1
Determination of Sample Size ............................................. 106
6.2
Summaries of Conduct of Study.......................................... 107
6.3
Summaries of Treatment Group Comparability ................... 108
6.4
Efficacy Analyses ................................................................ 108
6.4.1
Primary Efficacy Endpoint.................................................... 108
6.4.2
Secondary Efficacy Endpoints............................................. 109
6.4.2.1
Objective Response Rate.................................................... 109
6.4.2.2
Duration of Response.......................................................... 110
6.4.2.3
Patient-Reported Outcomes Disease Symptoms, 
Function and Health-Related Quality of Life 
EORTC Data ....................................................................... 110
6.4.3
Handling of Missing Data..................................................... 112
6.5
Safety Analyses................................................................... 112


Atezolizumab—F. Hoffmann-La Roche Ltd
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6.6
Pharmacokinetic Analyses................................................... 113
6.7
Exploratory Analyses........................................................... 114
6.7.1
Exploratory Analyses of Progression-Free 
Survival................................................................................ 114
6.7.1.1
Non-Protocol-Specified Anti-Cancer Therapy...................... 114
6.7.1.2
Sensitivity Analyses............................................................. 114
6.7.2
Pathologic and Clinical Response ....................................... 114
6.7.3
Analysis of Overall Survival at 3 Years................................ 115
6.7.4
Exploratory Patient-Reported Outcomes 
Analyses.............................................................................. 115
6.7.4.1
Patient-Reported Outcomes Disease and/or 
Treatment-Related SymptomsEORTC Data...................... 115
6.7.4.2
FACT-G, GP5 Single Item Data........................................... 115
6.7.4.3
Health Economic Data......................................................... 115
6.7.5
Exploratory Biomarker Analyses.......................................... 116
6.7.6
Subgroup Analyses ............................................................. 116
6.8
Interim Analyses .................................................................. 116
6.8.1
Planned Interim Analyses.................................................... 116
6.8.2
Optional Interim Analysis..................................................... 116
6.9
China subgroup analysis ..................................................... 117
7.
DATA COLLECTION AND MANAGEMENT ............................................. 118
7.1
Data Quality Assurance....................................................... 118
7.2
Electronic Case Report Forms............................................. 118
7.3
Source Data Documentation................................................ 118
7.4
Use of Computerized Systems ............................................ 119
7.5
Retention of Records........................................................... 119
8.
ETHICAL CONSIDERATIONS.................................................................. 120
8.1
Compliance with Laws and Regulations .............................. 120
8.2
Informed Consent................................................................ 120
8.3
Institutional Review Board or Ethics Committee.................. 121
8.4
Confidentiality...................................................................... 121
8.5
Financial Disclosure ............................................................ 122


Atezolizumab—F. Hoffmann-La Roche Ltd
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9.
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION ................................................................................... 122
9.1
Study Documentation .......................................................... 122
9.2
Protocol Deviations.............................................................. 122
9.3
Site Inspections ................................................................... 123
9.4
Administrative Structure....................................................... 123
9.5
Publication of Data and Protection of 
Trade Secrets...................................................................... 123
9.6
Protocol Amendments ......................................................... 124
10. REFERENCES ......................................................................................... 125
LIST OF TABLES
Table 1
Objectives and Corresponding Endpoints................................... 37
Table 2
Treatment Regimen and Order of Administration for Patients 
Who Undergo Primary Surgery................................................... 62
Table 3
Treatment Regimen and Order of Administration for Patients 
Who Undergo Neoadjuvant Chemotherapy or Interval 
Surgery ....................................................................................... 63
Table 4
Atezolizumab Infusion Guidelines............................................... 65
Table 5
Severity Grading Scale for Adverse Events Not Specifically 
Listed in NCI CTCAE .................................................................. 94
LIST OF FIGURES
Figure 1
Study Schema for Patients in the Primary Tumor-Reductive 
Surgery Group ............................................................................ 41
Figure 2
Study Schema for Patients in the Neoadjuvant 
Chemotherapy Group ................................................................. 42
Figure 3
Overview of the Type I Error Control......................................... 106
LIST OF APPENDICES
Appendix 1
Schedule of Assessments for Patients Who Underwent 
Primary Surgery........................................................................ 133


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Appendix 2
Schedule of Assessments for Patients Who Underwent 
Neoadjuvant Chemotherapy and Interval Surgery .................... 141
Appendix 3
Schedule of Pharmacokinetic, Immunogenicity, and 
Biomarker Samples a................................................................ 149
Appendix 4
Interim and Final Analyses for Overall Survival......................... 152
Appendix 5
European Organisation for Research and Treatment of 
Cancer Quality of Life Questionnaires ...................................... 153
Appendix 6
Patient Questionnaire EQ-5D-5L .............................................. 157
Appendix 7
Preexisting Autoimmune Diseases and Immune Deficiencies .. 159
Appendix 8
Anaphylaxis Precautions........................................................... 161
Appendix 9
Management of Atezolizumab-Specific Adverse Events........... 162
Appendix 10
Guidelines for Management of Patients Who Experience 
Specific Adverse Events Associated with Bevacizumab........... 191
Appendix 11
Response Evaluation Criteria in Solid Tumors, Version 1.1:  
Modified Excerpt from Original Publication ............................... 196
Appendix 12
Patient Questionnaire FACT-G Item GP5 ................................. 208
Appendix 13
Ovarian Pathology Handbook ................................................... 209


Atezolizumab—F. Hoffmann-La Roche Ltd
12/Protocol YO39523, Version 8
  
  
PROTOCOL ACCEPTANCE FORM
TITLE:
A PHASE III, MULTICENTER, RANDOMIZED
STUDY OF ATEZOLIZUMAB VERSUS PLACEBO
ADMINISTERED IN COMBINATION WITH
PACLITAXEL, CARBOPLATIN, AND 
BEVACIZUMAB FOR PATIENTS WITH 
NEWLY-DIAGNOSED STAGE III OR STAGE IV 
OVARIAN, FALLOPIAN TUBE, OR PRIMARY 
PERITONEAL CANCER
PROTOCOL NUMBER:
Roche YO39523
GOG3015
ENGOTov39
VERSION NUMBER:
8
EUDRACT NUMBER:
2016-003472-52
IND NUMBER:
130,637
NCT NUMBER
03038100
TEST PRODUCT:
Atezolizumab (RO5541267)
MEDICAL MONITOR:
, M.D., M.S.
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 
this form to the Sponsor or designee.  Contact details will be provided to the Investigator 
prior to study start.


Atezolizumab—F. Hoffmann-La Roche Ltd
13/Protocol YO39523, Version 8
  
  
PROTOCOL SYNOPSIS
TITLE:
A PHASE III, MULTICENTER, RANDOMIZED STUDY OF 
ATEZOLIZUMAB VERSUS PLACEBO ADMINISTERED IN 
COMBINATION WITH PACLITAXEL, CARBOPLATIN, AND 
BEVACIZUMAB FOR PATIENTS WITH NEWLY-DIAGNOSED 
STAGE III OR STAGE IV OVARIAN, FALLOPIAN TUBE, OR 
PRIMARY PERITONEAL CANCER
PROTOCOL NUMBER:
Roche YO39523
GOG3015
ENGOTov39
VERSION NUMBER:
8
EUDRACT NUMBER:
2016-003472-52
IND NUMBER:
130,637
NCT NUMBER
03038100
TEST PRODUCT:
Atezolizumab (RO5541267)
PHASE:
Phase III
INDICATION:
Ovarian cancer, fallopian tube cancer, primary peritoneal cancer, and 
cancers of extra-uterine Müllerian origin
SPONSOR:
F. Hoffmann-La Roche Ltd
Objectives and Endpoints
This study will evaluate the efficacy and safety of atezolizumab administered 
with paclitaxelcarboplatinbevacizumab compared with 
placebopaclitaxelcarboplatinbevacizumab in patients with newly diagnosed, untreated 
ovarian, fallopian tube, and/or primary peritoneal cancer.  Specific objectives and corresponding 
endpoints for the study are outlined below.
Table 1
Objectives and Corresponding Endpoints
Primary Efficacy Objective
Corresponding Endpoints
To evaluate the efficacy of atezolizumab 
versus placebo in combination with 
paclitaxel carboplatin bevacizumab 
among all patients and in those patients 
with PD-L1positive tumors 
Investigator-assessed PFS, defined as the time 
from randomization to the occurrence of disease 
progression, as determined by the investigator from 
tumor assessments per RECIST v1.1, or death 
from any cause during the study, whichever occurs 
first
OS, defined as the time from randomization to 
death from any cause 


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Secondary Efficacy Objectives
Corresponding Endpoints
Among patients with measurable residual disease in the primary surgery group:
To evaluate the efficacy of atezolizumab 
versus placebo in combination with 
paclitaxelcarboplatinbevacizumab
OR, defined as either a CR or PR as determined by 
the investigator with the use of RECIST v1.1 for 
patients with measurable residual disease after 
primary surgery
To evaluate the duration of efficacy 
observed with atezolizumab versus 
placebo in combination with 
paclitaxelcarboplatinbevacizumab 
DOR, defined as the time interval from first 
occurrence of a CR or PR to the time of disease 
progression, as determined by the investigator with 
the use of RECIST v1.1, or death from any cause, 
whichever comes first for patients with measurable 
residual disease after primary surgery
To evaluate PROs of function and 
HRQoL associated with atezolizumab 
versus placebo in combination with 
paclitaxel carboplatin bevacizumab, 
as measured by the functional 
andGHS/QoL scales of the EORTC 
QLQ-C30
Clinically-meaningful improvement, remaining 
stable, or deterioration in patient-reported 
function and HRQoL, defined as a 10-point 
increase, changes within 10 points, and a 10-
point decrease, respectively, from the baseline 
score on each of the functional (physical, role, 
emotional, and social) and GHS/QoL scales of the 
EORTC QLQ-C30
Among the patients in the neoadjuvant group:
To determine the impact of atezolizumab 
versus placebo in combination with 
paclitaxelcarboplatinbevacizumab on 
patient-reported abdominal symptoms of 
OC, as measured by two items from the 
abdominal/GI symptom scale of the 
EORTC QLQ-OV28
Clinically-meaningful improvement in 
patient-reported abdominal pain or bloating, 
defined as a 10-point decrease from the 
baseline score on either of the two items on the 
EORTC QLQ-OV28 abdominal/GI symptom scale
(items 31 and 32)
To evaluate PROs of function and 
HRQoL associated with atezolizumab 
versus placebo in combination with 
paclitaxel carboplatin bevacizumab, as 
measured by the functional and GHS/QoL 
scales of the EORTC QLQ-C30
Clinically-meaningful improvement in 
patient-reported function and HRQoL, defined as 
a 10-point increase from the baseline score on 
each of the functional (physical, role, emotional, 
and social) and GHS/QoL scales of the EORTC 
QLQ-C30
Safety Objective
Corresponding Endpoints
To evaluate the safety and tolerability of 
atezolizumab versus placebo in 
combination with 
paclitaxelcarboplatinbevacizumab
Occurrence and severity of adverse events, with 
severity determined in accordance to 
NCI CTCAE v4.0
Change from baseline in targeted vital signs
Change from baseline in targeted clinical 
laboratory test results
Pharmacokinetic Objective
Corresponding Endpoint
To characterize the pharmacokinetics of 
atezolizumab when administered in 
combination with 
paclitaxelcarboplatinbevacizumab
Minimum and maximum serum concentration of 
atezolizumab


Atezolizumab—F. Hoffmann-La Roche Ltd
15/Protocol YO39523, Version 8
Table 1
Objectives and Corresponding Endpoints (cont.)
Exploratory Objectives
Corresponding Endpoints
Among neoadjuvant patients only:  To 
evaluate PCR status and its association 
with clinical outcomes after 
administration of atezolizumab versus 
placebo in combination with 
paclitaxel carboplatin bevacizumab
Among patients who undergo neoadjuvant 
therapy prior to interval surgery, PCR status is 
defined as the clinical amount and histologic 
characteristics of residual disease assessed at 
the time of interval cytoreductive surgery
To evaluate the efficacy of atezolizumab 
versus placebo administered in 
combination with 
paclitaxel carboplatin bevacizumab
The OS rate at 3 years after randomization
To evaluate PROs of disease 
and/or treatment-related symptoms 
associated with atezolizumab 
versus placebo administered in 
combination with 
paclitaxel carboplatin bevacizumab, 
as measured by the EORTC QLQ-C30 
and QLQ-OV28
Mean and mean changes from the baseline score 
in disease and/or treatment-related symptoms by 
cycle and between treatment arms as assessed 
by all symptom items and/or scales of the 
EORTC QLQ-C30 and QLQ-OV28
To evaluate any treatment burden 
patients may experience in association 
with the addition of atezolizumab to 
paclitaxel carboplatin bevacizumab 
compared with 
placebo paclitaxel carboplatin 
bevacizumab, as measured by a 
single item (from GP5: "I am bothered by 
side effects of treatment") from the 
physical wellbeing subscale of the 
FACT-G Quality of Life instrument
Proportion of patients reporting each response 
option at each assessment timepoint by treatment 
arm for item GP5 from the FACT-G
To evaluate and compare between 
treatment arms patients' health utility as 
measured by the EQ-5D-5L to generate 
utility scores for use in economic models 
for reimbursement
Health utility scores of the EQ-5D-5L
Immunogenicity Objective
Corresponding Endpoint
To evaluate the immune response from 
patients who were administered 
atezolizumab
The incidence of ADAs against atezolizumab 
during treatment with atezolizumab administered 
in combination with 
paclitaxel carboplatin bevacizumab relative to 
the incidence of ADAs at the baseline
Exploratory Immunogenicity Objective
Corresponding Endpoint
To evaluate the potential effects of ADAs 
The relationship between ADA status and 
pharmacokinetics, safety, and efficacy


Atezolizumab—F. Hoffmann-La Roche Ltd
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Table 1
Objectives and Corresponding Endpoints (cont.)
Exploratory Biomarker Objective
Corresponding Endpoint
To assess predictive, prognostic, and 
pharmacodynamic exploratory 
biomarkers in archival and/or fresh 
tumor tissue and blood and their 
association with disease status and/or 
patient response to study treatment 
Association of tumor immune-mediated or disease 
type−related exploratory biomarkers (in archival 
and/or freshly obtained tumor tissues and plasma, 
whole blood, or serum) with disease status and/or 
response to administration of 
atezolizumabpaclitaxelcarboplatinbevacizumab; 
biomarkers may include but are not limited to:
CD8 as assessed with the use of IHC
Breast cancer susceptibility gene (BRCA) 
status, homologous recombination deficiency, 
and microsatellite instability as assessed with 
the use of DNA NGS
Molecular subtyping of ovarian cancer, as 
assessed by RNA profile
Association of cell-free tumor DNA with tumor 
burden and treatment response
To identify biomarkers that are 
associated with resistance to 
atezolizumab administered in 
combination with carboplatin and/or 
paclitaxel and/or bevacizumab activity, 
or can increase the knowledge and 
understanding of disease biology
The relationship between biomarkers in blood and 
tumor tissue between pretreatment and 
post-progression samples collected at the time of 
disease progression. These biomarkers may 
include but are not limited to:

Acquired mutations assessed with the use 
of DNA NGS
Changes in the tumor immune 
microenvironment and biology as assessed by 
RNA profile and IHC
ADA anti-drug antibody; CR complete response; DOR duration of response;
EORTC European Organisation for Research and Treatment of Cancer; FACT-G Functional 
Assessment of Cancer Therapy-General; GI gastrointestinal; GHS global health status;
HRQoL health-related quality of life; IHC immunohistochemistry; PCR pathologic and clinical 
response; NCI CTCAE National Cancer Institute Common Terminology Criteria for Adverse 
Events; NGS next-generation sequencing; OC ovarian cancer; OR objective response; 
OS overall survival; PFS progression-free survival; PR partial response; PRO patient-report 
outcome; QLQ-OV28 Quality of Life Questionnaire Ovarian Cancer Module 28; 
RECIST v1.1 Response Evaluation Criteria in Solid Tumors, Version 1.1.
Study Design
Description of Study
This is a Phase III, global, double-blind, two-arm, randomized study designed to evaluate the 
efficacy and safety of atezolizumab administered with paclitaxel carboplatin bevacizumab 
compared with placebo paclitaxel carboplatin bevacizumab in patients with Stage III or 
Stage IV ovarian, fallopian tube, or primary peritoneal cancer with macroscopic residual disease 
postoperatively (i.e., after primary tumor reductive surgery) or who will undergo neoadjuvant 
therapy followed by interval surgery.  Approximately 1300 patients will be randomized.  Patients 
will be randomized in a 1:1 ratio to one of the two treatment arms.
Eligible patients after primary tumor reductive surgery must be randomized within 42 days of 
primary surgery postoperatively and commence concurrent treatment with paclitaxel 
(175 mg/m2), carboplatin (area under the concentrationtime curve at 6 [AUC 6]), and 
atezolizumab or placebo (1200 mg) on Cycle 1, Day 1.  All treatments will be administered 


Atezolizumab—F. Hoffmann-La Roche Ltd
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intravenously, and each cycle will be 21 days long.  Bevacizumab (15 mg/kg) will be added to 
paclitaxel, carboplatin, and atezolizumab treatment starting with Cycle 2.  After 6 cycles of 
concurrent chemotherapybevacizumab (5 cycles) atezolizumab or placebo, patients will 
continue on maintenance bevacizumab atezolizumab or bevacizumab placebo treatment for 
a total (concurrent maintenance phases) of 22 cycles of atezolizumab or placebo and 
21 cycles of bevacizumab.  No additional cycles of maintenance anti-cancer therapy are 
permitted beyond 22 cycles of therapy in the front-line setting.  Study treatment will be 
discontinued at the time of disease progression, unacceptable toxicity, patient or physician 
decision to discontinue, death, or study termination by the Sponsor.
Eligible patients in the neoadjuvant therapy group will be randomized prior to the initiation of 
study treatment.  Patients in the neoadjuvant group will commence concurrent treatment with 
paclitaxel (175 mg/m2), carboplatin (AUC 6), bevacizumab (15 mg/kg), and atezolizumab or 
placebo (1200 mg) on Cycle 1, Day 1.  All treatments will be administered intravenously, and 
each cycle will be 21 days long.  Cycles 3 and 4 will consist of concurrent paclitaxel 
(175 mg/m2), carboplatin (AUC 6), and atezolizumab or placebo (1200 mg) with bevacizumab 
omitted peri-operatively.  Interval surgery will occur after Cycle 3 as soon as deemed clinically 
appropriate, but within a maximum of 6 weeks after receiving Cycle 3.  Within 6 weeks after 
interval surgery, patients will resume concurrent chemotherapybevacizumab atezolizumab or 
placebo for three more cycles (total of 6 cycles), however bevacizumab treatment will resume at 
Cycle 5 (i.e., bevacizumab is omitted for Cycle 4).  Upon completion of concurrent therapy, 
patients will commence maintenance treatment with bevacizumab atezolizumab or 
bevacizumabplacebo for a total of 22 cycles of atezolizumab or placebo, and 20 cycles of 
bevacizumab.  No additional cycles of maintenance anti-cancer therapy are permitted beyond 
22 cycles of therapy in the front-line setting.
After the completion of maintenance therapy (i.e., bevacizumab atezolizumab or placebo), 
patients will have an end-of-treatment assessment within 30 days of the last dose of study 
treatment and then enter the post-treatment follow-up period.  The expected study treatment 
duration for an individual patient is approximately 66 weeks for patients randomized after 
primary surgery and 70 weeks for patients randomized prior to neoadjuvant therapy.
Progression-free survival (PFS) will be ascertained by the investigator in accordance with 
radiographic criteria from RECIST v1.1 at fixed intervals.  All primary imaging data used for 
tumor assessment will also be collected by the Sponsor to enable a centralized Independent 
Review Committee audit of a prespecified subset of PFS data.  Overall survival (OS) will be 
determined by the investigator.  Tumor assessments will continue until confirmed disease 
progression or 5 years after the completion of all study treatment, whichever occurs first.  Safety 
and toxicity assessments will be conducted at each treatment cycle administration.
Patients will undergo a mandatory tumor biopsy sample collection, if clinically feasible, at the 
time of first evidence of radiographic disease progression according to RECIST v1.1.  Cytology 
from ascites, pleural effusion, and fine needle aspiration (FNA) is not adequate.  These samples 
will be retrospectively analyzed to evaluate and/or characterize pseudoprogression caused by 
immune cells (ICs) from true progression.  In addition, tumor tissue biomarkers related to 
resistance, disease progression, and clinical benefit of atezolizumab will be analyzed.
Option for additional enrollment in China
Study YO39523 will be enrolling patients globally.  Should the Study be opened in mainland 
China, the Sponsor is targeting a total enrollment of approximately 150 patients.  A China 
extension phase may be initiated if patients enrolled in the global enrollment phase is 
significantly less than the target.  Thus, the China subpopulation will include patients enrolled at 
sites in China during both the global enrollment phase and the China extension phase.  Patients 
from the China extension phase will be randomized in a 1:1 ratio to the two treatment arms.  
The patients enrolled in the China extension phase will undergo the same schedule of 
assessments and will receive paclitaxel, carboplatin, bevacizumab, and atezolizumab or 
placebo as in the global study.  Analyses based on the China subpopulation will be reported 
separately from the global study.
Number of Patients
Approximately 1300 patients with Stage III or Stage IV ovarian, fallopian tube, or primary 
peritoneal cancer (i.e., cancers of extra-uterine Müllerian origin) with macroscopic residual 
disease postoperatively (i.e., after primary tumor reductive surgery) or who will undergo 


Atezolizumab—F. Hoffmann-La Roche Ltd
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neoadjuvant therapy followed by interval surgery are expected to be randomized in this study.  
The enrollment of patients in the neoadjuvant setting will be capped at approximately 20%.
Target Population
Inclusion Criteria
Patients must meet the following criteria for study entry:

Signed Informed Consent Form (ICF)

Age 18 years

Able to comply with the study protocol, in the investigator’s judgment

Receive a histologic diagnosis of EOC, peritoneal primary carcinoma, or fallopian tube 
cancer fulfilling the following criteria:
All epithelial tumors of extra-uterine Müllerian origin by histology (FNA, cytology and/or 
cell block are not sufficient)
For patients who will undergo primary tumor reductive surgery: International Federation 
of Gynecological Oncologists (FIGO) Stage III with gross (macroscopic or palpable) 
residual disease or Stage IV
Measurable disease on postoperative imaging studies is not required for 
eligibility
FIGO stage is assessed following the completion of initial abdominopelvic 
surgery that provides the appropriate tissue for histologic evaluation and 
diagnosis and can be used for exploratory biomarker studies.
Primary tumor reductive surgery must be within 42 days of randomization.
For patients who will undergo neoadjuvant treatment and interval surgery:  Patients who 
receive neoadjuvant treatment must also plan to undergo interval surgery after Cycle 3.  
Mandatory biopsy tissue samples (e.g., core needle or surgically obtained; FNA or cell-
block from ascites and/or pleural effusion are inadequate) will be used to confirm 
histologically that the tumor is of extra-uterine Müllerian origin and to perform 
exploratory biomarker studies.
Patients who receive neoadjuvant therapy will include those patients who are not 
deemed surgically resectable to a state of no gross residual disease due to the 
extent and/or distribution of disease (e.g., unresectable miliary pattern of peritoneal 
carcinomatosis, significant diaphragmatic disease, significant involvement of the 
root of the mesentery, diffuse tumor in the omentum up to the greater curvature of 
the stomach, extensive miliary carcinomatosis at the root of the mesentery, tumor 
infiltration of the stomach, surface lesions on the liver).

Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2

Life expectancy 12 weeks

Adequate hematologic and end-organ function, defined by the following laboratory test 
results, obtained within 14 days prior to randomization:
ANC 1500 cells/L (without granulocyte colony stimulating factor support)
Lymphocyte count 500/L
Platelet count 100,000/L without transfusion
Hemoglobin 9.0 g/dL
Patients may be transfused to meet this criterion.
Serum creatinine 1.5 institutional upper limit of normal (ULN)
Serum bilirubin 1.5 ULN
Patients with known Gilbert disease who have serum bilirubin level 3 ULN 
may be enrolled in the study.
AST, ALT, and alkaline phosphatase (ALP) 2.5 ULN, with the following exceptions:
Patients with documented liver metastases:  AST and/or ALT 5 ULN
Patients with documented liver or bone metastases:  ALP 5 ULN.
For patients who do not receive therapeutic anticoagulation:  INR or aPTT 1.5 ULN


Atezolizumab—F. Hoffmann-La Roche Ltd
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
For patients who receive therapeutic anticoagulation:  stable anticoagulant regimen

Negative hepatitis B surface antigen (HBsAg) test at screening

Negative total hepatitis B core antibody (HBcAb) test at screening, or positive total HBcAb 
test followed by a negative hepatitis B virus (HBV) DNA test at screening
The HBV DNA test will be performed only for patients who have a positive total HBcAb 
test.

Negative hepatitis C virus (HCV) antibody test at screening, or positive HCV antibody test 
followed by a negative HCV RNA test at screening
The HCV RNA test will be performed only for patients who have a positive 
HCV antibody test.
A positive HCV RNA test is sufficient to diagnose active HCV infection in the absence of 
an HCV antibody test.

For women of childbearing potential:  agreement to remain abstinent (refrain from 
heterosexual intercourse) or use a contraceptive method with a failure rate of 1% per year 
during the treatment period and for at least 5 months after administration of the last dose of 
atezolizumab and 6 months after the last dose of bevacizumab, paclitaxel, or carboplatin, 
whichever is later
A woman is considered to be of childbearing potential if she is postmenarcheal, has not 
reached a postmenopausal state (12 continuous months of amenorrhea with no 
identified cause other than menopause), and has not undergone surgical sterilization 
(removal of ovaries, fallopian tubes, and/or uterus).
Examples of contraceptive methods with a failure rate of 1% per year include but are 
not limited to bilateral tubal ligation and/or occlusion, male sterilization, and intrauterine 
devices.
In countries with country-specific health authority mandates, contraceptive methods 
with a failure rate of 1% per year include bilateral tubal ligation/occlusion, male 
partner sterilization, established and proper use of estrogen-progestin combination 
hormonal contraceptives that inhibit ovulation, and intrauterine devices/systems.
The reliability of sexual abstinence should be evaluated in relation to the duration of the 
clinical study and the preferred and usual lifestyle of the patient.
Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation 
methods) and withdrawal are not acceptable methods of contraception.

Willingness and ability to comply with scheduled visits, treatment plans, laboratory tests,
and other study procedures, that include the completion of PRO questionnaires

Availability of a representative formalin-fixed, paraffin-embedded (FFPE) tumor specimen 
(screening baseline tissue) in paraffin blocks (preferred) or at least 20 unstained slides.
Patients with fewer than 20 unstained slides available at baseline may be eligible upon 
discussion with the medical monitor.
Tumor tissue should be of good quality based on total and viable tumor content and 
must be evaluated for PD-L1 expression prior to enrollment.  Patients whose tumor 
tissue is not evaluable for PD-L1 expression are not eligible for enrollment in the study.
If multiple screening baseline tumor specimens are submitted, patients may be eligible 
if at least one specimen is evaluable for PD-L1.  For the purpose of stratification, the 
PD-L1 score of the patient will be the maximum PD-L1 score among the samples.
Acceptable samples include tissue obtained from surgery or core needle 
biopsies (minimum three cores per paraffin block).
A paraffin block for FFPE tumor specimens is preferred.
FNA or cell pellets from ascites or pleural effusion are not acceptable.
Tumor tissue from bone metastases is not evaluable for PD-L1 expression and 
is not acceptable.

For patient enrolled in the extended China enrollment phase: residents in Mainland China, 
residents in Hong Kong and Taiwan of Chinese ancestry and enrolled at sites recognized 
by China’s National Products Administration (NMPA). 


Atezolizumab—F. Hoffmann-La Roche Ltd
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Exclusion Criteria
Patients who meet any of the following criteria will be excluded from enrollment in the study:

Received a current diagnosis of borderline epithelial ovarian tumor (formerly tumors of low 
malignant potential)

Have recurrent invasive epithelial ovarian, fallopian tube, or primary peritoneal cancer that 
was treated only with surgery (e.g., patients with Stage IA or Stage IB epithelial ovarian or 
fallopian tube cancers)
Patients who received a prior diagnosis of a borderline tumor that was surgically 
resected and who subsequently developed an unrelated, new invasive epithelial 
ovarian, fallopian tube, or primary peritoneal cancer are eligible for enrollment, if they 
have never received prior chemotherapy for any ovarian tumor.

Have non-epithelial ovarian tumors (e.g., germ cell tumors, sex cord stromal tumors)

Received prior radiotherapy to any portion of the abdominal cavity or pelvis
Prior focal radiation for localized cancer of the breast, head and neck, or skin is 
permitted, if it was completed 5 years prior to initiation of study treatment, and the 
patient remains free of recurrent or metastatic disease.

Received prior chemotherapy for any abdominal or pelvic tumor that include NACT for 
ovarian, primary peritoneal or fallopian tube cancer
Patients may have received prior chemotherapy for localized breast cancer, if it was 
completed 5 years prior to initiation of study treatment, and the patient remains free of 
recurrent or metastatic disease.

Received any biological and/or targeted therapy (including but not limited to vaccines, 
antibodies, tyrosine kinase inhibitors) or hormonal therapy for management and/or 
treatment of epithelial ovarian or peritoneal primary cancer

Have synchronous primary endometrial cancer

Have a prior history of primary endometrial cancer, except for the following:
A prior diagnosis of endometrial cancer is allowed if all of the following conditions are 
met:
Stage IA cancer
Superficial myometrial invasion, without lymphovascular invasion
Grade 3 or not poorly differentiated subtypes, and this includes papillary serous, 
clear cell or other FIGO Grade 3 lesions

With the exception of non-melanoma skin cancer and other specific malignancies as noted 
above, other invasive malignancies within the last 5 years or previous cancer treatment that 
contraindicates this protocol therapy (e.g., previous chemotherapy treatment for breast 
cancer completed 5 years ago is permitted as per above).

Are pregnant, lactating, or intend to become pregnant during the study

Have a history of severe allergic, anaphylactic, or other hypersensitivity reactions 
to chimeric or humanized antibodies or fusion proteins

Have a known hypersensitivity or allergy to biopharmaceutical agents produced in Chinese 
hamster ovary cells or any component of the atezolizumab and/or bevacizumab 
formulations

Have an active or history of autoimmune disease or immune deficiency that includes but is 
not limited to myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus 
erythematosus, rheumatoid arthritis, inflammatory bowel disease, antiphospholipid antibody 
syndrome, Wegener’s granulomatosis, Sjögren’s syndrome, Guillain-Barré syndrome, or 
multiple sclerosis (see protocol for a more comprehensive list of autoimmune diseases).  

Exceptions include the following:
Patients with a history of autoimmune-related hypothyroidism on a stable dose of thyroid 
replacement hormone are eligible.


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Patients with controlled Type 1 diabetes mellitus on a stable dose of insulin regimen are 
eligible.
Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with dermatologic 
manifestations only (e.g., patients with psoriatic arthritis would be excluded) are eligible 
for enrollment in the study provided that they meet all of the following conditions:
Rash must cover less than 10% of body surface area
Disease is well controlled at baseline and requires only low potency topical 
steroids
No acute exacerbations of underlying condition within the previous 12 months 
(i.e., does not require psoralen plus ultraviolet A radiation, methotrexate, 
retinoids, biologic agents, oral calcineurin inhibitors, high-potency or oral 
steroids)

Have a history of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis 
obliterans), drug-induced pneumonitis, idiopathic pneumonitis, or evidence of active 
pneumonitis based on a screening chest computed tomography (CT) scan, with the 
following exceptions
A history of radiation pneumonitis in the localized radiation field (fibrosis) is permitted.  
Patient must still meet all other radiotherapy exclusions listed above.

Have a positive test result for HIV

Have active tuberculosis

Have severe infections within 4 weeks prior to initiation of study treatment, including but not 
limited to hospitalization for complications of infection, bacteremia, or severe pneumonia

Have received therapeutic oral or IV antibiotic medication within 2 weeks prior to initiation of 
study treatment, with the following exceptions:
Patients who receive prophylactic antibiotic medication (e.g., urinary tract infection 
prophylaxis, prior to dental procedure) are eligible for enrollment.

Have significant cardiovascular disease, such as New York Heart Association cardiac 
disease (Class II or greater), myocardial infarction, or cerebrovascular accident within 
3 months prior to initiation of study treatment, unstable arrhythmias, or unstable angina
Patients with known coronary artery disease, congestive heart failure not meeting the 
above criteria, or 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.

Undergo major surgical procedure within 28 days prior to first bevacizumab dose, or 
anticipation of the need for a major surgical procedure during the course of the study except 
patients who receive NACT and will need interval surgery.  This may include but is not 
limited to laparotomy.  All incisions should be fully healed, as assessed clinically, prior to 
starting bevacizumab.
Consult with the Medical Monitor prior to patient entry for any questions related to the 
classification of surgical procedures.

Are administered treatment with a live attenuated vaccine within 4 weeks prior to initiation of 
study treatment, or anticipation of need for such a vaccine during the course of the study or 
within 5 months after the last dose of atezolizumab

Current treatment with anti-viral therapy for HBV

Have prior allogeneic bone marrow transplantation or solid organ transplant

Have 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

Have any approved or investigational anti-cancer therapy, including chemotherapy or 
hormonal therapy, with the following exceptions:
Hormone-replacement therapy or oral contraceptives are allowed.

Current or recent (within 10 days of initiation of study treatment) use of aspirin 
(325 mg/day) or clopidogrel 75 mg/day)


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
Are administered treatment with any other investigational agent or participation in another 
clinical study with anti-cancer therapeutic intent

Have prior treatment with CD137 agonists or immune checkpoint blockade therapies, 
antiPD-1, antiPD-L1, or anti-cytotoxic T-lymphocyte-associated protein 4 therapeutic 
antibodies

Have treatment with systemic immunostimulatory agents (including but not limited to 
interferons [IFNs], interleukin [IL]-2) within 4 weeks or 5 half-lives of the drug, whichever is 
longer, prior to initiation of study treatment

Have treatment with systemic immunosuppressive medications (including but not limited to 
prednisone, cyclophosphamide, azathioprine, methotrexate, thalidomide, and antitumor 
necrosis factor [TNF] agents) within 2 weeks prior to initiation of study treatment, with the 
following exceptions:
Patients who have received acute, low-dose, systemic immunosuppressant medications
or a one-time pulse dose of systemic immunosuppressant medication (e.g., 48 hours of
corticosteroids for a contrast allergy) are eligible for enrollment in the study.
The use of corticosteroids for chronic obstructive pulmonary disease and asthma, 
mineralocorticoids (e.g., fludrocortisone), or low-dose corticosteroids for patients with 
orthostatic hypotension or adrenocortical insufficiency is allowed.

Have inadequately-controlled hypertension (defined as systolic blood pressure 150 mmHg 
and/or diastolic blood pressure 100 mmHg)
Anti-hypertensive therapy to achieve these parameters is allowed.

Have prior history of hypertensive crisis or hypertensive encephalopathy

Have significant vascular disease (e.g., aortic aneurysm requiring surgical repair or recent 
peripheral arterial thrombosis) within 6 months prior to initiation of study treatment

Have a history of Grade 2 hemoptysis (2.5 mL of bright red blood per episode) within 
1 month prior to screening

Have evidence of active bleeding, bleeding diathesis, coagulopathy, tumor that involves 
major vessels (in the absence of therapeutic anticoagulation)

Have a history or evidence upon physical examination of any CNS disease, including 
primary brain tumor, CNS metastases, seizures not controlled with standard medical 
therapy, any brain metastases, or history of cerebrovascular accident (stroke), transient 
ischemic attack or subarachnoid hemorrhage within 6 months of the first date of treatment 
on this study.

History of leptomeningeal disease

History of Grade 4 venous thromboembolism

Have current use of full-dose oral or parenteral anticoagulants or thrombolytic agents for 
therapeutic purposes that has not been stable prior to initiation of study treatment, with the 
following exceptions:
The use of full-dose oral or parenteral anticoagulants is permitted as long as the INR or 
aPTT is within therapeutic limits according to the medical standard of the enrolling 
institution, and the patient has been receiving a stable dose of anticoagulants prior to 
initiation of study treatment.
Prophylactic anticoagulation for the patency of venous access devices is allowed, 
provided the activity of the agent results in an INR 1.5 ULN and aPTT is within 
normal limits prior to initiation of study treatment.
Deep venous thrombosis prophylaxis with low-molecular-weight heparin is permitted.

Have core biopsy or other minor surgical procedures within 7 days prior to the first dose of 
bevacizumab


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The interval of time between placement of a central vascular access device (CVAD; 
e.g., Port-a-cath) and the first dose of bevacizumab must be no shorter than 2 days with 
a well-healed incision
If placing a CVAD between bevacizumab doses, placement must occur at least 14 days 
from the prior (i.e, pre-CVAD placement) bevacizumab dose, and at least 7 days from 
the following (i.e., post-CVAD placement) bevacizumab dose.

Have a history of abdominal fistula or gastrointestinal perforation within 6 months prior to 
initiation of study treatment, with the following exceptions:
Patients with granulating incisions healing by secondary intention with no evidence of 
fascial dehiscence or infection are eligible but require weekly wound examinations.

Have clinical signs of gastrointestinal obstruction that require routine parenteral hydration, 
parenteral nutrition, or tube feeding

Have evidence of abdominal free air not explained by paracentesis or recent surgical 
procedure

Have serious, non-healing wound, active ulcer, or untreated bone fracture

Have proteinuria, as demonstrated by urine dipstick or 1.0 of protein in a urine 
protein-to-creatinine ratio and/or 24-hour urine collection
All patients with 2 protein on dipstick urinalysis at baseline must undergo a urine 
protein-to-creatinine ratio and/or 24-hour urine collection and demonstrate 1.0 of 
protein.

Have known sensitivity to any component of bevacizumab

Have known sensitivity to any component of paclitaxel

Have Grade 2 peripheral neuropathy as defined by the National Cancer Institute Common 
Terminology Criteria for Adverse Events, Version 4.0 (NCI CTCAE v4.0)

Have known history of severe allergic reactions to platinum-containing compounds

Have known history of severe hypersensitivity reactions to products that contain 
CremophorEL (e.g., cyclosporine for injection concentrate and teniposide for injection 
concentrate)
End of Study
The end of the study is expected to be approximately 55 months after the first patient is 
enrolled, when the approximate preplanned numbers of deaths among the PD-L1positive 
patients and the intent-to-treat (ITT) population have been observed.  Deaths will be monitored 
throughout the course of the study.  The sponsor has the right to close the study at any time if 
futility is observed (e.g., based on the predicted probability of success at the subsequent 
analysis).  The study timelines may be updated as needed.
Length of Study
The length of study is approximately 55 months from enrollment of the first patient to the “end of 
study” as described above
Investigational Medicinal Products
The investigational medicinal product (IMP) for this study is atezolizumab.
Atezolizumab
Atezolizumab will be supplied by the Sponsor as a sterile liquid in a single-use, 20-mL glass 
vial.  The vial contains approximately 20 mL (1200 mg) of atezolizumab solution.
Placebo
The placebo will be supplied by the Sponsor and will be identical in appearance to atezolizumab 
and comprise the same excipients but without atezolizumab drug product.
Non-Investigational Medicinal Products
Bevacizumab will be supplied by the Sponsor.  Paclitaxel and carboplatin will be used in 
commercially available formulations.  Bevacizumab will be considered an IMP by local 
regulations in some countries.


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Statistical Methods
Primary Analysis
The primary analysis populations for efficacy are the ITT population, defined as all patients 
randomized in the study, and the PD-L1positive subgroup, defined as the patients in the ITT 
population whose PD-L1 status is IC1/2/3 at the time of randomization.  Patients will be grouped 
in accordance with the treatment assigned at randomization.
The primary analysis population for safety is the Safety Population, defined as all randomized 
patients who receive at least one dose of the study medication.  Patients will be grouped in 
accordance with the treatment they actually receive, and all patients who received any dose of 
atezolizumab will be included in the atezolizumab treatment arm for analysis.
If the China extension phase is initiated, data from this phase will not be included in the primary 
analysis of the main study.  A separate analysis will be performed for the China subgroup, 
where data from the China extension phase and from the patients in the global enrollment 
phase from China will be combined and summarized (refer to the protocol and the statistical 
analysis plan [SAP] for further details).  All analyses discussed in this section will be restricted 
to the patients recruited in the global study only, unless noted.
Determination of Sample Size
Approximately 1300 patients will be randomized in the global study in a 1:1 ratio to the 
two treatment arms.
There are two co-primary efficacy endpoints:  investigator-assessed PFS and OS.  The overall 
Type I error rate will be controlled at a two-sided level of 0.05 to test PFS and OS in the 
PD-L1positive subgroup and the ITT population.  PFS in both the ITT and PD-L1positive 
subgroup will be tested in parallel at the same significance level of 0.002 (two-sided).  To test 
OS in both these specified populations, a hierarchical testing approach will be applied.  The 
alpha allocated to OS will be used first to test OS in the PD-L1positive subgroup.  If the 
significance is reached, the same alpha as used for the PD-L1positive subgroup OS testing 
will be passed to OS in the ITT.  Note that the OS testing sequence of the populations may be 
inverted.  The OS test in the PD-L1positive subgroup is initially assigned with an alpha level of 
0.046 and the actual alpha level will be determined by the results of the PFS tests.  If the PFS 
test in either the ITT or PD-L1positive population reaches significance, its assigned alpha of 
0.002 will be additively passed to OS.

The alpha level for OS will be 0.046 if neither of the PFS tests (in the ITT and 
PD-L1positive subgroup) reaches significance.

The alpha level for OS will be 0.048 if only one PFS test (in either the ITT or the 
PD-L1positive subgroup) reaches significance.

The alpha level for OS will be 0.05 if both the PFS tests (in the ITT and the PD-L1positive 
subgroup) reach significance.
The sample size of the study is determined by the number of patient deaths required to 
demonstrate efficacy in terms of OS in the PD-L1positive subgroup and the ITT population.  To 
detect an improvement in OS with the use of a log-rank test at a two-sided significance level of 
0.046, approximately 311 deaths in the PD-L1positive subgroup will be required to achieve 
81% power with a target hazard ratio (HR) of 0.72, and approximately 534 deaths in the ITT 
population to achieve 80% power with a target HR of 0.78.
Interim Analyses
There will be no interim analysis for PFS.  The primary analysis of PFS will take place when 
approximately 601 PFS events in the ITT and 347 PFS events in the PD-L1positive subgroup 
have occurred (whichever is later), which is expected at approximately 36 months after the first 
patient is enrolled in the study.  This provides 90% power to detect a PFS improvement of 
HR 0.7 in the ITT, and 91% power in the PD-L1positive subgroup with HR 0.62, at a 
two-sided significance level of 0.002.
Two interim analyses of OS will be performed on patients who are in the ITT and 
PD-L1positive populations.  The timing of the two interim analyses and the final analysis for 
OS depends on the results from the primary analysis of the co-primary endpoint of PFS.


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The calculation of the sample size and estimates of the analysis timelines are based on the 
following assumptions:

PFS and OS are exponentially distributed.

The median duration of PFS in the control arm is 18 months.

The median duration of OS in the control arm is 43 months.

The prevalence of PD-L1positive (IC1/2/3) patients is 60%.

The two interim and final analyses of OS use the Lan-DeMets alpha spending function to 
approximate the O’Brien-Fleming boundary.

The dropout rate is 5% over 12 months for PFS and OS.

The recruitment of 1300 patients will take place over 25 months


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Definition
1LOC
first-line ovarian cancer
ADA
anti-drug antibody, previously known as anti-therapeutic antibody 
(ATA)
AUC
area under the concentrationtime curve
CA
cancer antigen
COVID-19
Coronavirus disease 2019
CrCl
creatinine clearance
CT
computed tomography
ctDNA
circulating tumor DNA
CTL
cytotoxic T lymphocyte
Ctrough
trough concentration
CVAD
central vascular access device
DOR
duration of response
EC
Ethics Committee
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic Case Report Form
EDC
electronic data capture
EOC
epithelial ovarian cancer
EORTC 
European Organisation for Research and Treatment of Cancer
FACT-G
Functional Assessment of Cancer Therapy-General
FDA
U.S. Food and Drug Administration
FFPE
formalin-fixed, paraffin-embedded
FIGO
International Federation of Gynecological Oncologists
FNA
fine needle aspiration
GFR
glomerular filtration rate
GI
gastrointestinal
GOG
Gynecologic Oncology Group
HBcAb
hepatitis B core antibody
HBsAg
hepatitis B surface antigen
HBV
hepatitis B virus
HCV
hepatitis C virus
HIPAA
Health Insurance Portability and Accountability Act
HR
hazard ratio
HRQoL
health-related quality of life
IC
immune cell


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Abbreviation
Definition
ICF
Informed Consent Form
ICH
International Council on Harmonisation of Technical Requirements for 
Registration of Pharmaceuticals for Human Use
ICON
International Collaborative Ovarian Neoplasm
IDCC
independent Data Coordinating Center
iDMC
independent Data Monitoring Committee
IFN
interferon
IHC
immunohistochemistry
IL
interleukin
IMP
investigational medicinal product
IND
Investigational New Drug (application)
IRB
Institutional Review Board
IRR
infusion-related reactions
ITT
intent-to-treat
IWRS
interactive Web-based response system
MID
minimally important difference
MRI
magnetic resonance imaging
NACT
neoadjuvant chemotherapy
NCI CTCAE
National Cancer Institute Common Terminology Criteria for Adverse 
Events
NGS
next-generation sequencing
NSCLC
nonsmall cell lung cancer
OC
ovarian cancer
OR
objective response
ORR
objective response rate
OS
overall survival
PCR
pathologic and clinical response
PFS
progression-free survival
PK
pharmacokinetic
PRO
patient-reported outcome
PVC
polyvinyl chloride
Q3W
every 3 weeks
QLQ-OV28
Quality of Life Questionnaire Ovarian Cancer Module 28
R
resection margin
RCC
renal cell carcinoma
RECIST
Response Evaluation Criteria in Solid Tumors


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Abbreviation
Definition
RBR
Research Biosample Repository
SAP
statistical analysis plan
SARS CoV 2
severe acute respiratory syndrome coronavirus 2
SCORPION
Surgical Complications Related to Primary or Interval Debulking in 
Ovarian Neoplasm (study)
SMT
Study Management Team
TNF
tumor necrosis factor
TNFi
tumor necrosis factor alpha inhibitors
ULN
upper limit of normal
VEGF
vascular endothelial growth factor
WGS
whole genome sequencing


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1.
BACKGROUND
1.1
BACKGROUND ON OVARIAN, FALLOPIAN TUBE, AND 
PRIMARY PERITONEAL CANCERS
Ovarian, fallopian tube, and primary peritoneal cancers remain leading causes of 
cancer-related mortality among women worldwide.  Globally, epithelial ovarian 
cancer (EOC) affects 238,719 women annually and results in 140,200 cancer-related 
deaths, with an annual incidence of 65,584 (42,749 deaths) in Europe (Ferlay et al. 
2013) and 22,280 (14,240 deaths) in the United States (Siegel et al. 2016).  Epithelial 
ovarian cancer, fallopian tube cancer, and primary peritoneal cancer comprise of tumors 
of extra-uterine Müllerian origin,  share common clinical and biological behavior, and are 
typically grouped together in treatment paradigms and clinical investigations, as will be 
done in this current study.
The diagnosis of ovarian cancer (OC) in an early stage is uncommon because of its 
typically asymptomatic nature (Ebell et al. 2016).  Even patients with more 
advanced-stage disease typically experience only vague, non-specific symptoms that 
result in further delays in diagnosis.  Thus, most patients with OC already have 
advanced-stage, disseminated disease upon initial diagnosis, making the likelihood of 
cure remote.  The 5-year survival rate among patients with Stage I OC is 85%,
whereas the 5-year survival rates for patients with advanced Stage III or Stage IV OC 
are 39% and 17%, respectively (SEER Database).  Despite advances in perioperative 
and operative techniques, and a better understanding of the biology of OC, cure rates for 
OC have remained flat for more than a decade (Sopik et al. 2015).
The standard of care for OC at initial diagnosis includes primary tumor reduction
surgery, followed by platinum (carboplatin) and taxane (paclitaxel) systemic 
chemotherapy (McGuire 1996; Piccart 2000; Ozols et al. 2003, Ledermann et al. 2013).  
Recently, the Society of Gynecologic Oncology identified the initiation of chemotherapy 
within 42 days following primary cytoreductive surgery as a quality indicator for 
improving ovarian cancer care (SGO 2017).  In addition, due to the clinical benefit of 
adding the anti-vascular endothelial growth factor (VEGF) molecule bevacizumab to 
carboplatin and/or paclitaxel, the standard of care for patients who are newly-diagnosed 
with OC in an advanced stage in the European Union and other countries is now 
carboplatin and paclitaxel with bevacizumab.  Unfortunately, despite the high sensitivity 
of OC to initial platinum and taxane combination chemotherapy, the majority of women
who are diagnosed with advanced-stage disease will relapse and ultimately succumb to 
their cancer.  Many strategies that attempt to improve the clinical efficacy of first-line 
ovarian cancer (1LOC) cytotoxic chemotherapy regimens have been studied since 
carboplatin and paclitaxel were identified as the two key chemotherapies for OC.  Adding 
a third cytotoxic agent to the carboplatin and paclitaxel doublet only increased
hematologic toxicity, without commensurate increases in progression-free survival (PFS) 
and overall survival (OS), thus reinforcing the importance of carboplatin and paclitaxel as
the frontline regimen (Bookman et al. 2009).


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Despite the challenges observed with the manipulation or addition of cytotoxic 
chemotherapy agents to a carboplatin and paclitaxel doublet, the clinical experience with 
biological agents, notably bevacizumab, has been more promising.  Two randomized 
Phase III studies (Study Gynecology Oncology Group [GOG] 218; Study International 
Collaborative Ovarian Neoplasm [ICON]) of bevacizumab in patients with OC who are 
treatment naive, demonstrated improvement in PFS (Burger et al. 2011, 
Perren et al. 2011).  Study GOG218 combined the standard dose of bevacizumab 
(15 mg/kg every 3 weeks [Q3W]) with carboplatin and paclitaxel followed by 
bevacizumab monotherapy for 16 cycles, and showed a significant improvement in the 
Response Evaluation Criteria in Solid Tumors (RECIST)-determined PFS (i.e., excludes 
the cancer antigen [CA] 125 elevations and non-protocol therapies), with a reduction of 
35.5% in the risk of a PFS event and an increase of 6 months in the median PFS from 
12 months to 18 months (Burger et al. 2011).
A pronounced benefit was also identified in Study BO17707 (ICON7) in a subgroup of 
patients who were at a particularly high risk for cancer recurrence.  Patients who were 
treated with bevacizumab in this high-risk subgroup experienced a reduction of 27% in 
their risk for progression that corresponded to an improvement of 5.5 months in their 
PFS (Perren et al. 2011).  Furthermore, the treatment benefit in patients who were 
administered bevacizumab was evaluated in a subgroup analysis within Study GOG262, 
a Phase III study in which 80% of patients (including some in the neoadjuvant setting) 
were administered bevacizumab with chemotherapy (Chan et al. 2016).  Although the 
primary objective of Study GOG262 was to test the clinical benefit of treatment with 
carboplatin combined with weekly paclitaxel or paclitaxel (q21days), an analysis of 
patients administered carboplatin and paclitaxel (q21days) showed a longer PFS when 
bevacizumab was added to the treatment compared with patients for whom it was not 
added (14.7 months vs. 10.3 months).  This further supports the treatment benefit of the 
inclusion of bevacizumab in 1LOC treatment (Chan et al. 2016).  Study GOG218 and 
Study ICON7 led to the regulatory approval, in both the European Union and the United 
States, of bevacizumab combined with carboplatin and paclitaxel for the treatment of 
women with previously-untreated OC in an advanced stage.  The evidence to date from 
Study GOG262 continues to support this regimen as the best treatment standard 
for 1LOC.
Although maximizing surgical effort remains the cornerstone of 1LOC treatment, 
two seminal studies that evaluate the neoadjuvant approach against the traditional 
primary surgery, followed by adjuvant chemotherapy approach, demonstrated similar 
PFS and OS durations between the two approaches. (Vergote et al. 2010; Kehoe 2016).  
In addition to comparable survival metrics, both studies showed that the neoadjuvant 
approach was associated with markedly superior rates of optimal surgical tumor 
reduction (73% vs. 41%, p0.0001) and rates of achieving resection margin (R) 0 status
(39% vs. 17%, p0.0001), both strong prognostic factors for OC survival.  Furthermore, 
rates of postoperative complications, death, hemorrhage, and infection were less among 


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those who underwent neoadjuvant therapy prior to interval surgery (Vergote et al. 2010; 
Kehoe 2016).  More recently, supportive data from the Surgical Complications Related to 
Primary or Interval Debulking in Ovarian Neoplasm (SCORPION) study confirmed these 
data and provided additional evidence that demonstrated that patients with higher tumor 
load experienced statistically and clinically better emotional and cognitive functioning, 
and less nausea and/or vomiting, dyspnea, insomnia, and hair loss when treated with 
neoadjuvant therapy before interval surgery versus those patients who underwent 
primary tumor reduction surgery followed by chemotherapy (Fagotti et al. 2016).  
Bevacizumab has also been successfully employed into the neoadjuvant setting where it 
was incorporated upfront in 80% of the study population of Study GOG262 (Chan et al. 
2016) as well as in the final year of the SCORPION study when bevacizumab received 
Italian health authority approval for this indication (Fagotti et al. 2016).  In both studies, 
no new clinical or safety findings were cited with the use of bevacizumab in the 
neoadjuvant setting.
Although the strategy of neoadjuvant therapy followed by interval tumor reductive 
surgery treatment provides early clinical insight into the patient’s response to systemic 
therapy, no comprehensive set of pathologic parameters has been established to 
correlate histopathological and clinical responses in patients with OC.  Clinical 
parameters such as peritoneal carcinomatosis, bowel and/or stomach infiltration, liver 
metastases, and diaphragmatic, mesenteric, and/or omental disease, have been utilized 
in laparoscopic scoring systems to predict optimal cytoreduction, itself a favorable 
prognosticator in OC (Fagotti et al. 2011; Gomez-Hidalgo et al. 2015).  On the other 
hand, postneoadjuvant therapy histopathologic parameters such as fibrosis, necrosis, 
residual tumor percentage, and inflammation have been studied in association with 
survival and clinical outcome in ovarian cancer (Samrao et al. 2012).  Therefore, 
studying the associations between clinicopathologic parameters and clinical outcome in 
the neoadjuvant cohort of this study will further refine how therapeutic efficacy might be 
identified earlier for patients with OC.
Although surgery remains firmly fixed as a cornerstone of treatment for patients with OC, 
patient characteristics (e.g., performance status, comorbidities) coupled with the 
likelihood of technically achieving surgical R0 status make neoadjuvant therapy an 
attractive option for certain patients with newly-diagnosed OC in an advanced stage.  
Furthermore, the inclusion of patients undergoing neoadjuvant treatment into a 
prospective clinical study that investigates novel therapies scientifically offers a unique 
opportunity to advance our understanding of OC biology and response to treatments by 
systematically studying changes in tumor tissue over the course of treatment.
The current armamentarium of surgery, cytotoxic chemotherapy, and bevacizumab 
comprise key effective current treatment options for patients with OC, and serve as a 
foundation upon which this proposed study seeks to improve.


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1.2
BACKGROUND ON ATEZOLIZUMAB
Atezolizumab is a humanized immunoglobulin G1 monoclonal antibody that targets 
PD-L1 and inhibits the interaction between PD-L1 and its receptors, PD-1 and B7-1 (also 
known as CD80), both of which function as inhibitory receptors expressed on T cells.  
Therapeutic blockade of PD-L1 binding by atezolizumab has been shown to enhance the 
magnitude and quality of tumor-specific T-cell responses, resulting in improved 
anti-tumor activity (Fehrenbacher et al. 2016; Rosenberg et al. 2016).  Atezolizumab has 
minimal binding to Fc-receptors, thus eliminating detectable Fc-effector function and 
associated antibody-mediated clearance of activated effector T cells.
Atezolizumab shows anti-tumor activity in both nonclinical models and cancer patients
and is being investigated as a potential therapy in a wide variety of malignancies.  
Atezolizumab is being studied as a single agent in the advanced cancer and adjuvant 
therapy settings, as well as in combination with chemotherapy, targeted therapy, and 
cancer immunotherapy.
Atezolizumab is approved in several countries around the world (as a single agent 
and/or in combination) for the treatment of locally advanced or metastatic urothelial 
carcinoma, nonsmall cell lung cancer (NSCLC) , small-cell lung cancer, triple-negative 
breast cancer, hepatocellular carcinoma, and melanoma.
Refer to the Atezolizumab Investigator's Brochure for details on nonclinical and clinical 
studies.
Clinical Activity in Patients with Ovarian Cancer: Single Agent Activity
In the PCD4989g basket study (GO27831), 9 patients with OC were evaluable for 
response (Liu et al. 2019).  Efficacy results from these 9 patients showed the following:

An objective response rate (ORR): 2 of 9 patients (22.2%) with a confirmed 
response and 1 of 9 patients (22.2%) with a best OR of complete response

The duration of response for the two confirmed responders was 8.11 and 
30.6*months (where “*” denotes a censored value).

The 1-year OS rate was 44.4% (4 patients; 95% CI: 11.98 to 76.91).
1.3
STUDY RATIONALE AND BENEFIT-RISK ASSESSMENT
The PD-L1 pathway is an important checkpoint within the immune response to 
temporarily dampen immune responses in states of prolonged antigen stimulation, such 
as chronic infection or cancer.  PD-L1 is a cell-surface protein that downregulates 
immune responses through binding to its two receptors, PD-1 and B7.1.  PD-1 is an 
inhibitory receptor expressed on T cells following T-cell activation, and its expression is 
sustained in states of chronic stimulation (Blank et al. 2005; Keir et al. 2008).  B7.1 is a 
molecule expressed on antigen-presenting cells and activated T cells.  Binding of PD-L1 
to PD-1 and B7.1 inhibits T-cell proliferation and activation, cytokine production, and 
cytolytic activity, leading to the functional inactivation or exhaustion of T cells, and 


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reduced cytotoxic T lymphocyte (CTL)-mediated cancer cell killing (Butte et al. 2007; 
Yang et al. 2011).  Overexpression of PD-L1 on tumor cells has been reported to impede 
anti-tumor immunity, resulting in immune evasion (Blank and Mackensen 2007).  
Therefore, interrupting the PD-L1 pathway and generating a population of CTLs that can 
infiltrate tumors and specifically recognize and kill cancer cells represents an attractive 
strategy to restore tumor-specific T-cell immunity and produce an effective anti-tumor 
immune response. Emerging data highlight the importance of therapeutically targeting 
the PD-L1/PD-1 axis.  Indeed, encouraging clinical data with antiPD-L1/antiPD-1 
agents have consistently demonstrated significant survival benefits in patients with 
multiple advanced malignancies when T-cell responses against cancer are enhanced 
(Hodi et al. 2010; Kantoff et al. 2010; Chen et al. 2012).
Among patients with advanced malignancies (e.g., melanoma, renal cell carcinoma
(RCC), lung cancer, head and neck squamous cell cancer) who had progressed or 
relapsed after standard-of-care therapies, therapeutically reinvigorating their immune 
system by targeting the PD-L1/PD-1 axis resulted in deep, sustained clinical benefit.
Refer to the Atezolizumab Investigator's Brochure for detailed efficacy results.  In 
addition to therapeutic effects on these tumor sites, targeting the PD-L1/PD-1 axis has 
also demonstrated activity in patients with OC. The single-agent activity that was 
observed in patients with OC who were given different strategies to target the 
PD-L1/PD-1 axis support the immune system’s irrefutable role in patients with OC
(Hamanishi et al, 2015; Disis et al., 2015).  However, the modest responses observed 
leave room for improvement.
Critical events along the cancer-immunity cycle include the release of cancer cell 
antigens, efficient trafficking of cytotoxic T cells into the tumors, and eliciting and 
augmenting tumor-specific cell kill (Chen and Mellman 2013).  Cytotoxic agents are 
known to trigger a native immune response by inducing immunogenic cell death and
neoantigen release (Obeid et al. 2007; van den Boorn and Hartmann 2013).
Another key phase in the cancer immunity cycle hinges on effective infiltration of T cells 
into the tumor (Chen and Mellman 2013). VEGF inhibits efficient T cell infiltration 
(Chen and Mellman 2013); therefore, blocking VEGF may increase intratumoral T-cell
recruitment. This hypothesis bore out of the highly VEGF-driven RCC.  Here, the 
combination of bevacizumabatezolizumab resulted in both quantifiably more 
CD8tumor-infiltrating lymphocytes within the tumors and augmented tumor reduction
(Sznol et al. 2015). Analyses of longitudinal gene expression in tumors that are 
pretreatment, post-bevacizumab, and post-bevacizumabatezolizumab showed 
significant decreases of angiogenesis genes and increases of Th1 signaling genes.  
Importantly, these signatures of these Th1 signaling genes were delinked from the 
decrease in the angiogenesis-related genes, which indicates that bevacizumab alone 
resulted in some modulation of the tumor-immune microenvironment (Wallin et al. 2016).  
Bevacizumab has also been shown to normalize tumor-associated vasculature
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kill.  The importance of VEGF in EOC is well-studied (Jackson et al. 2015), and 
evidenced by the marked therapeutic activity seen with anti-VEGF agents, notably 
bevacizumab (Miyake et al. 2013; Yang et al. 2015).  Study YO39523 employs the 
current understanding of the role of VEGF in OC proliferation, metastasis, and, now, 
immune evasion (Motz et al. 2014).  This current study explores if clinical outcomes 
improve beyond the enhanced benefit already conferred by VEGF-targeting with 
bevacizumab (Burger et al. 2011; Perren et al., 2011).  Recent clinical observations, as 
highlighted above, substantiating the scientific rationale of combining anti-VEGF agents 
(e.g., bevacizumab) with immune checkpoint inhibitors, including the aforementioned 
report by Sznol and colleagues (2015), make bevacizumab plus atezolizumab 
particularly attractive.  In VEGF-driven tumors such as RCC and OC, bevacizumab has 
been shown to normalize the disorganized tumor associated vasculature.  This, in turn, 
promotes T cell infiltration and thus immune-mediated tumor cell kill.  Thus, harnessing 
the translational and clinical observations of this well-tolerated, two-pronged approach 
holds particularly great therapeutic promise for improving clinical outcomes for patients 
with ovarian cancer.
This notable efficacy of bevacizumab in patients with OC, coupled with the strong 
scientific rationale to combine VEGF-targeting with PD-L1 inhibition, warrant the addition 
of bevacizumab to atezolizumab to capitalize on these complementary therapeutic 
mechanisms.
Atezolizumab has been generally well tolerated in patients who were administered 
the treatment.  Adverse events with potentially immune-mediated causes consistent with 
an immunotherapeutic agent include rash, influenza-like illness, endocrinopathies, 
hepatitis or transaminitis, pneumonitis, colitis, and myasthenia gravis have been 
observed (refer to Atezolizumab Investigator's Brochure for detailed safety results).  To 
date, these events have been manageable with supportive treatment or interruption of 
atezolizumab treatment.  Certainly adding a novel agent into a treatment regimen must 
be fairly evaluated for possible risks of the entire treatment regimen.  Approximately 
8,000 patients in clinical trials and 5,000 patients in post-marketing have been exposed 
to atezolizumab to date, either as a single agent or in combination therapies.  A pivotal 
Phase III study (NCT 02366143) is being conducted by the Sponsor in the frontline lung 
cancer setting using the same regimen as in this study (paclitaxel
carboplatinbevacizumabatezolizumab).  This study is monitored by an independent 
Data Monitoring Committee (iDMC).  With >300 patients treated to date, the iDMC 
recommendations have been to continue the study with no changes to the study for 
safety reasons.
The safety profile of a combination regimen containing atezolizumab appears to be 
consistent with the known risks specific to the single molecules making up the 
combination treatment.  Immune-mediated risks were manageable with treatment 
(usually steroids) or interruption of atezolizumab therapy. Chemotherapy- and 
bevacizumab-related risks were manageable as per standard of care.


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This study will enroll patients with newly-diagnosed, previously-untreated advanced 
stage EOC, fallopian tube cancer, and primary peritoneal cancer (i.e., tumors of 
extra-uterine Müllerian origin).  Despite the administration of an active treatment regimen 
with carboplatin, paclitaxel and bevacizumab, the disease prognosis remains relatively 
poor and thus highlights the need to develop novel therapeutic studies for these patients.
The combination of atezolizumab with the standard-of-care backbone is hypothesized 
and expected to result in effective anti-tumor immunity with a favorable therapeutic 
index, and thus deliver enhanced clinical benefit to these patients.  On the basis of the 
promising efficacy data to date coupled with the manageable risk and tolerability of 
atezolizumab combination regimens, this study in patients with advanced-stage,
poor-prognosis ovarian cancer carries a favorable benefit-risk assessment.
The benefit-risk ratio for atezolizumab when administered in combination with paclitaxel, 
carboplatin, and bevacizumab is expected to be acceptable in this setting, as per 
individual health authorities assessments.
1.3.1
COVID-19 Benefit-Risk Assessment
In the setting of the Coronavirus disease 2019 (COVID-19) pandemic, patients with 
comorbidities, including those with cancer, are considered a more vulnerable population, 
with the potential for more severe clinical outcomes from COVID-19.  However, it is 
unclear whether or how systemic cancer therapies such as chemotherapy, targeted 
therapy, or immunotherapy impact the incidence or severity of COVID-19.
A possible consequence of inhibiting the PD-1/PD-L1 pathway may be the modulation of 
the host immune response to acute infection, which may result in immunopathology or 
dysregulated immune system defenses.  In nonclinical models, PD-1/PD-L1 blockade 
appears to be associated with serious exacerbation of inflammation in the setting of 
acute (as opposed to chronic) viral infection with lymphocytic choriomeningitis virus 
(Clone 13) (Frebel et al. 2012).  However, there are insufficient and inconsistent clinical 
data to assess if outcome from COVID-19 is altered by cancer immunotherapy.
Severe COVID-19 appears to be associated with a cytokine-release syndrome (CRS) 
involving the inflammatory cytokines interleukin (IL)-6, IL-10, IL-2, and interferon-
(Merad and Martin 2020).  While it is not known, there may be a potential for an 
increased risk of an enhanced inflammatory response if a patient develops severe acute 
respiratory syndrome coronavirus 2 (SARS-CoV-2) infection while receiving
atezolizumab.  At this time, there is insufficient evidence for causal association between 
atezolizumab and an increased risk of severe outcomes from COVID-19.
There may be potential synergy or overlap in clinical and radiologic features for 
immune-mediated pulmonary toxicity with atezolizumab and clinical and radiologic 
features for SARS-CoV-2related interstitial pneumonia.  Thus, investigators should use 


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their clinical judgment when evaluating and managing patients with pulmonary 
symptoms.
There are limited data concerning the possible interactions between cancer 
immunotherapy treatment and COVID-19 vaccination, and it is recognized that human 
immune responses are highly regulated and that immune modifying therapies may 
positively or negatively impact the efficacy and safety of COVID-19 vaccination 
(Society for Immunotherapy for Cancer [SITC] 2020).
Per recommendations of the National Comprehensive Cancer Network (NCCN) 
COVID-19 Vaccination Advisory Committee, COVID-19 vaccination is recommended 
for all patients with cancer receiving active therapy (including immune checkpoint 
inhibitors), with the understanding that there are limited safety and efficacy data in 
such patients (NCCN 2021).  Given the lack of clinical data, currently no 
recommendations can be made regarding the optimal sequence of COVID-19 
vaccination in patients who are receiving cancer immunotherapy (SITC 2020).  For 
patients enrolling in this study and receiving atezolizumab treatment, a decision to 
administer the vaccine to a patient should be made on an individual basis by the 
investigator in consultation with the patient.
In alignment with clinical practice procedures, factors to consider when making the 
individualized decision for patients receiving atezolizumab treatment to receive 
COVID-19 vaccination include the following:  the risk of SARS CoV 2 infection and 
potential benefit from the vaccine, the general condition of the patient and potential 
complications associated with SARS CoV 2 infection, underlying disease, and the 
severity of COVID-19 outbreak in a given area or region.  
The SITC and NCCN recommendations along with institutional guidelines should be 
used by the investigator when deciding on administering COVID 19 vaccines.  When 
administered,  COVID-19 vaccines must be given in accordance with the approved or 
authorized vaccine label.  Receipt of the COVID 19 vaccine is considered a concomitant 
medication and should be documented as such (see Section 4.4.1).
Neutropenia and lymphopenia associated with chemotherapy may increase the risk for 
developing an infection in patients receiving atezolizumab in combination with 
chemotherapy.
2.
OBJECTIVES AND ENDPOINTS
This study will evaluate the efficacy and safety of atezolizumab administered 
with paclitaxelcarboplatinbevacizumab compared with 
placebopaclitaxelcarboplatinbevacizumab in patients with newly diagnosed, 
untreated ovarian, fallopian tube, and/or primary peritoneal cancer.  Specific objectives 
and corresponding endpoints for the study are outlined below in Table 1.


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Table 1
Objectives and Corresponding Endpoints
Primary Efficacy Objective
Corresponding Endpoints
To evaluate the efficacy of atezolizumab 
versus placebo in combination with 
paclitaxel carboplatin bevacizumab 
among all patients and in those patients 
with PD-L1positive tumors 
Investigator-assessed PFS, defined as the time 
from randomization to the occurrence of disease 
progression, as determined by the investigator from 
tumor assessments per RECIST v1.1, or death 
from any cause during the study, whichever occurs 
first
OS, defined as the time from randomization to 
death from any cause 
Secondary Efficacy Objectives
Corresponding Endpoints
Among patients with measurable residual disease in the primary surgery group:
To evaluate the efficacy of atezolizumab 
versus placebo in combination with 
paclitaxel carboplatin bevacizumab
OR, defined as either a CR or PR as determined by 
the investigator with the use of RECIST v1.1 for 
patients with measurable residual disease after 
primary surgery
To evaluate the duration of efficacy 
observed with atezolizumab versus 
placebo in combination with 
paclitaxel carboplatin bevacizumab 
DOR, defined as the time interval from first 
occurrence of a CR or PR to the time of disease 
progression, as determined by the investigator with 
the use of RECIST v1.1, or death from any cause, 
whichever comes first for patients with measurable 
residual disease after primary surgery
To evaluate PROs of function and 
HRQoL associated with atezolizumab 
versus placebo in combination with 
paclitaxel carboplatin bevacizumab, 
as measured by the functional and 
GHS/QoL scales of the EORTC QLQ-C30
Clinically-meaningful improvement, remaining 
stable, or deterioration in patient-reported 
function and HRQoL, defined as a 10-point 
increase, changes within 10 points, and a 10-
point decrease, respectively, from the baseline 
score on each of the functional (physical, role, 
emotional, and social) and GHS/QoL scales of the 
EORTC QLQ-C30
Among the patients in the neoadjuvant group:
To determine the impact of atezolizumab 
versus placebo in combination with 
paclitaxel carboplatin bevacizumab on 
patient-reported abdominal symptoms of 
OC, as measured by two items from the 
abdominal/GI symptom scale of the 
EORTC QLQ-OV28
Clinically-meaningful improvement in 
patient-reported abdominal pain or bloating, defined 
as a 10-point decrease from the baseline score 
on either of the two items on the EORTC QLQ-
OV28 abdominal/GI symptom scale (items 31 
and 32)
To evaluate PROs of function and HRQoL 
associated with atezolizumab versus 
placebo in combination with 
paclitaxel carboplatin bevacizumab, as 
measured by the functional and GHS/QoL 
scales of the EORTC QLQ-C30
Clinically-meaningful improvement in 
patient-reported function and HRQoL, defined as a 
10-point increase from the baseline score on 
each of the functional (physical, role, emotional, 
and social) and GHS/QoL scales of the EORTC 
QLQ-C30


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Table 1
Objectives and Corresponding Endpoints (cont.)
Safety Objective
Corresponding Endpoints
To evaluate the safety and tolerability of 
atezolizumab versus placebo in 
combination with 
paclitaxel carboplatin bevacizumab
Occurrence and severity of adverse events, with 
severity determined in accordance to 
NCI CTCAE v4.0
Change from baseline in targeted vital signs
Change from baseline in targeted clinical 
laboratory test results
Pharmacokinetic Objective
Corresponding Endpoint
To characterize the pharmacokinetics of 
atezolizumab when administered in 
combination with 
paclitaxel carboplatin bevacizumab
Minimum and maximum serum concentration of 
atezolizumab
Exploratory Objectives
Corresponding Endpoints
Among neoadjuvant patients only: To 
evaluate PCR status and its association 
with clinical outcomes after 
administration of atezolizumab versus 
placebo in combination with 
paclitaxel carboplatin bevacizumab
Among patients who undergo neoadjuvant 
therapy prior to interval surgery, PCR status is 
defined as the clinical amount and histologic 
characteristics of residual disease assessed at 
the time of interval cytoreductive surgery
To evaluate the efficacy of atezolizumab 
versus placebo administered in 
combination with 
paclitaxelcarboplatinbevacizumab
The OS rate at 3 years after randomization
To evaluate PROs of disease 
and/or treatment-related symptoms 
associated with atezolizumab 
versus placebo administered in 
combination with 
paclitaxel carboplatin bevacizumab, 
as measured by the EORTC QLQ-C30 
and QLQ-OV28
Mean and mean changes from the baseline score 
in disease and/or treatment-related symptoms by 
cycle and between treatment arms as assessed 
by all symptom items and/or scales of the 
EORTC QLQ-C30 and QLQ-OV28
To evaluate any treatment burden 
patients may experience in association 
with the addition of atezolizumab to 
paclitaxel carboplatin bevacizumab 
compared with 
placebo paclitaxel carboplatin 
bevacizumab, as measured by a 
single item (from GP5: "I am bothered by 
side effects of treatment") from the 
physical wellbeing subscale of the 
FACT-G Quality of Life instrument
Proportion of patients reporting each response 
option at each assessment timepoint by treatment 
arm for item GP5 from the FACT-G
To evaluate and compare between 
treatment arms patients' health utility as 
measured by the EQ-5D-5L to generate 
utility scores for use in economic models 
for reimbursement
Health utility scores of the EQ-5D-5L


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Table 1
Objectives and Corresponding Endpoints (cont.)
Immunogenicity Objective
Corresponding Endpoint
To evaluate the immune response 
from patients who were administered 
atezolizumab
The incidence of ADAs against atezolizumab during 
treatment with atezolizumab administered in 
combination with 
paclitaxel carboplatin bevacizumab relative to the 
incidence of ADAs at the baseline
Exploratory Immunogenicity Objective
Corresponding Endpoint
To evaluate the potential effects of 
ADAs 
The relationship between ADA status and 
pharmacokinetics, safety, and efficacy
Exploratory Biomarker Objectives
Corresponding Endpoint
To assess predictive, prognostic, and 
pharmacodynamic exploratory 
biomarkers in archival and/or fresh 
tumor tissue and blood and their 
association with disease status and/or 
patient response to study treatment 
Association of tumor immune-mediated or disease 
type−related exploratory biomarkers (in archival 
and/or freshly obtained tumor tissues and plasma, 
whole blood, or serum) with disease status and/or 
response to administration of 
atezolizumabpaclitaxel carboplatin bevacizumab; 
biomarkers may include but are not limited to:
CD8 as assessed with the use of IHC
Breast cancer susceptibility gene (BRCA) status, 
homologous recombination deficiency, and 
microsatellite instability as assessed with the use 
of DNA NGS
Molecular subtyping of ovarian cancer, as assessed 
by RNA profile
Association of cell-free tumor DNA with tumor burden 
and treatment response
To identify biomarkers that are 
associated with resistance to 
atezolizumab administered in 
combination with carboplatin and/or 
paclitaxel and/or bevacizumab 
activity, or can increase the 
knowledge and understanding of 
disease biology
The relationship between biomarkers in blood and 
tumor tissue between pretreatment and 
post-progression samples collected at the time of 
disease progression. These biomarkers may include 
but are not limited to:
Acquired mutations assessed with the use of 
DNA NGS
Changes in the tumor immune microenvironment 
and biology as assessed by RNA profile and IHC
ADAanti-drug antibody; CRcomplete response; DORduration of response; 
EORTCEuropean Organisation for Research and Treatment of Cancer; FACT-GFunctional
Assessment of Cancer Therapy-General; GIgastrointestinal; GHS global health status;
HRQoLhealth-related quality of life; IHCimmunohistochemistry; NCI CTCAENational Cancer 
Institute Common Terminology Criteria for Adverse Events; NGSnext-generation sequencing; 
OCovarian cancer; ORobjective response; OSoverall survival; PCR pathologic and clinical 
response; PFSprogression-free survival; PRpartial response; PRO patient-report outcome; 
QLQ-OV28Quality of Life Questionnaire Ovarian Cancer Module 28; RECIST v1.1Response 
Evaluation Criteria in Solid Tumors, Version 1.1.


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3.
STUDY DESIGN
3.1
DESCRIPTION OF THE STUDY
3.1.1
Overview of Study Design
This is a Phase III, global, double-blind, two-arm, randomized study designed to 
evaluate the efficacy and safety of atezolizumab administered with 
paclitaxelcarboplatinbevacizumab compared with placebopaclitaxel
carboplatinbevacizumab in patients with Stage III or Stage IV ovarian, fallopian tube, 
or primary peritoneal cancer with macroscopic residual disease postoperatively 
(i.e., after primary tumor reductive surgery) or who will undergo neoadjuvant therapy 
followed by interval surgery.  Approximately 1300 patients will be randomized.  Patients 
will be randomized in a 1:1 ratio to one of the two treatment arms.
Eligible patients after primary tumor reductive surgery (see Figure 1) must be 
randomized within 42 days of primary surgery postoperatively and commence 
concurrent treatment with paclitaxel (175 mg/m2), carboplatin (area under the 
concentrationtime curve at 6 [AUC 6]), and atezolizumab or placebo (1200 mg) on 
Cycle 1, Day 1.  All treatments will be administered intravenously, and each cycle will be
21 days long.  Bevacizumab (15 mg/kg) will be added to paclitaxel, carboplatin, and 
atezolizumab treatment starting with Cycle 2.  After 6 cycles of concurrent 
chemotherapybevacizumab (5 cycles)atezolizumab or placebo, patients will continue 
on maintenance bevacizumabatezolizumab or bevacizumab placebo treatment for a 
total (concurrentmaintenance phases) of 22 cycles of atezolizumab or placebo and 
21 cycles of bevacizumab.  No additional cycles of maintenance anti-cancer therapy are 
permitted beyond 22 cycles of therapy in the front-line setting.  Study treatment will be 
discontinued at the time of disease progression, unacceptable toxicity, patient or 
physician decision to discontinue, death, or study termination by the Sponsor.
Eligible patients in the neoadjuvant therapy group (see Figure 2) will be randomized prior 
to the initiation of study treatment.  Patients in the neoadjuvant group will commence 
concurrent treatment with paclitaxel (175 mg/m2), carboplatin (AUC 6), 
bevacizumab (15 mg/kg), and atezolizumab or placebo (1200 mg) on Cycle 1, Day 1.  
All treatments will be administered intravenously, and each cycle will be 21 days long.  
Cycles 3 and 4 will consist of concurrent paclitaxel (175 mg/m2), carboplatin (AUC 6), 
and atezolizumab or placebo (1200 mg) with bevacizumab omitted peri-operatively.  
Interval surgery will occur after Cycle 3 as soon as deemed clinically appropriate, but 
within a maximum of 6 weeks after receiving Cycle 3.  Within 6 weeks after interval 
surgery, patients will resume concurrent chemotherapybevacizumabatezolizumab or 
placebo for three more cycles (total of six cycles), however bevacizumab treatment will 
resume at Cycle 5 (i.e., bevacizumab is omitted for Cycle 4).  Upon completion of 
concurrent therapy, patients will commence maintenance treatment with 
bevacizumabatezolizumab or bevacizumab placebo for a total of 22 cycles of 
atezolizumab or placebo, and 20 cycles of bevacizumab.  No additional cycles of 


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maintenance anti-cancer therapy are permitted beyond 22 cycles of therapy in the 
front-line setting.
After the completion of maintenance therapy (i.e., bevacizumabatezolizumab or 
placebo), patients will have an end-of-treatment assessment within 30 days of the last 
dose of study treatment and then enter the post-treatment follow-up period.  
The expected study treatment duration for an individual patient is approximately 
66 weeks for patients randomized after primary surgery and 70 weeks for patients 
randomized prior to neoadjuvant therapy.
Progression-free survival will be ascertained by the investigator in accordance with 
radiographic criteria from RECIST v1.1 at fixed intervals.  All primary imaging data used 
for tumor assessment will also be collected by the Sponsor to enable a centralized
Independent Review Committee audit of a prespecified subset of PFS data. Overall 
survival will be determined by the investigator.  Tumor assessments will continue until 
confirmed disease progression or 5 years after the completion of all study treatment, 
whichever occurs first.  Safety and toxicity assessments will be conducted at each 
treatment cycle administration.
Figure 1 and Figure 2 illustrate the study design.  A schedule of assessments is provided 
in Appendix 1 for patients who undergo primary surgery and in Appendix 2 for patients 
who undergo neoadjuvant chemotherapy or interval surgery, and a schedule of PK, 
ADA, and biomarker sampling is in Appendix 3.
Figure 1
Study Schema for Patients in the Primary Tumor-Reductive 
Surgery Group


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AUC area under the concentrationtime curve; Dx diagnosis; ECOG PS Eastern Cooperative 
Oncology Group performance status; ICimmune cell; OS overall survival; PFS progression-
free survival; q3wevery 3 weeks.
Figure 2
Study Schema for Patients in the Neoadjuvant 
Chemotherapy Group
AUC area under the concentrationtime curve; q3wevery 3 weeks.
Patients will undergo a mandatory tumor biopsy sample collection, if clinically feasible, 
at the time of first evidence of radiographic disease progression according to 
RECIST v1.1.  Cytology from ascites, pleural effusion, and fine needle aspiration (FNA) 
is not adequate.  These samples will be retrospectively analyzed to evaluate and/or 
characterize pseudoprogression caused by immune cells (ICs) from true progression.  
In addition, tumor tissue biomarkers related to resistance, disease progression, and 
clinical benefit of atezolizumab will be analyzed.
Option for additional enrollment in China: Study YO39523 will be enrolling patients 
globally. Should the Study be opened in mainland China, the Sponsor is targeting a total 
enrollment of approximately 150 patients. A China extension phase may be initiated if 
patients enrolled in the global enrollment phase is significantly less than the target. 
Thus, the China subpopulation will include patients enrolled at sites in China during both 
the global enrollment phase and the China extension phase. Patients from the China 
extension phase will be randomized in a 1:1 ratio to the two treatment arms.  The 
patients enrolled in the China extension phase will undergo the same schedule of 
assessments and will receive paclitaxel, carboplatin, bevacizumab, and atezolizumab or 
placebo as in the global study. Analyses based on the China subpopulation will be 
reported separately from the global study.


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3.1.2
Independent Data Monitoring Committee
An iDMC will evaluate safety data during the study.  Unblinded safety data will be 
reviewed by the iDMC on a periodic basis, approximately every 6 months from the time
the first patient is enrolled until after the primary PFS analysis.  In addition, the iDMC will 
review safety data when 12 patients have been enrolled into each treatment arm and 
have been administered treatment for at least two cycles.  The safety data will include 
demographic data, adverse events, serious adverse events, adverse events leading to 
treatment discontinuation, adverse events leading to death, all deaths, and relevant 
laboratory test result data.  The iDMC will not review efficacy data.  The iDMC and the 
Sponsor may request an interim iDMC meeting prior to the pre-specified 6-month 
interval, if needed.
All data summaries and analyses by treatment arm for iDMC review will be prepared by 
an external independent Data Coordinating Center (iDCC).  Following the data review, 
the iDMC will provide a recommendation as to whether the study may continue, whether 
study modifications and/or amendment(s) to the protocol should be implemented, or 
whether the study should be terminated.  The final decision will rest with the Sponsor.
Members of the iDMC will be external to the Sponsor and follow a separate 
iDMC Charter that outlines their roles and responsibilities, and a detailed monitoring 
plan.  After the primary PFS analysis, the iDMC will be dissolved, and the responsibility 
will be taken by the internal Study Management Team (SMT).  The SMT will review the 
data on serious adverse events and deaths at least once every 3 months until the last 
patient has completed the study treatment regimen.
Any outcomes from these safety reviews that affect study conduct will be communicated 
in a timely manner to the investigators for notification of the Institutional Review Boards
(IRBs) and/or Ethics Committees (ECs).
3.2
END OF STUDY AND LENGTH OF STUDY
The primary PFS analysis will be performed when approximately 601 PFS events in the 
intent-to-treat (ITT) population or approximately 347 PFS events among the
PD-L1positive subpopulation have occurred, whichever occurs last.
The end of the study is expected to be approximately 55 months after the first patient is 
enrolled, when the approximate preplanned numbers of deaths among the 
PD-L1positive patients and the ITT population have been observed (see Appendix 4).  
Deaths will be monitored throughout the course of the study. The sponsor has the right 
to close the study at any time if futility is observed (e.g., based on the predicted 
probability of success at the subsequent analysis).  The study timelines may be updated 
as needed.
Treatment will continue until disease progression, unacceptable toxicity, completion of
the study treatment (i.e., 22 cycles of atezolizumab or placebo), patient or physician 


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decision to discontinue, or death.  Tumor response data collection will continue if the 
patient prematurely ends treatment, provided there is no confirmed radiographic disease 
progression.  Tumor response data collection will also continue beyond the completion 
of the study treatment until radiographic disease progression is confirmed.  Follow-up 
data, including OS and subsequent anti-cancer therapies, will continue for each patient 
until patient death or study closure.
If a patient discontinues and/or withdraws from the study, tumor response data as well 
as follow-up and/or surveillance data (e.g., OS, subsequent anti-cancer therapies) will 
continue to be monitored and collected until patient death or study closure.
3.3
RATIONALE FOR STUDY DESIGN
3.3.1
Rationale for Atezolizumab Dose and Schedule
The atezolizumab fixed dose of 1200 mg Q3W was selected on the basis of both 
nonclinical studies and available clinical data from Study PCD4989g, as described 
below.
The target exposure for atezolizumab was projected on the basis of clinical and 
nonclinical parameters, including nonclinical tissue distribution data in tumor-bearing 
mice, target-receptor occupancy in the tumor, and observed atezolizumab interim 
pharmacokinetics in humans. The target trough concentration (Ctrough) was projected 
to be 6 g/mL on the basis of several assumptions that include:  1) 95% tumor-receptor 
saturation is needed for efficacy, and 2) the tumor interstitial concentrationto-plasma 
ratio is 0.30 on the basis of tissue distribution data in tumor-bearing mice.
In Study PCD4989g, the first-in-human study in patients with advanced solid tumors and 
hematologic malignancies, 30 patients were treated with atezolizumab at doses that 
ranged from 0.01 mg/kg to 20 mg/kg Q3W administered during the dose-escalation 
stage and 247 patients were treated with atezolizumab at doses of 10, 15, or 
20 mg/kg Q3W during the dose-expansion stage.  Anti-tumor activity has been observed 
across doses that ranged from 1 mg/kg to 20 mg/kg. There was no evidence of 
dose-dependent toxicity in Study PCD4989g.  The maximum tolerated dose of 
atezolizumab was not reached, and no dose-limiting toxicities were observed. Anti-drug 
antibodies (ADAs) to atezolizumab were associated with changes in pharmacokinetics 
for some patients in the lower dose cohorts (0.3, 1, and 3 mg/kg), but patients treated 
with doses of 10, 15, and 20 mg/kg maintained the expected Ctrough despite the detection 
of ADAs.  To date, no relationship has been observed between the development of 
measurable ADAs and safety or efficacy.  After review of available pharmacokinetic (PK)
and ADA data for a range of doses, 15 mg/kg Q3W was identified as the lowest 
atezolizumab dosing regimen to maintain Ctrough at 6 g/mL and further safeguard 
against interpatient variability and potential ADAs to lead to subtherapeutic levels of 
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Simulations do not suggest any clinically-meaningful differences in exposure following 
a fixed dose compared with a body weightadjusted dose (Bai et al. 2012).  Therefore, 
patients in this study will be treated Q3W at a fixed dose of 1200 mg.
Refer to Atezolizumab Investigator’s Brochure for details regarding nonclinical and 
clinical pharmacology of Atezolizumab.
3.3.2
Rationale for Patient Population
This study will enroll patients with newly-diagnosed Stage III or Stage IV ovarian, 
fallopian tube, or primary peritoneal cancer (i.e., cancers of extra-uterine Müllerian 
origin) who have macroscopic residual disease postoperatively (i.e., after primary tumor 
reductive surgery) or who will undergo neoadjuvant therapy followed by planned interval 
surgery.  The eligibility criteria for this study include patients who are at the highest risk 
for a poor clinical outcome and, therefore, represent those in great need for new, more 
effective treatments.
Because of their predisposition to present in an advanced stage with large tumor 
volume, EOC, fallopian tube carcinoma, and primary peritoneal carcinoma remain the 
leading cause of death among all gynecologic malignancies with poor 5-year survival 
rates at 39% (Stage III) and 17% (Stage IV) (Goff et al. 2012; Ferlay et al. 2013;
American Cancer Society 2016; Siegel et al. 2016).  Furthermore, certain tumor 
characteristics, such as postoperative macroscopic residual disease, and Stage IV 
disease, portend especially poor prognosis and a high risk for recurrence. Despite highly 
effective cytotoxic agents coupled with potent anti-angiogenic therapy, recurrence rates 
remain high for patients with advanced stage OC, thereby highlighting the need to avail 
novel and durable therapies for these patients and thus justify their inclusion into this 
study.
In addition to those patients with advanced stage, postoperative residual disease, this 
study also includes patients who are deemed not surgically resectable to a state of no 
gross residual disease, and thus are in need of neoadjuvant therapy first.  These 
patients are also at extreme high risk for a poor clinical outcome and in need of new, 
more effective treatments.
Although cytoreductive surgery constitutes the mainstay of treatment for EOC, an 
increase in data indicates that delivery of neoadjuvant therapy followed by interval 
surgery in certain patients, instead of performing surgery followed by chemotherapy, will 
likely provide equivalent clinical efficacy with more favorable perioperative morbidity and 
health-related quality of life (HRQoL) for some patients with EOC (Vergote et al. 2010; 
Kehoe 2016, Fagotti et al. 2016).  Indeed, two prospective randomized Phase III studies 
demonstrated equivalent survival rates among patients with advanced stage EOC who 
received either neoadjuvant therapy followed by interval surgery or primary tumor 
reduction surgery (Vergote et al. 2010; Kehoe 2016).  These data likely explain the 
increase in the use of neoadjuvant chemotherapy (NACT) in the United States


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(Hinchclilff et al. 2016).  In fact, in a 2009 survey for clinician members of the Society of 
Gynecologic Oncology, approximately 90% of respondents reported the use of NACT in 
11%25% of patients with 1LOC (Dewdney et al. 2010).  At the Memorial Sloan 
Kettering Cancer Center alone, the rate for NACT increased significantly (p0.037) from 
22% (56 of 256 patients) from 20082010, to 30% (98 of 330 patients) from 2010 until 
mid-2013 (Mueller et al. 2016).  The clinical emphasis on achieving complete surgical 
resection, along with fewer perioperative morbidities, collectively account for the 
increase in uptake of NACT for patients with newly-diagnosed OC, and highlight the 
need to include patients with OC who were treated with the use of a NACT paradigm into 
this study.
A 20% cap on patients in the NACT cohort is proposed for this Phase III study to ensure 
that (1) the mix of patients in this study approximates global clinical practice patterns,
and (2) the patient population does not become so heterogeneous so as to unduly bias 
or obscure the efficacy imparted by this immunotherapy based regimen.
3.3.3
Rationale for Control Group
To minimize the bias between the control and experimental patient groups, this study will 
administer a placebo to patients in the control group and ensure that patients, physician,
and the Sponsor remain blinded to the treatment that is assigned to each group.  
Paclitaxel, carboplatin, bevacizumab, and placebo treatment followed by bevacizumab
and/or placebo treatment is the comparator regimen for this patient population because
paclitaxel, carboplatin, and bevacizumab constitute the standard-of-care regimen for this 
patient population with advanced OC.
The cytotoxic doublet of carboplatin and paclitaxel represents the cytotoxic agents 
typically used for patients with newly-diagnosed, previously untreated EOC 
(McGuire et al. 1996; Ozols et al. 2003; Vergote et al. 2010). Attempts to add another 
cytotoxic agent to this platinum doublet added toxicity without improving clinical 
outcomes (Bookman et al. 2009). However, the anti-VEGF molecule, bevacizumab, 
became the first targeted biological agent to demonstrate prolonged and profound PFS 
improvements when added to carboplatin and/or paclitaxel and then administered as 
maintenance therapy, especially among patients with postoperative gross residual 
disease (ICON7 and Study GOG218; Burger et al. 2011; Perren et al. 2011).  
Study ICON7 showed that the addition of bevacizumab to chemotherapy led to a 
reduction of 13% in the risk of a PFS event (hazard ratio [HR]: 0.87; 
95% CI: 0.77 to 0.99, p0.04), and an improvement by 2.4 months (Perren et al. 2011).  
Similarly, Study GOG0218, which also combined bevacizumab with chemotherapy,
resulted in a reduction of approximately 35% in the risk of a PFS event (HR: 0.645; 
95% CI: 0.551 to 0.756, p 0.001) when censored for CA-125 progression, 
corresponding to a 6-month improvement in RECIST-defined PFS (from 12.0 months 
to 18.0 months; Burger et al. 2011). This improvement in clinical efficacy led to the 
approval of bevacizumab to be administered in combination with carboplatin and 


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paclitaxel followed by treatment of single-agent bevacizumab in patients with 1LOC in 
Europe and other countries globally, and incorporation into European treatment 
guidelines (Ledermann et al. 2013).
Of additional clinical interest within the ICON7 study (Oza et al. 2015) was the more 
pronounced benefit conferred by bevacizumab in patients with tumor characteristics that 
placed them at a high risk for recurrence and death (i.e., postoperative macroscopic 
residual and Stage IV disease).  Bevacizumab plus carboplatin and paclitaxel for these 
patients resulted in a reduction of 27% in the risk of a PFS event (HR: 0.73; 95%
CI: 0.61 to 0.88, p 0.0001), which corresponded to an improvement in median PFS 
from 10.5 months to 16.0 months.  There was also a reduction of 22% in the risk of 
death, which corresponded to an improvement in median OS from 30.2 months to 
39.7 months (Oza et al. 2015).
Recent clinical observations that support the scientific rationale for the combination of
anti-VEGF agents (e.g., bevacizumab) with immune checkpoint inhibitors make 
bevacizumabatezolizumab particularly attractive. Sznol and colleagues (2015) 
reported the first combinatorial clinical data demonstrating pronounced therapeutic 
benefit when bevacizumab was combined with atezolizumab in patients with metastatic 
RCC. In VEGF-driven tumors, bevacizumab has been shown to normalize the 
tumor-associated vasculature, and this, in turn, promotes T cell infiltration. The 
administration of bevacizumab in combination with atezolizumab further increases the 
immune infiltration and tumor growth control. Harnessing the translational and clinical 
observations of this well tolerated, 2-pronged approach against both VEGF and PD-L1 
holds particularly great therapeutic promise for patients with OC.
3.3.4
Rationale for Progression-Free Survival and Overall Survival 
as Co-Primary Endpoints
In this study, the co-primary efficacy endpoints will be investigator-assessed PFS and 
OS.  This study will test the hypothesis that treatment with atezolizumab added to 
paclitaxel, carboplatin, and bevacizumab will prolong PFS and OS compared with 
treatment with placebo plus paclitaxel, carboplatin, and bevacizumab.
The use of co-primary endpoints of PFS and OS is based on the complexity and
dynamic nature of treatment for patients with OC, and the clinical observations and 
lessons learned from other cancer immunotherapy studies. Wolchok and 
colleagues (2009) described the unique clinical trajectory of patients’ tumors when 
treated with immunomodulators and suggest short-term radiographic assessments may 
not capture the true efficacy of cancer immunomodulators. This is further exemplified by 
the superior and prolonged OS benefit conferred by atezolizumab, despite comparable 
PFS rates with docetaxel, as demonstrated in the randomized Phase II NSCLC 
Study GO28753 (POPLAR) (Fehrenbacher et al. 2016). The prolongation of OS in 
diseases such as recurrent NSCLC reflects the durable biological effects of cancer 
immunotherapies, such as atezolizumab.


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Because tumor response to treatment is dynamic, and the progressive decrease in 
tumor size alleviates disease burden and demonstrates clinical benefit, PFS remains an 
important, clinically-meaningful metric to demonstrate the efficacy of anti-cancer 
regimens for patients with OC. Furthermore, PFS is not subject to potential confounding 
by post-progression treatments (including antiPD-L1/PD-1 therapies) that may obscure 
OS improvements.  PFS benefit has been shown consistently across several prospective 
and retrospective studies of patients with OC who were administered a combination of 
chemotherapy and bevacizumab, thus reinforcing the importance of this clinical endpoint
(Burger et al. 2011, Perren et al. 2011; Aghajanian et al. 2012; Eskander et al. 2014; 
Coleman et al. 2015).
In acknowledgment of the clinical significance of both PFS and OS, the primary 
endpoints for this study will be both PFS and OS.  This study has been designed to 
detect a substantial magnitude of benefit in the ITT population with a target HR of 
0.70 for PFS and 0.78 for OS.
3.3.5
Rationale for Biomarker Assessments
Published results suggest that the expression of PD-L1 in tumors correlates with 
response to antiPD-1 and antiPD-L1 therapy (Topalian et al. 2012; Herbst et al. 2014; 
Borghaei et al. 2015; Fehrenbacher et al. 2016; Herbst et al. 2016; 
Rosenberg et al. 2016).  In the current study, screening baseline tumor specimens will 
be collected from patients and tested for PD-L1 expression by a central laboratory during 
the screening period.  Patients who participate in the study after primary tumor reductive 
surgery must provide a tumor specimen from that surgery.  Patients who will undergo 
neoadjuvant therapy followed by interval tumor reduction will need to provide a tumor 
specimen from a core needle biopsy (i.e., not from FNA or a cell block generated after 
centrifuging ascites and/or pleural fluid).  Only patients with evaluable tumor PD-L1 
expression will be enrolled in the study.  Randomization will be stratified by PD-L1 
expression. In addition to the assessment of PD-L1 status, other exploratory 
biomarkers, such as potential predictive and prognostic biomarkers related to the clinical 
benefit of atezolizumab, tumor immunobiology, mechanisms of resistance, or tumor type, 
may be analyzed.
Patients who undergo neoadjuvant therapy and participate in the biomarker cohort will 
undergo a mandatory biopsy tissue sample collection at Cycle 1, Day 15 and provide 
corresponding plasma.  This will enable a robust characterization of the temporal effects 
of systemic treatment with and without atezolizumab on the immune response 
(e.g., immune cell infiltration) and on circulating biomarkers (e.g., cell free tumor DNA).
Patients will undergo mandatory tumor biopsy sample collection, if deemed clinically 
feasible by the investigator, at the time of first evidence of radiographic disease 
progression to evaluate the utility of the biopsy specimen in distinguishing 
pseudoprogression (caused by ICs) from true progression. In addition, tumor tissue 


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biomarkers related to resistance, disease progression, and clinical benefit of 
atezolizumab will be analyzed.
Blood samples will be collected at baseline and during the study to evaluate changes in 
surrogate biomarkers.  Changes in biomarkers such as cytokines associated with T-cell 
activation, circulating tumor DNA (ctDNA) concentration, and T-cell subpopulations may 
provide evidence of biologic activity of atezolizumab in humans.  Correlations between 
these biomarkers and safety and efficacy endpoints will be explored to identify 
blood-based biomarkers that might predict which patients are more likely to benefit from 
atezolizumab.
Tumor tissue and blood samples collected at baseline and, if deemed clinically feasible
by the investigator, tumor tissue collected at the time of disease progression may enable 
DNA- and RNA-sequencing to identify somatic mutations and characteristics of the 
tumor-immune microenvironment predictive of response, and associated with 
progression to a more severe disease state. These newly-identified somatic mutations
and tumor microenvironment changes associated with acquired resistance to study 
treatment can increase the knowledge and understanding of disease biology.
Genomics is increasingly informing researchers’ understanding of disease pathobiology.  
Whole genome sequencing (WGS) provides a comprehensive characterization of the 
genome and, along with clinical data collected in this study, may increase the 
opportunity to develop new therapeutic approaches.  Data will be analyzed in the context 
of this study but also be explored in aggregate with data from other studies.  
The availability of a larger dataset will assist in the identification of important pathways, 
and guide the development of new targeted agents.
3.3.6
Rationale for Patient-Reported Outcome Assessments
Abdominal symptoms (e.g., bloating, increased abdominal size, abdominal pain) are 
ranked as the top symptoms in terms of frequency, severity, and duration by patients
with OC, and represent a significant burden in women with newly-diagnosed advanced 
disease (Olson et al. 2001; Goff et al. 2004; Matsuo et al. 2011; 
Friedlander and King 2013; Donovan et al. 2014). Prioritizing measurement of 
patient-reported abdominal symptoms in the neoadjuvant setting is important because 
these common advanced symptoms are most likely to be affected by early treatment and 
are critical in the assessment of clinical benefit (Donovan et al. 2014; Herzog et al. 
2014). In this study, improvements in the symptoms of bloating and abdominal pain will 
be assessed with the use of the valid and reliable European Organisation for the 
Research and Treatment of Cancer Quality of Life Questionnaire Ovarian Cancer 
Module 28 (EORTC QLQ-OV28) to provide a direct measure of clinical benefit in the 
neoadjuvant setting (Cull et al. 2001; Greimel et al. 2003).
The EORTC QLQ-OV28 includes a seven-item abdominal/gastrointestinal (GI) symptom 
scale (items 3137; see Appendix 5). Improvement in abdominal symptoms as 


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identified by item 31 ("Did you have abdominal pain?") and item 32 ("Do you have a 
bloated feeling in your abdomen/stomach?") will be assessed as key secondary 
endpoints among patients receiving neoadjuvant therapy to document the impact of 
atezolizumab on two of the most predominant and burdensome symptoms of advanced 
OC (Cella et al. 2003). Instead of analyzing the entire abdominal/GI scale, this 
secondary endpoint definition is based on an analysis of two single items that identify
and assess two distinct symptoms that are the most clinically relevant and important to 
newly diagnosed patients with advanced OC (Olson et al. 2001; Cella et al. 2003; Goff 
et al. 2004; Matsuo et al. 2011; Goff 2012; Friedlander and King 2013; Donovan et al. 
2014).
To provide supplementary information to describe clinical benefits in the overall patient 
population and support and inform on the benefit-risk assessment of atezolizumab 
therapy, a global assessment of the impact of treatment on patients’ functioning and 
HRQoL will be conducted and analyzed with the functional (role, physical, emotional, 
and social) and global health status and QoL scale scores of the validated, reliable 
EORTC QLQ-C30 (Aaronson et al. 1993). In addition, to evaluate any treatment burden 
patients may experience with the addition of atezolizumab, the proportion of patients 
who select each response option at each assessment timepoint by treatment arm will be
reported for single item GP5 (“I am bothered by side effects of treatment”) from the 
physical wellbeing subscale of the validated and reliable Functional Assessment of 
Cancer Therapy–General (FACT-G) Quality of Life Instrument–Version 4, (Cella et al. 
1997; Webster et al. 1999). Patients will also complete the validated EQ-5D-5L
(Herdman et al. 2011; Janssen et al. 2013; see Appendix 6) to generate utility scores to 
inform pharmacoeconomic evaluations.  As such, the utility results will not be included in 
the CSR.
Given the duration of treatment and the potential for long-term treatment impact, all 
patient-reported outcome (PRO) measures will be assessed while patients are enrolled 
in the study and after treatment discontinuation as defined in the schedule of 
assessments (see Appendix 1 and Appendix 2). Patients will complete all 
PRO questionnaires on paper at the study site.
4.
MATERIALS AND METHODS
4.1
PATIENTS
Approximately 1300 patients with Stage III or Stage IV ovarian, fallopian tube, or primary 
peritoneal cancer (i.e., cancers of extra-uterine Müllerian origin) with macroscopic 
residual disease postoperatively (i.e., after primary tumor reductive surgery) or who will 
undergo neoadjuvant therapy followed by interval surgery are expected to be 
randomized in this study.  The enrollment of patients in the neoadjuvant setting will be 
capped at approximately 20%.


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4.1.1
Inclusion Criteria
Patients must meet the following criteria for study entry:

Signed Informed Consent Form (ICF)

Age 18 years

Able to comply with the study protocol, in the investigator’s judgment

Receive a histologic diagnosis of EOC, peritoneal primary carcinoma, or 
fallopian tube cancer fulfilling the following criteria:
All epithelial tumors of extra-uterine Müllerian origin by histology (FNA, cytology 
and/or cell block are not sufficient)
For patients who will undergo primary tumor reductive surgery:  International 
Federation of Gynecological Oncologists (FIGO) Stage III with gross 
(macroscopic or palpable) residual disease or Stage IV
Measurable disease on postoperative imaging studies is not required for 
eligibility.
FIGO stage is assessed following the completion of initial 
abdominopelvic surgery that provides the appropriate tissue for 
histologic evaluation and diagnosis and can be used for exploratory 
biomarker studies.
Primary tumor reductive surgery must be within 42 days of 
randomization.
For patients who will undergo neoadjuvant treatment and interval surgery:  
Patients who receive neoadjuvant treatment must also plan to undergo interval 
surgery after Cycle 3.  Mandatory biopsy tissue samples (e.g., core needle or 
surgically obtained; FNA or cell-block from ascites and/or pleural effusion are 
inadequate) will be used to confirm histologically that the tumor is of 
extra-uterine Müllerian origin and to perform exploratory biomarker studies.
Patients who receive neoadjuvant therapy will include those patients who 
are not deemed surgically resectable to a state of no gross residual 
disease due to the extent and/or distribution of disease (e.g., unresectable 
miliary pattern of peritoneal carcinomatosis, significant diaphragmatic 
disease, significant involvement of the root of the mesentery, diffuse tumor 
in the omentum up to the greater curvature of the stomach, extensive 
miliary carcinomatosis at the root of the mesentery, tumor infiltration of the 
stomach, surface lesions on the liver).

Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2

Life expectancy 12 weeks


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
Adequate hematologic and end-organ function, defined by the following 
laboratory test results, obtained within 14 days prior to randomization:
ANC 1500 cells/L (without granulocyte colony stimulating factor support)
Lymphocyte count 500/L
Platelet count 100,000/L without transfusion
Hemoglobin 9.0 g/dL
Patients may be transfused to meet this criterion.
Serum creatinine 1.5institutional upper limit of normal (ULN)
Serum bilirubin 1.5ULN
Patients with known Gilbert disease who have serum bilirubin 
level 3ULN may be enrolled in the study.
AST, ALT, and ALP 2.5ULN, with the following exceptions:
Patients with documented liver metastases:  AST and/or ALT 5ULN
Patients with documented liver or bone metastases:  ALP 5ULN.
For patients who do not receive therapeutic anticoagulation:  INR or 
aPTT 1.5 ULN

For patients who receive therapeutic anticoagulation: stable anticoagulant regimen

Negative hepatitis B surface antigen (HBsAg) test at screening

Negative total hepatitis B core antibody (HBcAb) test at screening, or positive total 
HBcAb test followed by a negative hepatitis B virus (HBV) DNA test at screening
The HBV DNA test will be performed only for patients who have a positive total 
HBcAb test.

Negative hepatitis C virus (HCV) antibody test at screening, or positive 
HCV antibody test followed by a negative HCV RNA test at screening
The HCV RNA test will be performed only for patients who have a positive 
HCV antibody test.
A positive HCV RNA test is sufficient to diagnose active HCV infection in the 
absence of an HCV antibody test.

For women of childbearing potential:  agreement to remain abstinent (refrain from 
heterosexual intercourse) or use a contraceptive method with a failure rate 
of 1% per year during the treatment period and for at least 5 months after 
administration of the last dose of atezolizumab and 6 months after the last dose of 
bevacizumab, paclitaxel, or carboplatin, whichever is later
A woman is considered to be of childbearing potential if she is postmenarcheal, 
has not reached a postmenopausal state (12 continuous months of 
amenorrhea with no identified cause other than menopause), and has not 
undergone surgical sterilization (removal of ovaries, fallopian tubes, and/or 
uterus).


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Examples of contraceptive methods with a failure rate of 1% per year include 
but are not limited to bilateral tubal ligation and/or occlusion, male sterilization, 
and intrauterine devices.
In countries with country-specific health authority mandates, contraceptive 
methods with a failure rate of 1% per year include bilateral tubal 
ligation/occlusion, male partner sterilization, established and proper use of 
estrogen-progestin combination hormonal contraceptives that inhibit ovulation, 
and intrauterine devices/systems.
The reliability of sexual abstinence should be evaluated in relation to the 
duration of the clinical study and the preferred and usual lifestyle of the patient.
Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation 
methods) and withdrawal are not acceptable methods of contraception.

Willingness and ability to comply with scheduled visits, treatment plans, laboratory 
tests, and other study procedures, that include the completion of PRO questionnaires

Availability of a representative formalin-fixed, paraffin-embedded (FFPE) tumor 
specimen (screening baseline tissue) in paraffin blocks (preferred) or at least 
20 unstained slides.
Patients with fewer than 20 unstained slides available at baseline may be 
eligible upon discussion with the medical monitor.
Tumor tissue should be of good quality based on total and viable tumor content 
and must be evaluated for PD-L1 expression prior to enrollment.  Patients 
whose tumor tissue is not evaluable for PD-L1 expression are not eligible for 
enrollment in the study.
If multiple screening baseline tumor specimens are submitted, patients may be 
eligible if at least one specimen is evaluable for PD-L1.  For the purpose of 
stratification, the PD-L1 score of the patient will be the maximum PD-L1 score 
among the samples.
Acceptable samples include tissue obtained from surgery or core 
needle biopsies (minimum three cores per paraffin block).
A paraffin block for FFPE tumor specimens is preferred.
FNA or cell pellets from ascites or pleural effusion are not acceptable.
Tumor tissue from bone metastases is not evaluable for PD-L1 
expression and is not acceptable.

For patient enrolled in the extended China enrollment phase: residents in Mainland 
China, residents in Hong Kong and Taiwan of Chinese ancestry and enrolled at sites 
recognized by China’s National Products Administration (NMPA).


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4.1.2
Exclusion Criteria
Patients who meet any of the following criteria will be excluded from enrollment in the 
study:

Received a current diagnosis of borderline epithelial ovarian tumor (formerly tumors 
of low malignant potential)

Have recurrent invasive epithelial ovarian, fallopian tube, or primary peritoneal 
cancer that was treated only with surgery (e.g., patients with Stage IA or Stage IB
epithelial ovarian or fallopian tube cancers)
Patients who received a prior diagnosis of a borderline tumor that was 
surgically resected and who subsequently developed an unrelated, new 
invasive epithelial ovarian, fallopian tube, or primary peritoneal cancer are 
eligible for enrollment, if they have never received prior chemotherapy for any 
ovarian tumor.

Have non-epithelial ovarian tumors (e.g., germ cell tumors, sex cord stromal tumors)

Received prior radiotherapy to any portion of the abdominal cavity or pelvis
Prior focal radiation for localized cancer of the breast, head and neck, or skin is 
permitted, if it was completed 5 years prior to initiation of study treatment, and 
the patient remains free of recurrent or metastatic disease.

Received prior chemotherapy for any abdominal or pelvic tumor that include NACT 
for ovarian, primary peritoneal or fallopian tube cancer
Patients may have received prior chemotherapy for localized breast cancer, if it 
was completed 5 years prior to initiation of study treatment, and the patient 
remains free of recurrent or metastatic disease.

Received any biological and/or targeted therapy (including but not limited to 
vaccines, antibodies, tyrosine kinase inhibitors) or hormonal therapy for 
management and/or treatment of epithelial ovarian or peritoneal primary cancer

Have synchronous primary endometrial cancer

Have a prior history of primary endometrial cancer, except for the following:
A prior diagnosis of endometrial cancer is allowed if all of the following 
conditions are met:
Stage IA cancer
Superficial myometrial invasion, without lymphovascular invasion
Grade 3 or not poorly differentiated subtypes, and this includes papillary 
serous, clear cell or other FIGO Grade 3 lesions

With the exception of non-melanoma skin cancer and other specific malignancies as 
noted above, other invasive malignancies within the last 5 years or previous cancer 
treatment that contraindicates this protocol therapy (e.g., previous chemotherapy 
treatment for breast cancer completed 5 years ago is permitted as per above).

Are pregnant, lactating, or intend to become pregnant during the study


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
Have a history of severe allergic, anaphylactic, or other hypersensitivity reactions 
to chimeric or humanized antibodies or fusion proteins

Have a known hypersensitivity or allergy to biopharmaceutical agents produced in 
Chinese hamster ovary cells or any component of the atezolizumab and/or 
bevacizumab formulations

Have an active or history of autoimmune disease or immune deficiency that includes 
but is not limited to myasthenia gravis, myositis, autoimmune hepatitis, systemic 
lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, 
antiphospholipid antibody syndrome, Wegener’s granulomatosis, 
Sjögren’s syndrome, Guillain-Barré syndrome, or multiple sclerosis (see Appendix 7
for a more comprehensive list of autoimmune diseases).
Exceptions include the following:
Patients with a history of autoimmune-related hypothyroidism on a stable dose 
of thyroid replacement hormone are eligible.
Patients with controlled Type 1 diabetes mellitus on a stable dose of insulin 
regimen are eligible.
Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with 
dermatologic manifestations only (e.g., patients with psoriatic arthritis would be 
excluded) are eligible for enrollment in the study provided that they meet all of 
the following conditions:
Rash must cover less than 10% of body surface area
Disease is well controlled at baseline and requires only low potency 
topical steroids
No acute exacerbations of underlying condition within the previous 
12 months (i.e., does not require psoralen plus ultraviolet A radiation, 
methotrexate, retinoids, biologic agents, oral calcineurin inhibitors, 
high-potency or oral steroids)

Have a history of idiopathic pulmonary fibrosis, organizing pneumonia 
(e.g., bronchiolitis obliterans), drug-induced pneumonitis, idiopathic pneumonitis, 
or evidence of active pneumonitis based on a screening chest computed 
tomography (CT) scan, with the following exceptions
A history of radiation pneumonitis in the localized radiation field (fibrosis) is 
permitted.  Patient must still meet all other radiotherapy exclusions listed above.

Have a positive test result for HIV

Have active tuberculosis

Have severe infections within 4 weeks prior to initiation of study treatment, including 
but not limited to hospitalization for complications of infection, bacteremia, or severe 
pneumonia


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
Have received therapeutic oral or IV antibiotic medication within 2 weeks prior to 
initiation of study treatment, with the following exceptions:
Patients who receive prophylactic antibiotic medication (e.g., urinary tract 
infection prophylaxis, prior to dental procedure) are eligible for enrollment.

Have significant cardiovascular disease, such as New York Heart Association 
cardiac disease (Class II or greater), myocardial infarction, or cerebrovascular 
accident within 3 months prior to initiation of study treatment, unstable arrhythmias, 
or unstable angina
Patients with known coronary artery disease, congestive heart failure not 
meeting the above criteria, or 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.

Undergo major surgical procedure within 28 days prior to first bevacizumab dose, or 
anticipation of the need for a major surgical procedure during the course of the 
study except patients who receive NACT and will need interval surgery.  This may 
include but is not limited to laparotomy.  All incisions should be fully healed, as 
assessed clinically, prior to starting bevacizumab.
Consult with the Medical Monitor prior to patient entry for any questions related 
to the classification of surgical procedures.

Are administered treatment with a live attenuated vaccine within 4 weeks prior to 
initiation of study treatment, or anticipation of need for such a vaccine during the 
course of the study or within 5 months after the last dose of atezolizumab

Current treatment with anti-viral therapy for HBV

Have prior allogeneic bone marrow transplantation or solid organ transplant

Have 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

Have any approved or investigational anti-cancer therapy, including chemotherapy
or hormonal therapy, with the following exceptions:
Hormone-replacement therapy or oral contraceptives are allowed.

Current or recent (within 10 days of initiation of study treatment) use of aspirin 
(325 mg/day) or clopidogrel (75 mg/day)

Are administered treatment with any other investigational agent or participation in 
another clinical study with anti-cancer therapeutic intent

Have prior treatment with CD137 agonists or immune checkpoint blockade 
therapies, antiPD-1, antiPD-L1, or anti-cytotoxic T-lymphocyte-associated 
protein 4 therapeutic antibodies

Have treatment with systemic immunostimulatory agents (including but not limited to 
interferons [IFNs], interleukin [IL]-2) within 4 weeks or 5 half-lives of the drug, 
whichever is longer, prior to initiation of study treatment


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
Have treatment with systemic immunosuppressive medications (including but not 
limited to prednisone, cyclophosphamide, azathioprine, methotrexate, thalidomide, 
and antitumor necrosis factor [TNF] agents) within 2 weeks prior to initiation of 
study treatment, with the following exceptions:
Patients who have received acute, low-dose, systemic immunosuppressant 
medications or a one-time pulse dose of systemic immunosuppressant 
medication (e.g., 48 hours of corticosteroids for a contrast allergy) are eligible 
for enrollment in the study.
The use of corticosteroids for chronic obstructive pulmonary disease and 
asthma, mineralocorticoids (e.g., fludrocortisone), or low-dose corticosteroids for 
patients with orthostatic hypotension or adrenocortical insufficiency is allowed.

Have inadequately-controlled hypertension (defined as systolic blood pressure 
150 mmHg and/or diastolic blood pressure 100 mmHg)
Anti-hypertensive therapy to achieve these parameters is allowed.

Have prior history of hypertensive crisis or hypertensive encephalopathy

Have significant vascular disease (e.g., aortic aneurysm requiring surgical repair or 
recent peripheral arterial thrombosis) within 6 months prior to initiation of study 
treatment

Have a history of Grade 2 hemoptysis (2.5 mL of bright red blood per episode) 
within 1 month prior to screening

Have evidence of active bleeding, bleeding diathesis, coagulopathy, tumor that 
involves major vessels (in the absence of therapeutic anticoagulation)

Have a history or evidence upon physical examination of any CNS disease, 
including primary brain tumor, CNS metastases, seizures not controlled with 
standard medical therapy, any brain metastases, or history of cerebrovascular 
accident (stroke), transient ischemic attack or subarachnoid hemorrhage within 
6 months of the first date of treatment on this study.

History of leptomeningeal disease

History of Grade 4 venous thromboembolism

Have current use of full-dose oral or parenteral anticoagulants or thrombolytic 
agents for therapeutic purposes that has not been stable prior to initiation of study 
treatment, with the following exceptions:
The use of full-dose oral or parenteral anticoagulants is permitted as long as 
the INR or aPTT is within therapeutic limits according to the medical standard of 
the enrolling institution, and the patient has been receiving a stable dose of 
anticoagulants prior to initiation of study treatment.
Prophylactic anticoagulation for the patency of venous access devices is 
allowed, provided the activity of the agent results in an INR 1.5ULN and 
aPTT is within normal limits prior to initiation of study treatment.
Deep venous thrombosis prophylaxis with low-molecular-weight heparin is 
permitted.


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
Have core biopsy or other minor surgical procedures within 7 days prior to the first 
dose of bevacizumab
The interval of time between placement of a central vascular access device 
(CVAD; e.g., Port-a-cath) and the first dose of bevacizumab must be no shorter 
than 2 days with a well-healed incision
If placing a CVAD between bevacizumab doses, placement must occur at least 
14 days from the prior (i.e, pre-CVAD placement) bevacizumab dose, and at 
least 7 days from the following (i.e., post-CVAD placement) bevacizumab dose.

Have a history of abdominal fistula or gastrointestinal perforation within 6 months
prior to initiation of study treatment, with the following exceptions:
Patients with granulating incisions healing by secondary intention with no 
evidence of fascial dehiscence or infection are eligible but require weekly 
wound examinations.

Have clinical signs of gastrointestinal obstruction that require routine parenteral 
hydration, parenteral nutrition, or tube feeding

Have evidence of abdominal free air not explained by paracentesis or recent 
surgical procedure

Have serious, non-healing wound, active ulcer, or untreated bone fracture

Have proteinuria, as demonstrated by urine dipstick or 1.0 of protein in a urine 
protein-to-creatinine ratio and/or 24-hour urine collection
All patients with 2protein on dipstick urinalysis at baseline must undergo a 
urine protein-to-creatinine ratio and/or 24-hour urine collection and demonstrate
1.0 of protein.

Have known sensitivity to any component of bevacizumab

Have known sensitivity to any component of paclitaxel

Have Grade 2 peripheral neuropathy as defined by the National Cancer Institute 
Common Terminology Criteria for Adverse Events (NCI CTCAE), Version 4.0

Have known history of severe allergic reactions to platinum-containing compounds

Have known history of severe hypersensitivity reactions to products that contain 
Cremophor® EL (e.g., cyclosporine for injection concentrate and teniposide for 
injection concentrate)
4.2
METHOD OF TREATMENT ASSIGNMENT AND BLINDING
4.2.1
Treatment Assignment
This is a randomized, double-blind study.  After written informed consent has been 
obtained, all screening procedures and assessments have been completed, and 
eligibility has been established for a patient, the study site will obtain the patient’s 
identification number and treatment assignment from the interactive Web-based 
response system (IWRS).


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Randomization will occur in a 1:1 ratio with the use of a permuted-block randomization 
method. The same randomization method and ratio will be implemented for the China 
extension phase, if applicable.
Patients will be randomized to one of two treatment arms: 
atezolizumabcarboplatinpaclitaxelbevacizumab or 
placebocarboplatinpaclitaxelbevacizumab.  The randomization scheme is designed 
to ensure that an approximately equal number of patients will be enrolled in each 
treatment arm within the prognostic categories of the following stratification factors:

Stage and/or residual disease status (Stage III vs. Stage IV)

ECOG performance status (0 vs. 1 or 2)

Tumor PD-L1 status (IC0 vs. IC1/2/3)

Treatment strategy (adjuvant vs. neoadjuvant)
4.2.2
Blinding the Treatment Assignment
The Sponsor and its agents (with the exception of the IWRS service provider, laboratory 
personnel who perform PK or biomarker analyses, the external iDCC, and the 
iDMC members), study site personnel that includes the investigator, and the patient will 
be blinded to the treatment assignment.  After analysis of the first co-primary endpoint,
PFS, the Sponsor will be unblinded to the treatment assignment. The study site 
personnel with the inclusion of the investigator(s), and the patient, will remain blinded to 
the treatment assignment until the completion of the analysis of the second co-primary 
endpoint, OS.  Unblinding of site personnel and patients to the treatment assignment 
may be considered if the benefit-risk assessment at the time of the PFS analysis is 
favorable for unblinding of the data (see Section 4.2.3).
4.2.3
Unblinding the Treatment Assignment
Treatment codes should not be broken except in emergency situations in which 
knowledge of treatment assignment will affect ongoing treatment of the patient.  
If emergency unblinding of the treatment code becomes necessary, the investigator will 
be able to break the treatment code by contacting the IWRS.  Investigators are 
encouraged to consult with the Medical Monitor prior to emergency unblinding of the 
treatment code.  However, the investigator should inform the Medical Monitor that the 
treatment code has been broken.  The investigator should document the emergency and 
treatment unblinding process and provide an explanation for any premature treatment 
unblinding (e.g., accidental treatment unblinding, treatment unblinding due to serious 
adverse event).  After emergency unblinding occurs, medical- and study-related 
questions should be directed to the “Post-Unblinding Medical Monitor” (see 
Section 5.4.1).
As per health authority reporting requirements, the Sponsor will break the treatment 
code for all serious, unexpected suspected adverse reactions (see Section 5.7) that are 


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considered by the investigator or Sponsor to be related to study treatment.  
The treatment code will be available to the Sponsor's drug safety group through the 
IWRS.  The patient may continue to receive treatment, and the investigator, patient, and 
other Sponsor personnel will remain blinded to treatment assignment.
Treatment assignment will be unblinded to the Sponsor prior to the primary analysis of
PFS, after all data have been cleaned and verified and the database has been locked.
Treatment assignment will be unblinded to the investigator and patients after all data for 
the analysis of the co-primary endpoint of OS have been cleaned and verified and the 
database has been locked.  Unblinding of site personnel (i.e., investigator[s], 
study coordinators, research nurses, etc.) and patients may be considered earlier if the 
benefit-risk assessment at the time of the PFS analysis is favorable.
Whereas atezolizumab PK and ADA samples must be collected from patients who are 
assigned to the comparator arm to maintain the blinding of treatment assignment, 
PK and ADA assay results for atezolizumab in these patients are generally not needed 
for the safe conduct or proper interpretation of this study.  Study personnel who are 
responsible to perform PK and ADA assays will be unblinded to patients’ treatment 
assignments to identify appropriate samples to be analyzed.  Samples from patients 
assigned to the comparator arm will be analyzed only for atezolizumab concentration if
requested (e.g., to evaluate possible error in dosing).  Atezolizumab ADA samples 
collected on Day 1 of Cycle 1 may be analyzed for all patients, whereas subsequent 
samples from patients who are assigned to the comparator arm will not be analyzed for 
ADA unless requested.
4.3
STUDY TREATMENT
The product (IMP) for this study is atezolizumab.
4.3.1
Formulation, Packaging, and Handling
4.3.1.1
Atezolizumab and Placebo
Atezolizumab will be supplied by the Sponsor as a sterile liquid in a single-use, 20-mL 
glass vial.  The vial contains approximately 20 mL (1200 mg) of atezolizumab solution.  
For information on the formulation and handling of atezolizumab, refer to the 
Atezolizumab Investigator’s Brochure and Pharmacy Manual.
The placebo will be supplied by the Sponsor and will be identical in appearance to 
atezolizumab and comprise the same excipients but without atezolizumab drug product.  
The placebo should be handled, stored, and used in the same manner as atezolizumab.
4.3.1.2
Paclitaxel, Carboplatin, and Bevacizumab
Bevacizumab will be supplied by the Sponsor.  Paclitaxel and carboplatin will be used in 
commercially available formulations.  Bevacizumab will be considered an IMP by local 
regulations in some countries. For information on the formulation, packaging, and 


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handling of paclitaxel and carboplatin, refer to the local prescribing information for each 
drug.
4.3.2
Dosage, Administration, and Compliance
The treatment regimens are summarized in Section 3.
Any dose modification should be noted on the Study Drug Administration electronic 
Case Report Form (eCRF).  Cases of accidental overdose or medication error, along 
with any associated adverse events, should be reported as described in Section 5.5.
Guidelines for dosage modification and treatment interruption or discontinuation for 
patients who experience adverse events are provided in Appendix 9 and Appendix 10.
4.3.2.1
Timing and Sequence of Treatment Administration
The timing of treatment administration is shown in Appendix 1 and Appendix 2. All of the 
study treatments are administered intravenously. The sequence of administration is as 
follows in Table 2 and Table 3 for all treatment arms:


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Table 2
Treatment Regimen and Order of Administration for Patients Who 
Undergo Primary Surgery
Druga
Dose and 
Administration 
Route
Infusion Period
Cycle 1
Paclitaxel
175 mg/m2 IV

3 hours b
Carboplatin
AUC 6 IV b

Over approximately 30 minutes c
Atezolizumab or 
placebo
1200 mg IV

60 (15) minutes for the first dose
Cycles 26 (Concurrent Treatment)
Paclitaxel
175 mg/m2 IV

3 hours b
Carboplatin
AUC 6 IV b

Over approximately 30 minutes c
Bevacizumab
15 mg/kg IV

90 (15) minutes for the first dose 

60 (10) minutes for the second dose depending on 
patient tolerability of the first dose

30 (10) minutes for subsequent doses depending 
on patient tolerability of the second dose
Atezolizumab or 
Placebo
1200 mg IV

If the previous infusion of atezolizumab or placebo is 
well tolerated by the patient, then the infusion period 
may be reduced to 30 (10) minutes for subsequent 
doses.
Cycles 722 (Maintenance Treatment)
Bevacizumab
15 mg/kg IV

90 (15) minutes for the first dose 

60 (10) minutes for the second dose depending on 
patient tolerability of the first dose

30 (10) minutes for subsequent doses depending 
on patient tolerability of the second dose
Atezolizumab or 
Placebo
1200 mg IV

If the previous infusion of atezolizumab or placebo is 
well tolerated by the patient, then the infusion period 
may be reduced to 30 (10) minutes for subsequent 
doses.
Note:  Treatments should be administered in the order listed for each cycle.
a Institutional desensitization protocols may be implemented, if clinically indicated.
b Exceptions to the paclitaxel infusion time of 3 hours will be allowed for sites that have an 
institutional policy for infusion of paclitaxel more quickly (over 90 minutes) or more slowly (up to 
4 hours for the first infusion).
c Per institutional standard, carboplatin should be administered immediately after the completion 
of the paclitaxel administration.


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Table 3
Treatment Regimen and Order of Administration for Patients Who 
Undergo Neoadjuvant Chemotherapy or Interval Surgery
Drug a
Dose and 
Administration Route
Infusion Period
Cycles 1 and 2 (Concurrent Neoadjuvant Treatment)
Paclitaxel
175 mg/m2 IV

3 hours b
Carboplatin
AUC 6 IV b

Over approximately 30 minutes c
Bevacizumab
15 mg/kg IV

90 (15) minutes for the first dose 

60 (10) minutes for the second dose depending 
on patient tolerability of the first dose

30 (10) minutes for subsequent doses 
depending on patient tolerability of the second 
dose
Atezolizumab
or Placebo
1200 mg IV

60 (15) minutes for the first dose

If the previous infusion of atezolizumab or 
placebo is well tolerated by the patient, then the 
infusion period may be reduced to 
30 (10) minutes for subsequent doses.
Cycle 3 (Concurrent Neoadjuvant Treatment)
Paclitaxel
175 mg/m2 IV

3 hours b
Carboplatin
AUC 6 IV b

Over approximately 30 minutes c
Atezolizumab 
or Placebo
1200 mg IV

60 (15) minutes for the first dose 

If the previous infusion of atezolizumab or 
placebo is well tolerated by the patient, then the 
infusion period may be reduced to 
30 (10) minutes for subsequent doses.
Surgery
Cycle 4 (Concurrent Post-Neoadjuvant Treatment)
Paclitaxel
175 mg/m2 IV

3 hours b
Carboplatin
AUC 6 IV b

Over approximately 30 minutes c
Atezolizumab 
or Placebo
1200 mg IV

60 (15) minutes for the first dose 

If the previous infusion of atezolizumab or 
placebo is well tolerated by the patient, then the 
infusion period may be reduced to 
30 (10) minutes for subsequent doses.


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Table 3
Treatment Regimen and Order of Administration for Patients Who 
Undergo Neoadjuvant Chemotherapy or Interval Surgery (cont.)
Drug a
Dose and 
Administration Route
Infusion Period
Cycles 5 and 6 (Concurrent Post-Neoadjuvant Treatment)
Paclitaxel
175 mg/m2 IV

3 hours b
Carboplatin
AUC 6 IV b

Over approximately 30 minutes c
Bevacizumab
15 mg/kg IV

90 (15) minutes for the first dose 

60 (10) minutes for the second dose depending 
on patient tolerability of the first dose

30 (10) minutes for subsequent doses 
depending on patient tolerability of the second 
dose
Atezolizumab
or Placebo
1200 mg IV

60 (15) minutes for the first dose 

If the previous infusion of atezolizumab or 
placebo is well tolerated by the patient, then the 
infusion period may be reduced to 
30 (10) minutes for subsequent doses.
Cycles 722 (Maintenance Treatment)
Bevacizumab
15 mg/kg IV

90 (15) minutes for the first dose 

60 (10) minutes for the second dose depending 
on tolerability of first dose

30 (10) minutes for subsequent doses 
depending on tolerability of second dose
Atezolizumab 
or Placebo
1200 mg IV

If the previous infusion of atezolizumab or 
placebo is well tolerated by the patient, then the 
infusion period may be reduced to 
30 (10) minutes for subsequent doses.
Note:  Treatments should be administered in the order listed for each cycle.
a Institutional desensitization protocols may be implemented, if clinically indicated.
b Exceptions to the paclitaxel infusion time of 3 hours will be allowed for sites that have an 
institutional policy for infusion of paclitaxel more quickly (over 90 minutes) or more slowly 
(up to 4 hours for the first infusion).
c Per institutional standard, carboplatin should be administered immediately after the 
completion of the paclitaxel administration.
4.3.2.2
Atezolizumab and Placebo
Atezolizumab will be administered by IV infusion at a fixed dose of 1200 mg on Day 1 of 
each 21-day cycle for 22 cycles total or until disease progression, unacceptable toxicity, 
patient or physician’s decision to discontinue, patient death, or study termination by the 
Sponsor.
Administration of atezolizumab will be performed in a monitored setting where there is 
immediate access to trained personnel and adequate equipment and medicine to 


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manage potentially serious reactions.  For anaphylaxis precautions, see Appendix 8.  
Atezolizumab infusions will be administered per the instructions outlined in Table 4.
Table 4
Atezolizumab Infusion Guidelines
First Infusion
Subsequent Infusions

No premedication is permitted.

Atezolizumab should be infused over 
60 (15) minutes.

If clinically indicated, vital signs should be 
recorded during the infusion at 15, 30, 45, 
and 60 minutes (5 minutes for all 
timepoints) 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 experiences an 
infusion-related reaction with any 
previous infusion, premedication with 
antihistamines, antipyretics, and/or 
analgesics may be administered for 
subsequent doses at the discretion of the 
investigator.

Atezolizumab should be infused over 
30 (10) minutes if the previous infusion 
was tolerated without an infusion-related 
reaction, or 60 (15) minutes if the 
patient experiences an infusion-related 
reaction with the previous infusion.

If the patient experienced an 
infusion-related reaction with the previous 
infusion or if clinically indicated, vital 
signs should be recorded during the 
infusion and at 30 (10) minutes after the 
infusion.
Atezolizumab will be delivered in 250 mL 0.9% NaCl IV infusion bags.
Refer to the pharmacy manual for detailed instructions on drug preparation, storage, and 
administration.
Guidelines for medical management of infusion-related reactions (IRRs) are provided in 
the Appendix 9.
No dose modification of atezolizumab is allowed.
4.3.2.3
Bevacizumab, Paclitaxel, and Carboplatin
Bevacizumab
Bevacizumab will be administered at a dose of 15 mg/kg on Day 1 of each 21-day cycle.  
The initial dose of bevacizumab will be on the basis of the patient’s baseline weight.  
Doses should be verified by the treating physician and remain the same throughout the 
study unless the patient’s weight changes by 10%, provided that this aligns with 
standard institutional practice patterns.
See Appendix 10 for preparation, administration, and disposal details.


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Guidelines for dosage modification and treatment interruption or discontinuation are 
provided in Section 5.1.5 and in the Bevacizumab Investigator’s Brochure.
Paclitaxel
Institutions should follow their standard administration regimens for paclitaxel.  
In general, paclitaxel will be administered intravenously at a dose of 175 mg/m2 over a 
period of 3 hours, followed by carboplatin.
Paclitaxel injections must be diluted prior to infusion.  Paclitaxel should be diluted in 
0.9% Sodium Chloride Injection, USP; 5% Dextrose Injection, USP; 5% Dextrose and 
0.9% Sodium Chloride Injection, USP; or 5% Dextrose in Ringer’s Injection to a final 
concentration of 0.3 to 1.2 mg/mL.
Contact of the undiluted concentrate with plasticized polyvinyl chloride (PVC) equipment 
or devices used to prepare solutions for infusion is not recommended.  Paclitaxel should 
be administered through an in-line filter with a microporous membrane not greater than 
0.22 m.  Use of filter devices, such as IVEX-2filters, which incorporate short inlet and 
outlet PVC-coated tubing, has not resulted in significant leaching of 
bis(2-ethylhexyl)phthalate.
Sites should follow their institutional standard of care for dose adjustments and/or 
modifications in the event of patient weight changes and/or adverse events.  For 
paclitaxel infusion, exceptions to the infusion time of 3 hours will be allowed for sites that 
have an institutional policy of infusing paclitaxel more quickly (over a 90-minute time 
period) or more slowly (up to 4 hours for the first infusion).
Guidelines for dosage modification and treatment interruption or discontinuation are 
provided in Section 5.1.6.
Carboplatin
Carboplatin should be administered by IV infusion, immediately after the completion of 
paclitaxel administration, over a 15- to 30-minute time period to achieve an initial target
AUC of 6 mg/mL/min (Calvert formula dosing) with standard anti-emetics per local 
practice guidelines.
The carboplatin dose of AUC 6 will be calculated with the use of the Calvert formula 
(Calvert et al. 1989):
Calvert Formula
Total dose (mg)(target AUC)(glomerular filtration rate [GFR]25)
NOTE:  The GFR used in the Calvert formula to calculate AUC-based dosing should 
not exceed 125 mL/min.


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For the purposes of this protocol, the GFR is considered to be equivalent to the 
creatinine clearance (CrCl).  The CrCl is calculated by institutional guidelines or by the 
method of Cockcroft and Gault (1976) with the use of the following formula:
CrCl
(140age) (wt)
(0.85)
72 Scr
Where:
CrClcreatinine clearance in mL/min
agepatient's age in years 
wtpatient’s weight in kg
Scrserum creatinine in mg/dL
NOTE:  For patients with an abnormally low serum creatinine level, estimate GFR with 
the use of a minimum creatinine level of 0.7 mg/dL or cap the estimated GFR at 
125 mL/min.
If a patient’s GFR is estimated on the basis of serum creatinine measurements by the 
isotope dilution mass spectroscopy method, the U.S. Food and Drug 
Administration (FDA) recommends that physicians consider a cap on the dose of 
carboplatin for desired exposure to avoid potential toxicity due to overdosing.  On the 
basis of the Calvert formula described in the carboplatin label, the maximum doses can 
be calculated as follows:
Maximum carboplatin dose (mg)target AUC (mg min/mL)(GFR25 mL/min)
The maximum dose is on the basis of a GFR estimate that is capped at 125 mL/min for 
patients with normal renal function.  No higher estimated GFR values should be used.
For a target AUC6, the maximum dose is 6150900 mg.
For a target AUC5, the maximum dose is 5150750 mg.
For a target AUC4, the maximum dose is 4150600 mg.
Guidelines for dosage modification and treatment interruption or discontinuation are 
provided in Section 5.1.6.
4.3.3
Additional Required Medication
4.3.3.1
Prophylactic Measures for Carboplatin
Carboplatin is considered moderately to highly emetogenic.  Therefore, appropriate 
anti-emetic nonsteroidal medication (e.g., aprepitant) should be administered prior to the 
initiation of chemotherapy in accordance with the local practice and standard of care.


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4.3.3.2
Premedication for Paclitaxel
All patients should be medicated prior to paclitaxel administration to prevent severe 
hypersensitivity reactions.  Prior to administration of paclitaxel, all patients will receive 
either the institutional standard-of-care or the following premedication:

Dexamethasone 20 mg orally approximately 12 hours and 6 hours prior to the 
paclitaxel infusion
Patients may be treated with dexamethasone 10 to 20 mg IV within 1 hour prior 
to paclitaxel infusion if the patient did not take the oral dexamethasone.

Diphenhydramine 50 mg IV (or equivalent) 30 to 60 minutes prior to 
paclitaxel infusion

Cimetidine 300 mg IV or ranitidine 50 mg IV (or equivalent) 30 to 60 minutes prior to 
paclitaxel infusion
Because the effects of corticosteroids on T-cell proliferation have the potential to ablate 
early atezolizumab-mediated anti-tumor immune activity, it is recommended that 
dexamethasone doses be minimized to the extent that is clinically feasible.  
For example, if Cycle 1 is tolerated without apparent hypersensitivity reaction, a 
reduction in dexamethasone premedication dose should be considered for subsequent 
cycles if permitted by institutional standard of care.
4.3.4
Investigational Medicinal Product Accountability
The IMP required for completion of this study of atezolizumab will be provided by the 
Sponsor where required by local health authority regulations.  The study site 
(i.e., investigator or other authorized personnel [e.g., pharmacist]) is responsible for 
maintaining records of IMP delivery to the site, IMP inventory at the site, IMP use by 
each patient, and disposition or return of unused IMP, thus enabling reconciliation of all 
IMP received, and for ensuring that patients are provided with doses specified by the 
protocol.
The study site should follow all instructions included with each shipment of IMP.  The 
study site will acknowledge receipt of IMPs, with the use of the IWRS to confirm the 
shipment condition and content.  Any damaged shipments will be replaced.  The 
investigator or designee must confirm that appropriate temperature conditions have 
been maintained during transit, either by time monitoring (shipment arrival date and 
time) or temperature monitoring, for all IMPs received and that any discrepancies have 
been reported and resolved before use of the IMPs.  All IMPs must be stored in a 
secure, environmentally controlled, and monitored (manual or automated) area in 
accordance with the labeled storage conditions, with access limited to the investigator 
and authorized staff.
Only patients enrolled in the study may receive IMPs, and only authorized staff may 
supply or administer IMPs.


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IMPs either will be disposed of at the study site in accordance with the study site’s 
institutional standard operating procedure or returned to the Sponsor with the 
appropriate documentation.  The site’s method of destroying Sponsor-supplied IMPs
must be agreed to by the Sponsor.  The site must obtain written authorization from the 
Sponsor before any Sponsor-supplied IMP is destroyed, and IMP destruction must be 
documented on the appropriate form.
Accurate records of all IMPs received at, dispensed from, returned to, and disposed of 
by the study site should be recorded on the Drug Inventory Log.
Refer to the pharmacy manual and/or Atezolizumab Investigator's Brochure for 
information on IMP handling, including preparation and storage, and accountability.
4.3.5
Post-Study Access to Atezolizumab
Currently, the Sponsor does not have any plans to provide atezolizumab or any other 
study treatments or interventions to patients who have completed the study.  
The Sponsor may evaluate whether to continue to provide atezolizumab in accordance 
with the Roche Global Policy on Continued Access to Investigational Medicinal Product, 
available at the following Web site:
http://www.roche.com/policy_continued_access_to_investigational_medicines.pdf
4.4
CONCOMITANT THERAPY
Concomitant therapy includes any medication (e.g., prescription drugs, over-the-counter 
drugs, vaccines, herbal or homeopathic remedies, nutritional supplements) used by a 
patient in addition to protocol-mandated study treatment from 7 days prior to initiation of 
the study treatment to the treatment discontinuation visit.  All such medications should 
be reported to the investigator and recorded on the Concomitant Medications eCRF.
4.4.1
Permitted Therapy
Patients are permitted to use the following therapies during the study:

Oral contraceptives with a failure rate of 1% per year (See Section 4)

Hormone-replacement therapy

Prophylactic or therapeutic anticoagulation therapy (such as warfarin at a stable 
dose or low-molecular-weight heparin)

Megestrol acetate administered as an appetite stimulant 

Mineralocorticoids (e.g., fludrocortisone)

Inhaled or low-dose corticosteroids administered for chronic obstructive pulmonary 
disease or asthma

Low-dose corticosteroids administered for orthostatic hypotension or adrenocortical 
insufficiency


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
Vaccinations (such as influenza, COVID-19)
Live, attenuated vaccines are not permitted (see Section 4.4.3).
Premedication with antihistamines, antipyretics, and/or analgesics may be administered 
for the second and subsequent atezolizumab infusions only, at the discretion of the 
investigator.
In general, investigators should manage a patient’s care (including preexisting 
conditions) with supportive therapies other than those defined as cautionary or 
prohibited therapies (see Section 4.4.3) as clinically indicated, per local standard 
practice.  Patients who experience infusion-associated symptoms may be treated 
symptomatically with acetaminophen, ibuprofen, diphenhydramine, and/or H2-receptor 
antagonists (e.g., famotidine, cimetidine), or equivalent medications per local standard 
practice.  Serious infusion-associated events manifested by dyspnea, hypotension, 
wheezing, bronchospasm, tachycardia, reduced oxygen saturation, or respiratory 
distress should be managed with supportive therapies as clinically indicated 
(e.g., supplemental oxygen and 2-adrenergic agonists; see Appendix 8).
4.4.2
Cautionary Therapy for Atezolizumab-Treated Patients
4.4.2.1
Corticosteroids, Immunosuppressive Medications, and 
TNF-Alpha Inhibitors
Systemic corticosteroids, immunosuppressive medications, and TNF-alpha inhibitors 
(TNFi) may attenuate potential beneficial immunologic effects of treatment with 
atezolizumab.  Therefore, in situations in which systemic corticosteroids, 
immunosuppressive medications, or TNFi would be routinely administered, alternatives 
that include antihistamines should be considered.  For example, systemic corticosteroids 
for chemotherapy-induced nausea and vomiting (treatment or prophylactic) should be 
avoided and alternatives (e.g., aprepitant, 5-HT3 antagonists, etc.) should be utilized 
instead.  If the alternatives are not feasible, systemic corticosteroids, 
immunosuppressive medications, and TNFi (e.g., infliximab) may be administered at the 
discretion of the investigator (see Section 4.4.3).
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 the Atezolizumab Investigator's Brochure
for details).
4.4.2.2
Herbal Therapies
Concomitant use of herbal therapies is not recommended because their 
pharmacokinetics, safety profiles, and potential drug-drug interactions are generally 
unknown.  However, herbal therapies not intended for the treatment of cancer 
(see Section 4.4.3) may be used during the study at the discretion of the investigator.


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4.4.3
Prohibited Therapy
Use of the following concomitant therapies is prohibited:

Concomitant therapy intended for the treatment of cancer (including but not limited 
to chemo-, hormonal, immune-, radio-, herbal therapy, hyperthermic intraperitoneal 
chemotherapy [HIPEC], etc.), whether health authorityapproved or experimental, is 
prohibited for various time periods prior to initiation of the study treatment, 
depending on the agent (see Section 4.1.2), and during the study treatment phase 
until disease progression is documented.

Anti-cancer treatment prior to disease progression is prohibited for patients who 
have completed protocol-directed therapy and are in long-term follow-up.

Investigational therapy (other than protocol-mandated study treatment) is prohibited 
during study treatment.

Live, attenuated vaccines (e.g., FluMist) are prohibited within 4 weeks prior to 
randomization, during study treatment with atezolizumab, and for 5 months after the 
last dose of study treatment.

Systemic immunostimulatory agents (including, but not limited to, IFNs and IL-2) are 
prohibited within 4 weeks or five half-lives of the drug, whichever is longer, prior to 
initiation of study treatment and during study treatment because these agents could 
potentially increase the risk for autoimmune conditions when given in combination 
with atezolizumab.

Systemic corticosteroids may not be administered as a premedication to patients for 
whom CT scans with contrast are contraindicated (i.e., patients with contrast allergy 
or impaired renal clearance).  Such patients should undergo non-contrast CT scans
or magnetic resonance imaging (MRI) scans instead (see Section 4.5.5).
4.5
STUDY ASSESSMENTS
The schedules of assessments to be performed during the study are provided in
Appendix 1, Appendix 2, and Appendix 3.  All activities must be performed and 
documented for each patient.  Patients will be closely monitored for safety and 
tolerability throughout the study.  Patients should be assessed for toxicity prior to each 
dose; dosing will occur only if the clinical assessment and local laboratory test values 
are acceptable.
Randomization of patients with confirmed eligibility should be performed within 3 days 
before the first dose of study treatment.
During the treatment period, a time window of 5 days will apply to all scheduled
assessments, unless otherwise specified. All hematologic and serum chemistry
assessments required to be performed before dosing in any treatment cycle should be
performed within 3 days prior to dosing, unless otherwise specified.  Note:  Study 
assessments/cycles may be adjusted slightly to accommodate holidays, vacations, and 
unforeseen major life events.  Documentation to justify this decision should be provided.


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4.5.1
Informed Consent Forms and Screening Log
Written informed consent for participation in the study must be obtained before the 
performance of any study-related procedures (including screening evaluations).  
Informed Consent Forms for randomized patients and patients who are not subsequently 
randomized 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 screening log to 
record details of all patients screened and to confirm eligibility or record reasons for 
screening failure, as applicable.
4.5.2
Medical History and Demographic Data
Medical history includes clinically significant diseases, surgeries, cancer history 
(including prior cancer therapies and procedures), reproductive status, smoking 
history and use of alcohol and drugs of abuse.  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 the initiation 
of the study treatment will 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, dermatological, musculoskeletal, respiratory, gastrointestinal, 
genitourinary, and neurological systems.  Any abnormality identified at baseline should 
be recorded on the General Medical History and Baseline Conditions eCRF.
Limited, symptom-directed physical examinations should be performed at specified 
post-baseline visits and as clinically indicated.  Changes from baseline abnormalities 
should be recorded in patient notes.  New or worsened clinically significant abnormalities 
should be recorded as adverse events on the Adverse Event eCRF.
4.5.4
Vital Signs
Vital signs will include measurements of respiratory rate, pulse rate, and systolic and 
diastolic blood pressure while the patient is in a seated position, and temperature.
Vital signs should be measured at the beginning of each cycle before the first infusion 
and as clinically indicated.  In addition, vital signs should be measured at other specified 
timepoints as outlined in the schedule of assessments (see Appendix 1 and Appendix 2).
4.5.5
Tumor and Response Evaluations
For patients who have had primary tumor reductive surgery, an initial CT scan or MRI of 
at least the chest, abdomen, and pelvis is required to establish postsurgical (i.e., primary 


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cytoreductive surgery) baseline of the extent of residual disease within 28 days
(5 days) prior to randomization.  In the absence of disease progression, imaging that 
uses the same modality and encompasses the same field as in the initial pre-treatment 
evaluation should be repeated as follows:
1.
Every 9 weeks (5 days) from the date of randomization during the concurrent 
treatment phase
2.
Every 12 weeks (5 days) in the maintenance phase (the first scan in the 
maintenance phase is performed 12 weeks after the last scan in the concurrent 
treatment phase)
3.
Every 3 months (21 days) from the treatment completion visit for the first 2 years 
after completion of all protocol therapy
4.
Every 6 months (21 days) for the next 3 years, regardless of whether the patient 
showed measurable disease on the initial CT or MRI (see Appendix 1 and Appendix 
2)
5.
After 5 years of survival follow-up, as clinically indicated
For patients who will undergo neoadjuvant therapy followed by interval surgery, an initial 
CT scan or MRI of at least the chest, abdomen, and pelvis is required at baseline within 
28 days (5 days) prior to randomization.  In the absence of disease progression, 
imaging that uses the same modality and encompasses the same field as in the initial 
pretreatment evaluation should be repeated as follows:
1. Nine weeks (5 days) after the date of randomization
2. Within 12 weeks (5 days) after Cycle 3 (i.e., after interval tumor reductive surgery)
and as close as possible (within 14 days 5 days) to starting Cycle 4 to establish a 
post interval tumor reduction surgery baseline (CT scan or MRI of at least the chest, 
abdomen and pelvis is required)
3. Nine weeks (5 days) after the post interval tumor reduction surgery baseline scan
4. Every 12 weeks (5 days) in the maintenance phase (the first scan in the 
maintenance phase is performed 12 weeks (5 days) after the last scan in the 
concurrent treatment phase)
5. Every 3 months (21 days) from the treatment completion visit for the first 2 years 
after completion of all protocol therapy
6. Every 6 months (21 days) for the next 3 years.
7. After 5 years of survival follow-up, as clinically indicated
Baseline assessments must include CT scans (with oral or IV contrast) or MRI scans of 
the chest, abdomen, and pelvis.  A spiral CT scan of the chest may be obtained but is 
not a requirement.  If a CT scan with contrast is contraindicated (i.e., in patients with 
contrast allergy or impaired renal clearance), a non-contrast CT scan of the chest may 
be performed and MRI scans of the abdomen and pelvis should be performed.  
A CT scan with contrast or MRI scan of the head must be completed at screening to 


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evaluate CNS metastasis in all patients, if there is any clinical evidence of CNS 
involvement.  An MRI scan of the head is required if clinically indicated to confirm or 
dispel receipt of the diagnosis of CNS metastases in the event of an equivocal CT scan.  
Bone scans and CT scans of the neck should also be performed if clinically indicated.  
At the investigator’s discretion, other methods of assessment of measurable disease as 
per RECIST v1.1 may be used.
If a CT scan for tumor assessment is performed in a positron emission tomography 
and/or CT scanner, the CT acquisition must be consistent with the standards for a
full-contrast diagnostic CT scan.
All measurable and evaluable lesions should be re-assessed at each subsequent tumor 
evaluation.  The same radiographic procedures used to assess disease sites at 
screening should be used for subsequent tumor assessments (e.g., the same contrast 
protocol for CT scans).  The change from a CT to an MRI scan due to an allergic 
reaction to IV contrast is permissible.
Radiographic tumor assessment must be performed at designated fixed time intervals 
regardless of the cycle of the study treatment.  Responses will be assessed by the 
investigator with the use of RECIST v1.1 (see Appendix 11) for the co-primary endpoint.  
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.
Scans will be submitted to an independent review facility for prospective centralized 
auditing.
4.5.6
Laboratory, Biomarker, and Other Biological Samples
Samples for the following laboratory tests will be sent to the study site's local laboratory 
for analysis:

Hematology:  WBC count, hemoglobin, hematocrit, platelet count, differential count 
(neutrophils, eosinophils, basophils, monocytes, lymphocytes, other cells)

Chemistry panel (serum):  sodium, potassium, magnesium, glucose, BUN 
creatinine, albumin, calcium, total bilirubin, ALP, ALT, AST

Coagulation:  PT/INR, aPTT

HIV serology
All patients will be tested for HIV infection prior to inclusion into the study, and 
HIV-positive patients will be excluded from the clinical study.

HBV serology:  HBsAg, total HBcAb, and (if HBsAg test is negative and total HBcAb 
test is positive) HBV DNA


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If a patient has a negative HBsAg test and a positive total HBcAb test at 
screening, an HBV DNA test must also be performed to determine if the patient 
has an HBV infection.

HCV serology:  HCV antibody and (if HCV antibody test is positive) HCV RNA
If a patient has a positive HCV antibody test at screening, an HCV RNA test 
must be performed to determine if the patient has an active HCV infection.
A positive HCV RNA test is sufficient to diagnose active HCV infection in the 
absence of an HCV antibody test.

Pregnancy test
All women of childbearing potential will have a urine pregnancy test at 
screening.  For women of childbearing potential in countries with 
country-specific health authority mandates (e.g., Spain, Norway, Czech 
Republic, Poland, Germany, and Belgium), urine pregnancy tests will continue 
to be performed at the following specified visits:  on Day 1 of Cycles 222, at 
treatment discontinuation (unless administered within 30 days); and at 
3 months and 6 months after treatment discontinuation.  If a urine pregnancy 
test result is positive, it must be confirmed by a serum quantitative human 
chorionic gonadotropin and pelvic ultrasound (see Appendix 1 and Appendix 2).
A woman is considered to be of childbearing potential if she is postmenarcheal, 
has not reached a postmenopausal state (12 continuous months of 
amenorrhea with no identified cause other than menopause), and has not 
undergone surgical sterilization (removal of ovaries, fallopian tubes, and/or 
uterus).

Urinalysis (pH, specific gravity, glucose, protein, ketones, and blood); dipstick 
permitted

Thyroid-function testing (TSH, T3, [or total T3 for sites where free T3 is not 
performed], T4)

Serum CA-125
Results from the following tests will not be provided back to the site. The following 
samples will be sent to one or several central laboratories or to the Sponsor for analysis:

Serum samples for atezolizumab PK analysis through use of a validated assay

Serum samples for assessment of ADAs to atezolizumab through use of validated 
assays

Residual PK and ADA samples will be retained for further method development, 
validation and characterization or for testing for bevacizumab PK and ADA if 
deemed necessary.  Samples will be stored for up to 5 years after the final Clinical 
Study Report has been completed.

Plasma and whole blood samples for exploratory research on biomarkers

Screening baseline tumor tissue sample collected at baseline for determination of
PD-L1 expression and for exploratory research on biomarkers


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A representative FFPE tumor specimen in a paraffin block (preferred) or at least 
20 slides that contain unstained, freshly cut, serial sections must be submitted 
along with an associated pathology report prior to study enrollment.  After 
receipt of the signed ICF, patient retrieval and submission of an screening 
baseline tumor sample can occur outside the 28-day screening period.
For patients who undergo primary tumor reduction surgery, tumor tissue from 
that surgery must be submitted.  For those patients who undergo neoadjuvant 
treatment, tumor tissue samples from pre-treatment and at the time of interval 
cytoreduction are required.  Neoadjuvant patients who opt to be in the 
biomarker cohort are also required to provide tumor tissue during treatment 
collected on Cycle 1, Day 15.  A pretreatment tumor biopsy may also be 
performed if a patient's screening baseline tissue does not meet PD-L1 
eligibility criteria.  Samples must contain a minimum of 50 viable tumor cells 
that preserve cellular context and tissue architecture regardless of needle 
gauge or retrieval method.  Tumor tissue should be of good quality based on 
total and viable tumor content.  Acceptable samples include those from surgical 
resections or core needle biopsies (at least three cores [18 gauge minimum]), 
embedded in a single paraffin block.  FNA (i.e., samples that do not preserve 
histologic tissue architecture and yield cell suspension and/or smears), 
brushing, cell pellets from ascites and/or pleural effusion, lavage samples, and 
bone metastases are not acceptable. Remaining tumor tissue after material for 
biomarker analysis has been collected for enrolled patients will be returned to 
the site upon request or within 18 months after final closure of the study 
database, whichever occurs first. Remaining tumor tissue for patients who are 
not enrolled in the study will be returned to the site no later than 6 weeks after 
eligibility determination.

Tumor tissue sample collected during treatment for neoadjuvant patients who were 
enrolled into the biomarker cohort.
Tumor biopsy samples should be collected by core needle (18 gauge minimum)
biopsy.  Three cores should be submitted for evaluation. Radiographic 
guidance is permitted, if needed (e.g., CT, ultrasound).

Tumor tissue sample collected at the time of investigator-determined progression, if 
deemed clinically feasible by the investigator, for exploratory research on 
biomarkers
Biopsies should be performed within 40 days after progression or prior to the 
next anti-cancer therapy, whichever is sooner.  Acceptable samples include 
those from resections or core needle biopsies (1 FFPE block or at least 
15 unstained slides from no less than two cores [18 gauge minimum]).
Exploratory biomarker research may include but will not be limited to analysis of ctDNA, 
genes or gene signatures associated with tumor immunobiology, PD-L1, lymphocytes or 
cytokines associated with T-cell activation and may involve DNA or RNA extraction, 
analysis of somatic mutations, and use of WGS or next-generation sequencing (NGS).


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NGS will be performed by Foundation Medicine for post-progression samples.  
If performed by Foundation Medicine, the investigator can obtain results from these 
analyses in the form of an NGS report, which is available upon request directly from 
Foundation Medicine.  The investigator may share and discuss the results with the 
patient, unless the patient chooses otherwise.  The Foundation Medicine NGS assay 
has not been cleared or approved by health authorities.  The NGS report is generated 
for research purposes and is not provided to guide future treatment decisions.
Depending on country-specific regulations, the NGS report may not be available in all 
countries.
For sampling procedures, storage conditions, and shipment instructions, refer to the 
laboratory manual.
Unless the patient gives specific consent for leftover samples to be stored for optional 
exploratory research (see Section 4.5.11), biological samples will be destroyed when the 
final Clinical Study Report has been completed, with the following exceptions:

Plasma and serum samples collected for PK analysis and immunogenicity analysis
will be destroyed no later than 5 years after the final Clinical Study Report has been 
completed.

Blood samples collected for WGS will be stored until they are no longer needed or 
until they are exhausted.

Leftover plasma and tumor samples collected for biomarker analysis during the 
study will be destroyed no later than 15 years after the final Clinical Study Report
has been completed.
When a patient withdraws from the study, samples collected prior to the date of 
withdrawal may still be analyzed, unless the patient specifically requests that the 
samples be destroyed or local laws require destruction of the samples.
Data that arise from sample analysis will be subject to the confidentiality standards 
described in Section 8.4.
Given the complexity and exploratory nature of exploratory biomarker analyses, data 
derived from these analyses will generally not be provided to study investigators or 
patients unless required by law, with the exception of the report from the 
Foundation Medicine.  The aggregate results of any conducted research will be available 
in accordance with the effective Sponsor policy on study data publication.
4.5.7
Electrocardiograms
A 12-lead ECG is required at screening and as clinically indicated.  ECGs should be 
obtained on the same machine whenever possible.  Lead placement should be as 
consistent as possible.  ECG recordings should be performed after the patient has 
rested in a supine position for at least 10 minutes.


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For safety monitoring purposes, the investigator must review, sign, and date all 
ECG tracings.  Paper copies of ECG tracings will be maintained as part of the patient's 
permanent study file at the site.  Any morphologic waveform changes or other 
ECG abnormalities must be documented on the eCRF.
4.5.8
Patient-Reported Outcomes
To more fully characterize the clinical profile of atezolizumab, PRO data will be 
obtained through use of the following instruments:  EORTC QLQ-C30 and its ovarian 
cancer module EORTC QLQ-OV28; FACT-G single item GP5; and EQ-5D-5L.
Official versions of the PRO questionnaires, translated as appropriate into the local 
language, along with a booklet cover page, will be provided to sites in PDF format to 
print and distribute to patients.  The PRO questionnaires will be completed on paper in 
their entirety by the patient at the investigational site. To ensure instrument validity and 
that data standards meet health authority requirements, questionnaires must be 
completed by the patient at the start of the clinic visit before discussion of the patient's
health state, laboratory results, or health record; before administration of study 
treatment; and/or prior to the performance of any other study assessments that could 
bias patient's responses. If the patient is unable to complete the measure on her own,
interviewer assessment is allowed but may only be conducted by a member of the clinic 
staff who reads the questionnaire items to the patient verbatim; no interpretation, 
rephrasing, or rewording of the questions is allowed during interview-assisted 
completion.
Study personnel should review all questionnaires for completeness before the patient 
leaves the investigational site, and the hard copy originals of the questionnaires must be 
maintained as part of the patient’s medical record at the site for source data verification. 
These originals should have the study patient number and date and time of completion 
at the top of each page as well as the respondent’s initials and date of completion at the 
bottom of each page in compliance with good clinical practice. Sites will enter patient 
responses to the PRO questionnaires into the electronic data capture (EDC) system.
All patients will complete the questionnaires, beginning with the EORTC QLQ-C30 and 
followed by the QLQ-OV28, EQ-5D-5L, and FACT-G single item GP5 at timepoints 
corresponding with in-clinic visits, both while receiving study treatment and during the 
survival follow-up period. See Appendix 1 and Appendix 2 for the frequency and timing 
of PRO assessments. 
To generate data supporting the primary clinical efficacy endpoints (PFS, OS) while 
acknowledging the impact of the global COVID-19 pandemic, patients in the survival 
follow-up phase who are unable to visit the site in-person due to COVID-19 may 
complete PRO questionnaires via phone interview by site staff.  Instructions for phone 
administration of PROs will be provided to sites.


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4.5.8.1
EORTC QLQ-C30 and EORTC QLQ-OV28
The EORTC QLQ-C30 and its ovarian cancer module EORTC QLQ-OV28 are validated,
reliable self-report measures (Aaronson et al. 1993; Cull et al. 2001; Greimel et al. 2003; 
see Appendix 5).  The EORTC QLQ-C30 consists of 30 questions that assess 
five aspects of patient functions (physical, emotional, role, cognitive, and social), 
three symptom scales (fatigue, nausea and vomiting, pain), global health and/or 
quality of life, and six single items (dyspnea, insomnia, appetite loss, constipation, 
diarrhea, financial difficulties) with a recall period of the previous week.  Scale scores 
can be obtained for the multi-item scales.  The EORTC QLQ-OV28 consists of 28 items 
that includes a multi-item scale that assesses abdominal and/or gastrointestinal
symptoms, peripheral neuropathy, other chemotherapy side effects, hormonal 
symptoms, body image, attitudes toward disease and/or treatment, and sexuality of 
patients with local or advanced ovarian cancer who receive treatment by surgery with or 
without chemotherapy.
The EORTC QLQ-C30 and the QLQ-OV28 module take approximately 20 minutes to 
complete.
4.5.8.2
FACT-G Single Item GP5
The FACT-G instrument v4 (see Appendix 12) is a validated and reliable 27-item 
questionnaire comprised of four subscales that measure physical (7 items), social and 
family (7 items), emotional (6 items) and functional wellbeing (7 items), and is 
considered appropriate for use with patients with any form of cancer (Cella et al. 1997; 
Webster et al. 1999).  In this study, the single item GP5 (“I am bothered by side effects 
of treatment”) from the physical wellbeing subscale of the FACT-G has been selected for 
individual item analysis to document the level of bother of symptoms on patient’s lives. 
Patients will assess how true the statement “I am bothered by side effects of treatment” 
has been for them in the previous 7 days on a five-point scale (0, not at all; 1, a little bit; 
2, somewhat; 3, quite a bit; 4, very much). Single item GP5 from the FACT-G instrument 
takes less than a minute to complete.
4.5.8.3
EQ-5D-5L
The EQ-5D-5L is a validated self-report health status questionnaire that is used to 
calculate a health status utility score for use in health economic analyses 
(EuroQol Group 1990; Brooks 1996; Herdman et al. 2011; Janssen et al. 2013)
(see Appendix 6).  There are two components to the EQ-5D-5L:  a five-item health state 
profile that assesses mobility, self-care, usual activities, pain and discomfort, and anxiety
and depression, as well as a visual analogue scale that measures health state.  
Published weighting systems allow for the creation of a single composite score of the 
patient’s health status.  The EQ-5D-5L takes approximately 3 minutes to complete, and 
will be utilized in this study to inform pharmacoeconomic evaluations, and as such 
EQ-5D-5L data will not be included in the CSR.


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4.5.9
Eastern Cooperative Oncology Group Performance Status
ECOG performance status will be assessed with the use of the ECOG Performance 
Scale as previously described (Pignata et al. 2014).
4.5.10
Mandatory Samples for Whole Genome Sequencing
At participating sites, blood samples will be collected for DNA extraction to enable WGS 
and identify germline mutations that are predictive of response to study drug, associated 
with progression to a more severe disease state and/or susceptibility to develop 
adverse events, or can increase knowledge and understanding of disease biology.  
The blood samples may be sent to one or more laboratories for analysis.
Collection and submission of WGS samples is contingent upon the review and approval 
of the exploratory research and the WGS portion of the ICF by each site's IRB or EC 
and, if applicable, an appropriate regulatory body.  If a site has not been granted 
approval for WGS sampling, this section of the protocol will not be applicable at that site.
Genomics increases researchers’ understanding of disease pathobiology.  WGS 
provides a comprehensive characterization of the genome and, along with clinical data 
collected in this study, may increase the opportunity to develop new therapeutic 
approaches.  Data will be analyzed in the context of this study but also explored in 
aggregate with data from other studies.  The availability of a larger dataset will assist in 
identification of important pathways, and guide the development of new targeted agents.
For sampling procedures, storage conditions, and shipment instructions, refer to the 
laboratory manual.
Blood samples collected for WGS are to be stored until they are no longer needed or 
until they are exhausted.  However, the storage period will be in accordance with the 
IRB/EC-approved ICF and applicable laws (e.g., health authority requirements).
Patient medical information associated with WGS specimens is confidential and may be 
disclosed only to third parties as permitted by the ICF or a separate authorization for use 
and disclosure of personal health information signed by the patient, unless permitted or 
required by law.
Given the complexity and exploratory nature of the analyses, data derived from WGS 
specimens will 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.
4.5.11
Samples for Research Biosample Repository
4.5.11.1
Overview of the Research Biosample Repository
The Research Biosample Repository (RBR) is a centrally administered group of facilities 
used for the long-term storage of human biologic specimens that include body fluids, 


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solid tissues, and derivatives thereof (e.g., DNA, RNA, proteins, peptides).  The 
collection, storage, and analysis of RBR specimens will facilitate the rational design of 
new pharmaceutical agents and the development of diagnostic tests, which may allow 
for individualized drug therapy for patients in the future.
Tumor tissue, blood, and plasma from RBR specimens will be used to achieve the 
following objectives:

To study the association of biomarkers with efficacy, adverse events, or disease 
progression

To identify safety biomarkers that are associated with susceptibility to developing 
adverse events or can lead to improved adverse event monitoring or investigation

To increase knowledge and understanding of disease biology and drug safety

To study drug response that includes drug effects and the processes of drug 
absorption and disposition

To develop biomarker or diagnostic assays and establish the performance 
characteristics of these assays
4.5.11.2
Approval by the Institutional Review Board or Ethics 
Committee
Collection, storage and analysis of RBR samples to the RBR is contingent upon the 
review and approval of the exploratory research and the RBR portion of the ICF by each 
site's IRB or EC and, if applicable, an appropriate regulatory body.  If a site has not been
granted approval for RBR sampling, this section of the protocol will not be applicable at 
that site.
4.5.11.3
Sample Collection
The following samples will be stored in the RBR and used for research purposes, 
including but not limited to research on biomarkers related to atezolizumab, diseases, or 
drug safety:

Tumor tissue samples from biopsies performed at the investigator's discretion 
during the study

Leftover blood, plasma, and tumor tissue samples (except leftover tissue from 
archival FFPE blocks, which will be returned to sites) and any derivatives thereof 
(e.g., DNA, RNA, proteins, peptides) that include leftover tissue samples from 
additional tumor biopsies or medically indicated procedures (e.g., bronchoscopy, 
esophagogastroduodenoscopy, colonoscopy) performed at the investigator's 
discretion during the course of the study

A whole blood sample for DNA isolation will be collected from patients who have 
consented to optional RBR sampling at Cycle 1, Day 1 as shown in the schedules of 
assessments in Appendix 1 and Appendix 2.  If, however, the RBR genetic blood 
sample is not collected during the scheduled visit, it may be collected as soon as 
possible (after randomization) during the conduct of the clinical study.  Collection of 
whole blood will enable the evaluation of single nucleotide polymorphisms in genes 


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associated with immune biology that include but are not restricted to the target and 
pathway associated genes such as PD-L1, PD-1, and B7.1 as well as IL-8, IL-6, and 
related cytokines.  The sample may be processed with the use of techniques 
such as kinetic polymerase chain reaction and DNA sequencing.
The above samples may be sent to one or more laboratories for analysis of germline 
mutations or somatic mutations via WGS, NGS, or other genomic analysis methods.
Genomics increases researchers’ understanding of disease pathobiology.  WGS 
provides a comprehensive characterization of the genome and, along with clinical data 
collected in this study, may increase the opportunity to develop new therapeutic 
approaches.  Data will be analyzed in the context of this study but also explored in 
aggregate with data from other studies.  The availability of a larger dataset will assist in 
the identification of important pathways, and guide the development of new targeted 
agents.
For sampling procedures, storage conditions, and shipment instructions, refer to the 
laboratory manual.
RBR specimens are to be stored until they are no longer needed or until they are 
exhausted.  However, the RBR storage period will be in accordance with the IRB and/or 
EC-approved ICF and applicable laws (e.g., health authority requirements).
4.5.11.4
Confidentiality
RBR samples and associated data will be labeled with a unique patient identification 
number.
Patient medical information associated with RBR specimens is confidential and may be 
disclosed only to third parties as permitted by the ICF (or a separate authorization for 
use and disclosure of personal health information) signed by the patient, unless 
permitted or required by law.
Given the complexity and exploratory nature of the analyses of RBR specimens, data 
derived from these analyses will not be provided to study investigators or patients unless 
required by law.  The aggregate results of any conducted research will be available in 
accordance with the effective Sponsor policy on study data publication.
Data generated from RBR specimens must be available for inspection upon request by 
representatives of national and local health authorities, and Sponsor monitors, 
representatives, and collaborators, as appropriate.
Any inventions and patents that result from the inventions, improvements, and/or 
know-how that originates from the use of the RBR data will become and remain the 
exclusive and unburdened property of the Sponsor, except where otherwise agreed 
upon.


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4.5.11.5
Consent to Participate in the Research Biosample Repository
The ICF will contain a separate section that addresses participation in the RBR.  The 
investigator or authorized designee will explain to each patient the objectives, methods, 
and potential hazards of participation in the RBR.  Patients will be informed that they are 
free to refuse to participate and may withdraw their specimens at any time and for any 
reason during the storage period.  A separate, specific signature will be required to 
document a patient's agreement to provide optional RBR specimens.  Patients who 
decline to participate will not be requested to provide a separate signature.
The investigator should document whether or not the patient has provided consent to 
participate and (if applicable) the date(s) of consent, with completion of the 
RBR Research Sample Informed Consent eCRF.
In the event of an RBR participant's death or loss of competence, the participant's 
specimens and data will continue to be used as part of the RBR research.
A separate, specific signature is not required for mandatory RBR blood samples.
4.5.11.6
Withdrawal from the Research Biosample Repository
Patients who give consent to provide RBR specimens have the right to withdraw their 
specimens from the RBR at any time for any reason.  After withdrawal of consent, any 
remaining samples will be destroyed or will no longer be linked to the patient.  However, 
if RBR samples have been tested prior to withdrawal of consent, results from those tests 
will remain as part of the overall research data.  If a patient wishes to withdraw consent 
to the performance of tests on their specimens, the investigator must inform the Medical 
Monitor in writing of the patient's wishes through use of the appropriate RBR Subject 
Withdrawal Form and, if the study is ongoing, must enter the date of withdrawal on the 
RBR Research Sample Withdrawal of Informed Consent eCRF.  If a patient wishes to 
withdraw consent to the testing of his or her RBR samples after closure of the site, the 
investigator must inform the Sponsor by emailing the study number and patient number 
to the following email address:
global_rcr-withdrawal@roche.com
A patient's withdrawal from Study YO39523 does not, in itself, constitute withdrawal of 
specimens from the RBR.  Likewise, a patient's withdrawal of consent for testing of 
RBR samples does not constitute withdrawal from Study YO39523.
4.5.11.7
Monitoring and Oversight
RBR specimens will be tracked in a manner consistent with Good Clinical Practice by a 
quality-controlled, auditable, and appropriately validated laboratory information 
management system, to ensure compliance with data confidentiality as well as 
adherence to authorized use of specimens as specified in this protocol and in the ICF.  
Sponsor monitors and auditors will have direct access to appropriate parts of records 
related to patient participation in the RBR for verification of the data provided to the 


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Sponsor.  The site will permit monitoring, audits, IRB and/or EC review, and health 
authority inspections through direct access to source data and documents related to the 
RBR samples.
4.6
TREATMENT, PATIENT, STUDY, AND SITE DISCONTINUATION
4.6.1
Study Treatment Discontinuation
Patients must permanently discontinue study treatment or the attributable portion of the 
study treatment regimen (atezolizumab, placebo, paclitaxel, carboplatin, and/or 
bevacizumab) if they experience any of the following:

Intolerable toxicity related to study treatment that includes the 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 adverse event that requires study treatment discontinuation per the guidelines 
in Section 5.1 and the Atezolizumab Investigator's Brochure

Any medical condition that may jeopardize the patient’s safety if they continue 
study treatment

Investigator or Sponsor determination that treatment discontinuation is in the best 
interest of the patient

Use of another non-protocol anti-cancer therapy

Pregnancy

Symptomatic deterioration attributed to disease progression

Radiographic disease progression per RECIST v1.1
CA-125 elevations do not constitute disease progression and cannot be used 
for determining disease progression.
The primary reason for study treatment discontinuation should be documented on the 
appropriate eCRF.  Patients who discontinue all study treatments prematurely will not be 
replaced.
Patients will return to the clinic for a treatment discontinuation visit 30 days after the 
last dose of all study treatments.  The visit during 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 limited physical examination and CA-125, tumor 
response, and PRO assessments at the time intervals outlined in the schedules of 
assessments (see Appendix 1 and Appendix 2). Patients who discontinue study 
treatment for progressive disease or loss of clinical benefit, regardless of receipt of 
subsequent anti-cancer therapy, should continue to undergo limited physical 
examination, CA-125 and PRO assessments at the time intervals outlined in the 
schedules of assessments.


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After discontinuation of all study treatments, physical examination, CA-125 
assessments, and tumor response data as well as information on survival follow-up and 
new anti-cancer therapy will be collected via telephone calls, patient medical records, 
and/or clinic visits according to the schedule of activities (Appendix 1 and Appendix 2),
unless the patient withdraws consent specifically for follow-up and/or surveillance or the 
Sponsor terminates the study.  If a patient requests to be withdrawn from follow-up
and/or surveillance, this request must be documented in the source documents and 
signed by the investigator.  If the patient withdraws consent from the study that includes
follow-up and/or surveillance, the study staff may nevertheless use a public information 
source (e.g., country records) to obtain only information about survival status.
4.6.2
Patient Discontinuation from Study
Patients have the right to voluntarily withdraw from the study at any time for any reason.  
In addition, the investigator has the right to exclude a patient from the study at any time.  
If patients withdraw from study treatment, they will still continue follow-up, disease 
surveillance activities.
Reasons for withdrawal from the study may include but are not limited to:

Withdrawal of consent for the study (i.e., from the study treatment regimens and any 
follow-up and/or surveillance activities associated with the study)

Study termination or site closure

Patient non-compliance (e.g., missed doses and/or missed visits)
Every effort should be made to obtain information on patients who withdraw or are 
excluded from the study.  The primary reason for withdrawal or exclusion from the study 
should be documented on the appropriate eCRF.  Patients who withdraw or are 
excluded from the study will not be replaced.
Withdrawal or exclusion from the study must differentiate between either withdrawal or 
exclusion from study treatment with continued follow-up and/or surveillance 
(i.e., survival, post-study treatments), or withdrawal or exclusion from study treatment 
with no follow-up and/or surveillance (i.e., survival, post-study treatments).
4.6.3
Participants Lost to Follow-Up
If a participant does not return to the clinic for a required study visit, site personnel must 
attempt to contact the participant as soon as possible to reschedule the missed visit and 
counsel the participant on the importance of maintaining the visit schedule.  If the 
participant is unable or unwilling to comply with study visits, site personnel may
determine if there are ways to support participant participation.  If a participant does not
return to the clinic for scheduled visits and is not in contact with the site, site personnel 
must make every effort to regain contact with the participant.  Whenever possible, 
attempts should include three telephone calls followed by a certified letter (or equivalent) 
to the participant's last known mailing address.  These contact attempts should be 


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documented in the participant's medical record.  If the participant continues to be 
unreachable, he or she will be considered lost to follow-up and will be withdrawn from 
the study.
4.6.4
Study Discontinuation
The Sponsor has the right to terminate this study at any time.  Reasons for the 
termination of the study may include but are not limited to:

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.
4.6.5
Site Discontinuation
The Sponsor has the right to close a site at any time.  Reasons for the closure of a site 
may include but are not limited to:

Excessively slow recruitment

Poor protocol adherence

Inaccurate or incomplete data recording

Non-compliance with the International Council on Harmonisation of Technical 
Requirements for Registration of Pharmaceuticals for Human Use (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 on the basis of clinical experience with 
atezolizumab in completed and ongoing studies.  The anticipated important safety risks 
are outlined below (see Sections 5.1.15.1.4).
Measures will be taken to ensure the safety of patients who participate in this study, 
which includes the use of stringent inclusion and exclusion criteria and close monitoring 
of patients during the study.  Administration of atezolizumab will be performed in a 
monitored setting in which there is immediate access to trained personnel and adequate 
equipment and medication to manage potentially serious reactions. Guidelines for 
managing patients who experience anticipated adverse events, including criteria for 
dosage modification and treatment interruption or discontinuation, are provided in 
Appendix 9 and Appendix 10. All adverse events will be reported as described in 
Sections 5.25.6.


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Patients with active infection are excluded from study participation.  In the setting of a 
pandemic or epidemic, screening for active infections (including SARS-CoV-2) prior to 
and during study participation should be considered according to local or institutional 
guidelines or guidelines of applicable professional societies (e.g., American Society of 
Clinical Oncology or European Society for Medical Oncology).
Severe COVID-19 appears to be associated with a CRS involving the inflammatory 
cytokines IL-6, IL-10, IL-2, and IFN-(Merad and Martin 2020).  If a patient develops 
suspected CRS during the study, a differential diagnosis should include COVID-19, 
which should be confirmed or refuted through assessment of exposure history, 
appropriate laboratory testing, and clinical or radiologic evaluations per investigator 
judgment.  If a diagnosis of COVID-19 is confirmed, the disease should be managed as 
per local or institutional guidelines.
5.1.1
Risks Associated with Atezolizumab
Atezolizumab has been associated with risks such as IRRs and immune-mediated
hepatitis, pneumonitis, colitis, pancreatitis, diabetes mellitus, hypothyroidism, 
hyperthyroidism, adrenal insufficiency, hypophysitis, Guillain-Barré syndrome, 
myasthenic syndrome or myasthenia gravis, meningoencephalitis, myocarditis, nephritis, 
myositis, and severe cutaneous adverse reactions.  Immune-mediated reactions may 
involve any organ system and may lead to hemophagocytic lymphohistiocytosis and 
macrophage activation syndrome，which are considered to be potential risks for 
atezolizumab. See Appendix 9 of the protocol and refer to Section 6 of the 
Atezolizumab Investigator's Brochure for a detailed description of anticipated safety risks 
and the management guidelines for atezolizumab.
5.1.2
Risks Associated with Paclitaxel
Paclitaxel is known to cause myelosuppression, alopecia, peripheral neuropathy, 
myalgia, arthralgia, nausea, and vomiting.  Less commonly reported adverse events are 
hypersensitivity reactions, infections, bleeding, diarrhea, mucositis, liver function test
elevations, injection-site reactions, and cardiovascular effects such as hypotension, 
bradycardia, hypertension, arrhythmias, other ECG abnormalities, syncope, and venous 
thrombosis.
For more details with regard to the safety profile of paclitaxel, refer to the prescribing 
information for paclitaxel.
5.1.3
Risks Associated with Carboplatin
Carboplatin is known to cause bone marrow suppression, which includes
myelosuppression, anemia, and thrombocytopenia.  Carboplatin-based chemotherapy is 
considered to be moderately emetogenic.  Patients will be monitored for 
carboplatin-related adverse events.


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For more details with regard to the safety profile of carboplatin, refer to the prescribing 
information for carboplatin.
5.1.4
Risks Associated with Bevacizumab
The most common (1 of 10) side effects associated with bevacizumab include febrile 
neutropenia, leucopenia, neutropenia, thrombocytopenia, anorexia, hypomagnesaemia, 
hyponatremia, peripheral sensory neuropathy, dysarthria, headache, dysguesia, 
eye disorder, lacrimation increased, hypertension, thromboembolism (venous), dyspnea, 
rhinitis, epistaxis, cough, rectal hemorrhage, stomatitis, constipation, diarrhea, nausea, 
vomiting, abdominal pain, wound healing complications, exfoliative dermatitis, dry skin, 
skin discoloration, arthralgia, myalgia, proteinuria, ovarian failure, asthenia, fatigue, 
pyrexia, pain, mucosal inflammation, and weight decreased.
For more details with regard to the safety profile of bevacizumab, refer to the prescribing 
information for bevacizumab.
5.1.5
Bevacizumab Dose Modification and Management of Specific 
Adverse Events
At the start of each cycle without cytotoxic chemotherapy, the ANC must be >1000/µL 
and the platelet count must be ≥75,000 cells/µL. Dose adjustments for bevacizumab are 
permitted if the body weight changes 10% from the baseline body weight provided that 
this aligns with institutional guidelines; all subsequent doses should be modified 
accordingly. Dose reductions for adverse events are not recommended.  Criteria for 
treatment modifications and guidelines for the management of toxicities are summarized 
in Appendix 10.  If adverse events occur that necessitate withholding bevacizumab from 
patients, the dose will remain unchanged once treatment resumes.
Bevacizumab treatment may be temporarily suspended in patients who experience 
toxicity considered to be related to study treatment.  If bevacizumab has been withheld 
for 42 days from the date of the first missed dose because of toxicity, the patient 
should be discontinued from bevacizumab, unless resumption of treatment is approved 
following investigator discussion with the Medical Monitor.  Bevacizumab treatment may 
be suspended for reasons other than toxicity (e.g., surgical procedures).  The acceptable 
length of treatment interruption must be based on an assessment of benefit-risk by the 
investigator and in alignment with the protocol requirements for the duration of 
treatment and documented by the investigator.  The Medical Monitor is available to 
advise as needed.
5.1.6
Carboplatin and Paclitaxel Dose Modification and Management 
of Specific Adverse Events
At the start of each cycle with cytotoxic chemotherapy, the ANC must be 1500/L and 
the platelet count must be 100,000 cells/L.  Treatment may be delayed for up to 
42 days from the last dose to allow sufficient time for recovery.  Growth factors may be 
used in lieu of and/or in addition to a dose reduction for neutropenic fever or 


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Grade 4 neutropenia in accordance with institutional practice guidelines and/or the 
American Society of Clinical Oncology and the National Comprehensive Cancer Network
guidelines (Smith et al. 2015; NCCN 2016).
5.1.6.1
Carboplatin
Therapy with carboplatin should be discontinued in the case of an unresponsive tumor, 
progressive disease and/or occurrence of not tolerable side effects.  Reduction of the 
initial dosage by 20%25% or institutional guidelines (e.g., AUC 6, AUC 5, AUC 4) is 
recommended for patients present with risk factors such as prior myelosuppressive 
treatment.
For detailed information regarding the management of adverse events that are 
associated with carboplatin, refer to the prescribing information for carboplatin.
5.1.6.2
Paclitaxel
Subsequent doses of paclitaxel should be administered in accordance with individual 
patient tolerance to the treatment.  Patients who experience severe neutropenia 
(neutrophil count 500/L for 1 week) or severe peripheral neuropathy should receive 
a dose reduction of 20% or institutional guidelines (e.g., 175 mg/m2, 135 mg/m2, 
110 mg/m2) for subsequent doses.
For detailed information regarding the management of adverse events associated with
paclitaxel, refer to the prescribing information for paclitaxel.
5.1.7
Potential Overlapping Toxicities 
The risk of overlapping toxicities between atezolizumab, bevacizumab, carboplatin, and 
paclitaxel is thought to be minimal.  Nevertheless, the attribution and management of 
certain adverse events that have been associated with each agent separately 
(e.g., hepatotoxicity, skin, and gastrointestinal toxicity) may not be unambiguous when 
the agents are administered in combination.  It is theoretically possible that allergic or 
inflammatory adverse events associated with bevacizumab and these chemotherapeutic 
agents (e.g., hepatotoxicity) could be exacerbated by the immunostimulatory activity of 
atezolizumab.
5.2
SAFETY PARAMETERS AND DEFINITIONS
Safety assessments will consist of the monitoring and recording of adverse events
(includes serious adverse events and adverse events of special interest), performance of
protocol-specified safety laboratory assessments, measurement of protocol-specified 
vital signs, and completion of other protocol-specified tests that are deemed critical to 
the safety evaluation of the study.
Certain types of events require to be immediately reported to the Sponsor, as outlined in 
Section 5.4.


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5.2.1
Adverse Events
According to the ICH guideline for Good Clinical Practice, an adverse event is any 
untoward medical occurrence in a clinical investigation subject who is administered a 
pharmaceutical product, regardless of causal attribution.  An adverse event can be any 
of the following:

Any unfavorable and unintended sign (includes 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 (i.e., deterioration in the 
character, frequency, or severity of a known condition), except as described in 
Section 5.3.5.10

Recurrence of an intermittent medical condition (e.g., headache) that was not 
present at baseline

Any deterioration in a laboratory test value or other clinical test (e.g., ECG, X-ray) 
that is associated with symptoms, or leads to a change in the study treatment or the 
concomitant treatment, or discontinuation from the study treatment

Adverse events that are related to a protocol-mandated intervention, including those 
events that occur prior to the assignment of the 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 causes or leads to death)

Is life threatening (i.e., the adverse event, in the view of the investigator, places the 
patient at an 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 or incapacity (i.e., the adverse event 
results in the substantial disruption of the patient’s ability to conduct normal life 
functions)

Is a congenital anomaly or birth defect in a neonate or infant born to a mother who 
was exposed to study treatment

Is a significant medical event in the investigator’s judgment (e.g., may jeopardize the 
patient or require medical and/or surgical intervention to prevent one of the 
outcomes listed)
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., 24 hours after the notification of the event; see Section 5.4.2
instructions on how to report).
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., 24 hours after learning of the event; see Section 5.4.2 for 
instructions on how to report).  Adverse events of special interest for this study include 
the following:
5.2.3.1
General Adverse Events of Special Interest

Cases of potential drug-induced liver injury that include an elevated ALT or AST in 
combination with either an elevated bilirubin or clinical jaundice, as defined by 
Hy’s Law (see Section 5.3.5.7) and based on the following observations:
Treatment-emergent ALT or AST 3 baseline value in combination with total 
bilirubin 2 ULN (of which 35% is direct bilirubin)
Treatment-emergent ALT or AST 3 baseline value in combination with clinical 
jaundice

Suspected transmission of an infectious agent by the study treatment, defined as:
Any organism, virus, or infectious particle (e.g., prion protein transmitting 
transmissible spongiform encephalopathy), pathogenic or non-pathogenic, is 
considered an infectious agent.  A transmission of an infectious agent may be 
suspected from clinical symptoms or laboratory test result findings that indicate
an infection in a patient exposed to a medicinal product.  This term applies only 
when a contamination of study treatment is suspected.
5.2.3.2
Adverse Events of Special Interest for Atezolizumab

Pneumonitis

Colitis

Endocrinopathies:  diabetes mellitus, pancreatitis, adrenal insufficiency, 
hypothyroidism and hyperthyroidism

Hepatitis, which includes AST or ALT 10ULN

Systemic lupus erythematosus

Neurological disorders:  Guillain-Barré syndrome, myasthenic syndrome or 
myasthenia gravis, and meningoencephalitis


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
Events suggestive of hypersensitivity, infusion-related reactions, cytokine release 
syndrome, and systemic inflammatory response syndrome

Nephritis

Ocular toxicities (e.g., uveitis, retinitis, optic neuritis)

Myositis

Myopathies, including rhabdomyolysis

Grade 2 cardiac disorders (e.g., atrial fibrillation, myocarditis, pericarditis)

Severe cutaneous reactions (e.g., Stevens-Johnson syndrome, dermatitis bullous, 
toxic epidermal necrolysis)
5.2.3.3
Adverse Events of Special Interest for Bevacizumab

Grade 3 hypertension 

Grade 3 proteinuria

Any grade gastrointestinal perforation, abscesses, or gastrointestinal-fistulae

Grade 2 non-gastrointestinal fistula or abscess

Tracheoesophageal fistula

Grade 3 wound-healing complication

Hemorrhage
Any grade CNS bleeding
Grade 2 hemoptysis
Other Grade 3 hemorrhagic event

Any grade arterial thromboembolic event

Grade 3 venous thromboembolic event

Any grade posterior reversible encephalopathy syndrome

Grade 3 congestive heart failure
5.3
METHODS AND TIMING TO CAPTURE AND ASSESS
SAFETY PARAMETERS
The investigator is responsible to ensure that all adverse events (see Section 5.2.1) 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), severity (see Section 5.3.3), and 
causality (see Section 5.3.4).


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5.3.1
Adverse Event Reporting Period
Investigators will seek information on adverse events at each patient contact.  All 
adverse events, whether reported by the patient or noted by study personnel, will be 
recorded in the patient’s medical record and on the Adverse Event eCRF.
After informed consent has been obtained but prior to initiation of the study treatment, 
serious adverse events caused only by a protocol-mandated intervention (e.g., invasive
procedures such as biopsies, or discontinuation of medications) should be reported 
(see Section 5.4.2).
After the initiation of the study treatment, all adverse events will be reported until 30 days 
after the last dose of the study treatment (which includes study-related surgery) is 
administered or until the initiation of a new anti-cancer therapy, whichever occurs first.  
Serious adverse events and adverse events of special interest will continue to be 
reported until 90 days after the last dose of the study treatment (which includes 
study-related surgery) or until starting a new anti-cancer therapy, whichever occurs first.  
After this reporting period, serious adverse events believed to be related to prior 
exposure to study treatment, including study-related surgery, should be reported.
Instructions for reporting adverse events that occur after the adverse event reporting 
period are provided in Section 5.6.
5.3.2
Eliciting of Adverse Event Information
A consistent methodology for non-directive questions should be adopted to elicit
adverse event information during all patient evaluation visits.  Examples of non-directive 
questions include:

“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 (v4.0) will be used to 
assess the severity of an adverse event. Table 5 will be used to assess the severity of
adverse events that are not specifically listed in the NCI CTCAE.


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Table 5
Severity Grading Scale for Adverse 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; disabled; or limited to 
perform 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:  This information is on the basis of the most recent version of NCI CTCAE (v4.0), 
found at:  http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm
a Instrumental activities of daily living include the preparation of meals, shopping for 
groceries or clothes, use of the telephone, money management, etc.
b Examples of self-care activities of daily living include bathing, (un)dressing, 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 5.2.2 and Section 5.4.2).
d Grade 4 and Grade 5 events must be reported as serious adverse events 
(see Section 5.2.2 and Section 5.4.2).
5.3.4
Assessment of Causality of Adverse Events
Investigators should use their knowledge of the patient, the circumstances surrounding 
the event, and an evaluation of any potential alternative causes to determine whether an 
adverse event is considered to be related to the study treatment and indicate “yes” or 
“no” accordingly.  Guidance should be taken into consideration as follows:

Temporal relationship of event onset to the initiation of the study treatment

Course of the event, with special consideration of the effects of the dose reduction, 
discontinuation of the study treatment, or re-initiation of the study treatment
(as applicable)

Known association of the event with the study treatment or with similar treatments

Known association of the event with the disease of interest in this study

Presence of risk factors in the patient or use of concomitant medications known to 
increase the occurrence of the event

Presence of non-treatmentrelated factors that are known to be associated with the 
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For patients who receive combination therapy, causality will be assessed individually for 
each protocol-mandated therapy.
5.3.5
Procedures to Record Adverse Events
Investigators should use correct medical terminology and concepts when recording 
adverse events on the Adverse Event eCRF, and avoid colloquialisms and 
abbreviations.  Only one adverse event term should be recorded only in the event field 
on the Adverse Event eCRF.
5.3.5.1
Infusion-Related Reactions and Cytokine-Release Syndrome 
There may be significant overlap in signs and symptoms of IRRs and CRS.  While IRRs 
occur during or within 24 hours after treatment administration, time to onset of CRS may 
vary.  Differential diagnosis should be applied, particularly for late-onset CRS (occurring 
more than 24 hours after treatment administration), to rule out other etiologies such as 
delayed hypersensitivity reactions, sepsis or infections, HLH, tumor lysis syndrome, 
early disease progression, or other manifestations of systemic inflammation.
Adverse events that occur during or within 24 hours after study treatment administration 
and are judged to be related to study treatment infusion should be captured on the 
Adverse Event eCRF as a diagnosis (e.g., "infusion-related reaction" or 
"cytokinerelease syndrome").  Avoid ambiguous terms such as "systemic reaction."  
Cases of late-onset CRS should be reported as "cytokine-release syndrome" on the 
Adverse Event eCRF.  Associated signs and symptoms of an IRR should be recorded on 
the dedicated Infusion-Related Reaction eCRF.
If a patient experiences both a local and systemic reaction to a single administration
ofstudy treatment, each reaction should be recorded separately on the Adverse Event 
eCRF, with associated signs and symptoms of an IRR also recorded separately on the 
dedicated Infusion-Related Reaction eCRF.
In recognition of the challenges in clinically distinguishing between IRRs and CRS, 
consolidated guidelines for medical management of IRRs and CRS are provided in
Appendix 9.
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 the report, each individual event should be recorded on the 
Adverse Event eCRF.  If a diagnosis is subsequently identified, all previously reported 
adverse events based on signs and symptoms should be nullified and replaced by one 
adverse event report based on the single diagnosis, with a starting date that 
corresponds to the starting date of the first symptom of the eventual diagnosis.


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5.3.5.3
Adverse Events That Are Secondary to Other Events
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 initial event should be recorded as an independent event on 
the Adverse Event eCRF.  For example:

If a healthy adult patient vomits and experiences mild dehydration without additional 
treatment, vomiting should be reported only on the eCRF.

If a patient vomits and experiences severe dehydration, both events should be 
reported separately on the eCRF.

If a patient experiences a severe gastrointestinal hemorrhage that leads to renal 
failure, both events should be reported separately on the eCRF.

If a patient experiences dizziness that leads to a fall and consequent fracture, all 
three events should be reported separately on the eCRF.

If a patient experiences neutropenia that 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 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 visits.  Such events should be recorded only once on the 
Adverse Event eCRF.  The initial severity (i.e., 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., 24 hours after learning that the event became serious; 
see Section 5.4.2).  The Adverse Event eCRF should be updated and the event changed
to “serious” with all data fields related to the serious adverse events completed.
A recurrent adverse event is one that resolves between patient evaluation visits and then 
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 Test Result Values
Not every laboratory test result 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 the study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation)


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
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
It is the investigator’s responsibility to review all laboratory test result findings.  Medical 
and scientific judgment should be exercised in deciding whether an isolated laboratory 
test result abnormality should be classified as an adverse event.
If a clinically significant laboratory test result abnormality is a sign of a disease or 
syndrome (e.g., ALP and bilirubin 5 ULN associated with cholestasis), the diagnosis 
(i.e., cholestasis) should be recorded only on the Adverse Event eCRF.
If a clinically significant laboratory test result 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 test 
result 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 test result abnormality from 
patient visit to visit should be recorded only once on the Adverse Event eCRF 
(see Section 5.3.5.4 for details on how to record 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 the 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 result findings.  Medical and 
scientific judgment should be exercised in deciding whether an isolated vital sign value 
abnormality should be classified as an adverse event.
If a clinically significant vital sign value abnormality is a sign of a disease or syndrome 
(e.g., high blood pressure), the diagnosis (i.e., hypertension) should be recorded only on 
the Adverse Event eCRF.
Observations of the same clinically significant vital sign result abnormality from patient
visit to visit should be recorded only once on the Adverse Event eCRF 
(see Section 5.3.5.4 for details on how to record persistent adverse events).


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5.3.5.7
Abnormal Liver Function Test Results
The finding of an elevated ALT or AST (3baseline value) in combination with either 
an elevated total bilirubin (2ULN) or clinical jaundice in the absence of cholestasis or 
other causes of hyperbilirubinemia is considered an indicator of severe liver injury
(as defined by Hy’s Law).  Therefore, investigators must report the occurrence of the 
following as an adverse event:

Treatment-emergent ALT or AST 3 baseline value in combination with total 
bilirubin 2 ULN, of which 35% is direct bilirubin

Treatment-emergent ALT or AST 3 baseline value in combination with clinical 
jaundice
The most appropriate diagnosis or, if a diagnosis cannot be established, the abnormal 
laboratory test result values should be recorded on the Adverse Event eCRF 
(see Section 5.3.5.2) and reported to the Sponsor immediately (i.e., 24 hours after 
notification 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) and that are
attributed by the investigator solely to the progression of ovarian, fallopian tube, or 
primary peritoneal cancer should be recorded on the Death Attributed to Progressive 
Disease eCRF.  All other patient deaths during the study, regardless of the relationship 
to the study treatment, must be recorded on the Adverse Event eCRF and immediately 
reported to the Sponsor (see Section 5.4.2).  The iDMC will monitor the frequency of 
deaths from all causes.
Death should be considered an outcome and not a distinct event.  The event or condition 
that caused or contributed to the fatal outcome should be recorded as the single medical 
concept on the Adverse Event eCRF.  Generally, only one such event should be 
reported.  If the cause of death is unknown and cannot be ascertained at the time of 
reporting, “unexplained death” should be recorded on the Adverse Event eCRF.  If the 
cause of death later becomes available (e.g., after autopsy), “unexplained death” should 
be replaced by the established cause of death.  The term "sudden death" should not be 
used unless combined with the presumed cause of death (e.g., "sudden cardiac death").
Deaths that occur after the conclusion of 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 in a patient at the time of the 
screening visit for this study.  Such conditions should be recorded on the 
General Medical History and Baseline Conditions eCRF.


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A preexisting medical condition should be recorded only as an adverse event if the 
frequency, severity, or character of the condition deteriorates 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 with the inclusion of applicable descriptors 
(e.g., “more frequent headaches”).
5.3.5.10
Lack of Efficacy or Deterioration of Ovarian, Fallopian Tube, or 
Primary Peritoneal 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 only as efficacy assessment data.  In most cases, the expected pattern of 
progression will be on the basis of RECIST v1.1 criteria.  In rare cases, the 
determination of the clinical progression will be on the basis of the symptomatic 
deterioration.  However, every effort should be made to document the progression 
through the use of objective criteria.  If there is any uncertainty 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 the hospitalization (i.e., inpatient admission to a 
hospital) or prolonged hospitalization of a patient should be documented and reported as 
a serious adverse event (see 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 the administration of the 
study treatment or the performance of an efficacy measurement for the study)

Hospitalization for a preexisting condition, provided that all of the following criteria 
are met:
The hospitalization was planned prior to the study or was scheduled during the 
study when elective surgery became necessary because of the expected 
normal progression of the disease.
The patient has not experienced an adverse event.

Hospitalization due solely to progression of the underlying cancer
An event that leads to hospitalization under the following circumstances is not 
considered to be a serious adverse event, but should be reported as an adverse event 
instead:

Hospitalization that was necessary because of patient requirement for outpatient 
care outside of normal outpatient clinic operating hours


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


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and one to report the headache.  The "Accidental overdose" and "Medication error" 
boxes would need to be checked on both eCRF pages.
5.3.5.13
Patient-Reported Outcome Data
Adverse event reports will not be derived from PRO data by the Sponsor, and safety 
analyses will not be performed with the use of PRO data.  Sites are not expected to 
review the PRO data for adverse events. 
5.4
IMMEDIATE REPORTING REQUIREMENTS FROM 
INVESTIGATOR TO SPONSOR
Certain events require immediate reporting to allow the Sponsor to take appropriate 
measures to address potential new risks in a clinical study.  The investigator must report 
such events to the Sponsor immediately, and under no circumstances should the 
reporting take place 24 hours after the investigator is notified of the event.  Events that 
the investigator must report to the Sponsor within 24 hours after notification of the event, 
regardless of the relationship to the study treatment include:

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 5.2.1; see Section 5.4.2 for 
details on reporting requirements)

Pregnancies (see Section 5.4.3 for details on reporting requirements)
The investigator must report new significant follow-up information for these events to the 
Sponsor immediately (i.e., 24 hours after notification of the information).  New 
significant information includes:

New signs or symptoms or a change in the diagnosis

Significant new diagnostic test results

Change in causality on the basis of 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 to report serious adverse events 
to the local health authority and IRB and/or EC.
5.4.1
Medical Monitors and Emergency Medical Contacts
Medical Monitor Contact Information for All Sites
Medical Monitor/Roche Medical Responsible:
, M.D., M.S. (Primary)
Mobile Telephone No.:
Email:
Medical Monitor/Roche Medical Responsible:
, M.D. (Secondary)
Mobile Telephone No.:


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Email:
To ensure the safety of the study patients, an Emergency Medical Call Center Help Desk 
will access the Roche Medical Emergency List, escalate emergency medical calls, 
provide medical translation service (if necessary), connect the investigator with a Roche 
Medical Responsible (listed above and/or on the Roche Medical Emergency List), and 
track all calls.  The Emergency Medical Call Center Help Desk will be available 24 hours 
per day, 7 days per week.  Toll-free numbers for the Help Desk, and Medical Monitor 
and Medical Responsible contact information will be distributed to all investigators.
5.4.2
Reporting Requirements for Serious Adverse Events and 
Adverse Events of Special Interest
5.4.2.1
Events That Occur prior to the Initiation of the Study Treatment
After informed consent has been obtained from the patient but prior to the initiation of the 
study treatment, serious adverse events caused only by a protocol-mandated 
intervention should be reported.  The Serious Adverse Event or Adverse Event of 
Special Interest Reporting Form provided to the investigators should be completed and 
submitted to the Sponsor or its designee immediately (i.e., 24 hours after the
notification of the event), either by fax or emailed scan of the form via the fax number or 
email address provided to the investigators.
5.4.2.2
Events That Occur after the Initiation of the Study Treatment
After the initiation of the study treatment, serious adverse events and adverse events of 
special interest will be reported until 90 days after the last dose of the study treatment
(which includes study-related surgery) is administered or until initiation of a new 
anti-cancer therapy, whichever occurs first.  Investigators should record all case details 
that can be gathered immediately (i.e., within 24 hours after the notification of the event) 
on the Adverse Event eCRF and submit the report via the EDC system.  A report will be 
generated and sent to the Roche Safety Risk Management team by the EDC system.
In the event that the EDC system is unavailable, the paper Clinical Trial Serious Adverse 
Event/Adverse Event of Special Interest Reporting Form provided to the investigators 
should be completed and submitted to the Sponsor or its designee immediately 
(i.e., 24 hours after the notification of the event), either by fax or emailed scan of the 
form via the fax number or email address provided to the 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.


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5.4.3
Reporting Requirements for Pregnancies
5.4.3.1
Pregnancies in Female Patients
Female patients of childbearing potential will be instructed to immediately inform the 
investigator if they become pregnant during the study or within 5 months after the 
administration of the last dose of atezolizumab, and/or 6 months after the administration 
the last dose of bevacizumab, paclitaxel, or carboplatin, whichever is later.  A paper 
Clinical Study 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 with use of the fax 
number or email address provided to the investigators.  Pregnancy should not be 
recorded on the Adverse Event eCRF. The investigator should discontinue the 
administration of the study treatment and counsel the patient on 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 and/or the mother during or after the 
pregnancy, or a congenital anomaly and/or birth defect in the child) should be reported
on the Adverse Event eCRF.  In addition, the investigator will submit a Clinical Trial 
Pregnancy Reporting Form when updated information on the course and outcome of the 
pregnancy becomes available.
Attempts should be made to collect and report infant health information.  When permitted 
by the site, an Authorization for the Use and Disclosure of Infant Health Information 
would need to be signed by one or both parents (as per local regulations) to allow for 
follow-up on the infant.  If the authorization has been signed, the infant's health status at 
birth should be recorded on the Clinical Trial Pregnancy Reporting Form.  In addition, the 
Sponsor may collect follow-up information on the infant's health status at 6 and 
12 months after birth.
5.4.3.2
Abortions
The Sponsor considers spontaneous abortions medically significant events, and they 
should be classified as a serious adverse event, recorded on the Adverse Event eCRF, 
and reported to the Sponsor immediately (i.e., 24 hours after the notification of the 
event; see Section 5.4.2).
If a therapeutic or elective abortion was performed because of an underlying maternal or 
embryofetal toxicity, the toxicity should be classified as a serious adverse event, 
recorded on the Adverse Event eCRF, and reported to the Sponsor immediately (i.e., no 
more than 24 hours after learning of the event; see Section 5.4.2).  A therapeutic or 
elective abortion performed for reasons other than an underlying maternal or 
embryofetal toxicity is not considered an adverse event.
All abortions should be reported as pregnancy outcomes on the paper Clinical Trial 
Pregnancy Reporting Form.


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5.4.3.3
Congenital Anomalies and/or Birth Defects
Any congenital anomaly and/or birth defect in a child born to a female patient who is 
exposed to the study treatment should be classified as a serious adverse event, 
recorded on the Adverse Event eCRF, and reported to the Sponsor immediately 
(i.e., 24 hours after the notification 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 up on each adverse event until the event has resolved to 
baseline grade or better, the event is assessed as stable by the investigator, the patient 
completed the follow-up study period, or the patient withdraws consent.  Every effort 
should be made to follow up on all serious adverse events that are considered related to 
the study treatment or study-related procedures until a final outcome can be reported.
During the study period, resolution of adverse events should be documented with dates 
on the Adverse Event eCRF, and in the patient’s medical record to facilitate source data 
verification.
All pregnancies reported during the study period should be followed until pregnancy 
outcome.
5.5.2
Sponsor Follow-Up
For serious adverse events, adverse events of special interest, and pregnancies, the 
Sponsor or a designee may follow up by telephone, fax, electronic mail, and/or a 
monitoring visit to obtain additional case details and outcome information (e.g., from 
hospital discharge summaries, consultant reports, autopsy reports) in order to perform 
an independent medical assessment of the reported case.
5.6
ADVERSE EVENTS THAT OCCUR AFTER THE ADVERSE 
EVENT REPORTING PERIOD
After the end of the adverse event reporting period (defined as 90 days after the 
administration of the last dose of any study treatment), 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 Serious Adverse Event/Adverse Event of Special 
Interest Reporting Form using the fax number or email address provided to investigators.


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5.7
EXPEDITED REPORTING TO HEALTH AUTHORITIES, 
INVESTIGATORS, INSTITUTIONAL REVIEW BOARDS, AND 
ETHICS COMMITTEES
The Sponsor will promptly evaluate all serious adverse events and adverse events of 
special interest against cumulative product experience to identify and expeditiously 
communicate possible new safety findings to investigators, IRBs, ECs, and applicable 
health authorities on the basis of applicable legislation.
To determine the reporting requirements for single adverse event cases, the Sponsor 
will assess the expectedness of these events with the use of reference documents:

Atezolizumab Investigator’s Brochure

AVASTIN(bevacizumab) Investigator’s Brochure
The Sponsor will compare the severity of each event and the cumulative event 
frequency reported for the study with the severity and frequency reported in the 
applicable reference document.
Reporting requirements will also be on the basis of the investigator’s assessment of 
causality and seriousness, with permission to upgrade by the Sponsor as needed.
An iDMC will monitor the safety data during the study.  An aggregate report of any 
clinically-relevant imbalances that do not favor the test product will be submitted to 
health authorities.
6.
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN
The primary analysis populations for efficacy are the ITT population, defined as all 
patients randomized in the study, and the PD-L1positive subgroup, defined as the 
patients in the ITT population whose PD-L1 status is IC1/2/3 at the time of 
randomization. Patients will be grouped in accordance with the treatment assigned at 
randomization.
The primary analysis population for safety is the Safety Population, defined as all
randomized patients who receive at least one dose of the study medication.  Patients will 
be grouped in accordance with the treatment they actually receive, and all patients who 
received any dose of atezolizumab will be included in the atezolizumab treatment arm
for analysis.
If the China extension phase is initiated, data from this phase will not be included in the 
primary analysis of the main study. A separate analysis will be performed for the China 
subgroup, where data from the China extension phase and from the patients in the 
global enrollment phase from China will be combined and summarized (see
Section 6.9 and the statistical analysis plan [SAP] for further details). All analyses 




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The sample size of the study is determined by the number of patient deaths required to
demonstrate efficacy in terms of OS in the PD-L1positive subgroup and the 
ITT population.  To detect an improvement in OS with the use of a log-rank test at a 
two-sided significance level of 0.046, approximately 311 deaths in the PD-L1positive
subgroup will be required to achieve 81% power with a target HR of 0.72, and 
approximately 534 deaths in the ITT population to achieve 80% power with a target 
HR of 0.78.  The numbers of patient deaths needed for the OS analyses in the 
PD-L1positive subgroup and the ITT population are listed in Appendix 4 for other 
significance levels that could be assigned to the OS analyses.
There will be no interim analysis for PFS.  The primary analysis of PFS will take place 
when approximately 601 PFS events in the ITT and 347 PFS events in the 
PD-L1positive subgroup have occurred (whichever is later), which is expected at 
approximately 36 months after the first patient is enrolled in the study.  This provides 
90% power to detect a PFS improvement of HR0.7 in the ITT, and 91% power in the 
PD-L1positive subgroup with HR0.62, at a two-sided significance level of 0.002.
Two interim analyses of OS will be performed on patients who are in the ITT and 
PD-L1positive populations.  The timing of the two interim analyses and the final 
analysis for OS depends on the results from the primary analysis of the co-primary 
endpoint of PFS, which is listed in Appendix 4 and includes the pre-specified boundaries 
for the different scenarios.
The calculation of the sample size and estimates of the analysis timelines are based on 
the following assumptions:

PFS and OS are exponentially distributed.

The median duration of PFS in the control arm is 18 months.

The median duration of OS in the control arm is 43 months.

The prevalence of PD-L1positive (IC1/2/3) patients is 60%.

The two interim and final analyses of OS use the Lan-DeMets alpha spending 
function to approximate the O’Brien-Fleming boundary.

The dropout rate is 5% over 12 months for PFS and OS.

The recruitment of 1300 patients will take place over 25 months.
6.2
SUMMARIES OF CONDUCT OF STUDY
Enrollment, major protocol violations such as major deviations of the inclusion and/or 
exclusion criteria, and the discontinuation from the study will be summarized overall and 
by treatment arm for all randomized patients. The reasons for study discontinuation will 
be tabulated.


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6.3
SUMMARIES OF TREATMENT GROUP COMPARABILITY
Demographic variables such as age, sex, race/ethnicity, and baseline characteristics
(including the stratification variables) will be summarized by treatment arm for all
randomized patients. Continuous variables will be summarized with use of means, SDs,
medians, and ranges. Categorical variables will be summarized by proportions.
The baseline value of any variable will be defined as the last available value prior to the 
first administration of the study treatment.
6.4
EFFICACY ANALYSES
The primary efficacy analyses will be performed separately for the ITT population and 
the PD-L1positive subpopulation. For both analyses, patients are grouped according to 
the treatment assigned at randomization.
6.4.1
Primary Efficacy Endpoint
The two co-primary efficacy endpoints of investigator-assessed PFS and OS will be 
tested with the overall type I error controlled at a two-sided level of 0.05. Tests of PFS 
will be simultaneously performed in the ITT population and the PD-L1positive subgroup
at a two-sided alpha of 0.002.  OS will be assessed hierarchically: if the null hypothesis 
to compare OS in the PD-L1positive subgroup is rejected, OS in the ITT population will 
be tested, with a two-sided alpha between 0.046 and 0.05 used in both tests 
(see Section 6.1).  The sequence of the populations to test OS may be inverted from 
PD-L1ITT to ITTPD-L1 depending on data that are external to the study and/or the 
proportion of the patients in the PD-L1 subgroup within the ITT population.  The final 
hierarchical testing sequence for OS and any changes in the statistical design 
specifications that result from this potential change will be described in the SAP prior to 
the first lock of the database for the primary PFS analysis.
The null and alternative hypotheses regarding PFS or OS in the ITT population or 
PD-L1positive subpopulation can be phrased in terms of the survival functions SA(t) and 
SB(t) for Arm A (atezolizumab with paclitaxelcarboplatinbevacizumab) and Arm B
(placebo with paclitaxelcarboplatinbevacizumab), respectively:
H0 : SA(t) SB(t) versus H1 : SA(t) ≠ SB(t)
Progression-Free Survival
PFS is defined as the time from randomization to the occurrence of disease progression, 
as determined by investigators from tumor assessments, per RECIST v1.1, or death 
from any cause, whichever occurs first.  Patients who have not experienced disease 
progression or death at the time of analysis will be censored at the time of the last tumor 
assessment.  Patients with no post-baseline tumor assessment will be censored on the 
date of randomization plus 1 day.


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PFS will be compared between the treatment arms with the use of the stratified log-rank 
test.  The hazard ratio (HR) for disease progression or death will be estimated with the 
use of a stratified Cox proportional hazards model.  The 95% CI for the HR will be
provided.  The stratification factors will be the same as those of the randomization 
stratification factors: stage and/or surgical status (Stage III vs. Stage IV), ECOG 
performance status (0 vs. 1 or 2), tumor PD-L1 status (IC0 vs. IC1/2/3), and treatment 
strategy (adjuvant vs. neoadjuvant).  Results from an unstratified analysis will also be
provided.  The Kaplan-Meier methodology will be applied to estimate the median PFS for 
each treatment arm, and Kaplan-Meier curves will be developed.  The 
Brookmeyer-Crowley methodology will be used to construct the 95% CI for the median 
PFS for each treatment arm.
Overall Survival
OS is defined as the time from the date of randomization to the date of patient death 
from any cause. Patients who are alive at the time of the analysis data cutoff timepoint 
will be censored as of the last date they were known to be alive.  Patients with no 
post-baseline information will be censored as of the date of randomization plus 1 day. 
Analyses of OS are performed analogously to PFS and details are outlined above 
for PFS.
6.4.2
Secondary Efficacy Endpoints
6.4.2.1
Objective Response Rate
An OR is defined as either a confirmed CR or PR as determined by the investigator with 
the use of RECIST v1.1. OR will be assessed only in patients from the primary tumor 
reduction surgery group with measurable residual disease status after primary surgery.  
Patients from the primary cytoreductive surgery group with measurable residual disease 
status but who do not have a confirmed CR or PR (includes patients without a 
post-baseline tumor assessment) will be considered non-responders.  The ORR is 
defined as the proportion of patients with an OR.
The analysis population for ORR will be limited to all randomized patients who undergo 
primary cytoreductive surgery, but have residual measurable disease.  Because of the 
nature of primary tumor reduction surgery for OC patient, most patients will not have 
radiographically-measurable disease but will certainly have gross residual disease, 
which places them at a high risk for cancer recurrence and poor outcomes and makes 
them eligible for the novel treatments in this study.  This study is conducted in the 
front-line, postoperative setting, and the analysis population for the secondary endpoint 
of radiographically-determined ORR will be analyzed for all ITT patients who undergo 
primary tumor reduction surgery and have postoperative radiographically measurable
residual disease.
An estimate of ORR and its 95% CI will be calculated with the use of the 
Clopper-Pearson method for each treatment arm.  CIs for the difference in ORRs 


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between the two treatment arms will be determined with use of the normal approximation 
to the binomial distribution.
6.4.2.2
Duration of Response
Duration of response (DOR) will be assessed in patients from the primary tumor 
reduction surgery group who have residual measurable disease after primary surgery 
and who had an OR as determined by the investigator with the use of RECIST v1.1.  
DOR is defined as the time interval from the date of the first occurrence of a confirmed
CR or PR, whichever status is recorded first, until the first date that progressive disease 
or death is documented, whichever occurs first.  Patients who have not progressed or 
died at the time of the analysis will be censored at the time of the last tumor assessment.  
If no tumor assessments were performed after the date of the first occurrence of a CR or 
PR, DOR will be censored as of the date of the first occurrence of a CR or PR plus 
1 day.  DOR is on the basis of a non-randomized subset of patients (i.e., patients who 
achieved an OR); therefore, formal hypothesis testing will not be performed for this 
endpoint.  Comparisons between the treatment arms will be made for descriptive 
purposes. The methodologies detailed for the PFS analysis will be used for the DOR 
analysis.
6.4.2.3
Patient-Reported Outcomes Disease Symptoms, Function and 
Health-Related Quality of Life EORTC Data
Patient-Reported Abdominal Pain or Bloating and EORTC QLQ-OV28
For patients in the neoadjuvant therapy group, the proportion of patients in each arm 
who report a clinically-meaningful improvement in patient-reported abdominal pain or 
bloating, defined as a 10-point decrease from the baseline score on each of two items 
from the EORTC QLQ-OV28 abdominal/gastrointestinal (GI) symptom scale (items 
31 and 32), will be summarized at each post-baseline timepoint by treatment arm.
The Cochran-Mantel-Haenszel test, stratified by stage and/or residual disease status 
(Stage III vs. Stage IV), ECOG performance status (0 vs. 1 or 2), and tumor PD-L1 
status (IC0 vs. IC1/2/3) will be used to compare the proportion of patients who report a 
clinically-meaningful improvement in patient-reported abdominal pain or bloating at 
9 weeks after neoadjuvant therapy between the two treatment arms.  The difference in 
proportions will be provided, with its 95% CI, with the use of the Hauck-Anderson 
method.
Pre-specified subgroup analysis will also be performed in patients with ascites at 
baseline (who typically have significantly impaired HRQoL) and in patients with sufficient 
symptoms at baseline to allow detection of a 10-point improvement in a given symptom 
score.
The definition of improvement in patient-reported abdominal pain or bloating
(i.e., a 10-point decrease from the baseline score in QLQ-OV28 abdominal symptom 
items) is based on the standard analysis method for the EORTC QLQ-C30 that deems a 


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score change of 10 points on any item or scale to be clinically-meaningful (Osoba et al. 
1998; Fayers 2001a; Osoba 2002; Osoba et al. 2005; Brundage et al. 2007; Luckett et 
al. 2010; Cocks et al. 2011). Although the clinical meaningfulness of a 10-point change 
was established based on the EORTC QLQ-C30, the disease-specific modules, 
including the QLQ-OV28, were designed on the same structure using the same rating 
scale and are, therefore, applicable in this context. Additionally, other OC studies have 
used the 10-point minimally important difference (MID) threshold for the QLQ-OV28, 
demonstrating that a change of this magnitude is significant to patients with OC while 
setting a precedent for its use and supporting its utility in this context (Richter et al. 2012; 
Brotto et al. 2016; Fagotti et al. 2016).
A sensitivity analysis will be performed to evaluate the robustness of the published 
standard threshold for meaningful change of 10-points with the use of the raw data for 
the abdominal pain and bloating items of the EORTC QLQ-OV28. The proportion of 
patients in each arm reporting a 1-category decrease on each of the 4-point symptom 
scales of the EORTC QLQ-OV28 abdominal symptom items (items 31 and 32), will be 
summarized at each post-baseline timepoint by treatment arm. All analyses of the 
abdominal symptoms single item data that involve the 10-point MID will be replicated 
with this alternate MID threshold.
All EORTC QLQ-OV28 data will be scored according to the EORTC scoring manual 
(Fayers et al. 2001b). PRO completion, compliance rates, and reasons for missing data 
will be summarized at each timepoint by treatment arm.
Patient-Reported Function and HRQoL EORTC QLQ-C30
For patients in the neoadjuvant therapy subgroup, the proportion of patients in each arm 
who report a clinically-meaningful improvement in patient-reported function and HRQoL, 
defined as a ≥10-point increase from the baseline score on each of the functional 
(physical, role, emotional, and social) and global health status and/or QoL scales of the 
EORTC QLQ-C30, will be summarized at each post-baseline timepoint by treatment 
arm, and compared between treatment arms with the use of the stratified
Cochran-Mantel-Haenszel test specified above.
For patients in the primary surgery group, the proportion of patients in each arm who 
improve, remain stable or deteriorate in patient-reported functions and HRQoL, defined 
as a 10-point increase, changes within 10 points, and a 10-point decrease, 
respectively, from the baseline score on each of the functional (physical, role, emotional, 
and social) and global health status and/or QoL scales of the EORTC QLQ-C30 will be 
summarized at each post-baseline timepoint by treatment arm, and compared between 
treatment arms with the use of the stratified Cochran-Mantel-Haenszel test specified 
above.
The EORTC QLQ-C30 and QLQ-OV28 will be scored according to the EORTC scoring 
manual (Fayers et al. 2001b). Per Fayers et al. in the event that incomplete data exists, 


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if the scale has more than 50% of the constituent items completed, a pro-rated score will 
be computed.  For subscales with less than 50% of the items completed, the subscale 
will be considered missing. PRO completion, compliance rates, and reasons for missing
data will be summarized at each timepoint by treatment arm and surgery status.
6.4.3
Handling of Missing Data
For PFS, patients without a date of disease progression who have not died will be 
analyzed as censored observations on the date of the last tumor assessment visit.  If no 
post-baseline tumor assessment is available, PFS will be censored as of the date of 
randomization plus 1 day.  In the analysis of PFS for U.S. registration purposes, data for 
patients with a PFS event who missed two or more scheduled assessment visits 
immediately prior to the PFS event will be censored as of the last tumor assessment visit 
prior to the missed visits (see Section 6.4.1).
For OR, patients without a post-baseline assessment will be considered non-responders.
For OS, patients who are not reported as having died will be analyzed as censored 
observations on the date they were last known to be alive.  If no post-baseline data are 
available, OS will be censored as of the date of randomization plus 1 day.
For DOR, patients who have not progressed or died at the time of the analysis will be 
censored on the date of the last tumor assessment visit.  If no tumor assessment visits 
were conducted after the date of the first occurrence of a CR or PR, DOR will be
censored as of the date of the first occurrence of a CR or PR plus 1 day.
For the PRO disease symptom improvement, patient function and HRQoL endpoints, 
patients without a baseline assessment visit or a certain post-baseline assessment visit 
will be considered non-responders.
6.5
SAFETY ANALYSES
Safety analyses will include all patients who received at least one dose of the study
treatment, with patients grouped in accordance with the treatment actually administered.
If a patient receives any dose of atezolizumab, the patient will be included in the 
atezolizumab arm for analysis.
Safety will be assessed through summaries of adverse events, changes in laboratory
test results, changes in vital sign measurements, 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 the MedDRA terms.
Treatment-emergent events, defined as events that occur on or after the administration 
of the first dose of the study treatment will be summarized by MedDRA term, appropriate 
MedDRA levels, and NCI CTCAE v4.0 grade, regardless of the relationship to the study 
drug as assessed by the investigator.  For each patient, if multiple incidences of the 


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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 that lead to the discontinuation of the study drug by the patient

Adverse events that lead to the dose reduction or interruption of the study drug by 
the patient

Grade 3 adverse events

Grade 5 adverse events

Serious adverse events

Adverse events of special interest.
All deaths and causes of death will be summarized.
Relevant laboratory test result values will be summarized over time, with NCI CTCAE 
Grade 3 and Grade 4 values identified where appropriate.  Changes in NCI CTCAE 
grade will be tabulated by treatment arm.
ADA results will be summarized and listed by patient and treatment cycle. The 
immunogenicity analyses will include all patients enrolled in the study with ADA results, 
with patients grouped in accordance to the treatment administered.
The numbers and proportions of patients who are ADA positive and ADA-negative at 
baseline (baseline prevalence) and after baseline (post-baseline incidence) will be 
summarized by treatment group.  At the time of the determination of post-baseline 
incidence, patients are considered ADA positive if they are ADA negative or have 
missing data at baseline but develop an ADA response after study drug exposure 
(treatment-induced ADA response), or if they are ADA positive at baseline and the titer 
of one or more post-baseline samples is at least 0.60 titer units greater than the titer of 
the baseline sample (treatment-enhanced ADA response).  Patients are considered 
ADA negative if they are ADA negative or have missing data at baseline and all 
post-baseline samples are negative, or if they are ADA positive at baseline but do not 
have post-baseline samples with a titer that is at least 0.60 titer units greater than the 
titer of the baseline sample (treatment unaffected).
The relationship between ADA status and safety, efficacy, pharmacokinetics, and 
biomarker endpoints may be analyzed and reported via descriptive statistics.
6.6
PHARMACOKINETIC ANALYSES
PK samples will be collected in this study as outlined in Appendix 3.  Minimum and 
maximum atezolizumab serum concentration data will be tabulated and summarized.  
Descriptive statistics will include means, medians, ranges, and SDs, as appropriate.


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Additional PK and pharmacodynamic analyses will be conducted as appropriate.
6.7
EXPLORATORY ANALYSES
6.7.1
Exploratory Analyses of Progression-Free Survival
6.7.1.1
Non-Protocol-Specified Anti-Cancer Therapy
The impact of non-protocolspecified anti-cancer therapy on PFS will be assessed 
dependent on the number of patients who are administered non-protocolspecified 
anti-cancer therapy before a PFS event.  If 5% of patients were administered a
non-protocolspecified anti-cancer therapy before a PFS event in either treatment arm, a 
sensitivity analysis will be performed for the comparison between treatment arms in 
which patients who are administered non-protocolspecified anti-cancer therapy before 
a PFS event will be censored as of the last tumor assessment visit date before receipt of 
the non-protocolspecified anti-cancer therapy.
6.7.1.2
Sensitivity Analyses
Sensitivity analyses will be conducted to evaluate the potential impact of missing 
scheduled tumor assessment visits by patients on the primary analysis of PFS, as 
determined by the investigator with the use of a PFS event imputation rule.
If a patient misses two or more assessment visits that are scheduled immediately prior to 
the date of the PFS event, there will be two sets of sensitivity analyses conducted. In 
the first set, the patient will be counted as progressed as of the date of the first of these 
missing assessment visits. In the second set, the patient will be censored at the last 
tumor assessment prior to the missed visits.
Statistical methodologies that are analogous to those methodologies used in the primary 
analysis of PFS as specified in Section 6.4 will be applied for this sensitivity analysis.
6.7.2
Pathologic and Clinical Response
The pathologic and clinical response (PCR) status is defined as the extent of residual 
disease assessed at the time of interval cytoreductive surgery (i.e., clinico-pathologic
response).  The PCR status will be determined with clinical parameters that are 
observed at the time of the interval tumor reduction surgery, postoperative radiographic 
findings, and histologic parameters assessed centrally based on the surgical specimens 
from the interval tumor reduction surgery (Samrao et al. 2012; Burger et al. 2015; Nick et 
al. 2015; Fagotti et al. 2016). The analysis will include only the patients from the 
neoadjuvant subgroup.  The PCR status will be summarized for both treatment arms.
The relationship between PCR status and clinical outcome (e.g., PFS, OS, DOR) will be 
examined.
Guidance and examples for histopathologic evaluation of surgical specimens after 
interval cytoreduction are provided in the Ovarian Pathology Handbook and in 
Appendix 13.


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6.7.3
Analysis of Overall Survival at 3 Years
The OS rate at 3 years after randomization will be estimated with the use of the 
Kaplan-Meier methodology for each treatment arm, along with 95% CIs that are 
calculated with use of the standard error derived from Greenwood’s formula.  The 
95% CI for the difference in the OS rate between the two treatment arms will be 
estimated with use of the normal approximation method.
6.7.4
Exploratory Patient-Reported Outcomes Analyses
6.7.4.1
Patient-Reported Outcomes Disease and/or Treatment-Related
SymptomsEORTC Data
Summary statistics (mean, SD, median, and range) of absolute scores and mean 
changes from the baseline will be calculated for all disease and/or treatment-related 
symptom items and subscales of the EORTC QLQ-C30 and QLQ-OV28 at each 
assessment timepoint for each arm during the administration of the treatment and the 
survival follow-up period.  The mean (and 95% CI) and median of the absolute scores 
and the changes from the baseline will be reported for interval and continuous variables.  
Previously-published minimally-important differences will be used to identify meaningful 
change from the baseline within each treatment group on the disease and/or 
treatment-related symptoms scales (Osoba et al. 1998; Cocks et al. 2011).
The EORTC QLQ-C30 and QLQ-OV28 data will be scored according to the 
EORTC scoring manual (Fayers et al. 2001b). In the event of incomplete data, if the 
scale has more than 50% of the constituent items completed, a pro-rated score will be 
computed that is consistent with the scoring manual and the validation papers of the 
measure.  For subscales with less than 50% of the items completed, the subscale will be 
considered missing. PRO completion, compliance rates, and reasons for missing data 
will be summarized at each timepoint by treatment arm and surgery status.
6.7.4.2
FACT-G, GP5 Single Item Data
A descriptive analysis of absolute scores and the proportion of patients who selected
each response option at each assessment visit by treatment arm will be reported for item 
GP5 (“I am bothered by side effects of treatment”) from the FACT-G physical well-being 
subscale.  Item GP5 from Version 4 of the FACT-G questionnaire will be scored 
according to the FACIT scoring manual (Cella 1997).  PRO completion, compliance 
rates, and reasons for missing data will be summarized at each timepoint by treatment 
arm and surgery status.
6.7.4.3
Health Economic Data
Health economic data, as assessed by the EQ-5D-5L, will be evaluated for patients with 
a baseline assessment and at least one post-baseline EQ-5D-5L assessment. The 
results from the health economic data analyses will be reported separately from the 
clinical study report as they will be used in pharmacoeconomic analyses only.


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6.7.5
Exploratory Biomarker Analyses
Exploratory biomarker analyses in tumor tissues and plasma, whole blood, or serum will 
be conducted in an effort to understand the association of these markers with the study
drug response, including efficacy and/or adverse events. Results will be presented in a
separate report.
NGS data will be analyzed in the context of this study and explored in aggregate with 
data from other studies to increase researchers’ understanding of disease pathobiology 
and guide the development of new therapeutic approaches.
6.7.6
Subgroup Analyses
To assess the consistency of study results in the subgroups defined by demographic 
and baseline characteristics, PFS and OS in these subgroups will be examined.  
Summaries of PFS and OS, including unstratified HRs estimated with the use of 
Cox proportional hazards models and Kaplan-Meier estimates of the median, will be 
produced separately for each level of the categorical variables.
6.8
INTERIM ANALYSES
6.8.1
Planned Interim Analyses
There are no interim analyses planned for PFS in this study.
A total of three analyses of OS will be conducted:  two interim analyses and one final
analysis.  The timing of the two interim analyses and the final analysis for OS will 
depend on the results from the definitive analysis of the co-primary endpoint of PFS as 
described in Appendix 4.
To control the type I error for OS, the stopping boundaries for the OS interim and final 
analyses are to be computed with use of the Lan-DeMets approximation to the 
O’Brien-Fleming boundary (DeMets and Lan 1994).
6.8.2
Optional Interim Analysis
To adapt to information that may emerge during the course of this study, the Sponsor
may choose to conduct one interim efficacy analysis that includes the analysis of the
co-primary endpoints of PFS and OS before the primary analysis of PFS.  Below are the 
specifications in place to ensure that the study continues to meet the highest standards 
of integrity when an optional interim analysis is conducted.
The Sponsor will remain blinded. The interim analysis will be conducted by an external
statistical group and reviewed by the iDMC. Interactions between the iDMC and Sponsor 
will be carried out as specified in the iDMC Charter.
The decision to conduct the optional interim analysis, along with the rationale, timing,
and statistical details for the analysis, will be documented in the SAP, and the SAP will 
be submitted to the relevant health authorities at least 3 months prior to the conduct of 


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the interim analysis.  The iDMC Charter will document potential recommendations the 
iDMC can make to the Sponsor as a result of the analysis (e.g., terminate the study for 
positive efficacy, or for futility), and the iDMC Charter will be made available to the 
relevant health authorities.
If there is a potential for the study to be terminated for positive efficacy as a result of the
interim analysis, the type I error rate will be controlled to ensure that statistical validity is
maintained.  Specifically, the Lan-DeMets alpha-spending function that approximates the
O’Brien-Fleming boundary will be applied to determine the critical value for terminating 
due to positive efficacy at the interim analysis (DeMets and Lan 1994).  Additional 
criteria to recommend that the study be terminated for positive efficacy may be added to 
the iDMC charter.  If the study continues beyond the interim analysis, the critical value at 
the time of the final analysis would be adjusted accordingly to maintain the 
protocol-specified overall type I error rate, per standard Lan-DeMets methodology.
6.9
CHINA SUBGROUP ANALYSIS
Patients from China enrolled in the global enrollment phase and China extension phase 
will be combined in China subgroup analysis. The objective of the China subgroup
analyses is to assess the efficacy of atezolizumab in combination with 
paclitaxelcarboplatinbevacizumab as measured by PFS and OS in the subset of 
patients from China and to investigate the consistency in the treatment effects between 
the China subpopulation and the global population. 
Based on the current protocol assumptions a clinical cut-off for the China subpopulation
is planned after approximately 76 primary endpoint (PFS) events have occurred in the
ITT population and 43 events in PD-L1positive subgroup of the China subgroup, 
whichever occurs later. Analyses based on the China subgroup will be reported 
separately from the global study. The 76 PFS events in the China subgroup will provide 
an approximately 80% probability of observing at least 50% of the PFS risk reduction 
benefit (HR0.85) compared with that estimated for the global study (HR0.7) in the
ITT population. The 43 PFS events in the PD-L1positive subgroup of China subgroup 
will provide an approximately 81% probability of observing at least 50% of the PFS risk 
reduction benefit (HR 0.81) compared with that estimated for the global study 
(HR0.62) in PD-L1positive subgroup. The CCOD for China subgroup analysis may 
be revisited based on the data maturity from the China subpopulation to ensure a 
desired probability of observing a consistent treatment effect in reducing PFS risk 
estimated from global main study.
PK and ADA samples will not be collected for the patients enrolled in the sites in China.
Further details can be found in the SAP.


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7.
DATA COLLECTION AND MANAGEMENT
7.1
DATA QUALITY ASSURANCE
The Sponsor will be responsible for data management of this study, including quality 
checking of the data.  Data entered manually will be collected via EDC through use of 
eCRFs.  Sites will be responsible for data entry into the EDC system.  In the event of 
discrepant data, the Sponsor will request data clarification from the sites, which the sites 
will resolve electronically in the EDC system.
The Sponsor will produce an EDC Study Specification document that describes the 
quality control process to be performed on the data.  Electronic data will be sent directly 
to the Sponsor, with the use of the Sponsor’s standard procedures to handle and 
process the electronic transfer of these data.
eCRFs and correction documentation will be maintained in the EDC system’s audit trail.  
System backups for data stored by the Sponsor and records retention for the study data 
will be consistent with the Sponsor’s standard procedures.
PRO data will be collected on paper questionnaires.  The data from the questionnaires 
will be entered into the EDC system by site staff.
7.2
ELECTRONIC CASE REPORT FORMS 
eCRFs are to be completed through the use of a Sponsor-designated EDC system.  
Sites will receive training and have access to a manual that details 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 the patient data for his or her site in 
a readable format on a compact disc that must be kept with the study records.  
An acknowledgement of receipt of the compact disc is required.
7.3
SOURCE DATA DOCUMENTATION
Study monitors will perform ongoing source data verification and review to confirm that 
critical protocol data (i.e., source data) that are entered into the eCRFs by authorized 
site personnel are accurate, complete, and verifiable from source documents.
Source documents, whether in paper or electronic format, are those documents 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 test results notes, 
memoranda, PROs, evaluation checklists, pharmacy dispensing records, recorded data 
from automated instruments, copies of transcriptions that are verified and certified as 


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accurate and complete, microfiches, photographic negatives, microfilms or magnetic 
media, X-rays, patient files, and records maintained at pharmacies, laboratories, and 
medico-technical departments involved in the clinical study.
Before the study initiation, the types of source documents that are to be generated will 
be clearly defined in the Trial Monitoring Plan.  This includes any protocol data to be 
entered directly into the eCRFs (i.e., no prior written or electronic record of the data) and 
considered source data.
Source documents that are required to verify the validity and completeness of data 
entered into the eCRFs must not be obliterated or destroyed, but retained per the policy 
for retention of records described in Section 7.5.
To facilitate source data review and verification, the investigators and institutions must
provide the Sponsor with direct access to the applicable source documents and reports 
for study-related monitoring, Sponsor audits, and IRB and/or EC review.  The study site 
must also allow inspection by the applicable health authorities.
7.4
USE OF COMPUTERIZED SYSTEMS
When clinical observations are entered directly into a study site’s computerized medical 
record system (i.e., in lieu of the original hardcopy records), the electronic record can 
serve as the source document if the system has been validated in accordance with the 
health authority requirements that pertain to computerized systems used in clinical 
research.  An acceptable computerized data collection system allows the preservation of 
the original entry of data.  If the 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, the 
name of the person making the change, and the date of the change.
7.5
RETENTION OF RECORDS
Records and documents that pertain to the conduct of this study and the distribution of 
the IMP, including eCRFs, PRO data, ICFs, laboratory test results, and medication 
inventory records, must be retained by the Principal Investigator for a period of 15 years 
after the completion or discontinuation of the study or for the length of time required by 
the 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 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.


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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 on 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 Trial Directive 
(2001/20/EC and applicable local, regional, and national laws.
8.2
INFORMED CONSENT
The Sponsor’s sample ICF and the ancillary sample ICFs, such as a Child’s Informed 
Assent Form or Mobile Nursing ICF if applicable, will be provided to each site.  
If applicable, the forms will be provided in a certified translation of the local language.  
The Sponsor or its designee must review and approve any proposed deviations from the 
Sponsor’s sample ICFs or any alternate consent forms proposed by the site 
(collectively known as the “Consent Forms”) before IRB and/or EC submission.  The final 
IRB and/or EC-approved Consent Forms must be provided to the Sponsor for 
submission to the health authorities according to local requirements.
If applicable, the ICF will contain separate sections for 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 informed 
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 their participation in the study.  The case history or 
clinical records for each patient will document the informed consent process and that 
written informed consent was obtained prior to the participation in the study.
The Consent Forms should be revised whenever there are changes to the study 
procedures or when new information becomes available that may affect the willingness 
of the patient to participate in the study.  The final revised IRB and/or EC-approved 
Consent Forms must be provided to the Sponsor for submission to the health authorities.
Patients must re-consent to the most current version of the Consent Forms or to a 
significant new information and/or findings addendum in accordance with the applicable 


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laws and IRB and/or EC policy during their participation in the study within the adverse 
event reporting period.  For any updated or revised Consent Forms, the case history or 
clinical records for each patient will document the informed consent process and that 
written informed consent was obtained with the use of the updated and/or revised 
Consent Forms for the patient’s 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 a patient 
authorization to allow the 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 patients to authorize the use 
and disclosure of personal health information under the HIPAA regulations, the review, 
approval and other processes outlined above apply except that IRB review and approval 
may not be required per study site policies.
8.3
INSTITUTIONAL REVIEW BOARD OR ETHICS COMMITTEE
This protocol, the ICFs, any information to be provided to the patient, and relevant 
supporting information must be submitted to the IRB and/or EC by the Principal 
Investigator and reviewed and approved by the IRB and/or EC before the study is 
initiated.  In addition, any patient recruitment materials must be approved by the 
IRB and/or EC.
The Principal Investigator is responsible to provide written summaries of the status of the 
study to the IRB and/or EC annually or more frequently in accordance with the 
requirements, policies, and procedures established by the IRB and/or EC.  Investigators 
are also responsible to promptly inform the IRB and/or EC of any protocol amendments 
(see Section 9.6).
In addition to the requirements to report all adverse events to the Sponsor, investigators 
must comply with requirements for reporting serious adverse events to the local health 
authorities and the IRB and/or EC.  Investigators may receive written IND safety reports 
or other safety-related communications from the Sponsor.  Investigators are responsible 
to ensure that such reports are reviewed and processed in accordance with health 
authority requirements and the policies and procedures established by their IRB and/or 
EC, and archived in the site’s study file.
8.4
CONFIDENTIALITY
The Sponsor maintains the confidentiality standards by coding each patient that is 
enrolled in the study through the assignment of a unique patient identification number.  


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This means that patient names are not included in the datasets that are transmitted to 
any Sponsor location.
Patient medical information obtained for this study is confidential and may be disclosed 
only to third parties as permitted by the ICF or separate authorization for the use and 
disclosure of personal health information signed by the patient, unless permitted or 
required by law.
Medical information may be provided to a patient’s personal physician or other 
appropriate medical personnel who are responsible for the patient’s welfare and for 
treatment purposes.
Given the complexity and exploratory nature of biomarker analyses, data derived from 
these analyses will generally not be provided to the study investigators or patients 
unless required by law.  The aggregate results of any conducted research will be 
available in accordance with the effective Roche policy on study data publication 
(see Section 9.5).
Data generated by this study must be available for inspection upon request by the 
representatives of national and local health authorities, Sponsor monitors, 
representatives, and collaborators, and the IRB and/or EC for each study site, as 
appropriate.
8.5
FINANCIAL DISCLOSURE
Investigators will provide the Sponsor with sufficient, accurate financial information in 
accordance with the local regulations to allow the Sponsor to submit complete and 
accurate financial certifications or disclosure statements to the appropriate health 
authorities.  Investigators are responsible to provide information on financial interests 
during the course of the study and for 1 year after the completion of the study 
(i.e., last patient, last visit).
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, ICFs, and documentation of IRB and/or EC and governmental approval.  
In addition, at the end of the study, the investigator will receive the patient data, including 
an audit trail that contains a complete record of all changes made to the 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 the safety of patients 


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and the integrity of the data to the Sponsor and IRB and/or EC in accordance with 
established IRB and/or EC policies and procedures.  The Sponsor will review all protocol 
deviations and assess whether any represent a serious breach of Good Clinical Practice 
guidelines and require reporting to health authorities.  As per the Sponsor's standard 
operating procedures, prospective requests to deviate from the protocol, including 
requests to waive protocol eligibility criteria, are not allowed.
9.3
SITE INSPECTIONS
Site visits will be conducted by the Sponsor or an authorized representative to inspect 
the study data, patients’ medical records, and eCRFs. The investigator will permit 
national and local health authorities; Sponsor monitors, representatives, and 
collaborators; and the IRBs and/or ECs to inspect facilities and records that are relevant 
to this study.
9.4
ADMINISTRATIVE STRUCTURE
This study will be sponsored and managed by F. Hoffmann-La Roche Ltd.  
Approximately 300 sites globally will participate in the study, and approximately
1300 patients will be randomized to the study.
Randomization will occur through the IWRS.  Central facilities will be used for study 
assessments throughout the study (e.g., specified laboratory tests and PK analyses).  
Accredited local laboratories will be used for routine monitoring and local laboratory 
ranges will be collected.
9.5
PUBLICATION OF DATA AND PROTECTION OF 
TRADE SECRETS
Regardless of the outcome of a study, the Sponsor is dedicated to openly providing 
information on the study to healthcare professionals and the public, both at scientific 
congresses and in peer-reviewed journals. The Sponsor will comply with all 
requirements for the publication of the study results.  For more information, refer to the 
Roche Global Policy on Sharing of Clinical Study Information at the following Web site:
www.roche.com/roche_global_policy_on_sharing_of_clinical_study_information.pdf
The results of this study may be published or presented at scientific congresses.  For all 
clinical studies in patients that involve an IMP for which a marketing authorization 
application has been filed or approved in any country, the Sponsor aims to submit a 
journal manuscript that reports on the primary clinical study results within 6 months after 
the availability of the respective Clinical Study Report.  In addition, for all clinical studies 
on patients that involve an IMP for which a marketing authorization application has been 
filed or approved in any country, the Sponsor aims to publish results from the analyses 
of the additional endpoints and exploratory data that are clinically-meaningful and 
statistically sound.


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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 on the basis of the information from 
other studies that may not yet be available to the investigator.
In accordance with the standard editorial and ethical practices, the Sponsor will support 
only the publication of multicenter studies in their entirety, and not as individual center 
data.  In this case, a coordinating investigator will be designated by mutual agreement.
Authorship for publications will be determined by mutual agreement and in line with 
International Committee of Medical Journal Editors authorship requirements.  Any formal 
publication resulting from 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 the data from this study will become and remain the exclusive and 
unburdened property of the Sponsor, except where agreed upon otherwise.
9.6
PROTOCOL AMENDMENTS
Any protocol amendments will be prepared by the Sponsor.  Protocol amendments will 
be submitted to the IRB and/or EC and to regulatory authorities in accordance with the 
local regulatory requirements.
Approval must be obtained from the IRB and/or EC and regulatory authorities as locally 
required before the implementation of any changes, except for those changes that are 
necessary to eliminate an immediate hazard to patients or changes that involve only
logistical or administrative aspects (e.g., change in Medical Monitor or contact 
information).


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10.
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therapy (FACIT) measurement system: Validation of version 4 of the core 
questionnaire. Quality Life Res 1999;8:604.
Wolchok JD, Hoos A, O’Day S, et al. Guidelines for the evaluation of immune therapy 
activity in solid tumors: immune-related response criteria. Clin Cancer Res 
2009;15:741220.
Yang J, Riella LV, Chock S. The novel costimulatory programmed death 
ligand 1/B7.1 pathway is functional in inhibiting alloimmune responses in vivo. 
J Immunol 2011;187:11139.
Yang X, Shen F, Hu W, et al. New ways to successfully target tumor vasculature in 
ovarian cancer. Curr Opin Obstet Gynecol 2015;27:5865.


Atezolizumab—F. Hoffmann-La Roche Ltd
133/Protocol YO39523, Version 8
Appendix 1
Schedule of Assessments for
Patients Who Underwent Primary Surgery
Screening
Concurrent Treatment
Maintenance Treatment
Treatment 
Completion/
Early Terminationa
Post-Treatment 
Follow-up a
Day
–28 
to –1
Day
14 
to –1
Cycle a
Cycle a
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
Within 30days of 
the last dose of the 
study treatment
Q3Mo for 2 yr 
after the treatment 
completion visit, 
then Q6Mo for 
3 yr, then annually
Signed informed 
consent b
x
Demographic data
x
Medical history and 
baseline conditions
x
Complete physical 
examination c
x
Limited physical 
examination d
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
ECOG PS
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Vital signs e
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Adverse events f
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Concomitant 
medications
x g
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Hematologyh
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Urinalysis i
x
Urine proteini
x
x
x
x
x
x
x
x
x
x
x


Appendix 1
Schedule of Assessments for
Patients Who Underwent Primary Surgery (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
134/Protocol YO39523, Version 8
Screening
Concurrent Treatment
Maintenance Treatment
Treatment 
Completion/
Early Terminationa
Post-Treatment 
Follow-up a
Day
–28 
to –1
Day
14 
to –1
Cycle a
Cycle a
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
Within 30days of 
the last dose of the 
study treatment
Q3Mo for 2 yr 
after the treatment 
completion visit, 
then Q6Mo for 
3 yr, then annually
Serum chemistry j
x
x
x 
x
x
x
x
x
x j
x
x j
x
x j
x
x j
x
x j
x
x j
x
x j
x
x j
x j
TSH, free T3, free T4
x
x
x
x
x
x
x
HIV, HBV, HCV 
serology k
x
Urine pregnancy test 
(for patients of 
childbearing potential l
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
PT/INR, aPTT
x
12-lead ECG
x
Radiologic disease 
assessment   m, n, o
x
x
x
x
x
x
x
x
x
Serum CA-125 level p
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
EORTC QLQ-C30, 
QLQ-OV28, EQ-5D-5Lq
x
x
x
x
x
x
x
x
x q
FACT-G, GP5 single 
item r
x
x
x
x
x
x
x
x r
Samples for PK, ADA, 
and biomarkers
See Appendix 3 for Schedule of PK, ADA, and biomarker sampling


Appendix 1
Schedule of Assessments for
Patients Who Underwent Primary Surgery (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
135/Protocol YO39523, Version 8
Screening
Concurrent Treatment
Maintenance Treatment
Treatment 
Completion/
Early Terminationa
Post-Treatment 
Follow-up a
Day
–28 
to –1
Day
14 
to –1
Cycle a
Cycle a
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
Within 30days of 
the last dose of the 
study treatment
Q3Mo for 2 yr 
after the treatment 
completion visit, 
then Q6Mo for 
3 yr, then annually
Optional whole blood 
sample for RBR s
x
Atezolizumab/
placebo administration
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Bevacizumab 
administration
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Paclitaxel administration
x
x
x
x
x
x
Carboplatin 
administration
x
x
x
x
x
x
Screening baseline
FFPE tumor tissue 
block or 20 unstained 
slides t
x
Mandatory FFPE tumor 
tissue specimen at 
disease progression u
x


Appendix 1
Schedule of Assessments for
Patients Who Underwent Primary Surgery (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
136/Protocol YO39523, Version 8
ADAanti-drug antibody; CAcancer antigen; CRcomplete response; CT computed tomography; ECOG PSEastern Cooperative Oncology 
Group performance status; eCRFelectronic Case Report Form; EORTCEuropean Organisation for Research and Treatment of Cancer; 
FACT-GFunctional Assessment of Cancer Therapy-General; FFPEformalin-fixed, paraffin-embedded; HBVhepatitis B virus; HBcAbhepatitis 
B core antibody; HBsAghepatitis B surface antigen; HCVhepatitis C virus; MRImagnetic resonance imaging; PKpharmacokinetic; 
PRpartial response; PROpatient-reported outcome; Q3Moevery 3 months; Q6Moevery 6 months; QLQ-OV28Quality of Life Questionnaire 
Ovarian Cancer Module 28; RECIST Response Evaluation Criteria in Solid Tumors; UPCR urine protein-to-creatinine ratio; yryear.
Note:  Study assessments/cycles may be adjusted slightly to accommodate holidays, vacations, and unforeseen major life events.  Documentation 
to justify this decision should be provided.
a Each cycle is 21 days.  Study drug administration occurs on Day 1 (3 days) of each cycle.  All other events and assessments during the study 
treatment period (Cycle 1 through Cycle 22) must occur within 3 days prior to the administration (e.g., activities/assessments for Cycle 1, except 
the actual drug infusion, must be performed within 3 days before infusion of Cycle 1).  The end of the study treatment or early discontinuation 
visit should occur within 30 days after the last dose of the study treatment is administered.  The post-treatment follow-up visits will occur every 
3 months (21 days) for the first 2 years after the treatment completion visit, then every 6 months (21 days) for 3 years, and then annually 
(21 days). Post-treatment visits can be performed via telephone or clinic visit as indicated by assessment requirements.
b The Informed consent must be obtained prior to any study-specific procedure and within 28 days (7 days) before randomization.
c A complete physical examination should include an evaluation of the patient’s head, eyes, ears, nose, throat, and the cardiovascular, 
dermatological, musculoskeletal, respiratory, gastrointestinal, genitourinary, and neurological systems.  Any abnormality identified at the baseline 
should be recorded on the General Medical History and Baseline Conditions eCRF.
d Limited, symptom-directed physical examinations should be performed at specified visits and as clinically indicated.  Changes from baseline 
abnormalities should be recorded in the patient notes.  New or deteriorated clinically-significant abnormalities should be recorded as adverse 
events on the Adverse Event eCRF.
e Vital signs will include measurements of the respiratory rate, pulse rate, and systolic and diastolic blood pressure while the patient is in a seated 
position, and body temperature.  Vital signs should be measured prior to the first study treatment infusion of the cycle, as clinically indicated, and 
at other specified timepoints as outlined in the schedule of activities.


Appendix 1
Schedule of Assessments for
Patients Who Underwent Primary Surgery (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
137/Protocol YO39523, Version 8
f
All serious adverse events and adverse events of special interest, regardless of their relationship to the study drug, will be reported until 90 days 
after the last dose of the study drug is administered or the initiation of new anti-cancer therapy, whichever occurs first.  All other adverse events, 
regardless of the relationship to the study drug, will be reported until 30 days after the last dose of the study drug is administered or the initiation 
of new anti-cancer therapy, whichever occurs first.  After this period, the investigator should report any serious adverse events that are believed 
to be related to prior study drug treatment.
g Concomitant medications need to be collected within 7 days prior to starting study treatment.
h Hematology consists of CBC, including hemoglobin, WBC count with differential (neutrophils, lymphocytes, eosinophils, monocytes, basophils, 
and other cells), and platelet count.
i
Patients must demonstrate negativity for proteinuria (see Section 4.1.2).  Urine protein is no longer required for patients who discontinue 
bevacizumab for reasons other than proteinuria.  However, for those who discontinue bevacizumab due to proteinuria, urine protein is required 
until proteinuria returns to baseline or until the end of the study, whichever occurs first.
j
Serum chemistry includes BUN, creatinine, sodium, potassium, magnesium, calcium, glucose, total bilirubin, ALT, AST, ALP, and albumin.  
Serum chemistry eligibility must be confirmed during the screening period before randomization.  After Cycle 1, serum magnesium may be 
performed as clinically indicated.  Serum chemistry samples performed during the maintenance phase and at treatment discontinuation may be 
performed at each cycle, instead of every other cycle, in accordance to country-specific health authority mandates (e.g., Spain).
k All patients will be tested for HIV infection prior to enrollment into the study, and HIV-positive patients will be excluded from the study.  All 
patients will be tested for HBsAg and total HBcAb at the baseline.  If a patient has a negative HBsAg test and a positive total HBcAb test at 
screening, an HBV DNA test must also be performed to determine if the patient has an HBV infection.  If a patient has a positive HCV antibody 
test at screening, an HCV RNA test must also be performed to determine if the patient has an HCV infection.
l
Urine pregnancy tests beyond Cycle 1 for Cycles 222, at treatment discontinuation, and at 3 and 6 months after treatment discontinuation must 
be performed in accordance to country-specific health authority mandates (e.g., Spain, Norway, Czech Republic, Poland, Germany, and 
Belgium).


Appendix 1
Schedule of Assessments for
Patients Who Underwent Primary Surgery (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
138/Protocol YO39523, Version 8
m All radiographic assessments will be performed according to the time interval (e.g., 9 weeks, 12 weeks, etc.) with the corresponding windows per 
Section 4.5.5 regardless of the treatment cycle.  For patients who have had primary tumor reductive surgery, an initial CT scan or MRI of at least 
the chest, abdomen, and pelvis is required to establish postsurgical (i.e., primary cytoreductive surgery) baseline of the extent of residual 
disease within 28 days prior to randomization.  In the absence of disease progression, imaging that uses the same modality and encompasses 
the same field as in the initial pre-treatment evaluation should be repeated (1) every 9 weeks during the concurrent treatment phase, (2) every 
12 weeks in the maintenance phase (the first scan in the maintenance phase is performed 12 weeks after the last scan in the concurrent 
treatment phase), (3) every 3 months for the first 2 years after completion of all protocol therapy, (4) and then every 6 months for the next 
3 years, regardless of whether the patient showed measurable disease on the initial CT or MRI.  CT scans or MRIs after 5 years of survival 
follow-up may be done, as clinically indicated.  Head/neck imaging at screening is dictated by clinical judgment.  If a tumor assessment is 
performed within 30 days prior to the scan scheduled at the treatment completion/early termination visit, then a specific treatment 
completion/early termination tumor assessment does not need to be performed.
n A CT scan or MRI of at least the patient’s chest, abdomen, and pelvis is required to establish the postsurgical (i.e., primary cytoreductive 
surgery) baseline for the extent of residual disease within 28 days prior to the initiation of study treatment (Scan 1).
o Follow-Up Radiographic Assessment of Disease:  In the absence of disease progression and/or allergic reaction to IV contrast, imaging with the 
same modality and field as the initial pretreatment evaluation should be repeated at the following time intervals (i.e., 9 weeks, 12 weeks, etc.) 
with the corresponding windows per Section 4.5.5 regardless whether the patient had measurable disease on the initial CT or MRI and 
regardless of the treatment cycle.
Scans 2 and 3:  Every 9 weeks from randomization during the concurrent treatment phase (approximately after Cycle 3 and Cycle 6, but 
may vary).
Scans 4, 5, 6, and 7:  Every 12 weeks after the last scan during the concurrent treatment phase, which is now during the maintenance 
phase (approximately after Cycle 10, Cycle 14, Cycle 18, and Cycle 22).
After the treatment completion visit, every 3 months for 2 years, then every 6 months for 3 years.  CT scans or MRIs after 5 years of 
survival follow-up may be done, as clinically indicated.


Appendix 1
Schedule of Assessments for
Patients Who Underwent Primary Surgery (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
139/Protocol YO39523, Version 8
p Baseline prechemotherapy value is required.  When available, also include the presurgical value.  CA-125 after 5 years may be done as clinically 
indicated.
q All PRO questionnaires must be completed in their entirety by the patient at the investigational site at the start of the clinic visit before discussion 
of the patient’s health state, laboratory test results, or health records, before the administration of the study treatment, and/or prior to the 
performance of any other study assessments (e.g., scans) that could bias the patient’s responses.
The EORTC QLQ-C30, QLQ-OV28, and EQ-5D-5L questionnaires must be administered and completed by patients in that order at the following 
assessment timepoints during each treatment and post-treatment period:
Concurrent treatment:  At baseline (Cycle 1, Day 1) (3 days), and on Day 1 (3 days) of every other cycle thereafter until 
Cycle 6 (i.e., every 6 weeks)
Maintenance treatment:  At Cycle 8, Day 1 (3 days) and on Day 1 (3 days) of each cycle every 12 weeks thereafter until Cycle 22
Treatment discontinuation or completion:  At the end of the treatment or discontinuation visit within 30 days of the administration of the last 
dose of the study treatment
Post-treatment follow-up:  Patients who discontinue study treatment for progressive disease or loss of clinical benefit or any other reason, 
regardless of receipt of subsequent anti-cancer therapy will complete the PROs after the treatment completion visit, every 3 months 
(21 days) for the first year of the survival follow-up period; every 6 months (21 days) for the second year of the survival follow-up period; 
and every year (21 days) for the final 3 years of the survival follow-up period. Patients in the survival follow-up phase who are unable to 
visit the site in-person due to COVID-19 may complete the PRO questionnaires via phone interview by site staff.
r
The single-item GP5 from the FACT-G questionnaire will be the final measure to be administered and must be completed by patients at the 
following assessment timepoints during each treatment and post-treatment period:
Concurrent treatment:  At Cycle 3, Day 1 (3 days), and on Cycle 5, Day 1 (3 days)
Maintenance treatment:  At Cycle 8, Day 1 (3 days), and on Day 1 (3 days) of each cycle every 12 weeks thereafter until Cycle 22
Treatment discontinuation or completion:  At the end of the treatment or discontinuation visit within 30 days of the administration of the last 
dose of the study treatment
Post-treatment follow-up:  Patients who discontinue study treatment for progressive disease or loss of clinical benefit or any other reason, 
regardless of receipt of subsequent anti-cancer therapy will complete FACT-G GP5 after the treatment completion visit, every 3 months 
(21 days) for the first year of the survival follow-up period; every 6 months (21 days) for the second year of the survival follow-up period; 
every year (21 days) for the final 3 years of the survival follow-up period. Patients in the survival follow-up phase who are unable to visit 
the site in-person due to COVID-19 may complete the PRO questionnaires via phone interview by site staff.


Appendix 1
Schedule of Assessments for
Patients Who Underwent Primary Surgery (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
140/Protocol YO39523, Version 8
s Whole blood for DNA isolation will be collected from patients who have consented to optional RBR sampling at Cycle 1, Day 1. If the RBR 
genetic blood sample is not collected during the scheduled visit, it may be collected after randomization during the clinical study.
t
Tumor tissue should be of good quality based on the total and viable tumor content (sites will be informed if the quality of the submitted 
specimen is inadequate to determine tumor PD-L1 status).  An FFPE block or at least 20 unstained slides should be provided.  Fine-needle 
aspiration, brushing, cell pellets from pleural effusion, lavage samples, and bone metastases are not acceptable.  For core needle biopsy 
specimens, at least three cores (18 gauge minimum) should be submitted for evaluation.  Submission of the screening tumor sample can occur 
outside the 28-day screening period in conjunction with obtaining the informed consent.  Primary surgery must be within 42 days of 
randomization.
u The collection of a sample at disease progression is mandatory if clinically feasible.  Preferably, samples collected at the time of radiographic 
progression should be collected from growing lesions.  An FFPE block or at least 15 unstained slides should be provided.  Fine-needle 
aspiration, brushing, cell pellets from pleural effusion, lavage samples, and bone metastases are not acceptable.  For core needle biopsy 
specimens, at no fewer than two cores (18 gauge minimum) should be submitted for evaluation.


Atezolizumab—F. Hoffmann-La Roche Ltd
141/Protocol YO39523, Version 8
Appendix 2
Schedule of Assessments for
Patients Who Underwent Neoadjuvant Chemotherapy and Interval Surgery
Screening
Concurrent 
Neoadjuvant 
Treatment
Presurgical/
Surgery Visit
Concurrent 
Post-
neoadjuvant 
Treatment
Maintenance Treatment
Completion of 
Treatment/
Early 
Termination
Visit a
Post-
Treatment 
Follow-Up a
Cycle a
Cycle a
Cycle a
Day
–28 
to -1
Day
14 
to –1
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
Within 
30 days of 
last dose of 
study 
treatment
Q3Mo for 2 yr 
after the 
treatment 
completion 
visit, then 
Q6Mo for 3 yr, 
then annually
Written informed 
consent b
x
Demographic data
x
Medical history and 
baseline conditions
x
Complete physical 
examination c
x
Limited physical 
examination d
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
ECOG PS
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Vital signs e
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Adverse eventsf
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Concomitant 
medicationsg
x f
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Hematologyh
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x


Appendix 2
Schedule of Assessments for
Patients who Underwent Neoadjuvant Chemotherapy and Interval Surgery (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
142/Protocol YO39523, Version 8
Screening
Concurrent 
Neoadjuvant 
Treatment
Presurgical/
Surgery Visit
Concurrent 
Post-
neoadjuvant 
Treatment
Maintenance Treatment
Completion of 
Treatment/
Early 
Termination
Visit a
Post-
Treatment 
Follow-Up a
Cycle a
Cycle a
Cycle a
Day
–28 
to -1
Day
14 
to –1
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
Within 
30 days of 
last dose of 
study 
treatment
Q3Mo for 2 yr 
after the 
treatment 
completion 
visit, then 
Q6Mo for 3 yr, 
then annually
Urinalysis i
x
Urine protein i
x
x
x
x
x
x
x
x
x
x
x
Serum chemistry j
x
x
x
x
x
x
x
x
x j
x
x j
x
x j
x
x j
x
x j
x
x j
x
x j
x
x j
x j
TSH, free T3, and 
free T4
x
x
x
x
x
x
x
HIV, HBV, HCV 
serology k
x
Urine pregnancy test 
(if childbearing 
potential exists) l
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
PT/INR, aPTT
x
12-lead ECG
x
Radiographic disease 
assessment m, n
x
x
x
x
x
x
x
x
x
Serum CA-125 level o
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x


Appendix 2
Schedule of Assessments for
Patients who Underwent Neoadjuvant Chemotherapy and Interval Surgery (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
143/Protocol YO39523, Version 8
Screening
Concurrent 
Neoadjuvant 
Treatment
Presurgical/
Surgery Visit
Concurrent 
Post-
neoadjuvant 
Treatment
Maintenance Treatment
Completion of 
Treatment/
Early 
Termination
Visit a
Post-
Treatment 
Follow-Up a
Cycle a
Cycle a
Cycle a
Day
–28 
to -1
Day
14 
to –1
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
Within 
30 days of 
last dose of 
study 
treatment
Q3Mo for 2 yr 
after the 
treatment 
completion 
visit, then 
Q6Mo for 3 yr, 
then annually
EORTC QLQ-C30, 
QLQ-OV28, 
EQ-5D-5L p
x
x
x
x
x
x
x
x
x
x p
FACT-G, GP5 single 
item q
x
x
x
x
x
x
x
x q
Blood samples for 
PK, ADA , and 
biomarkers
See Appendix 3 for schedule of PK, ADA, and biomarker sampling.
Optional whole blood 
sample for RBR
x r
Atezolizumab/
placebo 
administration
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Bevacizumab 
administration
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Paclitaxel 
administration
x
x
x
x
x
x


Appendix 2
Schedule of Assessments for
Patients who Underwent Neoadjuvant Chemotherapy and Interval Surgery (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
144/Protocol YO39523, Version 8
Screening
Concurrent 
Neoadjuvant 
Treatment
Presurgical/
Surgery Visit
Concurrent 
Post-
neoadjuvant 
Treatment
Maintenance Treatment
Completion of 
Treatment/
Early 
Termination
Visit a
Post-
Treatment 
Follow-Up a
Cycle a
Cycle a
Cycle a
Day
–28 
to -1
Day
14 
to –1
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
Within 
30 days of 
last dose of 
study 
treatment
Q3Mo for 2 yr 
after the 
treatment 
completion 
visit, then 
Q6Mo for 3 yr, 
then annually
Carboplatin 
administration
x
x
x
x
x
x
Screening baseline
FFPE tumor tissue 
block or 20 unstained 
slides s
x
Biopsy t
x
FFPE tumor tissue 
sample from surgical 
material
x
Mandatory FFPE 
tumor tissue 
specimen at disease 
progression u
x


Appendix 2
Schedule of Assessments for
Patients who Underwent Neoadjuvant Chemotherapy and Interval Surgery (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
145/Protocol YO39523, Version 8
ADA anti-drug antibody; CAcancer antigen; CRcomplete response; CT computed tomography; ECOG PSEastern Cooperative Oncology 
Group performance status; eCRFelectronic Case Report Form; EORTCEuropean Organisation for Research and Treatment of Cancer; 
FACT-GFunctional Assessment of Cancer Therapy-General; FFPEformalin-fixed, paraffin-embedded; HBVhepatitis B virus; HBcAb hepatitis 
B core antibody; HBsAg hepatitis B surface antigen; HCVhepatitis C virus; MRImagnetic resonance imaging; PKpharmacokinetic; 
PRpartial response; PROpatient-reported outcome; Q3Mo every 3 months; Q6Moevery 6 months;; QLQ-OV28 Quality of Life 
Questionnaire Ovarian Cancer Module 28; RECIST Response Evaluation Criteria in Solid Tumors; UPCR urine protein-to-creatinine ratio; 
yr year.
Note:  Study assessments/cycles may be adjusted slightly to accommodate holidays, vacations, and unforeseen major life events.  Documentation 
to justify this decision should be provided.
a Each cycle is 21 days.  Study drug administration occurs on Day 1 (3 days) of each cycle.  All other events and assessments during the study 
treatment period (Cycle 1 through Cycle 22) must occur within 3 days prior to the administration (e.g., activities/assessments for Cycle 1, except 
the actual drug infusion, must be performed within 3 days before infusion of Cycle 1).  The end of the study treatment or early discontinuation 
visit should occur within 30 days after the last dose of the study treatment is administered.  The post-treatment follow-up visits will occur every 
3 months (21 days) for the first 2 years after the treatment completion visit, then every 6 months (21 days) for 3 years, and then annually 
(21 days). Post-treatment visits can be performed via telephone or clinic visit as indicated by assessment requirements.
b The Informed consent must be obtained prior to any study-specific procedure and within 28 days (7 days) before randomization.
c A complete physical examination should include an evaluation of the patient’s head, eyes, ears, nose, throat, and the cardiovascular, 
dermatological, musculoskeletal, respiratory, gastrointestinal, genitourinary, and neurological systems.  Any abnormality identified at the baseline 
should be recorded on the General Medical History and Baseline Conditions eCRF.
d Limited, symptom-directed physical examinations should be performed at specified visits and as clinically indicated.  Changes from baseline 
abnormalities should be recorded in the patient notes.  New or deteriorated clinically-significant abnormalities should be recorded as adverse 
events on the Adverse Event eCRF.
e Vital signs will include measurements of the respiratory rate, pulse rate, and systolic and diastolic blood pressure while the patient is in a seated 
position, and body temperature.  Vital signs should be measured prior to the first study treatment infusion of the cycle, as clinically indicated, and 
at other specified timepoints as outlined in the schedule of activities.
f
All serious adverse events and adverse events of special interest, regardless of their relationship to the study drug, will be reported until 90 days 
after the last dose of the study drug is administered or the initiation of new anti-cancer therapy, whichever occurs first.  All other adverse events, 
regardless of the relationship to the study drug, will be reported until 30 days after the last dose of the study drug is administered or the initiation 
of new anti-cancer therapy, whichever occurs first.  After this period, the investigator should report any serious adverse events that are believed 
to be related to prior study drug treatment.


Appendix 2
Schedule of Assessments for
Patients who Underwent Neoadjuvant Chemotherapy and Interval Surgery (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
146/Protocol YO39523, Version 8
g Concomitant medications need to be collected within 7 days prior to starting study treatment.
h Hematology consists of CBC, including hemoglobin, WBC count with differential (neutrophils, lymphocytes, eosinophils, monocytes, basophils, 
and other cells), and platelet count.
i
Patients must demonstrate negativity for proteinuria (see Section 4.1.2).  Urine protein is no longer required for patients who discontinue 
bevacizumab for reasons other than proteinuria.  However, for those who discontinue bevacizumab due to proteinuria, urine protein is required 
until proteinuria returns to baseline or until the end of the study, whichever occurs first.
j
Serum chemistry includes BUN, creatinine, sodium, potassium, magnesium, calcium, glucose, total bilirubin, ALT, AST, ALP, and albumin.  
Serum chemistry eligibility must be confirmed during the screening period before randomization.  After Cycle 1, serum magnesium may be 
performed as clinically indicated.  Serum chemistry samples performed during the maintenance phase and at treatment discontinuation may be 
performed at each cycle, instead of every other cycle, in accordance to country-specific health authority mandates (e.g., Spain).
k All patients will be tested for HIV infection prior to enrollment into the study, and HIV-positive patients will be excluded from the study.  All 
patients will be tested for HBsAg and total HBcAb at the baseline.  If a patient has a negative HBsAg test and a positive total HBcAb test at 
screening, an HBV DNA test must also be performed to determine if the patient has an HBV infection.  If a patient has a positive HCV antibody 
test at screening, an HCV RNA test must also be performed to determine if the patient has an HCV infection.
l
Urine pregnancy tests beyond Cycle 1 for Cycles 222, at treatment discontinuation, and at 3 and 6 months after treatment discontinuation must 
be performed in accordance to country-specific health authority mandates  (e.g., Spain, Norway, Czech Republic, Poland, Germany, and Belgium).
m All radiographic assessments will be performed according to the time interval (e.g., 9 weeks, 12 weeks, etc.) with the corresponding windows per 
Section 4.5.5 regardless of the treatment cycle.  The initial CT scan/MRI of at least the patient’s chest, abdomen, and pelvis is required within 
28 days of randomization to establish the first baseline prior to starting neoadjuvant therapy and interval cytoreductive surgery.  A CT scan or 
MRI of at least the patient’s chest, abdomen, and pelvis is required to establish the new baseline (i.e., postsurgical from interval cytoreductive 
surgery) for the extent of residual disease within 14 days prior to re-initiation of study treatment (Scan 3).  CT scans or MRIs after 5 years of 
survival follow-up may be done as clinically indicated.  Head/neck imaging at screening is dictated by clinical judgment.  If a tumor assessment is 
performed within 30 days prior to the scan scheduled at the treatment completion/early termination visit, then a specific treatment 
completion/early termination tumor assessment does not need to be performed.


Appendix 2
Schedule of Assessments for
Patients who Underwent Neoadjuvant Chemotherapy and Interval Surgery (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
147/Protocol YO39523, Version 8
n Follow-Up Radiographic Assessment of Disease:  In the absence of disease progression and/or allergic reaction to IV contrast, imaging with the 
same modality and field as the initial pretreatment evaluation should be repeated at the following time intervals (i.e., 9 weeks, 12 weeks, etc.) 
with the corresponding windows per Section 4.5.5 regardless whether the patient had measurable disease on the initial CT or MRI and 
regardless of the treatment cycle:
Concurrent treatment phase Scan 2: 9 weeks from randomization during the concurrent treatment phase (approximately end of Cycle 3).
Scan 3:  postsurgical scan done after interval cytoreductive surgery and as close as possible (within 14 days) to starting Cycle 4 during the 
concurrent treatment phase. 
Scan 4:  9 weeks from Scan 3 (i.e., postsurgical scan done after interval cytoreductive surgery) during the concurrent treatment phase 
(approximately end of Cycle 6).  Tumor assessment scans during the concurrent treatment phase must be done every 9 weeks, regardless 
of treatment cycle.
Maintenance phase Scans 5, 6, and 7:  Every 12 weeks after the last scan during the concurrent treatment phase, which is now during the 
maintenance phase (approximately after Cycle 10, Cycle 14, Cycle 18, and Cycle 22).
After the treatment completion visit, every 3 months for 2 years, then every 6 months for 3 years.  CT scans or MRIs after 5 years of 
survival follow-up may be done, as clinically indicated.
o Baseline prechemotherapy value is required.  When available, also include the presurgical value.  CA-125 after 5 years may be done as clinically 
indicated.
p All PRO questionnaires must be completed in their entirety by the patient at the investigational site at the start of the clinic visit before discussion 
of the patient’s health state, laboratory test results, or health records, before the administration of the study treatment, and/or prior to the 
performance of any other study assessments (e.g., scans) that could bias the patient’s responses.
The EORTC QLQ-C30, QLQ-OV28, and EQ-5D-5L questionnaires must be administered and completed by patients in that order at the following 
assessment timepoints during each treatment and post-treatment period:
Concurrent Treatment:  At baseline (Cycle 1, Day 1) (± 3 days); post Cycle 3/pre-Interval Surgery visit (± 3 days); post-Interval Surgery at 
Cycle 4, Day 1 (±3 days); Cycle 6, Day 1 (± 3 days)
Maintenance Treatment:  At Cycle 8, Day 1 (± 3 days) and on Day 1 (± 3 days) of each cycle every 12 weeks thereafter until Cycle 22
Treatment Discontinuation or completion: At the end of treatment or discontinuation visit within 30 days of the administration of the last 
dose of the study treatment


Appendix 2
Schedule of Assessments for
Patients who Underwent Neoadjuvant Chemotherapy and Interval Surgery (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
148/Protocol YO39523, Version 8
Post-Treatment Follow-up:  Patients who discontinue study treatment for progressive disease or loss of clinical benefit or any other reason, 
regardless of receipt of subsequent anti-cancer therapy will complete the PROs after the treatment completion visit, every 3 months 
(21 days) for the first year of the survival follow-up period; every 6 months (21 days) for the second year of the survival follow-up period; 
and every year (21 days) for the final 3 years of the survival follow-up period. Patients in the survival follow-up phase who are unable to 
visit the site in-person due to COVID-19 may complete the PRO questionnaires via phone interview by site staff.
q The single-item GP5 from the FACT-G questionnaire will be the final measure to be administered and must be completed by patients at the 
following assessment timepoints during each treatment and post-treatment period:
Concurrent treatment:  At the post Cycle 3/pre-Interval Surgery visit (3 days), and on Cycle 6, Day 1 (3 days)
Maintenance treatment:  At Cycle 8, Day 1 (3 days), and on Day 1 (3 days) of each cycle every 12 weeks thereafter until Cycle 22
Treatment discontinuation or completion:  At the end of the treatment or discontinuation visit within 30 days of the administration of the last 
dose of the study treatment
Post-treatment follow-up:  Patients who discontinue study treatment for progressive disease or loss of clinical benefit or any other reason, 
regardless of receipt of subsequent anti-cancer therapy will complete FACT-G GP5 after the treatment completion visit, every 3 months 
(21 days) for the first year of the survival follow-up period; every 6 months (21 days) for the second year of the survival follow-up period; 
every year (21 days) for the final 3 years of the survival follow-up period. Patients in the survival follow-up phase who are unable to visit the 
site in-person due to COVID-19 may complete the PRO questionnaires via phone interview by site staff.
r
Whole blood for DNA isolation will be collected from patients who have consented to optional RBR sampling at Cycle 1, Day 1.  If the RBR 
genetic blood sample is not collected during the scheduled visit, it may be collected after randomization during the clinical study.
s Tumor tissue should be of good quality based on the total and viable tumor content (sites will be informed if the quality of the submitted 
specimen is inadequate to determine tumor PD-L1 status).  An FFPE block or at least 20 unstained slides should be provided.  Fine-needle 
aspiration, brushing, cell pellets from pleural effusion, lavage samples, and bone metastases are not acceptable.  For core needle biopsy 
specimens, at least three cores (18 gauge minimum) should be submitted for evaluation.  Submission of the screening tumor sample from 
needle core biopsy or laparoscopy can occur outside the 28-day screening period in conjunction with obtaining the informed consent.
t
For patients who are enrolled in the biomarker cohort; tumor biopsy samples should be collected by core needle (18 gauge minimum) or 
excisional biopsy at Cycle 1, Day 15.  Three cores per paraffin block should be submitted for analysis.
u The collection of a sample at disease progression is mandatory if clinically feasible.  Preferably, samples collected at the time of radiographic 
progression should be collected from growing lesions.  An FFPE block or at least 15 unstained slides should be provided.  Fine-needle 
aspiration, brushing, cell pellets from pleural effusion, lavage samples, and bone metastases are not acceptable.  For core needle biopsy 
specimens, at no fewer than two cores (18 gauge minimum) should be submitted for evaluation.


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Appendix 3
Schedule of Pharmacokinetic, Immunogenicity, and Biomarker Samples a
Sample Type
Visit
Timepoint
Patients who undergo primary surgery
Patients who undergo NACT interval surgery
(and, where applicable, the biomarker
cohort only; n100)
Screening
(Day 28 to Day 1)



Randomization

Atezolizumab/placebo biomarker (tissue)
Atezolizumab/placebo biomarker (tissue)
Cycle 1, Day 1
Prior to the first infusion (up to 
24 hours prior)
Atezolizumab/placebo pharmacokinetics (serum) b
Atezolizumab/placebo ADA (serum) b
Atezolizumab/placebo biomarker (blood, plasma c)
Atezolizumab/placebo pharmacokinetics (serum) b
Atezolizumab/placebo ADA (serum) b
Atezolizumab/placebo biomarker (blood, plasma c)
30 minutes (15 minutes) after 
end of infusion
Atezolizumab/placebo pharmacokinetics (serum) b
Atezolizumab/placebo pharmacokinetics (serum) b
Cycle 1, Day 15


Atezolizumab/placebo biomarker (tissue) 
(biomarker cohort only; n100) 
Atezolizumab/placebo biomarker (plasma c) 
(biomarker cohort only; n100) 
Cycle 2
Prior to the first infusion (up to 
24 hours prior)
Atezolizumab/placebo pharmacokinetics (serum) b
Atezolizumab/placebo ADA (serum) b
Atezolizumab/placebo biomarker (plasma c)
Atezolizumab/placebo pharmacokinetics (serum) b
Atezolizumab/placebo ADA (serum) b
Atezolizumab/placebo biomarker (plasma c)
Cycle 3
Prior to the first infusion (up to 
24 hours prior)
Atezolizumab/placebo pharmacokinetics (serum) b
Atezolizumab/placebo ADA (serum) b
Atezolizumab/placebo pharmacokinetics (serum) b
Atezolizumab/placebo ADA (serum) b
30 minutes (15 minutes) after 
the end of infusion
Atezolizumab/placebo pharmacokinetics (serum) b
Atezolizumab/placebo pharmacokinetics (serum) b


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Appendix 3
Schedule of Pharmacokinetic, Immunogenicity, and Biomarker Samples a (cont.)
Sample Type
Visit
Timepoint
Patients who undergo primary surgery
Patients who undergo NACT interval surgery
(and, where applicable, the biomarker
cohort only; n100)
Cycle 4
Prior to the first infusion (up to 
24 hours prior)
Atezolizumab/placebo pharmacokinetics (serum) b
Atezolizumab/placebo ADA (serum) b
Atezolizumab/placebo biomarker (plasma c, d)
Atezolizumab/placebo pharmacokinetics (serum) b
Atezolizumab/placebo ADA (serum) b
Atezolizumab/placebo biomarker (plasma c, d)
Cycle 8 and 
Cycle 16
Prior to the first infusion (up to 
24 hours prior)
Atezolizumab/placebo pharmacokinetics (serum) b
Atezolizumab/placebo ADA (serum) b

At surgical visit


Atezolizumab/placebo biomarker (tissue) 
Atezolizumab/placebo biomarker (plasma c, d) 
At disease 
progressione

Atezolizumab/placebo biomarker
(tissue, plasma c, d)
Atezolizumab/placebo biomarker
(tissue, plasma c, d)
Treatment
discontinuation/
completion visit f
(24 hours)
Atezolizumab/placebo pharmacokinetics (serum) b
Atezolizumab/placebo ADA (serum) b
Atezolizumab/placebo biomarker (plasma c, d)
Atezolizumab/placebo pharmacokinetics (serum) b
Atezolizumab/placebo ADA (serum) b
90 days after last 
dose of 
atezolizumabh
(1 weekg)
Atezolizumab/placebo pharmacokinetics (serum) b
Atezolizumab/placebo ADA (serum) b
Atezolizumab/placebo pharmacokinetics (serum) b
Atezolizumab/placebo ADA (serum) b


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Appendix 3
Schedule of Pharmacokinetic, Immunogenicity, and Biomarker Samples a (cont.)
ADA anti-drug antibody; NACT neoadjuvant chemotherapy.
Note:  Study assessments/cycles may be adjusted slightly to accommodate holidays, vacations, and unforeseen major life events.  Documentation to 
justify this decision should be provided.
a Pharmacokinetic and ADA samples will not be collected for the patients enrolled in the sites in China.
b Patients who discontinue atezolizumab/placebo no longer need to provide pharmacokinetics/ADA samples.
c EDTA plasma.
d This may include WGS and/or RBR samples.  Refer to the laboratory manual for details.
e Samples should be collected from either RECIST progression or investigators-determined clinical progression
f
Patients who complete the study treatment period will return to the clinic for a treatment completion visit at 30 days from the administration of the last 
dose of the study drug.  Patients who discontinue the study drug prematurely will return to the clinic for a treatment discontinuation visit 30 days after 
the administration of the last dose of the study drug.  The visit at which the response assessment shows progressive disease may be designated as 
the treatment discontinuation visit.
g Samples greater than one week are acceptable.
h Can be combined with the Month 3 Survival Follow-Up visit when appropriate. 


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Appendix 4
Interim and Final Analyses for Overall Survival
Different Scenarios
of PFS Testing
Alpha 
Level
OS Analysis 
Type
Time from 
(months)
Information
Fraction (%)
No. of 
Events
Stopping 
Boundary (HR)
Stopping Boundary 
(p-value)
PFS is not 
statistically 
significant in either 
PD-L1or ITT
0.046
1st IA
36
60
187
320
0.6728
0.7382
0.0066
2nd IA
45
80
249
427
0.7447
0.7984
0.0200
FA
56
100
311
534
0.7913
0.8364
0.0390
PFS is statistically 
significant in either 
PD-L1or ITT, but 
not both
0.048
1st IA
36
60
185
317
0.6734
0.7393
0.0072
2nd IA
45
80
246
422
0.7449
0.7987
0.0209
FA
56
100
308
528
0.7920
0.8368
0.0407
PFS is statistically 
significant in both 
PD-L1and ITT
0.050
1st IA
35
60
182
313
0.6729
7395
0.0075
2nd IA
44
80
243
418
0.7455
0.7995
0.0220
FA
55
100
304
522
0.7922
0.8371
0.0423
FAfinal analysis, FPfirst patient in; HRhazard ratio; IAinterim analysis, ITTintent-to-treat; OSoverall survival; 
PFSprogression-free survival.


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Appendix 5
European Organisation for Research and Treatment of Cancer 
Quality of Life Questionnaires
Do not reproduce or distribute.  The Sponsor will provide sites with all instruments to be 
completed in this study.
Table 1
Quality of Life Questionnaire Core 30


Appendix 5
European Organisation for Research and Treatment of Cancer 
Quality of Life Questionnaires (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
154/Protocol YO39523, Version 8
Table 1
Quality of Life Questionnaire Core 30 (cont.)


Appendix 5
European Organisation for Research and Treatment of Cancer 
Quality of Life Questionnaires (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
155/Protocol YO39523, Version 8
Table 2
Quality of Life Questionnaire Ovarian Cancer Module 28


Appendix 5
European Organisation for Research and Treatment of Cancer 
Quality of Life Questionnaires (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
156/Protocol YO39523, Version 8
Table 2
Quality of Life Questionnaire Ovarian Cancer Module 28 (cont.)


Atezolizumab—F. Hoffmann-La Roche Ltd
157/Protocol YO39523, Version 8
Appendix 6 Patient Questionnaire EQ-5D-5L
Do not reproduce or distribute.  The Sponsor will provide sites with all instruments to be 
completed in this study.


Appendix 6 Patient Questionnaire EQ-5D-5L (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
158/Protocol YO39523, Version 8


Atezolizumab—F. Hoffmann-La Roche Ltd
159/Protocol YO39523, Version 8
Appendix 7 Preexisting Autoimmune Diseases and Immune 
Deficiencies
Study patients should be carefully questioned regarding their history of acquired or 
congenital immune deficiencies or autoimmune disease.  Subjects with any history of 
immune deficiencies or autoimmune disease listed in the table are excluded from 
participating in the study.  Possible exceptions to this exclusion could be subjects with a 
medical history of entities such 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 enrollment in this study.  In addition, transient autoimmune 
manifestations of an acute infectious disease that resolved upon treatment of the 
infectious agent (e.g., acute Lyme arthritis) are not excluded from the study.  Caution 
should be used when considering atezolizumab for patients who have previously 
experienced a severe or life-threatening skin adverse reaction while receiving another 
immunostimulatory anti-cancer agent.  The Medical Monitor is available to advise on any 
uncertainty over autoimmune exclusions.


Appendix 7
Preexisting Autoimmune Diseases and Immune Deficiencies
(cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
160/Protocol YO39523, Version 8
Table 1
Autoimmune Diseases and Immune Deficiencies
Acute disseminated 
encephalomyelitis
Addison disease
Ankylosing spondylitis
Antiphospholipid antibody 
syndrome
Aplastic anemia
Autoimmune hemolytic 
anemia
Autoimmune hepatitis
Autoimmune 
hypoparathyroidism
Autoimmune hypophysitis
Autoimmune myocarditis
Autoimmune oophoritis
Autoimmune orchitis
Autoimmune 
thrombocytopenic purpura
Behçet disease
Bullous pemphigoid
Chronic fatigue syndrome
Chronic inflammatory 
demyelinating 
polyneuropathy
Churg-Strauss syndrome
Crohn disease 
Dermatomyositis
Diabetes mellitus type 1
Dysautonomia
Epidermolysis bullosa 
acquisita
Gestational pemphigoid
Giant cell arteritis
Goodpasture syndrome
Graves disease
Guillain-Barré syndrome
Hashimoto disease
IgA nephropathy
Inflammatory bowel disease
Interstitial cystitis
Kawasaki disease
Lambert-Eaton myasthenia 
syndrome
Lupus erythematosus
Lyme disease - chronic
Meniere syndrome
Mooren ulcer
Morphea
Multiple sclerosis
Myasthenia gravis
Neuromyotonia
Opsoclonus myoclonus 
syndrome
Optic neuritis
Ord thyroiditis
Pemphigus
Pernicious anemia
Polyarteritis nodosa
Polyarthritis
Polyglandular autoimmune 
syndrome
Primary biliary cholangitis
Psoriasis
Reiter syndrome
Rheumatoid arthritis
Sarcoidosis
Scleroderma
Sjögren’s syndrome
Stiff-Person syndrome
Takayasu arteritis
Ulcerative colitis
Vitiligo
Vogt-Koyanagi-Harada 
disease
Wegener granulomatosis


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Appendix 8 Anaphylaxis Precautions
These guidelines are intended as a reference and should not supersede pertinent local 
or institutional standard operating procedures.
REQUIRED EQUIPMENT AND MEDICATION
The following equipment and medication are needed in the event of a suspected 
anaphylactic reaction during study treatment administration in a clinical setting:

Monitoring devices:  ECG monitor, blood pressure monitor, oxygen saturation 
monitor, and thermometer

Oxygen

Epinephrine for subcutaneous, IV, and/or endotracheal use in accordance with 
standard practice

Antihistamines

Corticosteroids

Intravenous infusion solutions, tubing, catheters, and tape
PROCEDURES
In the event that a patient suffers a suspected anaphylactic reaction during a 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 as required by the 
patient’s status and directed by the physician in charge.
6. Continue to observe the patient and document observations.


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162/Protocol YO39523, Version 8
Appendix 9
Management of Atezolizumab-Specific Adverse Events
DOSE MODIFICATIONS
There will be no dose modifications for atezolizumab in this study.
TREATMENT INTERRUPTION
Atezolizumab treatment may be temporarily suspended in patients experiencing toxicity 
considered to be related to study treatment. If corticosteroids are initiated for treatment 
of the toxicity, they must be tapered over 1 month to the equivalent of 10 mg/day oral 
prednisone before atezolizumab can be resumed.  If atezolizumab is withheld for 
12 weeks after event onset, the patient will be discontinued from atezolizumab.  
However, atezolizumab may be withheld for 12 weeks to allow for patients to taper off 
corticosteroids prior to resuming treatment.  Atezolizumab can be resumed after being 
withheld for 12 weeks if the patient is likely to derive clinical benefit.  The decision to 
re-challenge patients with atezolizumab should be based on the investigator's 
assessment of benefit-risk and documented by the investigator.  The Medical Monitor is 
available to advise as needed.  Atezolizumab treatment may be suspended for reasons 
other than toxicity (e.g., surgical procedures).  The acceptable length of treatment 
interruption must be based on an assessment of benefit-risk by the investigator and in 
alignment with the protocol requirements for the duration of treatment and documented 
by the investigator.  The Medical Monitor is available to advise as needed.
MANAGEMENT GUIDELINES
Toxicities associated or possibly associated with atezolizumab treatment should be 
managed according to standard medical practice.  Additional tests, such as autoimmune 
serology or biopsies, should be used to evaluate for a possible immunogenic etiology, 
when clinically indicated.
Although most immune-mediated adverse events observed with atezolizumab have 
been mild and limiting, such events should be recognized early and treated promptly to 
avoid potential major complications.  Discontinuation of atezolizumab may not have an 
immediate therapeutic effect, and in severe cases, immune-mediated toxicities may 
require acute management with topical corticosteroids, systemic corticosteroids, or other 
immunosuppressive agents. 
The investigator should consider the benefitrisk balance a given patient may be 
experiencing prior to further administration of atezolizumab.  In patients who have met 
the criteria for permanent discontinuation, resumption of atezolizumab may be 
considered if the patient is deriving benefit and has fully recovered from the 
immune-mediated event. The decision to re-challenge patients with atezolizumab should 
be based on investigator's assessment of benefitrisk and documented by the 


Appendix 9
Management of Atezolizumab-Specific Adverse Events (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
163/Protocol YO39523, Version 8
investigator (or an appropriate delegate).  The Medical Monitor is available to advise as 
needed.
PULMONARY EVENTS
Dyspnea, cough, fatigue, hypoxia, pneumonitis, and pulmonary infiltrates have been 
associated with the administration of atezolizumab.  Patients will be assessed for 
pulmonary signs and symptoms throughout the study and will also have computed 
tomography (CT) scans of the chest performed at every tumor assessment.
All pulmonary events should be thoroughly evaluated for other commonly reported 
etiologies such as pneumonia or other infection, lymphangitic carcinomatosis, pulmonary 
embolism, heart failure, chronic obstructive pulmonary disease, or pulmonary 
hypertension.  Management guidelines for pulmonary events are provided in Table 1.


Appendix 9
Management of Atezolizumab-Specific Adverse Events (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
164/Protocol YO39523, Version 8
Table 1
Management Guidelines for Pulmonary Events, Including 
Pneumonitis
Event
Management
Pulmonary 
event, Grade 1 

Continue atezolizumab and monitor closely.

Re-evaluate on serial imaging.

Consider patient referral to pulmonary specialist.

For Grade 1 pneumonitis, consider withholding atezolizumab.
Pulmonary 
event, Grade 2

Withhold atezolizumab for up to 12 weeks after event onset. a

Refer patient to pulmonary and infectious disease specialists and 
consider bronchoscopy or BAL.

Initiate treatment with corticosteroids equivalent to 12 mg/kg/day 
oral prednisone 

If event resolves to Grade 1 or better, resume atezolizumab. b

If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and contact 
Medical Monitor. cFor recurrent events, or events with no 
improvement after 48-72 hours of corticosteroids, treat as a 
Grade 3 or 4 event.
Pulmonary 
event, Grade 3 
or 4

Permanently discontinue atezolizumab and contact Medical 
Monitor. c

Bronchoscopy or BAL is recommended.

Initiate treatment with corticosteroids equivalent to 12 mg/kg/day 
IV methylprednisolone.

If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent.

If event resolves to Grade 1 or better, taper corticosteroids over 
1 month.
BALbronchoscopic alveolar lavage.
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after event 
onset) to allow for corticosteroids (if initiated) to be reduced to 10 mg/day oral 
prednisone or equivalent.  The acceptable length of the extended period of time must
be based on an assessment of benefit-risk by the investigator and in alignment with 
the protocol requirements for the duration of treatment and documented by the 
investigator. The Medical Monitor is available to advise as needed.
b If corticosteroids have been initiated, they must be tapered over 1 month to 
10 mg/day oral prednisone or equivalent before atezolizumab can be resumed.
c Resumption of atezolizumab may be considered in patients who are deriving benefit 
and have fully recovered from the immune-mediated event.  The decision to 
re-challenge patients should be based on investigator's assessment of benefit-risk and 
documented by the investigator (or an appropriate delegate). The Medical Monitor is 
available to advise as needed.


Appendix 9
Management of Atezolizumab-Specific Adverse Events (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
165/Protocol YO39523, Version 8
HEPATIC EVENTS
Immune-mediated hepatitis has been associated with the administration of 
atezolizumab.  Eligible patients must have adequate liver function, as manifested by 
measurements of total bilirubin and hepatic transaminases, and liver function will be 
monitored throughout study treatment.  Management guidelines for hepatic events are 
provided in Table 2.
Patients with right upper-quadrant abdominal pain and/or unexplained nausea or 
vomiting should have liver function tests (LFTs) performed immediately and reviewed 
before administration of the next dose of study drug.
For patients with elevated LFTs, concurrent medication, viral hepatitis, and toxic or 
neoplastic etiologies should be considered and addressed, as appropriate.
Table 2
Management Guidelines for Hepatic Events
Event
Management
Hepatic event, 
Grade 1

Continue atezolizumab.

Monitor LFTs until values resolve to within normal limits or to baseline 
values. 
Hepatic event, 
Grade 2
All events:

Monitor LFTs more frequently until return to baseline values. 
Events of 5 days’ duration:

Withhold atezolizumab for up to 12 weeks after event onset. a

Initiate treatment with corticosteroids equivalent to 12 mg/kg/day oral 
prednisone.If event resolves to Grade 1 or better, resume 
atezolizumab. b

If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and contact 
Medical Monitor. c
LFTliver function test.
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after event 
onset) to allow for corticosteroids (if initiated) to be reduced to 10 mg/day oral 
prednisone or equivalent.  The acceptable length of the extended period of time must be 
based on an assessment of benefit-risk by the investigator and in alignment with the 
protocol requirements for the duration of treatment and documented by the investigator.  
The Medical Monitor is available to advise as needed.
b If corticosteroids have been initiated, they must be tapered over 1 month to the 
equivalent of 10 mg/day oral prednisone before atezolizumab can be resumed.
c Resumption of atezolizumab may be considered in patients who are deriving benefit and 
have fully recovered from the immune-mediated event. The decision to re-challenge 
patients with atezolizumab should be based on investigator's assessment of benefit-risk 
and documented by the investigator (or an appropriate delegate).  The Medical Monitor is 
available to advise as needed.


Appendix 9
Management of Atezolizumab-Specific Adverse Events (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
166/Protocol YO39523, Version 8
Table 2
Management Guidelines for Hepatic Events (cont.)
Event
Management
Hepatic event, 
Grade 3 or 4

Permanently discontinue atezolizumab and contact Medical Monitor. c

Consider patient referral to gastrointestinal specialist for evaluation 
and liver biopsy to establish etiology of hepatic injury. 

Initiate treatment with corticosteroids equivalent to 12 mg/kg/day oral 
prednisone.

If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent.

If event resolves to Grade 1 or better, taper corticosteroids over 
1 month.
LFTliver function test.
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after event 
onset) to allow for corticosteroids (if initiated) to be reduced to 10 mg/day oral prednisone 
or equivalent.  The acceptable length of the extended period of time must be based on an 
assessment of benefit-risk by the investigator and in alignment with the protocol 
requirements for the duration of treatment and documented by the investigator.  The 
Medical Monitor is available to advise as needed.
b If corticosteroids have been initiated, they must be tapered over 1 month to 10 mg/day 
oral prednisone or equivalent before atezolizumab can be resumed.
c Resumption of atezolizumab may be considered in patients who are deriving benefit and 
have fully recovered from the immune-mediated event.  The decision to re-challenge 
patients with atezolizumab should be based on investigator's assessment of benefit-risk 
and documented by both the investigator (or an appropriate delegate). The Medical 
Monitor is available to advise as needed.
GASTROINTESTINAL EVENTS
Immune-mediated colitis has been associated with the administration of atezolizumab.  
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. 


Appendix 9
Management of Atezolizumab-Specific Adverse Events (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
167/Protocol YO39523, Version 8
Table 3
Management Guidelines for Gastrointestinal Events (Diarrhea or 
Colitis)
Event
Management
Diarrhea or 
colitis, Grade 1

Continue atezolizumab.

Initiate symptomatic treatment.

Endoscopy is recommended if symptoms persist for 7 days.

Monitor closely.
Diarrhea or 
colitis, Grade 2

Withhold atezolizumab for up to 12 weeks after event onset. a

Initiate symptomatic treatment.

Patient referral to GI specialist is recommended.

For recurrent events or events that persist 5 days, initiate treatment 
with 12 mg/kg/day oral prednisone or equivalent. 

If event resolves to Grade 1 or better, resume atezolizumab. b

If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and contact 
Medical Monitor. c
Diarrhea or 
colitis, Grade 3

Withhold atezolizumab for up to 12 weeks after event onset. a

Refer patient to GI specialist for evaluation and confirmatory biopsy.

Initiate treatment with corticosteroids equivalent to 12 mg/kg/day 
IV methylprednisolone and convert to 12 mg/kg/day oral prednisone 
or equivalent upon improvement.

If event resolves to Grade 1 or better, resume atezolizumab. b

If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and contact 
Medical Monitor. c
GIgastrointestinal.
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after event 
onset) to allow for corticosteroids (if initiated) to be reduced to 10 mg/day oral 
prednisone or equivalent.  The acceptable length of the extended period of time must be 
based on an assessment of benefit-risk by the investigator and in alignment with the 
protocol requirements for the duration of treatment and documented by the investigator.  
The Medical Monitor is available to advise as needed.
b If corticosteroids have been initiated, they must be tapered over 1 month to 10 mg/day 
oral prednisone or equivalent before atezolizumab can be resumed.
c Resumption of atezolizumab may be considered in patients who are deriving benefit and 
have fully recovered from the immune-mediated event.  The decision to re-challenge 
patients with atezolizumab should be based on investigator's assessment of benefitrisk 
and documented by the investigator (or an appropriate delegate). The Medical Monitor is 
available to advise as needed.


Appendix 9
Management of Atezolizumab-Specific Adverse Events (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
168/Protocol YO39523, Version 8
Table 3
Management Guidelines for Gastrointestinal Events (Diarrhea or 
Colitis) (cont.)
Event
Management
Diarrhea or 
colitis, Grade 4

Permanently discontinue atezolizumab and contact Medical Monitor. c

Refer patient to GI specialist for evaluation and confirmation biopsy.

Initiate treatment with corticosteroids equivalent to 12 mg/kg/day 
IV methylprednisolone and convert to 12 mg/kg/day oral prednisone or 
equivalent upon improvement.

If event does not improve within 48 hours after initiating corticosteroids, 
consider adding an immunosuppressive agent.

If event resolves to Grade 1 or better, taper corticosteroids over 
1 month.
GIgastrointestinal.
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after event onset) 
to allow for corticosteroids (if initiated) to be reduced to 10 mg/day oral prednisone or 
equivalent.  The acceptable length of the extended period of time must be based on an 
assessment of benefit-risk by the investigator and in alignment with the protocol 
requirements for the duration of treatment and documented by the investigator.  The 
Medical Monitor is available to advise as needed.
b If corticosteroids have been initiated, they must be tapered over 1 month to 10 mg/day 
oral prednisone or equivalent before atezolizumab can be resumed.
c Resumption of atezolizumab may be considered in patients who are deriving benefit and 
have fully recovered from the immune-mediated event.  The decision to re-challenge 
patients with atezolizumab should be based on investigator's assessment of benefit-risk and 
documented by the investigator (or an appropriate delegate).  The Medical Monitor is 
available to advise as needed.
ENDOCRINE EVENTS
Thyroid disorders, adrenal insufficiency, diabetes mellitus, and pituitary disorders have 
been associated with the administration of atezolizumab.  Management guidelines for 
endocrine events are provided in Table 4.
Patients with unexplained symptoms such as headache, fatigue, myalgias, impotence, 
constipation, or mental status changes should be investigated for the presence of 
thyroid, pituitary, or adrenal endocrinopathies.  The patient should be referred to an 
endocrinologist if an endocrinopathy is suspected.  Thyroid-stimulating hormone, free 
triiodothyronine, and thyroxine levels should be measured to determine whether thyroid 
abnormalities are present.  Pituitary hormone levels and function tests (e.g., TSH, 
growth hormone, luteinizing hormone, follicle-stimulating hormone, testosterone, 
prolactin, adrenocorticotropic hormone [ACTH] levels, and ACTH stimulation test) and 
magnetic resonance imaging (MRI) of the brain (with detailed pituitary sections) may 
help to differentiate primary pituitary insufficiency from primary adrenal insufficiency.


Appendix 9
Management of Atezolizumab-Specific Adverse Events (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
169/Protocol YO39523, Version 8
Table 4
Management Guidelines for Endocrine Events
Event
Management
Asymptomatic 
hypothyroidism

Continue atezolizumab.

Initiate treatment with thyroid replacement hormone.

Monitor TSH closely.
Symptomatic 
hypothyroidism

Withhold atezolizumab.

Initiate treatment with thyroid replacement hormone.

Monitor TSH closely.

Consider patient referral to endocrinologist.

Resume atezolizumab when symptoms are controlled and 
thyroid function is improving.
Asymptomatic 
hyperthyroidism
TSH 0.1 mU/L and 0.5 mU/L:

Continue atezolizumab.

Monitor TSH every 4 weeks.

Consider patient referral to endocrinologist.
TSH 0.1 mU/L:

Follow guidelines for symptomatic hyperthyroidism.
Consider patient referral to endocrinologist.
Symptomatic 
hyperthyroidism

Withhold atezolizumab.

Initiate treatment with anti-thyroid drug such as methimazole 
or carbimazole as needed.

Consider patient referral to endocrinologist.

Resume atezolizumab when symptoms are controlled and 
thyroid function is improving.

Permanently discontinue atezolizumab and contact Medical 
Monitor for life-threatening immune-mediated
hyperthyroidism. c


Appendix 9
Management of Atezolizumab-Specific Adverse Events (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
170/Protocol YO39523, Version 8
Table 4
Management Guidelines for Endocrine Events (cont.)
Event
Management
Symptomatic adrenal 
insufficiency, 
Grade 24 

Withhold atezolizumab for up to 12 weeks after event 
onset. a

Refer patient to endocrinologist.

Perform appropriate imaging.

Initiate treatment with corticosteroids equivalent to 
12 mg/kg/day IV methylprednisolone and convert to 
12 mg/kg/day oral prednisone or equivalent upon 
improvement.

If event resolves to Grade 1 or better and patient is stable on 
replacement therapy, resume atezolizumab. b

If event does not resolve to Grade 1 or better or patient is not 
stable on replacement therapy while withholding 
atezolizumab, permanently discontinue atezolizumab and 
contact Medical Monitor. c
Hyperglycemia, 
Grade 1 or 2 

Continue atezolizumab.

Investigate for diabetes. If patient has Type 1 diabetes, treat 
as a Grade 3 event.  If patient does not have Type 
1 diabetes, treat as per institutional guidelines.

Monitor for glucose control.
Hyperglycemia, 
Grade 3 or 4

Withhold atezolizumab.

Initiate treatment with insulin.

Evaluate for diabetic ketoacidosis and manage as per 
institutional guidelines.

Monitor for glucose control.

Resume atezolizumab when symptoms resolve and glucose 
levels are stable.
MRImagnetic resonance imaging.
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after event 
onset) to allow for corticosteroids (if initiated) to be reduced to 10 mg/day oral 
prednisone or equivalent.  The acceptable length of the extended period of time must 
be based on an assessment of benefit-risk by the investigator and in alignment with 
the protocol requirements for the duration of treatment and documented  by the 
investigator.  The Medical Monitor is available to advise as needed.
b If corticosteroids have been initiated, they must be tapered over 1 month to 
10 mg/day oral prednisone or equivalent before atezolizumab can be resumed.
c Resumption of atezolizumab may be considered in patients who are deriving benefit 
and have fully recovered from the immune-mediated.  event.  The decision to 
re-challenge patients with atezolizumab should be based on investigator's assessment 
of benefitrisk and documented by the investigator (or an appropriate delegate).  The 
Medical Monitor is available to advise as needed.


Appendix 9
Management of Atezolizumab-Specific Adverse Events (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
171/Protocol YO39523, Version 8
Table 4
Management Guidelines for Endocrine Events (cont.)
Event
Management
Hypophysitis 
(pan-hypopituitarism), 
Grade 2 or 3 

Withhold atezolizumab for up to 12 weeks after event 
onset. a

Refer patient to endocrinologist.

Perform brain MRI (pituitary protocol).

Initiate treatment with 12 mg/kg/day IV methylprednisolone 
or equivalent and convert to 12 mg/kg/day oral prednisone 
or equivalent upon improvement.

Initiate hormone replacement if clinically indicated.

If event resolves to Grade 1 or better, resume 
atezolizumab. b

If event does not resolve to Grade 1 or better while 
withholding atezolizumab, permanently discontinue 
atezolizumab and contact Medical Monitor. c

For recurrent hypophysitis, treat as a Grade 4 event.
Hypophysitis 
(pan-hypopituitarism), 
Grade 4 

Permanently discontinue atezolizumab and contact Medical 
Monitor. c

Refer patient to endocrinologist.

Perform brain MRI (pituitary protocol).

Initiate treatment with corticosteroids equivalent to 
12 mg/kg/day IV methylprednisolone and convert to 
12 mg/kg/day oral prednisone or equivalent upon 
improvement.

Initiate hormone replacement if clinically indicated.
MRImagnetic resonance imaging.
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after event 
onset) to allow for corticosteroids (if initiated) to be reduced to 10 mg/day oral 
prednisone or equivalent.  The acceptable length of the extended period of time must 
be based on an assessment of benefitrisk by the investigator and in alignment with 
the protocol requirements for the duration of treatment and documented by the 
investigator.  The Medical Monitor is available to advise as needed.
b If corticosteroids have been initiated, they must be tapered over 1 month to 
10 mg/day oral prednisone or equivalent before atezolizumab can be resumed.
c Resumption of atezolizumab may be considered in patients who are deriving benefit 
and have fully recovered from the immune-mediated event.  The decision to 
re-challenge patients with atezolizumab should be based on investigator's assessment 
of benefitrisk and documented by the investigator (or an appropriate delegate).  The 
Medical Monitor is available to advise as needed.
OCULAR EVENTS
An ophthalmologist should evaluate visual complaints (e.g., uveitis, retinal events).  
Management guidelines for ocular events are provided in Table 5.


Appendix 9
Management of Atezolizumab-Specific Adverse Events (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
172/Protocol YO39523, Version 8
Table 5
Management Guidelines for Ocular Events
Event
Management
Ocular event, 
Grade 1 

Continue atezolizumab.

Patient referral to ophthalmologist is strongly recommended.

Initiate treatment with topical corticosteroid eye drops and topical 
immunosuppressive therapy.

If symptoms persist, treat as a Grade 2 event.
Ocular event, 
Grade 2

Withhold atezolizumab for up to 12 weeks after event onset. a

Patient referral to ophthalmologist is strongly recommended.

Initiate treatment with topical corticosteroid eye drops and topical 
immunosuppressive therapy.

If event resolves to Grade 1 or better, resume atezolizumab. b

If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and contact 
Medical Monitor. c
Ocular event, 
Grade 3 or 4

Permanently discontinue atezolizumab and contact Medical 
Monitor. c

Refer patient to ophthalmologist.

Initiate treatment with 12 mg/kg/day oral prednisone or equivalent.

If event resolves to Grade 1 or better, taper corticosteroids over 
1 month.
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after event 
onset) to allow for corticosteroids (if initiated) to be reduced to 10 mg/day oral 
prednisone or equivalent.  The acceptable length of the extended period of time must be 
based on an assessment of benefitrisk by the investigator and in alignment with the 
protocol requirements for the duration of treatment and documented by the 
investigator.  The Medical Monitor is available to advise as needed.
b If corticosteroids have been initiated, they must be tapered over 1 month to 
10 mg/day oral prednisone or equivalent before atezolizumab can be resumed.
c Resumption of atezolizumab may be considered in patients who are deriving benefit and 
have fully recovered from the immune-mediated event.  The decision to re-challenge 
patients with atezolizumab should be based on investigator's assessment of benefit-risk 
and documented by the investigator (or an appropriate delegate).  The Medical Monitor
is available to advise as needed.


Appendix 9
Management of Atezolizumab-Specific Adverse Events (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
173/Protocol YO39523, Version 8
IMMUNE-MEDIATED MYOCARDITIS
Immune-mediated myocarditis has been associated with the administration of 
atezolizumab.  Immune-mediated myocarditis should be suspected in any patient 
presenting with signs or symptoms suggestive of myocarditis, including, but not limited 
to, laboratory (e.g., B-type natriuretic peptide) or cardiac imaging abnormalities, 
dyspnea, chest pain, palpitations, fatigue, decreased exercise tolerance, or syncope.  
Myocarditis may also be a clinical manifestation of myositis 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 
GI illness), ischemic events, underlying arrhythmias, exacerbation of preexisting cardiac 
conditions, or progression of malignancy.  
All patients with possible myocarditis should be urgently evaluated by performing cardiac 
enzyme assessment, an ECG, a chest X-ray, an echocardiogram, and a cardiac MRI as 
appropriate per institutional guidelines.  A cardiologist should be consulted.  An 
endomyocardial biopsy may be considered to enable a definitive diagnosis and 
appropriate treatment, if clinically indicated.
Patients with signs and symptoms of myocarditis, in the absence of an identified 
alternate etiology, should be treated according to the guidelines in Table 6.


Appendix 9
Management of Atezolizumab-Specific Adverse Events (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
174/Protocol YO39523, Version 8
Table 6
Management Guidelines for Immune-Mediated Myocarditis
Event
Management
Immune-mediated
myocarditis, Grade 24

Permanently discontinue atezolizumab and contact Medical 
Monitor. a

Refer patient to cardiologist.

Initiate treatment as per institutional guidelines and consider 
antiarrhythmic drugs, temporary pacemaker, ECMO, or VAD as 
appropriate.

Initiate treatment with corticosteroids equivalent to 12 mg/kg/day 
IV methylprednisolone and convert to 12 mg/kg/day oral prednisone 
or equivalent upon improvement.

If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent.

If event resolves to Grade 1 or better, taper corticosteroids 
over1 month.
ECMOextracorporeal membrane oxygenation; VAD ventricular assist device.
a Resumption of atezolizumab may be considered in patients who are deriving benefit and have 
fully recovered from the immune-mediated event.  The decision to re-challenge patients with 
atezolizumab should be based on investigator's assessment of benefit-risk and documented by 
the investigator (or an appropriate delegate). The Medical Monitor is available to advise as 
needed.
INFUSION-RELATED REACTIONS AND CYTOKINE-RELEASE SYNDROME
No premedication is indicated for the administration of Cycle 1 of atezolizumab.  
However, patients who experience an infusion-related reaction (IRR) or cytokine-release 
syndrome (CRS) with atezolizumab may receive premedication with antihistamines,
anti-pyretics, and/or analgesics (e.g., acetaminophen) for subsequent infusions.  
Metamizole (dipyrone) is prohibited in treating atezolizumab-associated IRRs because of 
its potential for causing agranulocytosis.
IRRs are known to occur with the administration of monoclonal antibodies and have 
been reported with atezolizumab.  These reactions, which are thought to be due to 
release of cytokines and/or other chemical mediators, occur within 24 hours of 
atezolizumab administration and are generally mild to moderate in severity.
CRS is defined as a supraphysiologic response following administration of any immune 
therapy that results in activation or engagement of endogenous or infused T cells and/or 
other immune effector cells.  Symptoms can be progressive, always include fever at the 
onset, and may include hypotension, capillary leak (hypoxia), and end-organ dysfunction 
(Lee et al. 2019).  CRS has been well documented with chimeric antigen receptor T-cell 
therapies and bispecific T-cell engager antibody therapies but has also been reported 


Appendix 9
Management of Atezolizumab-Specific Adverse Events (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
175/Protocol YO39523, Version 8
with immunotherapies that target PD-1 or PD-L1 (Rotz et al. 2017; Adashek and 
Feldman 2019), including atezolizumab.
There may be significant overlap in signs and symptoms of IRRs and CRS, and in 
recognition of the challenges in clinically distinguishing between the two, consolidated 
guidelines for medical management of IRRs and CRS are provided in Table 5
Severe COVID-19 appears to be associated with a CRS involving the inflammatory 
cytokines IL-6, IL-10, IL-2, and IFN-(Merad and Martin 2020).  If a patient develops 
suspected CRS during the study, a differential diagnosis should include COVID-19, 
which should be confirmed or refuted through assessment of exposure history, 
appropriate laboratory testing, and clinical or radiologic evaluations per investigator 
judgment.  If a diagnosis of COVID-19 is confirmed, the disease should be managed as 
per local or institutional guidelines.


Appendix 9
Management of Atezolizumab-Specific Adverse Events (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
176/Protocol YO39523, Version 8
Table 5
Management Guidelines for Infusion-Related Reactions and 
Cytokine-Release Syndrome
Event
Management
Grade 1 a
Fever b with or 
without 
constitutional 
symptoms

Immediately interrupt infusion.

Upon symptom resolution, wait for 30 minutes and then restart infusion at 
half the rate being given at the time of event onset.

If the infusion is tolerated at the reduced rate for 30, the infusion rate may 
be increased to the original rate.

If symptoms recur, discontinue infusion of this dose.

Administer symptomatic treatment, c including maintenance of IV fluids for 
hydration.

In case of rapid decline or prolonged CRS (2 days) or in patients with 
significant symptoms and/or comorbidities, consider managing as per 
Grade 2.

For subsequent infusions, consider administration of oral premedication 
with antihistamines, anti-pyretics, and/or analgesics, and monitor closely 
for IRRs and/or CRS.
Grade 2 a
Fever b with 
hypotension not 
requiring 
vasopressors
and/or
Hypoxia requiring 
low-flow oxygen d
by nasal cannula or 
blow-by

Immediately interrupt infusion.

Upon symptom resolution, wait for 30 minutes and then restart infusion at 
half the rate being given at the time of event onset.

If symptoms recur, discontinue infusion of this dose.

Administer symptomatic treatment. c

For hypotension, administer IV fluid bolus as needed.

Monitor cardiopulmonary and other organ function closely (in the ICU, if 
appropriate).  Administer IV fluids as clinically indicated, and manage 
constitutional symptoms and organ toxicities as per institutional practice.

Rule out other inflammatory conditions that can mimic CRS (e.g., sepsis).  
If no improvement within 24 hours, initiate workup and assess for signs 
and symptoms of HLH or MAS as described in this appendix.

Consider IV corticosteroids (e.g., methylprednisolone 2 mg/kg/day or 
dexamethasone 10 mg every 6 hours).

Consider anti-cytokine therapy.

Consider hospitalization until complete resolution of symptoms.  If no 
improvement within 24 hours, manage as per Grade 3, that is, hospitalize 
patient (monitoring in the ICU is recommended), permanently discontinue 
atezolizumab, and contact Medical Monitor. e

If symptoms resolve to Grade 1 or better for 3 consecutive days, the next 
dose of atezolizumab may be administered.  For subsequent infusions, 
consider administration of oral premedication with antihistamines, 
anti-pyretics, and/or analgesics and monitor closely for IRRs and/or CRS.

If symptoms do not resolve to Grade 1 or better for 3 consecutive days, 
contact Medical Monitor.


Appendix 9
Management of Atezolizumab-Specific Adverse Events (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
177/Protocol YO39523, Version 8
Table 7
Management Guidelines for Infusion-Related Reactions and 
Cytokine-Release Syndrome (cont.)
Event
Management
Grade 3 a
Fever b with 
hypotension 
requiring a 
vasopressor (with 
or without 
vasopressin)
and/or
Hypoxia requiring 
high-flow oxygen d
by nasal cannula, 
face mask, 
non-rebreather 
mask, or Venturi 
mask

Permanently discontinue atezolizumab and contact Medical Monitor. e

Administer symptomatic treatment. c

For hypotension, administer IV fluid bolus and vasopressor as needed.

Monitor cardiopulmonary and other organ function closely; monitoring 
in the ICU is recommended.  Administer IV fluids as clinically indicated, 
and manage constitutional symptoms and organ toxicities as per 
institutional practice.

Rule out other inflammatory conditions that can mimic CRS 
(e.g., sepsis).  If no improvement within 24 hours, initiate workup and 
assess for signs and symptoms of HLH or MAS as described in this 
appendix.

Administer IV corticosteroids (e.g., methylprednisolone 2 mg/kg/day or 
dexamethasone 10 mg every 6 hours).

Consider anti-cytokine therapy.

Hospitalize patient until complete resolution of symptoms.  If no 
improvement within 24 hours, manage as per Grade 4, that is, admit 
patient to ICU and initiate hemodynamic monitoring, mechanical 
ventilation, and/or IV fluids and vasopressors as needed; for patients 
who are refractory to anti-cytokine therapy, experimental treatments 
may be considered at the discretion of the investigator and in 
consultation with the Medical Monitor.
Grade 4 a
Fever b with 
hypotension 
requiring multiple 
vasopressors 
(excluding 
vasopressin)
and/or
Hypoxia requiring 
oxygen by positive 
pressure (e.g., 
CPAP, BiPAP, 
intubation and 
mechanical 
ventilation)

Permanently discontinue atezolizumab and contact Medical Monitor. e

Administer symptomatic treatment. c

Admit patient to ICU and initiate hemodynamic monitoring, mechanical 
ventilation, and/or IV fluids and vasopressors as needed.  Monitor 
other organ function closely.  Manage constitutional symptoms and 
organ toxicities as per institutional practice.

Rule out other inflammatory conditions that can mimic CRS 
(e.g., sepsis).  If no improvement within 24 hours, initiate workup and 
assess for signs and symptoms of HLH or MAS as described in this 
appendix.

Administer IV corticosteroids (e.g., methylprednisolone 2 mg/kg/day or 
dexamethasone 10 mg every 6 hours).

Consider anti-cytokine therapy.  For patients who are refractory to 
anti-cytokine therapy, experimental treatments f may be considered at 
the discretion of the investigator and in consultation with the Medical 
Monitor.

Hospitalize patient until complete resolution of symptoms.


Appendix 9
Management of Atezolizumab-Specific Adverse Events (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
178/Protocol YO39523, Version 8
Table 7
Management Guidelines for Infusion-Related Reactions and 
Cytokine-Release Syndrome (cont.)
ASTCTAmerican Society for Transplantation and Cellular Therapy; BiPAPbi-level positive 
airway pressure; CARchimeric antigen receptor; CPAPcontinuous positive airway 
pressure; CRScytokine-release syndrome; CTCAECommon Terminology Criteria for 
Adverse Events; eCRFelectronic Case Report Form; HLHhemophagocytic 
lymphohistiocytosis; ICUintensive care unit; IRRinfusion-related reaction; 
MASmacrophage activation syndrome; NCCNNational Cancer Comprehensive Network; 
NCINational Cancer Institute.
Note:  These management guidelines have been adapted from NCCN guidelines for 
management of CAR T-cellrelated toxicities (Version 2.2019).
a Grading system for these management guidelines is based on ASTCT consensus grading 
for CRS.  NCI CTCAE v4.0 should be used when reporting severity of IRRs, CRS, or organ 
toxicities associated with CRS on the Adverse Event eCRF.  Organ toxicities associated 
with CRS should not influence overall CRS grading.
b Fever is defined as temperature 38C not attributable to any other cause.  In patients who 
develop CRS and then receive anti-pyretic, anti-cytokine, or corticosteroid therapy, fever is 
no longer required when subsequently determining event severity (grade).  In this case, the 
grade is driven by the presence of hypotension and/or hypoxia.
c Symptomatic treatment may include oral or IV antihistamines, anti-pyretics, analgesics, 
bronchodilators, and/or oxygen.  For bronchospasm, urticaria, or dyspnea, additional 
treatment may be administered as per institutional practice.
d Low flow is defined as oxygen delivered at 6 L/min, and high flow is defined as oxygen 
delivered at 6 L/min.
e Resumption of atezolizumab may be considered in patients who are deriving benefit and 
have fully recovered from the event.  The decision to re-challenge patients with 
atezolizumab should be based on investigator's assessment of benefit-risk and documented 
by the investigator (or an appropriate delegate).  The Medical Monitor is available to advise 
as needed.  For subsequent infusions, administer oral premedication with antihistamines, 
anti-pyretics, and/or analgesics, and monitor closely for IRRs and/or CRS.  Premedication 
with corticosteroids and extending the infusion time may also be considered after assessing
the benefitrisk ratio.
f
Refer to Riegler et al. (2019).
PANCREATIC EVENTS
Symptoms of abdominal pain associated with elevations of amylase and lipase, 
suggestive of pancreatitis, have been associated with the administration of 
atezolizumab.  The differential diagnosis of acute abdominal pain should include 
pancreatitis.  Appropriate work-up should include an evaluation for ductal obstruction, as 
well as serum amylase and lipase tests.  Management guidelines for pancreatic events, 
including pancreatitis, are provided in Table 8.


Appendix 9
Management of Atezolizumab-Specific Adverse Events (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
179/Protocol YO39523, Version 8
Table 8
Management Guidelines for Pancreatic Events, Including 
Pancreatitis 
Event
Management
Amylase and/or lipase 
elevation, Grade 2
Amylase and/or lipase 1.52.0ULN:

Continue atezolizumab.

Monitor amylase and lipase weekly.

For prolonged elevation (e.g., 3 weeks), consider treatment 
with 10 mg/day oral prednisone or equivalent.
Asymptomatic with amylase and/or lipase 2.05.0ULN:
Treat as a Grade 3 event.
Amylase and/or lipase 
elevation, Grade 3 or 4

Withhold atezolizumab for up to 12 weeks after event 
onset. a

Refer patient to GI specialist.

Monitor amylase and lipase every other day.

If no improvement, consider treatment with 12 mg/kg/day 
oral prednisone or equivalent.

If event resolves to Grade 1 or better, resume 
atezolizumab. b

If event does not resolve to Grade 1 or better while 
withholding atezolizumab, permanently discontinue 
atezolizumab and contact Medical Monitor. c

For recurrent events, permanently discontinue atezolizumab 
and contact Medical Monitor. c
GIgastrointestinal.
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after event onset) 
to allow for corticosteroids (if initiated) to be reduced to 10 mg/day oral prednisone or 
equivalent.  The acceptable length of the extended period of time must be based on an 
assessment of benefit-risk by the investigator and in alignment with the protocol 
requirements for the duration of treatment and documented by the investigator. The 
Medical Monitor is available to advise as needed.
b If corticosteroids have been initiated, they must be tapered over 1 month to 10 mg/day 
oral prednisone or equivalent before atezolizumab can be resumed.
c Resumption of atezolizumab may be considered in patients who are deriving benefit and 
have fully recovered from the immune-mediated event.  The decision to re-challenge 
patients with atezolizumab should be based on investigator's assessment of benefit-risk and 
documented by both the investigator (or an appropriate delegate).  The Medical Monitor is 
available to advise as needed.


Appendix 9
Management of Atezolizumab-Specific Adverse Events (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
180/Protocol YO39523, Version 8
Table 8
Management Guidelines for Pancreatic Events, Including 
Pancreatitis (cont.)
Event
Management
Immune-mediated
pancreatitis, Grade 2 or 3

Withhold atezolizumab for up to 12 weeks after event 
onset. a

Refer patient to GI specialist.

Initiate treatment with corticosteroids equivalent to 
12 mg/kg/day IV methylprednisolone and convert to 
12 mg/kg/day oral prednisone or equivalent upon 
improvement.

If event resolves to Grade 1 or better, resume 
atezolizumab. b

If event does not resolve to Grade 1 or better while 
withholding atezolizumab, permanently discontinue 
atezolizumab and contact Medical Monitor. c

For recurrent events, permanently discontinue atezolizumab 
and contact Medical Monitor. c
Immune-mediated
pancreatitis, Grade 4

Permanently discontinue atezolizumab and contact Medical 
Monitor. c

Refer patient to GI specialist.

Initiate treatment with corticosteroids equivalent to 
12 mg/kg/day IV methylprednisolone and convert to 
12 mg/kg/day oral prednisone or equivalent upon 
improvement.

If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive 
agent.

If event resolves to Grade 1 or better, taper corticosteroids 
over 1 month.
GIgastrointestinal.
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after event onset) 
to allow for corticosteroids (if initiated) to be reduced to 10 mg/day oral prednisone or 
equivalent.  The acceptable length of the extended period of time must be based on an 
assessment of benefit-risk by the investigator and in alignment with the protocol 
requirements for the duration of treatment and documented by the investigator.  The 
Medical Monitor is available to advise as needed.
b If corticosteroids have been initiated, they must be tapered over 1 month to 10 mg/day 
oral prednisone or equivalent before atezolizumab can be resumed.
c Resumption of atezolizumab may be considered in patients who are deriving benefit and 
have fully recovered from the immune-mediated event.  The decision to re-challenge 
patients with atezolizumab should be based on investigator's assessment of benefit-risk and 
documented by the investigator (or an appropriate delegate).  The Medical Monitor is 
available to advise as needed.


Appendix 9
Management of Atezolizumab-Specific Adverse Events (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
181/Protocol YO39523, Version 8
DERMATOLOGIC EVENTS
Treatment-emergent rash has been associated with atezolizumab.  The majority of 
cases of rash were mild in severity and self-limiting, with or without pruritus. Although 
uncommon, cases of severe cutaneous adverse reactions such as Stevens-Johnson 
syndrome and toxic epidermal necrolysis have been reported with atezolizumab.
A dermatologist should evaluate persistent and/or severe rash or pruritus.  A biopsy 
should be considered unless contraindicated.  Management guidelines for dermatologic 
events are provided in Table 9.
Table 9
Management Guidelines for Dermatologic Events
Event
Management
Dermatologic 
event, Grade 1 

Continue atezolizumab.

Consider treatment with topical corticosteroids and/or other symptomatic 
therapy (e.g., antihistamines).
Dermatologic 
event, Grade 2 

Continue atezolizumab.

Consider patient referral to dermatologist.

Initiate treatment with topical corticosteroids.

Consider treatment with higher-potency topical corticosteroids if event 
does not improve.

If unresponsive to topical corticosteroids, consider oral prednisone 
0.5 mg/kg/day.
Dermatologic 
event, Grade 3 

Withhold atezolizumab for up to 12 weeks after event onset. a

Refer patient to dermatologist.

Initiate treatment with 10 mg/day oral prednisone or equivalent, 
increasing dose to 12 mg/kg/day if event does not improve within 
4872 hours.

If event resolves to Grade 1 or better, resume atezolizumab. b

If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and contact 
Medical Monitor. c
Dermatologic 
event, Grade 4

Permanently discontinue atezolizumab and contact Medical Monitor. c


Appendix 9
Management of Atezolizumab-Specific Adverse Events (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
182/Protocol YO39523, Version 8
Stevens-Johnson 
syndrome or 
toxic epidermal 
necrolysis, (any 
grade)
Additional guidance for Stevens-Johnson syndrome or toxic epidermal 
necrolysis:

Withhold atezolizumab for suspected Stevens-Johnson syndrome or 
toxic epidermal necrolysis.

Confirm diagnosis by referring patient to a specialist (dermatologist, 
ophthalmologist or urologist as relevant) for evaluation and, if indicated, 
biopsy.

Follow the applicable treatment and management guidelines above.

If Stevens-Johnson syndrome or toxic epidermal necrolysis, 
permanently discontinue atezolizumab.
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after event onset) 
to allow for corticosteroids (if initiated) to be reduced to 10 mg/day oral prednisone or 
equivalent.  The acceptable length of the extended period of time must be based on an 
assessment of benefit-risk by the investigator and in alignment with the protocol 
requirements for the duration of treatment and documented by the investigator.  The 
Medical Monitor is available to advise as needed.
b If corticosteroids have been initiated, they must be tapered over 1 month to 10 mg/day 
oral prednisone or equivalent before atezolizumab can be resumed.
c Resumption of atezolizumab may be considered in patients who are deriving benefit and 
have fully recovered from the immune-mediated event.  The decision to re-challenge 
patients with atezolizumab should be based on investigator's assessment of benefit-risk and 
documented by the investigator (or an appropriate delegate).  The Medical Monitor is 
available to advise as needed.
NEUROLOGIC DISORDERS
Myasthenia gravis and Guillain-Barré syndrome have been observed with single-agent 
atezolizumab.  Patients may present with signs and symptoms of sensory and/or motor 
neuropathy.  Diagnostic work-up is essential for an accurate characterization to 
differentiate between alternative etiologies.  Management guidelines for neurologic 
disorders are provided in Table 10.


Appendix 9
Management of Atezolizumab-Specific Adverse Events (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
183/Protocol YO39523, Version 8
Table 10 Management Guidelines for Neurologic Disorders
Event
Management
Immune-
mediated
neuropathy, 
Grade 1

Continue atezolizumab.

Investigate etiology.
Immune-
mediated
neuropathy, 
Grade 2 

Withhold atezolizumab for up to 12 weeks after event onset. a

Investigate etiology and refer patient to neurologist.

Initiate treatment as per institutional guidelines.

If event resolves to Grade 1 or better, resume atezolizumab. b

If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and contact 
Medical Monitor. c
Immune-
mediated
neuropathy, 
Grade 3 or 4

Permanently discontinue atezolizumab and contact Medical Monitor. c 

Refer patient to neurologist.

Initiate treatment as per institutional guidelines.
Myasthenia 
gravis and 
Guillain-Barré 
syndrome (any 
grade)

Permanently discontinue atezolizumab and contact Medical Monitor. c

Refer patient to neurologist.

Initiate treatment as per institutional guidelines.

Consider initiation of 12 mg/kg/day oral or IV prednisone or equivalent.
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after event 
onset) to allow for corticosteroids (if initiated) to be reduced to 10 mg/day oral prednisone 
or equivalent.  The acceptable length of the extended period of time must be based on an 
assessment of benefit-risk by the investigator and in alignment with the protocol 
requirements for the duration of treatment and documented by the investigator.  The 
Medical Monitor is available to advise as needed.
b If corticosteroids have been initiated, they must be tapered over 1 month to 10 mg/day 
oral prednisone or equivalent before atezolizumab can be resumed.
c Resumption of atezolizumab may be considered in patients who are deriving benefit and 
have fully recovered from the immune-mediated event.  The decision to re-challenge 
patients with atezolizumab should be based on investigator's assessment of benefitrisk 
and documented by the investigator (or an appropriate delegate).  The Medical Monitor is 
available to advise as needed.


Appendix 9
Management of Atezolizumab-Specific Adverse Events (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
184/Protocol YO39523, Version 8
IMMUNEMEDIATED MENINGOENCEPHALITIS
Immune-mediated meningoencephalitis is an identified risk associated with the 
administration of atezolizumab.  Immune-mediated meningoencephalitis should be 
suspected in any patient presenting with signs or symptoms suggestive of meningitis or 
encephalitis, including, but not limited to, headache, neck pain, confusion, seizure, motor 
or sensory dysfunction, and altered or depressed level of consciousness.  
Encephalopathy from metabolic or electrolyte imbalances needs to be distinguished from 
potential meningoencephalitis resulting from infection (bacterial, viral, or fungal) or 
progression of malignancy, or secondary to a paraneoplastic process.
All patients being considered for meningoencephalitis should be urgently evaluated with 
a CT scan and/or MRI scan of the brain to evaluate for metastasis, inflammation, or 
edema.  If deemed safe by the treating physician, a lumbar puncture should be 
performed and a neurologist should be consulted.
Patients with signs and symptoms of meningoencephalitis, in the absence of an 
identified alternate etiology, should be treated according to the guidelines in Table 11.
Table 11 Management Guidelines for Immune-Mediated
Meningoencephalitis
Event
Management
Immune-mediated
meningoencephalitis, 
all grades

Permanently discontinue atezolizumab and contact Medical Monitor. a

Refer patient to neurologist.

Initiate treatment with 12 mg/kg/day IV methylprednisolone or 
equivalent and convert to 12 mg/kg/day oral prednisone or equivalent 
upon improvement.

If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent.

If event resolves to Grade 1 or better, taper corticosteroids over 
1 month.
a Resumption of atezolizumab may be considered in patients who are deriving benefit and have 
fully recovered from the immune-mediated event.  The decision to re-challenge patients with 
atezolizumab should be based on investigator's assessment of benefitrisk and documented 
by the investigator (or an appropriate delegate).  The Medical Monitor is available to advise as 
needed.
RENAL EVENTS
Immune-mediated nephritis has been associated with the administration of 
atezolizumab.  Eligible patients must have adequate renal function, and renal function, 
including serum creatinine, should be monitored throughout study treatment.  Patients 


Appendix 9
Management of Atezolizumab-Specific Adverse Events (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
185/Protocol YO39523, Version 8
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 12.
Table 12 Management Guidelines for Renal Events
Event
Management
Renal event, 
Grade 1

Continue atezolizumab.

Monitor kidney function, including creatinine and urine protein, 
closely until values resolve to within normal limits or to baseline 
values. 
Renal event, 
Grade 2

Withhold atezolizumab for up to 12 weeks after event onset. a

Refer patient to renal specialist.

Initiate treatment with corticosteroids equivalent to 
12 mg/kg/day oral prednisone.

If event resolves to Grade 1 or better, resume atezolizumab. b

If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and 
contact Medical Monitor. c
Renal event, 
Grade 3 or 4

Permanently discontinue atezolizumab and contact Medical 
Monitor. 

Refer patient to renal specialist and consider renal biopsy.

Initiate treatment with corticosteroids equivalent to 
12 mg/kg/day oral prednisone.

If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent.

If event resolves to Grade 1 or better, taper corticosteroids over 
1 month.
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after 
event onset) to allow for corticosteroids (if initiated) to be reduced to the equivalent 
of 10 mg/day oral prednisone.  The acceptable length of the extended period of 
time must be based on an assessment of benefit-risk by the investigator and in 
alignment with the protocol requirements for the duration of treatment and 
documented by the investigator.  The Medical Monitor is available to advise as 
needed.
b If corticosteroids have been initiated, they must be tapered over 1 month to the 
equivalent of 10 mg/day oral prednisone before atezolizumab can be resumed.


Appendix 9
Management of Atezolizumab-Specific Adverse Events (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
186/Protocol YO39523, Version 8
c Resumption of atezolizumab may be considered in patients who are deriving benefit 
and have fully recovered from the immune-mediated event.  The decision to 
re-challenge patients with atezolizumab should be based on investigator's 
assessment of benefitrisk and documented by the investigator (or an appropriate 
delegate).  The Medical Monitor is available to advise as needed.
IMMUNE-MEDIATED MYOSITIS
Immune-mediated myositis has been associated with the administration of atezolizumab.  
Myositis or inflammatory myopathies are a group of disorders sharing the common 
feature of inflammatory muscle injury; dermatomyositis and polymyositis are among the 
most common disorders.  Initial diagnosis is based on clinical (muscle weakness, muscle 
pain, skin rash in dermatomyositis), biochemical (serum creatine kinase increase), and 
imaging (electromyography/MRI) features, and is confirmed with a muscle biopsy.  
Patients with possible myositis should be referred to a rheumatologist or neurologist.  
Patients with possible myositis should be monitored for signs of myocarditis.
Patients with signs and symptoms of myositis, in the absence of an identified alternate 
etiology, should be treated according to the guidelines in Table 13.
Table 13 Management Guidelines for Immune-Mediated Myositis
Event
Management
Immune-
mediated
myositis, Grade 1

Continue atezolizumab.

Refer patient to rheumatologist or neurologist. 

Initiate treatment as per institutional guidelines.
Immune-
mediated
myositis, Grade 2

Withhold atezolizumab for up to 12 weeks after event onset a
and contact Medical Monitor.

Refer patient to rheumatologist or neurologist.

Initiate treatment as per institutional guidelines.

Consider treatment with corticosteroids equivalent to 
12 mg/kg/day IV methylprednisolone and convert to 
12 mg/kg/day oral prednisone or equivalent upon 
improvement.

If corticosteroids are initiated and event does not improve 
within 48 hours after initiating corticosteroids, consider adding 
an immunosuppressive agent.

If event resolves to Grade 1 or better, resume atezolizumab. b

If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and 
contact Medical Monitor. c


Appendix 9
Management of Atezolizumab-Specific Adverse Events (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
187/Protocol YO39523, Version 8
Table 13 Management Guidelines for Immune-Related Myositis (cont.)
Immune-
mediated
myositis, Grade 3

Withhold atezolizumab for up to 12 weeks after event onset a
and contact Medical Monitor.

Refer patient to rheumatologist or neurologist.

Initiate treatment as per institutional guidelines.  Respiratory 
support may be required in more severe cases.

Initiate treatment with corticosteroids equivalent to 
12 mg/kg/day IV methylprednisolone, or higher-dose bolus if 
patient is severely compromised (e.g., cardiac or respiratory 
symptoms, dysphagia, or weakness that severely limits 
mobility); convert to 12 mg/kg/day oral prednisone or 
equivalent upon improvement.

If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent.

If event resolves to Grade 1 or better, resume atezolizumab. b

If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and 
contact Medical Monitor. c

For recurrent events, treat as a Grade 4 event.
Immune-
mediated
myositis, Grade 4

Permanently discontinue atezolizumab and contact Medical 
Monitor. c

Refer patient to rheumatologist or neurologist.

Initiate treatment as per institutional guidelines.  Respiratory 
support may be required in more severe cases.

Initiate treatment with corticosteroids equivalent to 
12 mg/kg/day IV methylprednisolone, or higher-dose bolus if 
patient is severely compromised (e.g., cardiac or respiratory 
symptoms, dysphagia, or weakness that severely limits 
mobility); convert to 12 mg/kg/day oral prednisone or 
equivalent upon improvement.

If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent.

If event resolves to Grade 1 or better, taper corticosteroids 
over 1 month.
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after 
event onset) to allow for corticosteroids (if initiated) to be reduced to the equivalent 
of 10 mg/day oral prednisone.  The acceptable length of the extended period of 
time must be based on an assessment of benefitrisk by the investigator and in 
alignment with the protocol requirements for the duration of treatment and 
documented by the investigator.  The Medical Monitor is available to advise as 
needed.
b If corticosteroids have been initiated, they must be tapered over 1 month to the 
equivalent of 10 mg/day oral prednisone before atezolizumab can be resumed.


Appendix 9
Management of Atezolizumab-Specific Adverse Events (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
188/Protocol YO39523, Version 8
c Resumption of atezolizumab may be considered in patients who are deriving benefit 
and have fully recovered from the immune-mediated event.  The decision to 
re-challenge patients with atezolizumab should be based on investigator's 
assessment of benefitrisk and documented by the investigator (or an appropriate 
delegate).  The Medical Monitor is available to advise as needed.
HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS AND MACROPHAGE 
ACTIVATION SYNDROME
Immune-mediated reactions may involve any organ system and may lead to 
hemophagocytic lymphohistiocytosis (HLH) and macrophage activation syndrome 
(MAS), which are considered to be potential risks for atezolizumab.
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 (IL-2) receptor (soluble CD25) elevated 2 standard deviations 
above age-adjusted laboratory-specific norms
Patients with suspected MAS should be diagnosed according to published criteria for 
systemic juvenile idiopathic arthritis by Ravelli et al. (2016).  A febrile patient should be 
classified as having MAS if the following criteria are met:

Ferritin 684 mg/L (684 ng/mL)


Appendix 9
Management of Atezolizumab-Specific Adverse Events (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
189/Protocol YO39523, Version 8

At least two of the following:
–
Platelet count 181 109/L (181,000/L)
–
AST 48 U/L
–
Triglycerides 1.761 mmol/L (156 mg/dL)
–
Fibrinogen 3.6 g/L (360 mg/dL)
Patients with suspected HLH or MAS should be treated according to the guidelines in 
Table 14.
Table 14 Management Guidelines for Suspected Hemophagocytic 
Lymphohistiocytosis or Macrophage Activation Syndrome
Event
Management
Suspected HLH 
or MAS

Permanently discontinue atezolizumab and contact Medical 
Monitor.

Consider patient referral to hematologist.

Initiate supportive care, including intensive care monitoring if 
indicated per institutional guidelines.

Consider initiation of IV corticosteroids, an immunosuppressive 
agent, and/or anti-cytokine therapy.

If event does not respond to treatment within 24 hours, contact 
Medical Monitor and initiate treatment as appropriate according to 
published guidelines (La Rosée 2015; Schram and Berliner 2015; 
La Rosée et al. 2019)..

If event resolves to Grade 1 or better, taper corticosteroids over 
1 month.
HLH hemophagocytic lymphohistiocytosis; MAS macrophage activation syndrome.
REFERENCES
Adashek ML, Feldman M. Cytokine release syndrome resulting from antiprogrammed 
death-1 antibody: raising awareness among community oncologist. J Oncol 
Practice 2019;15:5024.
La Rosée P. Treatment of hemophagocytic lymphohistiocytosis in adults. Hematology 
Am Soc Hematol Educ 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.


Appendix 9
Management of Atezolizumab-Specific Adverse Events (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
190/Protocol YO39523, Version 8
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.
Ravelli A, Minoia F, Davi S, et al. 2016 classification criteria for macrophage activation 
syndrome complicating systemic juvenile idiopathic arthritis: a European League 
Against Rheumatism/American College of Rheumatology/Paediatric Rheumatology 
International Trials Organisation Collaborative Initiative. Ann Rheum Dis 
2016;75:4819.
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.


Atezolizumab—F. Hoffmann-La Roche Ltd
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Appendix 10
Guidelines for Management of Patients Who Experience Specific 
Adverse Events Associated with Bevacizumab
Event
Action to Be Taken
GI perforation, any grade

Permanently discontinue bevacizumab. 
Fistulae 
Internal fistula not arising in the 
GI tract

Consider permanent discontinuation of 
bevacizumab.
Tracheoesophageal fistula, any 
grade

Permanently discontinue bevacizumab.
Fistula, any type, Grade 4

Permanently discontinue bevacizumab.
Hypertension
Medically significant hypertension 
not adequately controlled with 
antihypertensive therapy

Permanently discontinue bevacizumab.
Hypertensive crisis 

Permanently discontinue bevacizumab.
Hypertensive encephalopathy

Permanently discontinue bevacizumab. 
Congestive heart failure, Grade3

Permanently discontinue bevacizumab.
PRES

Permanently discontinue bevacizumab.
Nephrotic syndrome

Permanently discontinue bevacizumab. 
Thrombosis/embolism
Venous thrombosis, Grade 3

Withhold bevacizumab until patient is on a stable 
dose of anticoagulation. a
Recurrent venous thrombosis, 
Grade 3

Permanently discontinue bevacizumab.
Venous thrombosis, Grade 4

Permanently discontinue bevacizumab.
Arterial thrombosis/embolism, any 
grade

Permanently discontinue bevacizumab.
Hemorrhage
Grade 2 hemoptysis (2.5 mL of 
bright red blood per episode)

Permanently discontinue bevacizumab.
Grade 3, 4 bleeding

Permanently discontinue bevacizumab.
Bleeding in patients on full-dose 
anticoagulant therapy

Permanently discontinue bevacizumab. b
CNS bleeding, any grade

Permanently discontinue bevacizumab.


Appendix 10
Guidelines for Management of Patients Who Experience Specific 
Adverse Events Associated with Bevacizumab (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
192/Protocol YO39523, Version 8
Event
Action to Be Taken
Major surgery or wound-healing 
complication

Withhold bevacizumab until the wound is fully 
healed.

If the wound does not fully heal despite withholding 
treatment, permanently discontinue bevacizumab.
Hypersensitivity/allergic reactions 

Permanently discontinue bevacizumab.
Infusion-associated events

See footnote. c
Febrile neutropenia, Grade 4 d

Withhold bevacizumab until resolution.
Decreased platelet count, Grade 4 d

Withhold bevacizumab until resolution to Grade1.
GIgastrointestinal; NCI CTCAENational Cancer Institute Common Terminology Criteria for 
Adverse Events; PRESposterior reversible encephalopathy syndrome; ULNupper limit of 
normal.
Note:  All grades are per NCI CTCAE, Version 4.
The above events should be reported as adverse events.
a Patients on heparin treatment should have a therapeutic aPTT between 1.5 2.5 ULN.  
Patients on coumadin derivatives should have an INR between 2.0 and 3.0 assessed in 
two consecutive measurements 1 4 days apart.  Patients on full-dose low-molecular-weight 
heparins should receive the appropriate dose based on the weight of the patient according to 
package insert.
b Follow guidelines of the treating institution.  Standard procedures such as antagonization with 
protamine or vitamin K and infusion of vitamin K dependent factors should be considered 
dependent on the severity of the bleeding.
c Instructions for Preparation, Administration, and Disposal of Bevacizumab.
d Bevacizumab should be temporarily withheld in the event of Grade 4 febrile neutropenia and/or 
Grade 4 thrombocytopenia (regardless of the relationship to treatment), because these 
conditions are predisposing factors for an increased bleeding tendency.
Preparation and disposal:  Bevacizumab should be prepared per institutional standard 
by a healthcare professional using aseptic technique.  Withdraw the necessary amount 
of bevacizumab and dilute in a total volume of 100 ml of 0.9% sodium chloride injection, 
USP.  If the total bevacizumab dose exceeds 1000 mg, dilute the calculated 
bevacizumab dose with a sufficient amount of 0.9% NaCl solution to keep the final 
concentration at 1.416.5 mg/mL.  Keep 100 mL as the minimal volume administered 
(i.e., minimize the infusion volume as much as possible).  For patients who weigh more 
than 110 kg, refer to the Avastin® Investigator’s Brochure for the infusion preparation for 
this protocol.  Bevacizumab infusions should not be administered or mixed with dextrose 
or glucose solutions.  Discard any unused portion left in a vial, as the product contains 
no preservatives.  Parenteral drug products should be inspected visually for particulate 
matter and discoloration prior to administration.  Diluted bevacizumab should be used 
within 8 hours at room temperature or within 24 hours at 2°C8°C.


Appendix 10
Guidelines for Management of Patients Who Experience Specific 
Adverse Events Associated with Bevacizumab (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
193/Protocol YO39523, Version 8
Administration:  Although no data are available specifically on bevacizumab, in general, 
patients experiencing mild to moderate hypersensitivity/infusion reactions (Grade 1 
or 2 of the NCI CTCAE infusion-related reactions), in particular after the first exposure,
may tolerate re-administration of the agent at reduced infusion rates and with treatment 
using antihistamines and corticosteroids after complete resolution of symptoms.  
Re-challenge is generally discouraged in patients who experienced a severe initial 
reaction (Grade 3 or 4). 
A rate-regulating device should be used for all bevacizumab infusions.  When the 
bevacizumab IV bag is empty, 50 ml of 0.9% sodium chloride solution, USP, will be 
added to the IV bag or an additional bag will be hung, and the infusion will be continued 
for a volume equal to that of the tubing to ensure complete delivery of the bevacizumab.  
The initial dose will be delivered over 90 (15) minutes.  If the first infusion is tolerated 
without any infusion-associated adverse events (i.e., fever and/or chills), the second 
infusion may be delivered over 60 (10) minutes.  If the 60-minute infusion is well 
tolerated, all subsequent infusions may be delivered over 30 (10) minutes.  
Bevacizumab infusions may be slowed or interrupted for patients who experience 
infusion-associated symptoms.  If infusion-related symptoms occur, patients should be 
treated in accordance with the best medical practice, and patients will be monitored until 
adequate resolution of signs and symptoms. The total infusion time, therefore, should 
always be either 90, 60, or 30 minutes.  If more saline is infused, the extent of saline 
infusion does not factor into the trial drug infusion time.
Should extravasation of bevacizumab infusion occur, the following steps should be 
taken: 

Discontinue the infusion.

Treat the extravasation according to institutional guidelines for extravasation of a 
non-caustic agent.  

If a significant volume of bevacizumab remains, restart the infusion at a more 
proximal site in the same limb or on the other side.

Treat the infiltration according to institutional guidelines for infiltration of a 
non-caustic agent.
In the event of a suspected anaphylactic reaction during bevacizumab infusion: 
1.
Stop the trial drug infusion. 
2.
Apply a tourniquet proximal to the injection site to slow systemic absorption of 
bevacizumab.  Do not obstruct arterial flow in the limb. 
3.
Maintain an adequate airway. 


Appendix 10
Guidelines for Management of Patients Who Experience Specific 
Adverse Events Associated with Bevacizumab (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
194/Protocol YO39523, Version 8
4.
Administer antihistamines, corticosteroids, epinephrine, or other medications as 
required. 
5.
Continue to observe the patient, document observations and administer further 
treatment as required.
6.
Permanently discontinue bevacizumab.
Event
Action to be Taken
Proteinuria a
Grade 1 
(urine dipstick 1and either urine 
protein/creatinine ratio of 1.0 or 24-hr 
urine protein collection 
0.15 to1.0 g/24 hr)

No bevacizumab modifications.
Grade 2 
(urine dipstick 2to 3and either urine 
protein/creatinine ratio of 1.0 to3.5 or 
24-hr urine protein collection 1.0 
to3.5 g/24 hr)

For 2dipstick, may administer bevacizumab
and obtain urine protein/creatinine ratio or 24-hr 
urine prior to next dose.

For 3dipstick, obtain urine protein/creatinine 
ratio or 24-hr urine prior to administration of 
bevacizumab.

Hold bevacizumab if urine protein/creatinine 
ratio 2 or 24-hr urine protein 2 g/24 hr.  May 
resume bevacizumab when urine 
protein/creatinine ratio is 2 or 24-hr urine 
protein is 2 g/24 hr.
Grade 3
(urine dipstick 4and either urine 
protein/creatinine ratio of 3.5 or 
urinary protein collection 3.5 g/24 hr)

Hold bevacizumab.  Resume when 
protein/creatinine ratio is 2 or 24-hr urine 
protein is 2 g/24 hr.
a Performing only a urine protein/creatinine ratio or only a 24-hr urine protein collection may be 
performed in lieu of a urine dipstick. For urine dipstick of 2, a confirmatory urine 
protein/creatinine ratio or 24-hr urine protein collection is required.
For context, urine protein/creatinine ratio may be used to establish and monitor 
proteinuria.  The urine protein/creatinine ratio in a spot urine sample has been shown to 
adequately estimate the amount of protein (in grams) excreted in 24 hours of urine.  For 
example, a urine protein/creatinine ratio of 1 is equivalent to a 24-hr urine protein of 
1 gram. 


Appendix 10
Guidelines for Management of Patients Who Experience Specific 
Adverse Events Associated with Bevacizumab (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
195/Protocol YO39523, Version 8
If manually calculating the urine protein/creatinine ratio, one of the following formulae 
can be used, depending on the units in which the urine creatinine is reported:
1.
If both urine protein and urine creatinine are reported in mg/dL, the urine 
protein/creatinine ratio(urine protein) / (urine creatinine)
2.
If urine creatinine is reported in mmol/L, the urine protein/creatinine ratio[(urine 
protein)(0.088)] / (urine creatinine)


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Appendix 11
Response Evaluation Criteria in Solid Tumors, Version 1.1:  
Modified Excerpt from Original Publication
Selected sections from the Response Evaluation Criteria in Solid Tumors (RECIST), 
Version 1.11 are presented below, with slight modifications and the addition of 
explanatory text as needed for clarity.2
MEASURABILITY OF TUMOR AT BASELINE
DEFINITIONS
At baseline, tumor lesions/lymph nodes will be categorized measurable or 
non-measurable as follows.
a.
Measurable Tumor 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 of:

10 mm by CT or MRI scan (CT/MRI scan slice thickness/interval no greater 
than 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 no greater than 5 mm).  At baseline and in follow-up, 
only the short axis will be measured and followed.  See also notes below on “Baseline 
Documentation of Target and Non-Target Lesions” for information on lymph node 
measurement.
b.
Non-Measurable Tumor Lesions
Non-measurable tumor lesions encompass small lesions (longest diameter 10 mm or 
pathological lymph nodes with 10 to 15 mm short axis), 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
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.
2
For consistency within this document, the section numbers and cross-references to other 
sections within the article have been deleted and minor formatting changes have been made.


Appendix 11
Response Evaluation Criteria in Solid Tumors, Version 1.1:  
Modified Excerpt from Original Publication (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
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masses/abdominal organomegaly identified by physical examination that is not 
measurable by reproducible imaging techniques.
c.
Special Considerations Regarding Lesion Measurability
Bone lesions, cystic lesions, and lesions previously treated with local therapy require 
particular comment, as outlined below.
Bone lesions:

Bone scan, positron emission tomography (PET) scan, or plain films are not 
considered adequate imaging techniques to measure 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.  Study protocols should detail the 
conditions under which such lesions would be considered measurable.
TARGET LESIONS:  SPECIFICATIONS BY METHODS OF MEASUREMENTS
a.
Measurement of 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.


Appendix 11
Response Evaluation Criteria in Solid Tumors, Version 1.1:  
Modified Excerpt from Original Publication (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
198/Protocol YO39523, Version 8
b.
Method of Assessment
The same method of assessment and the same technique should be used to 
characterize each identified and reported lesion at baseline and during study.  
Imaging-based evaluation should always be the preferred option.
Clinical Lesions.  Clinical lesions will be considered measurable only when they are 
superficial and 10 mm in diameter as assessed using calipers (e.g., skin nodules).  
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, MRI.  CT is the best currently available and reproducible method to measure lesions 
selected for response assessment.  This guideline has defined measurability of lesions 
on CT scan on the basis of the assumption that CT slice thickness is 5 mm or less.  
When CT scans have slice thickness greater than 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 on a different modality 
and interpretation of non-target disease or new lesions since the same lesion may 
appear to have a different size using a new modality.
Ultrasound.  Ultrasound is not useful in assessment of lesion size and should not be 
used as a method of measurement.
Endoscopy, Laparoscopy, Tumor Markers, Cytology, Histology.  The utilization of 
these techniques for objective tumor evaluation cannot generally be advised.


Appendix 11
Response Evaluation Criteria in Solid Tumors, Version 1.1:  
Modified Excerpt from Original Publication (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
199/Protocol YO39523, Version 8
TUMOR RESPONSE EVALUATION
ASSESSMENT OF OVERALL TUMOR BURDEN AND 
MEASURABLE DISEASE
To assess objective response or future progression, it is necessary to estimate the 
overall tumor burden at baseline and to use this as a comparator for subsequent 
measurements.  Measurable disease is defined by the presence of at least 
one measurable lesion, as detailed above.
BASELINE DOCUMENTATION 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 in instances where 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 
recorded as non-target lesions (even if the size is 10 mm by CT scan).
Target lesions should be selected on the basis of their size (lesions with the longest 
diameter) and be representative of all involved organs but, additionally, 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.  Nodal size is normally 
reported as two dimensions in the plane in which the image is obtained (for CT scan, 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 
10 mm are considered non-pathological and should not be recorded or followed.


Appendix 11
Response Evaluation Criteria in Solid Tumors, Version 1.1:  
Modified Excerpt from Original Publication (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
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Lesions irradiated within 3 weeks prior to Cycle 1, Day 1 may not be counted as target 
lesions.
A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all 
target lesions will be calculated and reported as the baseline sum of diameters.  If lymph 
nodes are to be included in the sum, then, as noted above, only the short axis is added 
into the sum.  The baseline sum of diameters will be used as a reference to further 
characterize any objective tumor regression in the measurable dimension of the disease.
All other lesions (or sites of disease), including pathological lymph nodes, should be 
identified as non-target lesions and should also be recorded at baseline.  Measurements 
are not required and these lesions should be followed as “present,” “absent,” or in rare 
cases “unequivocal progression.”
In addition, it is possible to record multiple non-target lesions involving the same organ 
as a single item on the Case Report Form (CRF) (e.g., “multiple enlarged pelvic lymph 
nodes” or “multiple liver metastases”).
RESPONSE CRITERIA
a.
Evaluation of Target Lesions
This section provides the definitions of the criteria used to determine objective tumor 
response for target lesions.

Complete response (CR):  disappearance of all target lesions
Any pathological lymph nodes (whether target or non-target) must have 
reduction in short axis to 10 mm.

Partial response (PR):  at least a 30% decrease in the sum of diameters of target 
lesions, taking as reference the baseline sum of diameters

Progressive disease (PD):  at least a 20% increase in the sum of diameters of target 
lesions, taking as reference the smallest sum on study (nadir), including baseline
In addition to the relative increase of 20%, the sum must also demonstrate 
an absolute increase of at least 5 mm.
The appearance of one or more new lesions is also considered progression.

Stable disease (SD):  neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest sum on study
b.
Special Notes on the Assessment of Target Lesions
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 


Appendix 11
Response Evaluation Criteria in Solid Tumors, Version 1.1:  
Modified Excerpt from Original Publication (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
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baseline examination), even if the nodes regress to 10 mm on study.  This means that 
when lymph nodes are included as target lesions, the sum of lesions may not be zero 
even if CR criteria are met since a normal lymph node is defined as having a short axis 
10 mm.
Target Lesions That Become Too Small to Measure.  While on study, all lesions 
(nodal and non-nodal) 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 measure 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 BML (below measurable limit) 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 BML should also be ticked.)
To reiterate, however, if the radiologist is able to provide an actual measure, that should 
be recorded, even if it is below 5 mm, and, in that case, BML should not be ticked.
Lesions That Split or Coalesce on Treatment.  When non-nodal lesions fragment, the 
longest diameters of the fragmented portions should be added together to calculate the 
target lesion sum.  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 maximal 
longest diameter for the coalesced lesion.
c.
Evaluation of Non-Target Lesions
This section provides the definitions of the criteria used to determine the tumor response 
for the group of non-target lesions.  Although 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 protocol.

CR:  disappearance of all non-target lesions and (if applicable) normalization of 
tumor marker level)


Appendix 11
Response Evaluation Criteria in Solid Tumors, Version 1.1:  
Modified Excerpt from Original Publication (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
202/Protocol YO39523, Version 8
All lymph nodes must be non-pathological in size (10 mm short axis).

Non-CR/Non-PD:  persistence of one or more non-target lesion(s) and/or 
(if applicable) maintenance of tumor marker level above the normal limits

PD:  unequivocal progression of existing non-target lesions
The appearance of one or more new lesions is also considered progression.
d.
Special Notes on Assessment of Progression of Non-Target Disease
When the Patient Also Has Measurable Disease.  In this setting, to achieve 
unequivocal progression on the basis of the non-target disease, there must be an overall 
level of substantial worsening in non-target disease in a magnitude that, even in the 
presence of SD or PR in target disease, 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 disease in the face of SD or PR of target disease will therefore be extremely 
rare.
When the Patient Has Only Non-Measurable Disease.  This circumstance arises in 
some Phase III studies when it is not a criterion of study entry to have measurable 
disease.  The same general concepts apply here 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-target 
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 or may be described in protocols as “sufficient to require a 
change in therapy.”  If unequivocal progression is seen, the patient should be considered 
to have had overall PD at that point.  Although 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.
e.
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 


Appendix 11
Response Evaluation Criteria in Solid Tumors, Version 1.1:  
Modified Excerpt from Original Publication (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
203/Protocol YO39523, Version 8
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, then progression should be declared using the date of 
the initial scan.
EVALUATION OF RESPONSE
a.
Timepoint Response (Overall Response)
It is assumed that at each protocol-specified timepoint, a response assessment occurs.  
Table 1 provides a summary of the overall response status calculation at each timepoint 
for patients who have measurable disease at baseline.
When patients have non-measurable (therefore non-target) disease only, Table 2 is to 
be used.


Appendix 11
Response Evaluation Criteria in Solid Tumors, Version 1.1:  
Modified Excerpt from Original Publication (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
204/Protocol YO39523, Version 8
Table 1
Timepoint Response:  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 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.
Table 2
Timepoint Response:  Patients with Non-Target Lesions Only
Non-Target Lesions
New Lesions
Overall Response
CR
No
CR
Non-CR/non-PD
No
Non-CR/non-PD a
Not all evaluated
No
NE
Unequivocal PD
Yes or no
PD
Any
Yes
PD
CRcomplete response; NEnot evaluable; PDprogressive disease.
a “Non-CR/non-PD” is preferred over “stable disease” for non-target 
disease since stable disease is increasingly used as an endpoint for 
assessment of efficacy in some studies; thus, assigning “stable disease” 
when no lesions can be measured is not advised.
b.
Missing Assessments and Not-Evaluable Designation
When no imaging/measurement is done at all at a particular timepoint, the patient is not 
evaluable at that timepoint.  If only a subset of lesion measurements are made at an 
assessment, usually the case is also considered not evaluable at that timepoint, unless a 
convincing argument can be made that the contribution of the individual missing 
lesion(s) would not change the assigned timepoint response.  This would be most likely 


Appendix 11
Response Evaluation Criteria in Solid Tumors, Version 1.1:  
Modified Excerpt from Original Publication (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
205/Protocol YO39523, Version 8
to happen in the case of PD.  For example, if a patient had a baseline sum of 50 mm 
with three measured lesions and, during the study, only two lesions were assessed, but 
those gave a sum of 80 mm; the patient will have achieved PD status, regardless of the 
contribution of the missing lesion.
If one or more target lesions were not assessed either because the scan was not done 
or the scan could not be assessed because of poor image quality or obstructed view, the 
response for target lesions should be “unable to assess” since the patient is not 
evaluable.  Similarly, if one or more non-target lesions are not assessed, the response 
for non-target lesions should be “unable to assess” except where there is clear 
progression.  Overall response would be “unable to assess” if either the target response 
or the non-target response is “unable to assess,” except where this is clear evidence of 
progression as this equates with the case being not evaluable at that timepoint.


Appendix 11
Response Evaluation Criteria in Solid Tumors, Version 1.1:  
Modified Excerpt from Original Publication (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
206/Protocol YO39523, Version 8
Table 3
Best Overall Response When Confirmation Is Required
Overall Response at 
First Timepoint
Overall Response at 
Subsequent Timepoint
Best Overall Response
CR
CR
CR
CR
PR
SD, PD, or PR a
CR
SD
SD, provided minimum duration for SD 
was met; otherwise, PD
CR
PD
SD, provided minimum duration for SD 
was met; otherwise, PD
CR
NE
SD, provided minimum duration for SD 
was met; otherwise, NE
PR
CR
PR
PR
PR
PR
PR
SD
SD
PR
PD
SD, provided minimum duration for SD 
was met; otherwise, PD
PR
NE
SD, provided minimum duration for SD 
was met; otherwise, NE
NE
NE
NE
CRcomplete response; NEnot evaluable; PDprogressive disease; PRpartial response; 
SDstable disease.
a If a CR is truly met at the first timepoint, any disease seen at a subsequent timepoint, 
even disease meeting PR criteria relative to baseline, qualifies as PD at that point 
(since disease must have reappeared after CR).  Best response would depend on whether 
the minimum duration for SD was met.  However, sometimes CR may be claimed when 
subsequent scans suggest small lesions were likely still present and in fact the patient had 
PR, not CR, at the first timepoint.  Under these circumstances, the original CR should be 
changed to PR and the best response is PR.
c.
Special Notes on Response Assessment
When nodal disease is included in the sum of target lesions and the nodes decrease to 
“normal” size (10 mm), they may still have a measurement reported on scans.  This 
measurement should be recorded even though the nodes are normal in order not to 
overstate progression should it be based on increase in size of the nodes.  As noted 
earlier, this means that patients with CR may not have a total sum of “zero” on the CRF.
Patients with a global deterioration of 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 


Appendix 11
Response Evaluation Criteria in Solid Tumors, Version 1.1:  
Modified Excerpt from Original Publication (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
207/Protocol YO39523, Version 8
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 disease as shown in Tables 13.
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.
If a patient undergoes an excisional biopsy or other appropriate approach (e.g., multiple 
passes with large core needle) of a new lesion or an existing solitary progressive lesion 
that following serial sectioning and pathological examination reveals no evidence of 
malignancy (e.g., inflammatory cells, fibrosis, etc.), then the new lesion or solitary 
progressive lesion will not constitute disease progression.
In studies for which patients with advanced disease are eligible (i.e., primary disease still 
or partially present), the primary tumor should also be captured as a target or non target 
lesion, as appropriate.  This is to avoid an incorrect assessment of CR if the primary 
tumor is still present but not evaluated as a target or non-target lesion. 


Atezolizumab—F. Hoffmann-La Roche Ltd
208/Protocol YO39523, Version 8
Appendix 12
Patient Questionnaire FACT-G Item GP5
Do not reproduce or distribute.  The Sponsor will provide sites with all instruments to be 
completed in this study.


Atezolizumab—F. Hoffmann-La Roche Ltd
209/Protocol YO39523, Version 8
Appendix 13
Ovarian Pathology Handbook
Pathology v1, Jul 2017.
Ovarian Pathology Handbook
YO39523/GOG-3015/ENGOT-ov39 Ovarian Pathology
This guide serves to help identify morphological changes indicative of
residual disease in ovarian cancer patients following neoadjuvant
treatment.
Background: Tumor cells may demonstrate nuclear alterations such
as enlargement, hyperchromasia, chromatin clumping and smudging,
eosinophilia, and vacuolization with foamy/clear cell changes.
Stromal alterations consist of dense fibrosis, inflammation, foamy
histiocytes, cholesterol clefts, necrosis, and dystrophic calcifications.
Similar morphologic changes associated with neoadjuvant
chemotherapy or chemoradiation in other sites (e.g., pancreas,
breast, rectum, esophagus) have also been described [Chang 2008,
Becker 2003, Junker 2001, Hartman 2012].
Four easily reproducible histological characteristics, seen by
hematoxylin-eosin, have been identified and may be associated with
clinical outcome: Residual Tumor (RT), Fibrosis, Necrosis and
Inflammation [Samrao 2012]. A scoring system has been developed to
assessing the parameters in each tissue section (see over the page).
Should you have any questions about the content or use of this material,
please contact:
MD, MS at Genentech
Email:
Slides from each site must be evaluated for:
> Residual Tumor
> Fibrosis
> Necrosis
> Inflammation
All slides from each of the following sites must be
evaluated by H&E:
1. Omentum
2. Left pericolic or pelvic peritoneum
3. Right pericolic or pelvic peritoneum
4. Cul de sac peritoneum
5. Left or Right ovary
6. The location of the disease initially making this disease
unresectable to no gross residual disease (R0) in primary
tumor reductive surgery
This handbook was developed by
, MD, MS
, Genentech – A member of the Roche family) and
, MD
)



SAP_001.pdf: 
 
Official Title: 
A Phase III, Multicenter, Randomized, Study of Atezolizumab Versus 
Placebo Administered in Combination With Paclitaxel, Carboplatin, 
and Bevacizumab to Patients With Newly-Diagnosed Stage III or 
Stage IV Ovarian, Fallopian Tube, or Primary Peritoneal Cancer 
NCT Number: 
NCT03038100 
Document Date: 
SAP Version 3: 06-Dec-2021 
 
 
 


STATISTICAL ANALYSIS PLAN AMENDMENT 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.
Atezolizumab—F. Hoffmann-La Roche Ltd
Statistical Analysis Plan YO39523
STATISTICAL ANALYSIS PLAN
TITLE:
A PHASE III, MULTICENTER, RANDOMIZED, STUDY OF 
ATEZOLIZUMAB VERSUS PLACEBO ADMINISTERED IN 
COMBINATION WITH PACLITAXEL, CARBOPLATIN, AND 
BEVACIZUMAB TO PATIENTS WITH NEWLY-DIAGNOSED 
STAGE III OR STAGE IV OVARIAN, FALLOPIAN TUBE, OR 
PRIMARY PERITONEAL CANCER
PROTOCOL NUMBER:
YO39523 (GOG-3015, ENGOTov39)
STUDY DRUG:
Atezolizumab (RO5541267)
VERSION NUMBER:
3
IND NUMBER:
130637
EUDRACT NUMBER:
2016-003472-52
SPONSOR:
F. Hoffmann-La Roche Ltd
PLAN PREPARED BY:
, M.S.
DATE FINAL:
Version 1: 16 September 2019
DATE AMENDED
Version 2: 14 November 2019
Version 3: See electronic date stamp below
Date and Time(UTC)        Reason for Signing                              Name
Company Signatory
06-Dec-2021 16:03:42


Atezolizumab—F. Hoffmann-La Roche Ltd
2/Statistical Analysis Plan YO39523
STATISTICAL ANALYSIS PLAN AMENDMENT
RATIONALE
This Statistical Analysis Plan (SAP) Version 3 for Study YO39523 has been amended to 
incorporate a following change:

In Section 2.5, additional description of End of Study has been included 
Additional minor changes have been made to improve clarity and consistency.


Atezolizumab—F. Hoffmann-La Roche Ltd
3/Statistical Analysis Plan YO39523
TABLE OF CONTENTS
STATISTICAL ANALYSIS PLAN AMENDMENT RATIONALE............................. 2
1.
BACKGROUND ............................................................................................ 6
2.
STUDY DESIGN........................................................................................... 6
2.1
Study Objectives...................................................................... 8
2.2
Protocol Synopsis.................................................................. 11
2.2.1
Endpoints............................................................................... 11
2.3
Type I Error Control............................................................... 11
2.4
Determination of Sample Size ............................................... 13
2.4.1
Assumptions.......................................................................... 14
2.4.2
Co-Primary Endpoint:  Progression-Free Survival................. 14
2.4.3
Co-Primary Endpoint:  Overall Survival ................................. 14
2.4.4
Sample Size for the China Extension Period......................... 14
2.5
End of Study.......................................................................... 15
3.
STUDY CONDUCT..................................................................................... 15
3.1
Randomization....................................................................... 15
3.2
Data Monitoring ..................................................................... 15
4.
STATISTICAL METHODS .......................................................................... 16
4.1
Analysis Populations ............................................................. 16
4.2
Analysis of Study Conduct..................................................... 16
4.3
Analysis of Treatment Group Comparability .......................... 16
4.4
Efficacy Analysis.................................................................... 17
4.4.1
Primary Efficacy Endpoint...................................................... 17
4.4.1.1
Progression-Free Survival ..................................................... 17
4.4.1.2
Overall Survival ..................................................................... 17
4.5
Independent Review Facility.................................................. 18
4.5.1
Secondary Efficacy Endpoints............................................... 18
4.5.1.1
Objective Response Rate (ORR)........................................... 18
4.5.1.2
Duration of Objective Response............................................ 18
4.5.1.3
Patient-Reported Outcomes Disease Symptoms, 
Function and Health-Related Quality of Life 
EORTC Data ......................................................................... 19


Atezolizumab—F. Hoffmann-La Roche Ltd
4/Statistical Analysis Plan YO39523
4.5.2
Sensitivity Analyses............................................................... 20
4.5.2.1
Sensitivity Analyses of Progression-Free Survival................. 21
4.5.2.2
Sensitivity Analyses of Overall Survival................................. 21
4.5.3
Subgroup Analyses ............................................................... 21
4.5.4
Exploratory Analyses............................................................. 22
4.5.4.1
Exploratory Patient-Reported Outcomes 
Analyses................................................................................ 22
4.5.4.2
Exploratory Biomarker Analyses............................................ 24
4.6
Pharmacokinetic and Pharmacodynamic 
Analyses................................................................................ 24
4.7
Safety Analyses..................................................................... 24
4.7.1
Exposure of Study Medication............................................... 24
4.7.2
Adverse Events ..................................................................... 24
4.7.3
Laboratory Data..................................................................... 25
4.7.4
Vital Signs and ECOG Performance Status........................... 26
4.7.5
Anti-Drug Antibody ................................................................ 26
4.8
Missing Data.......................................................................... 26
4.9
Interim Analyses .................................................................... 26
4.9.1
Overall Survival ..................................................................... 26
5.
CHINA SUBGROUP ANALYSIS................................................................. 27
6.
REFERENCES ........................................................................................... 29
LIST OF TABLES
Table 1
Objectives and Corresponding Endpoints..................................... 8
Table 2
Interim and Final Analyses of Overall Survival............................ 27
LIST OF FIGURES
Figure 1
Study Schema for Patients in the Primary Tumor-Reductive 
Surgery Group .............................................................................. 7
Figure 2
Study Schema for Patients in the Neoadjuvant 
Chemotherapy Group ................................................................... 7
Figure 3
Overall of Type I Error Control .................................................... 13




Atezolizumab—F. Hoffmann-La Roche Ltd
6/Statistical Analysis Plan YO39523
1.
BACKGROUND
This Statistical Analysis Plan (SAP) describes the analyses that are planned to be 
performed for the Clinical Study Report (CSR) of Study YO39523 (IMagyn050).
It is anticipated that positive results from Study YO39523 will support the submission of 
filing applications globally for the use of atezolizumab in combination with paclitaxel, 
carboplatin, and bevacizumab in patients with newly diagnosed Stage III or Stage IV
ovarian, fallopian tube, or primary peritoneal cancer. For purposes of registration, the 
analyses outlined in this SAP will supersede those specified in the Protocol.
Please refer to Section 1 of the Protocol for more details about atezolizumab and the study 
rationale of Study YO39523.
2.
STUDY DESIGN
This is a Phase III double-blind, two-arm, randomized study designed to evaluate the 
efficacy 
and 
safety 
of 
atezolizumab 
(1200 mg) 
administered 
with 
paclitaxel (175 mg/m2)carboplatin (area under the concentrationtime curve at 
6 [AUC 6]) bevacizumab (15 mg/kg) compared with placebopaclitaxel carboplatin
bevacizumab in patients with Stage III or Stage IV ovarian, fallopian tube, or primary 
peritoneal cancer with macroscopic residual disease postoperatively (i.e., after primary 
tumor reductive surgery) or who will undergo neoadjuvant therapy followed by interval 
surgery.  Approximately 1300 patients will be randomized, in a 1:1 ratio, to one of the two 
treatment arms. After the enrollment of global cohort finishes, additional Chinese patients 
from mainland China might continue to enroll into the China extension cohort. Chinese 
patients enrolled in global cohort combined with patients in China extension cohort will 
consist of China subgroup. 
More details about the study design could be found in Appendix 1, Protocol Synopsis.
Figure 1 and Figure 2 illustrate the study design.


Atezolizumab—F. Hoffmann-La Roche Ltd
7/Statistical Analysis Plan YO39523
Figure 1
Study Schema for Patients in the Primary Tumor-Reductive 
Surgery Group
AUC area under the concentrationtime curve; Dx diagnosis; ECOG PS Eastern Cooperative 
Oncology Group performance status; OS overall survival; PFS progression-free survival; 
PD-L1 programmed deathligand 1; q3wevery 3 weeks.
Figure 2
Study Schema for Patients in the Neoadjuvant 
Chemotherapy Group
AUC area under the concentrationtime curve; q3wevery 3 weeks.
Patients will undergo a mandatory tumor biopsy sample collection, if clinically feasible, 
at the time of first evidence of radiographic disease progression according to Response 
Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST v1.1).  Cytology from ascites, 


Atezolizumab—F. Hoffmann-La Roche Ltd
8/Statistical Analysis Plan YO39523
pleural effusion, and fine needle aspiration (FNA) is not adequate.  These samples will be 
retrospectively analyzed to evaluate and/or characterize pseudoprogression caused by 
immune cells (ICs) from true progression.  In addition, tumor tissue biomarkers related to 
resistance, disease progression, and clinical benefit of atezolizumab will be analyzed.
2.1
STUDY OBJECTIVES
Study objectives and corresponding endpoints for the study are outlined below (Table 1).
Table 1
Objectives and Corresponding Endpoints
Primary Efficacy Objective
Corresponding Endpoints
To evaluate the efficacy of atezolizumab 
versus placebo in combination with 
paclitaxel carboplatin bevacizumab 
among all patients and in those patients 
with PD-L1positive tumors 
Investigator-assessed PFS, defined as the time 
from randomization to the occurrence of disease 
progression, as determined by the investigator from 
tumor assessments per RECIST v1.1, or death 
from any cause during the study, whichever occurs 
first
OS, defined as the time from randomization to 
death from any cause 
Secondary Efficacy Objectives
Corresponding Endpoints
Among patients with measurable residual disease in the primary surgery group*:
To evaluate the efficacy of atezolizumab 
versus placebo in combination with 
paclitaxel carboplatin bevacizumab 
among all patients and in those patients 
with PD-L1positive tumors
OR, defined for primary surgery patients with 
measurable disease at baseline who achieved a 
documented unconfirmed response [i.e., either a 
partial response (PR) or a complete response (CR)] 
on the basis of investigator assessment using 
RECIST v1.1. 
To evaluate the duration of efficacy 
observed with atezolizumab versus 
placebo in combination with 
paclitaxel carboplatin bevacizumab 
among all patients and in those patients 
with PD-L1positive tumors
DOR, is defined for primary surgery patients who 
had an objective response as the time from the first 
occurrence of a documented unconfirmed response 
(CR or PR) to the date of disease progression on 
the basis of investigator assessment using 
RECIST v1.1 or death from any cause, whichever 
occurs first.  


Atezolizumab—F. Hoffmann-La Roche Ltd
9/Statistical Analysis Plan YO39523
Table 1
Objectives and Corresponding Endpoints (cont.)
Secondary Efficacy Objectives (cont.)
Corresponding Endpoints (cont.)
Among the patients in the neoadjuvant group:
To determine the impact of atezolizumab 
versus placebo in combination with 
paclitaxel carboplatin bevacizumab on 
patient-reported abdominal symptoms of 
OC, as measured by two items from the 
abdominal/GI symptom scale of the 
EORTC QLQ-OV28
Among the patients in the primary surgery 
and neoadjuvant group:
Proportion of patients with clinically-meaningful 
improvement in patient-reported abdominal pain 
or bloating, defined as a 10-point decrease from 
the baseline score on either of the two items on 
the EORTC QLQ-OV28 abdominal/GI symptom 
scale (items 31 and 32)
To evaluate PROs of HRQoL associated 
with atezolizumab versus placebo in 
combination with 
paclitaxel carboplatin bevacizumab, as 
measured by the functional and global 
health status (GHS)/QoL scales of the 
EORTC QLQ-C30
In the neoadjuvant group:  Proportion of patients 
with clinically-meaningful improvement in patient-
reported function and HRQoL, defined as a 
10-point increase from the baseline score on 
each of the functional (physical, role, emotional, 
and social) and GHS/QoL scales of 
the EORTC QLQ-C30
In the primary surgery group:  Proportion of 
patients with clinical improvement, remaining
stable, or deterioration in patient-reported function 
and HRQoL, defined as a 10-point increase, 
changes within 10 points, and a 10-point 
decrease, respectively, from the baseline score 
on each of the functional (physical, role, 
emotional, and social) and GHS/QoL scales of the 
EORTC QLQ-C30
Safety Objective
Corresponding Endpoints
To evaluate the safety and tolerability of 
atezolizumab versus placebo in 
combination with 
paclitaxel carboplatin bevacizumab
Occurrence and severity of adverse events, with 
severity determined in accordance to 
NCI CTCAE v4.0
Change from baseline in targeted vital signs
Change from baseline in targeted clinical 
laboratory test results 
Pharmacokinetic Objective
Corresponding Endpoint
To characterize the pharmacokinetics of 
atezolizumab when administered in 
combination with 
paclitaxel carboplatin bevacizumab
Minimum and maximum serum concentration of 
atezolizumab


Atezolizumab—F. Hoffmann-La Roche Ltd
10/Statistical Analysis Plan YO39523
Table 1
Objectives and Corresponding Endpoints (cont.)
Exploratory Objectives
Corresponding Endpoints
Among neoadjuvant patients only: To 
evaluate PCR status and its association 
with clinical outcomes after 
administration of atezolizumab versus 
placebo in combination with 
paclitaxel carboplatin bevacizumab
Among patients who undergo neoadjuvant 
therapy prior to interval surgery, PCR status is 
defined as the clinical amount and histologic 
characteristics of residual disease assessed at 
the time of interval cytoreductive surgery
To evaluate the efficacy of atezolizumab 
versus placebo administered in 
combination with 
paclitaxelcarboplatinbevacizumab
The OS rate at 3 years after randomization
To evaluate PROs of disease 
and/or treatment-related symptoms 
associated with atezolizumab 
versus placebo administered in 
combination with 
paclitaxel carboplatin bevacizumab, 
as measured by the EORTC QLQ-C30 
and QLQ-OV28
Mean and mean changes from the baseline score 
in disease and/or treatment-related symptoms by 
cycle and between treatment arms as assessed 
by all symptom items and/or scales of the 
EORTC QLQ-C30 and QLQ-OV28
To evaluate any treatment burden 
patients may experience in association 
with the addition of atezolizumab to 
paclitaxel carboplatin bevacizumab 
compared with 
placebo paclitaxel carboplatin 
bevacizumab, as measured by a 
single item (from GP5: "I am bothered by 
side effects of treatment") from the 
physical wellbeing subscale of the 
FACT-G Quality of Life instrument
Proportion of patients reporting each response 
option at each assessment timepoint by treatment 
arm for item GP5 from the FACT-G


Atezolizumab—F. Hoffmann-La Roche Ltd
11/Statistical Analysis Plan YO39523
Table 1
Objectives and Corresponding Endpoints (cont.)
Immunogenicity Objective
Corresponding Endpoint
To evaluate the immune response from 
patients who were administered 
atezolizumab
The incidence of ADAs against atezolizumab 
during treatment with atezolizumab administered 
in combination with 
paclitaxel carboplatin bevacizumab relative to 
the incidence of ADAs at the baseline
Exploratory Immunogenicity Objective
Corresponding Endpoint
To evaluate the potential effects of ADAs 
The relationship between ADA status and 
pharmacokinetics, safety, and efficacy
ADAanti-drug antibody; CRcomplete response; DORduration of response; 
EORTCEuropean Organisation for Research and Treatment of Cancer; EQ-5D-5LEuroQoL 
5 Dimension, 5 Level Questionnaire; FACT-GFunctional Assessment of Cancer 
Therapy-General; GIgastrointestinal; HRQoLhealth-related quality of life; 
IHCimmunohistochemistry; PCR pathologic and clinical response; NCI CTCAENational 
Cancer Institute Common Terminology Criteria for Adverse Events; NGSnext-generation 
sequencing; OCovarian cancer; ORobjective response; OSoverall survival; 
PFSprogression-free survival; PRpartial response; PRO patient-report outcome; 
QLQ-C30Quality of Life Questionnaire Core 30; QLQ-OV28Quality of Life Questionnaire 
Ovarian Cancer Module 28; RECIST v1.1Response Evaluation Criteria in Solid Tumors, 
Version 1.1.
2.2
PROTOCOL SYNOPSIS
The Protocol Synopsis is in Appendix 1.  For additional details, see the Schedules of 
Assessments in Appendix 2, Appendix 3, and Appendix 4.
2.2.1
Endpoints
See the Protocol Synopsis in Appendix 1 for a description of the primary outcome 
measures.
2.3
TYPE I ERROR CONTROL
The type I error (alpha []) for this study is 0.05 (two-sided).  Type I error will be controlled 
for the following efficacy endpoints in intent-to-treat (ITT) and programmed deathligand 1 
(PDL1)positive populations: 

Co-primary efficacy endpoint of investigator-assessed progression-free survival 
(PFS) by RECIST v1.1 (ITT and PD-L1-positive populations).

Co-primary efficacy endpoint of overall survival (OS) (ITT and PD-L1-positive
populations).
In IMagyn050, the control of type I error rate at 5% is performed using a combination of 
alpha split and hierarchical testing procedures. The alpha of this study is fully controlled 
by the closed test procedure (Dmitrienko et al. 2013).
Based on the potential scenarios regarding the alpha level for the final analysis of OS, the 
boundaries for statistical significance and the expected timing of each interim analyses 


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and the final analysis were determined based on the Lan-DeMets implementation of the 
O’Brien-Fleming use function (DeMets et al. 1994).
Interim analyses are described in 
Section 4.9.1.
The alpha level for OS was determined at the time of the primary PFS analysis. The total 
alpha (0.05) was divided among the two co-primary endpoints composed of PFS tested 
in the intent-to-treat (ITT) and PD-L1-positive population (PFS0.004) and in the ITT 
(OS0.046), and maintained a fixed sequence for the testing (i.e., PFS in ITT and PD-L1-
positive tested first) as per Figure 3.




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subgroup and the ITT population are listed in Appendix 4 for other significance levels that 
could be assigned to the OS analyses.
2.4.1
Assumptions
The calculation of the sample size and estimates of the analysis timelines are based on 
the following assumptions:

PFS and OS are exponentially distributed.

The median duration of PFS in the control arm is 18 months.

The median duration of OS in the control arm is 43 months.

The prevalence of PDL1positive (IC1/2/3) patients is 60%.

The two interim and final analyses of OS use the Lan-DeMets alpha spending 
function to approximate the O’Brien-Fleming boundary.

The dropout rate is 5% over 12 months for PFS and OS.

The recruitment of 1300 patients will take place over 25 months.
2.4.2
Co-Primary Endpoint:  Progression-Free Survival
The primary analysis of PFS will take place when approximately 601 PFS events in the 
ITT and 347 PFS events in the PDL1positive subgroup have occurred, which is 
expected at approximately 36 months after the first patient is enrolled in the study.  
This provides 90% power to detect a PFS improvement of HR0.7 in the ITT population, 
and 91% power in the PDL1positive subgroup with HR0.62, at a two-sided 
significance level of 0.002.
2.4.3
Co-Primary Endpoint: Overall Survival
The numbers of patient deaths needed for the OS analyses in the PDL1positive 
subgroup and the ITT population are listed in Section 4.9.1 for possible significance levels 
that could be assigned to the OS analyses. For example, to detect an improvement in OS 
with the use of a log-rank test at a two-sided significance level of 0.046, approximately 
311 deaths in the PD-L1positive subgroup will be required to achieve 81% power with a 
target HR of 0.72, and approximately 534 deaths in the ITT population to achieve 80% 
power with a target HR of 0.78.
Two interim analyses of OS will be performed on patients who are in the ITT and 
PD-L1positive populations. The timing of the two interim analyses and the final analysis 
for OS depends on the results from the primary analysis of the co-primary endpoint of PFS, 
which is listed in Section 4.9.1 and includes the pre-specified boundaries for the different 
scenarios.
2.4.4
Sample Size for the China Extension Period
Refer to Section 6.9 of the Protocol for more details.


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2.5
END OF STUDY
The study will continue until the approximate pre-planned numbers of deaths among the 
PD-L1-positive patients and the ITT population have been observed (see Appendix 4 of 
the study protocol). In addition, the Sponsor has the right to close the study at any time if 
futility is observed (e.g., based on the predicted probability of success at the subsequent 
analysis).
3.
STUDY CONDUCT
3.1
RANDOMIZATION
Randomization occurs in a 1:1 ratio using a permuted-block randomization method into 
one of two treatment arms:  atezolizumabpaclitaxelcarboplatinbevacizumab or 
placebopaclitaxel carboplatinbevacizumab. The randomization scheme is designed 
to ensure that an approximately equal number of patients will be enrolled in each treatment 
arm within the baseline characteristics of the following stratification factors:

Stage and/or residual disease status (Stage III vs. Stage IV)

Eastern Cooperative Oncology Group (ECOG) performance status (0 vs. 1 or 2)

Tumor PD-L1 status (IC0 vs. IC1/2/3)

Treatment strategy (adjuvant vs. neoadjuvant)
3.2
DATA MONITORING
An independent Data Monitoring Committee (iDMC) will monitor safety and study conduct 
on a periodic basis.  Members of the iDMC will be external to the Sponsor and will follow 
a charter that outlines their roles and responsibilities.  The iDMC will meet approximately 
every 6 months from the point of FPI to review unblinded safety and study conduct data 
prepared by an independent Data Coordinating Center (iDCC).  The safety data will 
include demographic data, adverse events (AEs), serious adverse events (SAEs), and 
relevant laboratory data.
Following each data review, the iDMC will provide recommendations to the Sponsor as to 
whether the study should continue or be amended, or whether the study should be 
stopped on the basis of safety (i.e., evidence of harm).  The Sponsor’s Data Review Board 
(DRB; a group consisting of employees of the Sponsor empowered to make critical 
decisions) will make a decision on the basis of the iDMC’s recommendations.  The DRB 
of the Sponsor will either accept or reject this recommendation. The final decision will rest 
with the Sponsor. 
Any outcomes of these safety reviews that affect study conduct will be communicated in 
a timely manner to the investigators for notification of the Institutional Review 
Boards/Ethics Committees (IRBs/ECs).
Members of the iDMC will be external to the Sponsor and will follow a separate iDMC 
Charter that outlines their roles and responsibilities, as well as a detailed monitoring plan. 


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In addition, iDMC will make assessment respect to the PFS audit strategy, and send their 
recommendation to the Sponsor without revealing any numeric value (see Appendix 5).
4.
STATISTICAL METHODS
4.1
ANALYSIS POPULATIONS
The analysis populations are defined as follows:

The ITT population is defined as all randomized patients, whether or not the 
assigned study treatment was received.

The PD-L1-positive subpopulation is defined as patients in the ITT population whose 
PD-L1 status is IC1/2/3 at the time of randomization.

The ORR-evaluable population is defined as primary surgery patients in the ITT 
population with measurable disease at baseline.

The PD-L1ORR-evaluable population is defined as primary surgery patients in the 
PD-L1-positive subpopulation with measurable disease at baseline.

The duration of response (DOR)-evaluable population is defined as patients with an 
objective response.

The patient-reported outcome (PRO)-evaluable population is defined as patients in 
the ITT population with a baseline and 1 post-baseline PRO assessment.

The safety-evaluable population is defined as patients who received any amount of 
any study drug.

The pharmacokinetic (PK)-evaluable population is defined as all patients who 
received any dose of study medication and who have at least one post-baseline 
PK sample available.
For all efficacy analyses, patients will be grouped according to the treatment assigned at 
randomization.
For safety analyses, patients will be grouped according to whether any amount of 
atezolizumab was received, including cases in which atezolizumab was received in error.
4.2
ANALYSIS OF STUDY CONDUCT
Study enrollment, patient disposition, reasons for discontinuation from the study treatment 
and reason for study termination will be summarized for all patients in the ITT population.
Protocol deviations, including violations of inclusion/exclusion criteria and deviations 
during study conduct will be reported and summarized.
4.3
ANALYSIS OF TREATMENT GROUP COMPARABILITY
Demographics, baseline disease characteristics, and ovarian cancer history will be 
compared between both treatment arms.  Descriptive baseline summaries of continuous 
data will present the group mean, standard deviation, median, ranges and inter-quartile 


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ranges, as appropriate.  Descriptive baseline summaries of discrete data will present the 
category counts as frequencies and percentages.
The baseline value of any efficacy variable will be defined as the last available value 
recorded prior to randomization.
The baseline value of any non-efficacy variable will be defined as the last available value 
recorded prior to the first administration of study medication.
Previous and concomitant cancer therapy will also be summarized, including radiotherapy 
and surgery, as well as subsequent anti-cancer therapy.  Previous and concurrent 
diseases and medications will also be summarized.
4.4
EFFICACY ANALYSIS
All efficacy analyses will be performed on both the ITT population and PD-L1-positive
subpopulation.
4.4.1
Primary Efficacy Endpoint
4.4.1.1
Progression-Free Survival
Progression-free survival (PFS) is defined as the time from randomization to the 
occurrence of disease progression, as determined by investigators from tumor 
assessments, per RECIST v1.1, or death from any cause, whichever occurs first.  Patients 
who have not experienced disease progression or death at the time of analysis will be 
censored at the time of the last tumor assessment.  Patients with no post-baseline tumor 
assessment or death will be censored on the date of randomization+1 day.
Progression-free survival (PFS) will be analyzed simultaneously in the ITT and 
PD-L1-positive subgroup (see Section 2.2.1). The following analyses will be performed 
for both PFS endpoints described above:

Treatment comparisons will be based on the stratified log-rank test. The 
stratification factors will be those used for randomization (see Section 3.1) and will 
be obtained from the IxRS.  Results from an un-stratified analysis and a stratified 
analysis using eCRF-collected stratification factors will also be provided.

The HR will be estimated using a stratified Cox regression model with the same 
stratification variables used for the stratified log-rank test, and the 95% CI for the HR 
will be provided.  Results from an un-stratified analysis will also be provided.

Kaplan-Meier methodology will be used to estimate median PFS for each treatment 
arm and to construct survival curves 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).
4.4.1.2
Overall Survival
Overall survival is defined as the time from the date of randomization to the date of death 
due to any cause.  Patients who are not reported as having died at the time of analysis 


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will be censored at the date when they were last known to be alive.  Patients who do not 
have post-baseline information will be censored at the date of randomization1 day.  
Testing of OS is outlined in Section 2.3 and analysis of OS is performed analogously to 
PFS in the section above. OS is hierarchically tested in the PD-L1-positive and ITT
population (see Section 2.4).
4.5
INDEPENDENT REVIEW FACILITY
The imaging data used for tumor assessment will be collected by the Sponsor to enable 
centralized, independent review of response endpoints by an Independent Review 
Committee (IRC).  An independent imaging group will be used to evaluate tumor 
assessments for determination of progression and response rate according to 
RECIST v1.1 for the primary analysis.  Imaging studies (computed tomography 
[CT]/magnetic resonance imaging [MRI]/bone scans) will be acquired according to a 
standard protocol and will be forwarded to the independent reviewers.  Investigator tumor 
assessments will not be reconciled with the IRC tumor assessments.  Further details will 
be included in the IRC Charter.  Details of imaging handling procedures are also described 
in a separate laboratory manual.  An independent Data Monitoring Committee (iDMC) will 
be in charge to evaluate and assess if the level of bias in local evaluations is unacceptable 
OR if a full independent review is unnecessary (see Section 3.2).
4.5.1
Secondary Efficacy Endpoints
4.5.1.1
Objective Response Rate (ORR)
An objective response is defined for primary surgery patients with measurable disease at 
baseline who achieved a documented unconfirmed response [i.e., either a partial 
response (PR) or a complete response (CR)] on the basis of investigator assessment 
using RECIST v1.1.  Patients not meeting this criterion, including patients without any 
post-baseline tumor assessment, will be considered as non-responders.  Objective 
response rate is defined as the proportion of primary surgery patients with measurable 
disease at baseline who have an objective response. 
Objective response rate will be compared between treatment arms using the stratified 
Cochran-Mantel-Haenszel test.  Primary surgery and neoadjuvant patients (see 
Section 4.5.4.1) will be evaluated separately.  The stratification factors will be the same 
as those described for the analysis of the primary endpoint of PFS.  The difference in ORR 
between treatment arms will be calculated, and its 95% CI will be calculated using the 
normal approximation to the binomial distribution.  An estimate of ORR will be calculated 
for each treatment arm, and its 95% CI will be calculated using the Clopper-Pearson 
method.  ORR is simultaneously assessed in the ITT and PD-L1 populations with 
measurable disease at baseline.
4.5.1.2
Duration of Objective Response
Duration of response is defined for primary surgery patients who had an objective 
response as the time from the first occurrence of a documented unconfirmed response 
(CR or PR) to the date of disease progression on the basis of investigator assessment 


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using RECIST v1.1 or death from any cause, whichever occurs first.  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 the objective response (CR or PR), patient will be censored at the date of 
the first occurrence of the objective response1 day.
The analysis of DOR is based on a non-randomized subset of patients (those who 
achieved an unconfirmed response); therefore, no formal hypothesis testing will be 
performed.  Comparisons between treatment arms will be made for descriptive purposes 
only.  The methodologies described for the analysis of PFS will be used for the analysis 
of DOR except that the analysis will not be stratified. 
4.5.1.3
Patient-Reported Outcomes Disease Symptoms, Function and 
Health-Related Quality of Life EORTC Data
Patient-Reported Abdominal Pain or Bloating and EORTC QLQ-OV28:  For patients 
in the neoadjuvant therapy group, the proportion of patients in each arm who report a 
clinically-meaningful improvement in patient-reported abdominal pain or bloating, defined 
as a 10-point decrease from the baseline score on each of two items from the 
European Organisation for Research and Treatment of Cancer Quality of Life Questionn
aire Ovarian Cancer Module 28 (EORTC QLQ-OV28)
abdominal/gastrointestinal 
(GI) 
symptom scale (items 31 and 32), will be summarized at each post-baseline timepoint by 
treatment arm.
The Cochran-Mantel-Haenszel test, stratified by stage and/or residual disease status 
(Stage III vs. Stage IV), ECOG performance status (0 vs. 1 or 2), and tumor PD-L1 status 
(IC0 vs. IC1/2/3) will be used to compare the proportion of patients who report a 
clinically-meaningful improvement in patient-reported abdominal pain or bloating at 
9 weeks after neoadjuvant therapy between the two treatment arms.  The difference in 
proportions will be provided, with its 95% CI, with the use of the Hauck-Anderson method. 
Pre-specified subgroup analysis will also be performed in patients with ascites at baseline 
(who typically have significantly impaired HRQoL) and in patients with sufficient symptoms 
at baseline to allow detection of a 10-point improvement in a given symptom score. 
The definition of improvement in patient-reported abdominal pain or bloating 
(i.e., a 10-point decrease from the baseline score in QLQ-OV28 abdominal symptom 
items) is based on the standard analysis method for the EORTC QLQ-C30 that deems a 
score change of 10 points on any item or scale to be clinically meaningful 
(Osoba et al. 1998; Fayers 2001a; Osoba 2002; Osoba et al. 2005; Brundage et al. 2007; 
Luckett et al. 2010; Cocks et al. 2011).  Although the clinical meaningfulness of a 10-point 
change was established based on the EORTC QLQ-C30, the disease-specific modules, 
including the QLQ-OV28, were designed on the same structure using the same rating 
scale and are, therefore, applicable in this context.  Additionally, other OC studies have 
used the 10-point minimally important difference (MID) threshold for the QLQ-OV28, 


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demonstrating that a change of this magnitude is significant to patients with OC while 
setting a precedent for its use and supporting its utility in this context (Richter et al. 2012; 
Brotto et al. 2016; Fagotti et al. 2016).
A sensitivity analysis will be performed to evaluate the robustness of the published 
standard threshold for meaningful change of 10-points with the use of the raw data for the 
abdominal pain and bloating items of the EORTC QLQ-OV28.  The proportion of patients 
in each arm reporting a 1-category decrease on each of the 4-point symptom scales of the 
EORTC QLQ-OV28 abdominal symptom items (items 31 and 32), will be summarized at 
each post-baseline timepoint by treatment arm.  All analyses of the abdominal symptoms 
single item data that involve the 10-point MID will be replicated with this alternate 
MID threshold.
All EORTC QLQ-OV28 data will be scored according to the EORTC scoring manual 
(Fayers et al. 2001b). PRO completion, compliance rates, and reasons for missing data 
will be summarized at each timepoint by treatment arm.
Patient-Reported Function and HRQoL EORTC QLQ-C30:  For patients in the 
neoadjuvant therapy subgroup, the proportion of patients in each arm who report a 
clinically-meaningful improvement in patient-reported function and HRQoL, defined as a 
≥10-point increase from the baseline score on each of the functional (physical, role, 
emotional, and social) and GHS/QoL scales of the EORTC QLQ-C30, will be summarized 
at each post-baseline timepoint by treatment arm, and compared between treatment arms 
with the use of the stratified Cochran-Mantel-Haenszel test specified above.
For patients in the primary surgery group, the proportion of patients in each arm who 
improve, remain stable or deteriorate in patient-reported functions and GHS/QoL, defined 
as a 10-point increase, changes within 10 points, and a 10-point decrease, respectively, 
from the baseline score on each of the functional (physical, role, emotional, and social) 
and GHS/QoL scales of the EORTC QLQ-C30 will be summarized at each post-baseline 
timepoint by treatment arm, and compared between treatment arms with the use of the
stratified Cochran-Mantel-Haenszel test specified above.
The EORTC QLQ-C30 and QLQ-OV28 will be scored according to the EORTC scoring 
manual (Fayers et al. 2001b). Per Fayers et al. (2001b), in the event that incomplete data 
exists, if the scale has more than 50% of the constituent items completed, a pro-rated 
score will be computed.  For subscales with less than 50% of the items completed, the 
subscale will be considered missing.  PRO completion, compliance rates, and reasons for 
missing data will be summarized at each timepoint by treatment arm and surgery status.
4.5.2
Sensitivity Analyses
Statistical methodologies that are analogous to those methodologies used in the primary 
analysis of PFS and OS as specified in Section 4.4.1.1 will be applied for sensitivity 
analyses.


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4.5.2.1
Sensitivity Analyses of Progression-Free Survival
Censoring for Non-Protocol Therapy:
Non-protocol therapy is defined as any 
anti-cancer therapy other than study treatment that typically is the subsequent line of 
therapy. The impact of NPT on the co-primary endpoint of investigator-assessed PFS will 
be evaluated.
A sensitivity analysis will be performed in which data for patients who 
received NPT will be censored at the last tumor assessment date before the patient 
received NPT.
PFS by IRC: An analysis of PFS on the basis of the IRC assessments will be performed 
using the same methodology as specified for PFS on the basis of investigator assessment. 
Missing Assessments:
A sensitivity analysis will be performed when disease 
progression occurs after two or more consecutive missed tumor assessments, these 
events will not be counted; rather, the patient will be censored at the patient’s last tumor 
assessment prior to the missing assessments. If disease progression occurs after one 
missed tumor assessments, the event will be counted at the respective event date.
Additional sensitivity analyses may be considered if appropriate.
4.5.2.2
Sensitivity Analyses of Overall Survival
Accounting for Second-Line Immunotherapy Use:  Quickly evolving development of 
checkpoint inhibitors may lead to increased PD-1/PD-L1 treatment options for patients in 
the second-line triple-negative breast cancer, either via trial participation or newly 
approved medicines in this class.  Second-line usage of such inhibitors by patients 
progressing on this first-line trial could result in biased estimate of the treatment effect on 
OS. To account for this possibility of bias the following sensitivity analyses will be 
conducted.
Censoring for Treatment Switching:  Treatment switching is defined as any checkpoint 
inhibitor therapy other than study treatment as subsequent line of therapy.  Censoring for 
treatment switching will be applied to OS, analogue to censoring for NPT for PFS, see 
above.
Additional sensitivity analyses may be considered if appropriate.
4.5.3
Subgroup Analyses
To assess the consistency of study results in the subgroups defined by demographic 
baseline characteristics, biomarker status, PFS and OS in these subgroups will be 
examined.  Summaries of PFS and OS, including unstratified HRs estimated with the use 
of Cox proportional hazards models and Kaplan-Meier estimates of the median, will be 
produced separately for each level of the categorical variables.


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4.5.4
Exploratory Analyses
Analysis of ORR in Patients of Neoadjuvant Group:  An objective response among 
neoadjuvant patients is defined for those patients with measurable disease at baseline 
who achieved a documented unconfirmed response (i.e., either a partial response [PR] or 
a complete response [CR]) on the basis of investigator assessment using RECIST v1.1 
prior to interval cytoreductive surgery.  Patients not meeting this criterion, including 
patients without any post-baseline tumor assessment, will be considered as 
non-responders.  Objective response rate (ORR) among neoadjuvant patients is defined 
as the proportion of neoadjuvant patients with measurable disease at baseline who have 
an objective response, see the definition of Section 4.4.2.1, before interval surgery.
Pathologic and Clinical Response:  The pathologic and clinical response (PCR) status 
is defined as the extent of residual disease assessed at the time of interval cytoreductive 
surgery (i.e., clinico-pathologic response) for neoadjuvant patients. Patients whose PCR 
assessment is missing or invalid are counted as not achieving PCR.  The PCR status will 
be summarized for both treatment arms, and its relationship with clinical outcome (e.g., 
PFS, OS, DOR) will be examined.
Guidance and examples for histopathologic evaluation of surgical specimens after interval 
cytoreduction are provided in the Ovarian Pathology Handbook and in Appendix 13 of the 
Protocol.
Analysis of PFS2:  PFS2 is defined as the time from randomization to second disease 
progression, or death from any cause, whichever first. Patients alive and for whom a 
second disease progression has not been observed should be censored at the last time 
known to be alive and without second objective disease progression.
The method of 
analysis of PFS2 is analogue to that for the primary endpoint, PFS.
Analysis of Overall Survival at Three Years:  The OS rate at three years after 
randomization will be estimated with the use of the Kaplan-Meier methodology for each 
treatment arm, along with 95% CIs that are calculated with use of the standard error 
derived from Greenwood’s formula.  The 95% CI for the difference in the OS rate between 
the two treatment arms will be estimated with use of the normal approximation method.
4.5.4.1
Exploratory Patient-Reported Outcomes Analyses
Patient-Reported Outcomes Disease and/or Treatment-Related SymptomsEORTC 
Data:  Summary statistics (mean, SD, median, and range) of absolute scores and mean 
changes from the baseline will be calculated for all disease and/or treatment-related 
symptom items and subscales of the EORTC QLQ-C30 and QLQ-OV28 at each 
assessment timepoint for each arm during the administration of the treatment and the 
survival follow-up period.  The mean (and 95% CI) and median of the absolute scores and 
the changes from the baseline will be reported for interval and continuous variables.  
Previously-published minimally-important differences will be used to identify meaningful 


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change from the baseline within each treatment group on the disease and/or 
treatment-related symptoms scales (Osoba et al. 1998; Cocks et al. 2011).
FACT-G, GP5 Single Item Data:
A descriptive analysis of absolute scores and the 
proportion of patients who selected each response option at each assessment visit by 
treatment arm will be reported for item GP5 (“I am bothered by side effects of treatment”) 
from the Functional Assessment of Cancer Therapy-General (FACT-G) physical well-
being subscale.  Item GP5 from Version 4 of the FACT-G questionnaire will be scored 
according to the FACIT scoring manual (Cella 1997).  PRO completion, compliance rates, 
and reasons for missing data will be summarized at each timepoint by treatment arm and 
surgery status.
Health Economic Data:  Health economic data will be used in pharmacoeconomic 
analyses only and not presented in CSR.
Psychometric 
Properties 
of 
Single 
Abdominal 
Pain 
and 
Bloating 
ItemsEORTC QLQ-OV28 Data:  Analyses will be conducted in all randomized patients 
to assess whether the psychometric properties of the single abdominal pain and bloating 
items from the EORTC QLQ-OV28 are comparable to those of the abdominal/GI scale. 
These 
analyses 
will 
include 
test-retest 
reliability, 
construct 
validity, 
and 
sensitivity/responsiveness to change. Where possible, analyses will be conducted on the 
combined primary and neoadjuvant chemotherapy/interval surgery patient sample.
However, in general, analyses will be split by group to account for the different assessment 
schedules applied in each patient group. These analyses will mirror, to the extent possible, 
exploratory psychometric analyses conducted with archival in-house clinical trial data 
(AURELIA) and thus provide a point of comparison for verification of the psychometric 
properties of the single abdominal pain and bloating items.
Test-retest reliability will be assessed separately in the primary surgery and neoadjuvant 
chemotherapy/interval surgery patients from Day 1, Cycle 1 to the first available follow-up 
(6 and 9 weeks after baseline, respectively) using intraclass correlation coefficients (ICC). 
Patients will be identified for inclusion in this analysis based on the stability of their scores 
on the health status item of the EORTC-QLQ-30.
Two forms of construct validity, convergent/divergent and known-groups will be assessed 
using patients’ Day 1, Cycle 1 data. Analyses will be conducted in both the overall 
randomized patient sample and separately by group. Convergent/divergent validity will 
be assessed using correlations between the abdominal/GI scale/items and relevant PROs 
(i.e., EORTC QLQ-C30, EQ-5D, and other scales in the EORTC OV28 module). Known-
groups validity will be assessed using t-tests/ANOVA (or non-parametric equivalents, as 
appropriate) on severity groups defined by scores on the physical, role, and social 
functioning scales of the EORTC QLQ-C30.


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Sensitivity (i.e., responsiveness) to change will be assessed from baseline to multiple 
follow-up cycles (up to 1 year of survival after treatment discontinuation) using ANOVA (or 
non-parametric equivalent, as appropriate). Defined change groups will be created using 
relevant PRO scales. In addition, longitudinal analysis (e.g., multilevel models, 
generalized estimating equation models) will be conducted to examine change in the 
abdominal/GI scale/items over the course of the study up to one year of survival after 
treatment discontinuation. Data will be presented graphically using spaghetti plots to chart 
each patients’ individual growth trajectory.
4.5.4.2
Exploratory Biomarker Analyses
Exploratory biomarker analyses in tumor tissues and plasma, whole blood, or serum will 
be conducted in an effort to understand the association of these markers with the study
drug response, including efficacy and/or AEs.  Results will not be presented in the CSR.
4.6
PHARMACOKINETIC AND PHARMACODYNAMIC ANALYSES
Maximum and minimum atezolizumab serum concentration data (Cmin and Cmax) will be 
tabulated and summarized.  Descriptive statistics will include means, medians, ranges, 
standard deviations (SDs), and percentage of coefficient of variation (%CV), as 
appropriate. Descriptive statistics of atezolizumab concentrations by treatment-emergent 
anti-drug antibody (ADA) status will also be reported.
Additional PK analyses may be conducted if deemed appropriate based on the availability 
of data. These additional analyses may not be included in the CSR for this study.
4.7
SAFETY ANALYSES
All safety analyses will be performed on the safety population, i.e., all patients who receive 
any dose of study medication (see Section 4.1).
Safety will be assessed through summaries of AEs, 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.  Non-overlapping visit windows will be 
assigned to post-baseline assessments, e.g., assessments falling between Days 22 
and 32 will be reported under Week 4.
4.7.1
Exposure of Study Medication
Study treatment (atezolizumab, placebo, paclitaxel, carboplatin, and bevacizumab) 
exposure, including but not limited to treatment duration, dose intensity, number of cycles 
and total cumulative dose will be summarized with descriptive statistics as appropriate.  
The number of missed doses will also be displayed.
4.7.2
Adverse Events
Verbatim description of AEs will be mapped to Medical Dictionary for Regulatory Activities 
(MedDRA) thesaurus terms and graded according to the National Cancer Institute 
Common Terminology Criteria for Adverse Events, Version 4.0 (NCI CTCAE v4.0).  


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Adverse events, occurring on or after the first dose of study treatment will be summarized 
by mapped term, appropriate thesaurus level, and NCI CTCAE grade regardless of 
relationship to study drug, as assessed by the investigator. For each patient, if multiple 
incidences of the same AEs occur, the maximum severity reported will be used in the 
summaries.
After informed consent has been obtained but prior to initiation of study drug, only SAEs
caused by a protocol-mandated intervention should be reported, e.g., SAEs related to 
invasive procedures such as biopsies.
After the initiation of the study treatment, all AEs will be reported until 30 days after the 
last dose of the study treatment (which includes study-related surgery) is administered or 
until the initiation of a new anti-cancer therapy, whichever occurs first.  Serious adverse 
events and AEs of special interest (AESIs) will continue to be reported until 90 days after 
the last dose of the study treatment (which includes study related surgery) or until starting 
a new anti-cancer therapy, whichever occurs first.  After this reporting period, SAEs
believed to be related to prior exposure to study treatment, including study-related surgery, 
should be reported.
Summary tables including but not limited to the following will be provided:

AEs

SAEs

AEs leading to study treatment discontinuation 

AEs leading to dose reduction or interruption

Treatment-related AEs

Severe adverse events (Grade 3)

AEs leading to death

AEs by highest NCI CTCAE Grade

Sponsor-defined AESI
Multiple occurrences of the same event will be counted once at the maximum severity.  All 
listings of AEs will include all AEs with onset on or after the first study drug treatment up 
to the data cutoff date.
All deaths and causes of death will be summarized by treatment as well.
4.7.3
Laboratory Data
Laboratory data will be classified according to NCI CTCAE v4.0 and will be summarized 
descriptively over time including change from baseline.  Highest NCI CTCAE grade 
post-baseline will also be reported and shift tables from baseline to worst value during the 
study post-baseline will be presented. Of note, abnormal laboratory data that are clinically 
significant will be reported as AEs and summarized in the AE tables.


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A Hy’s law analysis will be provided.  The potential Hy’s law quadrant is defined as the 
occurrence of either of the following:

Treatment-emergent ALT or AST3upper limit of normal (ULN) (or baseline value 
if baseline value was above the ULN) in combination with total bilirubin 2 ULN (of 
which 35% is direct bilirubin).

Treatment-emergent ALT or AST >3 ULN (or baseline value if baseline value was
above the ULN) in combination with clinical jaundice.
4.7.4
Vital Signs and ECOG Performance Status
Vital signs will be summarized descriptively by treatment arm over time including change 
from baseline. ECOG performance status will also be summarized over time.
4.7.5
Anti-Drug Antibody
Incidence of ADAs against atezolizumab will be presented by treatment arm in both the 
neoadjuvant and primary surgery groups. The analyses of PK and key efficacy and safety
data by ADA status will be conducted to explore the potential impact of immunogenicity 
as appropriate.
4.8
MISSING DATA
The handling of missing data is summarized in Section 4.4 for each endpoint.
4.9
INTERIM ANALYSES
4.9.1
Overall Survival
A total of three analyses of OS will be performed (two interim analyses and one final 
analysis).  The number of events, statistical boundaries (i.e., significance level), and timing 
of the two interim analyses and the final analysis for OS depending on the results of the 
definitive analysis of the co-primary endpoint PFS (i.e., final alpha allocated to OS, 
0.050.046). The 1st interim analysis will be conducted at the same time as the 
primary analysis of PFS, which is estimated to be 36 months after first patients enrolled, 
and when approximately 60% of the total OS events required for the final analysis have 
occurred. If the pre-specified information fraction of OS analysis is not achieved at the 
time of the PFS primary analysis, the first interim analysis of OS will still be conducted, 
and the alpha-spent will be adjusted accordingly. The 2nd interim analysis will occur when 
approximately 80% of the total OS events required for the final analysis have occurred.
The pre-specified information fraction for OS at first and second interim analyses (i.e., 
approximately 60% and 80% of the total number of events, respectively) are described in 
Table 2 below and in Section 4.4.1.
Overall survival
will be tested at the significance level determined using the 
O’Brien-Fleming -spending function such that the overall type I error rate will be 
maintained at the 0.05 level (DeMets and Lan 1994).


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Table 2
Interim and Final Analyses of Overall Survival
5.
CHINA SUBGROUP ANALYSIS
China subgroup includes patients enrolled in global enrollment phase and the China 
extension phase. The timing of China subgroup analysis depends on the data maturity 
and pre-specified number of PFS events from China subgroup.
The analysis populations will be equally defined as per Section 4.1, but will only be based 
on patients who are residents of the People’s Republic of China.  Analyses of study 
conduct will be performed as described in Section 4.2.  Summaries of demographics, 
disease history, baseline disease characteristics, and patient treatment history will be 
produced as described in Section 4.3.
Data from patients who are lost to follow-up or without disease progression or death as of 
the clinical data cutoff date for China subgroup analysis will be censored at the time of the 
last tumor assessment when the patient was known to be progression-free (i.e., an overall 
response other than “progressive disease” or “not evaluable”) or at the time of 
randomization plus one day if there is no post-baseline tumor assessment or all 
post-baseline tumor assessments have overall responses of “not evaluable.”
The unstratified 
Cox 
proportional 
hazards model 
will 
be 
used 
to 
estimate 
investigator-assessed PFS HR between the two treatment groups and its 95% CI.  
An unstratified two-sided log-rank test will provide a comparison for investigator-assessed
PFS in this subgroup in a descriptive manner.  Plots of the Kaplan-Meier estimate for 
investigator-assessed PFS will be produced, including medians and confidence limits. The 
analysis of OS data will be analogous to the ones described above for PFS.


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The analysis of other endpoints will use the same methods for global cohorts but with 
exploratory purpose only.
Safety data for the China subgroup will be analyzed as described in Section 4.7.


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6.
REFERENCES
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Brotto L, Brundage M, Hoskins P, et al. Randomized study of sequential 
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doi: 10.1007/s00520-015-2873-8. Epub: 25 August 2015.
Brundage M, Osoba D, Bezjak A, et al. Lessons learned in the assessment of
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Cella D. Manual of the Functional Assessment of Chronic Illness Therapy (FACIT) 
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Education (CORE), Evanston Northwestern Healthcare and Northwestern 
University, 1997.
Cocks K. King MT, Velikova G, et al. Evidence-based guidelines for determination of 
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Treatment of Cancer Quality of Life Questionnaire Core 30. J Clin Oncol 
2011;29:8996.
DeMets DL, Lan KK. Interim analysis: the alpha spending function approach. Stat Med 
1994;13:1341- 52; discussion 1353-6.
Dmitrienko A, D’Agostino RB Sr, Huque MF. Key multiplicity issues in clinical drug 
development. Stats Med; 2013;32(7):1079-111.
Fagotti A, Ferrandina G, Vizielli G, et al. Phase III randomised clinical trial comparing 
primary surgery versus neoadjuvant chemotherapy in advanced epithelial ovarian 
cancer with high tumour load (SCORPION trial): Final analysis of peri-operative 
outcome. Eur J Cancer 2016;59:2233.
Fayers P, Aaronson N, Bjordal K, et al. on behalf of the EORTC Quality of Life Group. 
The EORTC QLQ-C30 scoring manual. 3rd ed. Brussels: European Organisation for 
Research and Treatment of Cancer; 2001b.
Fayers PM. Interpreting quality of life data: population-based reference data for 
theEORTC QLQ-C30. Eur J Cancer 2001a;37:13314.
Luckett T, King M, Butow P, et al. Assessing health-related quality of life in gynecologic 
oncology: a systematic review of questionnaires and their ability to detect clinically 
important differences and change. Int J Gynecol Cancer 2010;20:66484. doi: 
10.1111/IGC.0b013e3181dad379.
National Cancer Institute. SEER cancer statistics review 1975-2013 [resource on the 
internet]. 2016. Available from: 
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Osoba D, Bezjak A, Brundage M, et al. Analysis and interpretation of health-related 
quality-of-life data from clinical trials: basic approach of The National Cancer 
Institute of Canada Clinical Trials Group. Eur J Cancer 2005;41:2807.
Osoba D, Rodrigues G, Myles J, et al. Interpreting the significance of changes in 
health-related quality-of-life scores. J Clin Oncol 1998;16:13944.
Osoba D. A taxonomy of the uses of health-related quality-of-life instruments in cancer 
care and the clinical meaningfulness of the results. Med Care 
2002;40(6 Suppl):III-31.
Richter R, Oskay-Oezcelik G, Chekerov R, et al. Health-related quality of life during 
sequential chemotherapy with carboplatin followed by weekly paclitaxel in 
advanced ovarian cancer: a multicenter phase II study of the North Eastern 
German Society of Gynecological Oncology. Anticancer Research 
2012;32:39676.


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Appendix 1
Protocol Synopsis
TITLE:
A 
PHASE 
III, 
MULTICENTER, 
RANDOMIZED 
STUDY 
OF 
ATEZOLIZUMAB 
VERSUS 
PLACEBO 
ADMINISTERED
IN 
COMBINATION 
WITH 
PACLITAXEL, 
CARBOPLATIN, 
AND 
BEVACIZUMAB FOR PATIENTS WITH NEWLY-DIAGNOSED 
STAGE III OR STAGE IV OVARIAN, FALLOPIAN TUBE, OR 
PRIMARY PERITONEAL CANCER
PROTOCOL NUMBER:
Roche YO39523
GOG3015
ENGOTov39
VERSION NUMBER:
8
EUDRACT NUMBER:
2016-003472-52
IND NUMBER:
130,637
NCT NUMBER
03038100
TEST PRODUCT:
Atezolizumab (RO5541267)
PHASE:
Phase III
INDICATION:
Ovarian cancer, fallopian tube cancer, primary peritoneal cancer, and 
cancers of extra-uterine Müllerian origin
SPONSOR:
F. Hoffmann-La Roche Ltd
Objectives and Endpoints
This study will evaluate the efficacy and safety of atezolizumab administered 
with paclitaxelcarboplatinbevacizumab compared with 
placebopaclitaxelcarboplatinbevacizumab in patients with newly diagnosed, untreated 
ovarian, fallopian tube, and/or primary peritoneal cancer.  Specific objectives and corresponding 
endpoints for the study are outlined below.
Table 1
Objectives and Corresponding Endpoints
Primary Efficacy Objective
Corresponding Endpoints
To evaluate the efficacy of atezolizumab 
versus placebo in combination with 
paclitaxel carboplatin bevacizumab 
among all patients and in those patients 
with PD-L1positive tumors 
Investigator-assessed PFS, defined as the time 
from randomization to the occurrence of disease 
progression, as determined by the investigator from 
tumor assessments per RECIST v1.1, or death 
from any cause during the study, whichever occurs 
first
OS, defined as the time from randomization to 
death from any cause 


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Secondary Efficacy Objectives
Corresponding Endpoints
Among patients with measurable residual disease in the primary surgery group:
To evaluate the efficacy of atezolizumab 
versus placebo in combination with 
paclitaxelcarboplatinbevacizumab
OR, defined as either a CR or PR as determined by 
the investigator with the use of RECIST v1.1 for 
patients with measurable residual disease after 
primary surgery
To evaluate the duration of efficacy 
observed with atezolizumab versus 
placebo in combination with 
paclitaxelcarboplatinbevacizumab 
DOR, defined as the time interval from first 
occurrence of a CR or PR to the time of disease 
progression, as determined by the investigator with 
the use of RECIST v1.1, or death from any cause, 
whichever comes first for patients with measurable 
residual disease after primary surgery
To evaluate PROs of function and 
HRQoL associated with atezolizumab 
versus placebo in combination with 
paclitaxel carboplatin bevacizumab, 
as measured by the functional 
andGHS/QoL scales of the EORTC 
QLQ-C30
Clinically-meaningful improvement, remaining 
stable, or deterioration in patient-reported 
function and HRQoL, defined as a 10-point 
increase, changes within 10 points, and a 10-
point decrease, respectively, from the baseline 
score on each of the functional (physical, role, 
emotional, and social) and GHS/QoL scales of the 
EORTC QLQ-C30
Among the patients in the neoadjuvant group:
To determine the impact of atezolizumab 
versus placebo in combination with 
paclitaxelcarboplatinbevacizumab on 
patient-reported abdominal symptoms of 
OC, as measured by two items from the 
abdominal/GI symptom scale of the 
EORTC QLQ-OV28
Clinically-meaningful improvement in 
patient-reported abdominal pain or bloating, 
defined as a 10-point decrease from the 
baseline score on either of the two items on the 
EORTC QLQ-OV28 abdominal/GI symptom scale
(items 31 and 32)
To evaluate PROs of function and 
HRQoL associated with atezolizumab 
versus placebo in combination with 
paclitaxel carboplatin bevacizumab, as 
measured by the functional and GHS/QoL 
scales of the EORTC QLQ-C30
Clinically-meaningful improvement in 
patient-reported function and HRQoL, defined as 
a 10-point increase from the baseline score on 
each of the functional (physical, role, emotional, 
and social) and GHS/QoL scales of 
the EORTC QLQ-C30
Safety Objective
Corresponding Endpoints
To evaluate the safety and tolerability of 
atezolizumab versus placebo in 
combination with 
paclitaxelcarboplatinbevacizumab
Occurrence and severity of adverse events, with 
severity determined in accordance to 
NCI CTCAE v4.0
Change from baseline in targeted vital signs
Change from baseline in targeted clinical 
laboratory test results
Pharmacokinetic Objective
Corresponding Endpoint
To characterize the pharmacokinetics of 
atezolizumab when administered in 
combination with 
paclitaxelcarboplatinbevacizumab
Minimum and maximum serum concentration of 
atezolizumab


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Table 1
Objectives and Corresponding Endpoints (cont.)
Exploratory Objectives
Corresponding Endpoints
Among neoadjuvant patients only:  To
evaluate PCR status and its association
with clinical outcomes after
administration of atezolizumab versus
placebo in combination with
paclitaxel carboplatin bevacizumab
Among patients who undergo neoadjuvant
therapy prior to interval surgery, PCR status is
defined as the clinical amount and histologic
characteristics of residual disease assessed at
the time of interval cytoreductive surgery
To evaluate the efficacy of atezolizumab
versus placebo administered in
combination with
paclitaxel carboplatin bevacizumab
The OS rate at 3 years after randomization
To evaluate PROs of disease
and/or treatment-related symptoms
associated with atezolizumab
versus placebo administered in
combination with
paclitaxel carboplatin bevacizumab,
as measured by the EORTC QLQ-C30
and QLQ-OV28
Mean and mean changes from the baseline score
in disease and/or treatment-related symptoms by
cycle and between treatment arms as assessed
by all symptom items and/or scales of the
EORTC QLQ-C30 and QLQ-OV28
To evaluate any treatment burden
patients may experience in association
with the addition of atezolizumab to
paclitaxel carboplatin bevacizumab
compared with
placebo paclitaxel carboplatin 
bevacizumab, as measured by a
single item (from GP5: "I am bothered by
side effects of treatment") from the
physical wellbeing subscale of the
FACT-G Quality of Life instrument
Proportion of patients reporting each response
option at each assessment timepoint by treatment
arm for item GP5 from the FACT-G
To evaluate and compare between
treatment arms patients' health utility as
measured by the EQ-5D-5L to generate
utility scores for use in economic models
for reimbursement
Health utility scores of the EQ-5D-5L
Immunogenicity Objective
Corresponding Endpoint
To evaluate the immune response from
patients who were administered
atezolizumab
The incidence of ADAs against atezolizumab
during treatment with atezolizumab administered
in combination with
paclitaxel carboplatin bevacizumab relative to
the incidence of ADAs at the baseline
Exploratory Immunogenicity Objective
Corresponding Endpoint
To evaluate the potential effects of ADAs 
The relationship between ADA status and
pharmacokinetics, safety, and efficacy


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Table 1
Objectives and Corresponding Endpoints (cont.)
Exploratory Biomarker Objective
Corresponding Endpoint
To assess predictive, prognostic, and 
pharmacodynamic exploratory 
biomarkers in archival and/or fresh 
tumor tissue and blood and their 
association with disease status and/or 
patient response to study treatment 
Association of tumor immune-mediated or disease 
type−related exploratory biomarkers (in archival 
and/or freshly obtained tumor tissues and plasma, 
whole blood, or serum) with disease status and/or 
response to administration of 
atezolizumabpaclitaxelcarboplatinbevacizumab; 
biomarkers may include but are not limited to:
CD8 as assessed with the use of IHC
Breast cancer susceptibility gene (BRCA) 
status, homologous recombination deficiency, 
and microsatellite instability as assessed with 
the use of DNA NGS
Molecular subtyping of ovarian cancer, as 
assessed by RNA profile
Association of cell-free tumor DNA with tumor 
burden and treatment response
To identify biomarkers that are 
associated with resistance to 
atezolizumab administered in 
combination with carboplatin and/or 
paclitaxel and/or bevacizumab activity, 
or can increase the knowledge and 
understanding of disease biology
The relationship between biomarkers in blood and 
tumor tissue between pretreatment and 
post-progression samples collected at the time of 
disease progression. These biomarkers may 
include but are not limited to:

Acquired mutations assessed with the use 
of DNA NGS
Changes in the tumor immune 
microenvironment and biology as assessed by 
RNA profile and IHC
ADA anti-drug antibody; CR complete response; DOR duration of response; 
EORTC European Organisation for Research and Treatment of Cancer; FACT-G Functional 
Assessment of Cancer Therapy-General; GI gastrointestinal; GHS global health status;
HRQoL health-related quality of life; IHC immunohistochemistry; PCR pathologic and clinical 
response; NCI CTCAE National Cancer Institute Common Terminology Criteria for Adverse 
Events; NGS next-generation sequencing; OC ovarian cancer; OR objective response; 
OS overall survival; PFS progression-free survival; PR partial response; PRO patient-report 
outcome; QLQ-OV28 Quality of Life Questionnaire Ovarian Cancer Module 28; 
RECIST v1.1 Response Evaluation Criteria in Solid Tumors, Version 1.1.
Study Design
Description of Study
This is a Phase III, global, double-blind, two-arm, randomized study designed to evaluate the 
efficacy and safety of atezolizumab administered with paclitaxel carboplatin bevacizumab 
compared with placebo paclitaxel carboplatin bevacizumab in patients with Stage III or 
Stage IV ovarian, fallopian tube, or primary peritoneal cancer with macroscopic residual disease 
postoperatively (i.e., after primary tumor reductive surgery) or who will undergo neoadjuvant 
therapy followed by interval surgery.  Approximately 1300 patients will be randomized.  Patients 
will be randomized in a 1:1 ratio to one of the two treatment arms.
Eligible patients after primary tumor reductive surgery must be randomized within 42 days of 
primary surgery postoperatively and commence concurrent treatment with paclitaxel 
(175 mg/m2), carboplatin (area under the concentrationtime curve at 6 [AUC 6]), and 
atezolizumab or placebo (1200 mg) on Cycle 1, Day 1.  All treatments will be administered 


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intravenously, and each cycle will be 21 days long.  Bevacizumab (15 mg/kg) will be added to 
paclitaxel, carboplatin, and atezolizumab treatment starting with Cycle 2.  After 6 cycles of 
concurrent chemotherapybevacizumab (5 cycles) atezolizumab or placebo, patients will 
continue on maintenance bevacizumab atezolizumab or bevacizumab placebo treatment for 
a total (concurrent maintenance phases) of 22 cycles of atezolizumab or placebo and 
21 cycles of bevacizumab.  No additional cycles of maintenance anti-cancer therapy are 
permitted beyond 22 cycles of therapy in the front-line setting.  Study treatment will be 
discontinued at the time of disease progression, unacceptable toxicity, patient or physician 
decision to discontinue, death, or study termination by the Sponsor.
Eligible patients in the neoadjuvant therapy group will be randomized prior to the initiation of 
study treatment.  Patients in the neoadjuvant group will commence concurrent treatment with 
paclitaxel (175 mg/m2), carboplatin (AUC 6), bevacizumab (15 mg/kg), and atezolizumab or 
placebo (1200 mg) on Cycle 1, Day 1.  All treatments will be administered intravenously, and 
each cycle will be 21 days long.  Cycles 3 and 4 will consist of concurrent paclitaxel 
(175 mg/m2), carboplatin (AUC 6), and atezolizumab or placebo (1200 mg) with bevacizumab 
omitted peri-operatively.  Interval surgery will occur after Cycle 3 as soon as deemed clinically 
appropriate, but within a maximum of 6 weeks after receiving Cycle 3.  Within 6 weeks after 
interval surgery, patients will resume concurrent chemotherapybevacizumab atezolizumab or 
placebo for three more cycles (total of 6 cycles), however bevacizumab treatment will resume at 
Cycle 5 (i.e., bevacizumab is omitted for Cycle 4).  Upon completion of concurrent therapy, 
patients will commence maintenance treatment with bevacizumab atezolizumab or 
bevacizumabplacebo for a total of 22 cycles of atezolizumab or placebo, and 20 cycles of 
bevacizumab.  No additional cycles of maintenance anti-cancer therapy are permitted beyond 
22 cycles of therapy in the front-line setting.
After the completion of maintenance therapy (i.e., bevacizumab atezolizumab or placebo), 
patients will have an end-of-treatment assessment within 30 days of the last dose of study 
treatment and then enter the post-treatment follow-up period.  The expected study treatment 
duration for an individual patient is approximately 66 weeks for patients randomized after 
primary surgery and 70 weeks for patients randomized prior to neoadjuvant therapy.
Progression-free survival (PFS) will be ascertained by the investigator in accordance with 
radiographic criteria from RECIST v1.1 at fixed intervals.  All primary imaging data used for 
tumor assessment will also be collected by the Sponsor to enable a centralized Independent 
Review Committee audit of a prespecified subset of PFS data.  Overall survival (OS) will be 
determined by the investigator.  Tumor assessments will continue until confirmed disease 
progression or 5 years after the completion of all study treatment, whichever occurs first.  Safety 
and toxicity assessments will be conducted at each treatment cycle administration.
Patients will undergo a mandatory tumor biopsy sample collection, if clinically feasible, at the 
time of first evidence of radiographic disease progression according to RECIST v1.1.  Cytology 
from ascites, pleural effusion, and fine needle aspiration (FNA) is not adequate.  These samples 
will be retrospectively analyzed to evaluate and/or characterize pseudoprogression caused by 
immune cells (ICs) from true progression.  In addition, tumor tissue biomarkers related to 
resistance, disease progression, and clinical benefit of atezolizumab will be analyzed.
Option for additional enrollment in China
Study YO39523 will be enrolling patients globally.  Should the Study be opened in mainland 
China, the Sponsor is targeting a total enrollment of approximately 150 patients.  A China 
extension phase may be initiated if patients enrolled in the global enrollment phase is 
significantly less than the target.  Thus, the China subpopulation will include patients enrolled at 
sites in China during both the global enrollment phase and the China extension phase.  Patients 
from the China extension phase will be randomized in a 1:1 ratio to the two treatment arms.  
The patients enrolled in the China extension phase will undergo the same schedule of 
assessments and will receive paclitaxel, carboplatin, bevacizumab, and atezolizumab or 
placebo as in the global study.  Analyses based on the China subpopulation will be reported 
separately from the global study.
Number of Patients
Approximately 1300 patients with Stage III or Stage IV ovarian, fallopian tube, or primary 
peritoneal cancer (i.e., cancers of extra-uterine Müllerian origin) with macroscopic residual 
disease postoperatively (i.e., after primary tumor reductive surgery) or who will undergo 


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neoadjuvant therapy followed by interval surgery are expected to be randomized in this study.  
The enrollment of patients in the neoadjuvant setting will be capped at approximately 20%.
Target Population
Inclusion Criteria
Patients must meet the following criteria for study entry:

Signed Informed Consent Form (ICF)

Age 18 years

Able to comply with the study protocol, in the investigator’s judgment

Receive a histologic diagnosis of EOC, peritoneal primary carcinoma, or fallopian tube 
cancer fulfilling the following criteria:
All epithelial tumors of extra-uterine Müllerian origin by histology (FNA, cytology and/or 
cell block are not sufficient)
For patients who will undergo primary tumor reductive surgery: International Federation 
of Gynecological Oncologists (FIGO) Stage III with gross (macroscopic or palpable) 
residual disease or Stage IV
Measurable disease on postoperative imaging studies is not required for 
eligibility
FIGO stage is assessed following the completion of initial abdominopelvic 
surgery that provides the appropriate tissue for histologic evaluation and 
diagnosis and can be used for exploratory biomarker studies.
Primary tumor reductive surgery must be within 42 days of randomization.
For patients who will undergo neoadjuvant treatment and interval surgery:  Patients who 
receive neoadjuvant treatment must also plan to undergo interval surgery after Cycle 3.  
Mandatory biopsy tissue samples (e.g., core needle or surgically obtained; FNA or cell-
block from ascites and/or pleural effusion are inadequate) will be used to confirm 
histologically that the tumor is of extra-uterine Müllerian origin and to perform 
exploratory biomarker studies.
Patients who receive neoadjuvant therapy will include those patients who are not 
deemed surgically resectable to a state of no gross residual disease due to the 
extent and/or distribution of disease (e.g., unresectable miliary pattern of peritoneal 
carcinomatosis, significant diaphragmatic disease, significant involvement of the 
root of the mesentery, diffuse tumor in the omentum up to the greater curvature of 
the stomach, extensive miliary carcinomatosis at the root of the mesentery, tumor 
infiltration of the stomach, surface lesions on the liver).

Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2

Life expectancy 12 weeks

Adequate hematologic and end-organ function, defined by the following laboratory test 
results, obtained within 14 days prior to randomization:
ANC 1500 cells/L (without granulocyte colony stimulating factor support)
Lymphocyte count 500/L
Platelet count 100,000/L without transfusion
Hemoglobin 9.0 g/dL
Patients may be transfused to meet this criterion.
Serum creatinine 1.5 institutional upper limit of normal (ULN)
Serum bilirubin 1.5 ULN
Patients with known Gilbert disease who have serum bilirubin level 3 ULN 
may be enrolled in the study.
AST, ALT, and alkaline phosphatase (ALP) 2.5 ULN, with the following exceptions:
Patients with documented liver metastases:  AST and/or ALT 5 ULN
Patients with documented liver or bone metastases:  ALP 5 ULN.
For patients who do not receive therapeutic anticoagulation:  INR or aPTT 1.5 ULN


Atezolizumab—F. Hoffmann-La Roche Ltd
37/Statistical Analysis Plan YO39523

For patients who receive therapeutic anticoagulation:  stable anticoagulant regimen

Negative hepatitis B surface antigen (HBsAg) test at screening

Negative total hepatitis B core antibody (HBcAb) test at screening, or positive total HBcAb 
test followed by a negative hepatitis B virus (HBV) DNA test at screening
The HBV DNA test will be performed only for patients who have a positive total HBcAb 
test.

Negative hepatitis C virus (HCV) antibody test at screening, or positive HCV antibody test 
followed by a negative HCV RNA test at screening
The HCV RNA test will be performed only for patients who have a positive 
HCV antibody test.
A positive HCV RNA test is sufficient to diagnose active HCV infection in the absence of 
an HCV antibody test.

For women of childbearing potential:  agreement to remain abstinent (refrain from 
heterosexual intercourse) or use a contraceptive method with a failure rate of 1% per year 
during the treatment period and for at least 5 months after administration of the last dose of 
atezolizumab and 6 months after the last dose of bevacizumab, paclitaxel, or carboplatin, 
whichever is later
A woman is considered to be of childbearing potential if she is postmenarcheal, has not 
reached a postmenopausal state (12 continuous months of amenorrhea with no 
identified cause other than menopause), and has not undergone surgical sterilization 
(removal of ovaries, fallopian tubes, and/or uterus).
Examples of contraceptive methods with a failure rate of 1% per year include but are 
not limited to bilateral tubal ligation and/or occlusion, male sterilization, and intrauterine 
devices.
In countries with country-specific health authority mandates, contraceptive methods 
with a failure rate of 1% per year include bilateral tubal ligation/occlusion, male 
partner sterilization, established and proper use of estrogen-progestin combination 
hormonal contraceptives that inhibit ovulation, and intrauterine devices/systems.
The reliability of sexual abstinence should be evaluated in relation to the duration of the 
clinical study and the preferred and usual lifestyle of the patient.
Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation 
methods) and withdrawal are not acceptable methods of contraception.

Willingness and ability to comply with scheduled visits, treatment plans, laboratory tests, 
and other study procedures, that include the completion of PRO questionnaires

Availability of a representative formalin-fixed, paraffin-embedded (FFPE) tumor specimen 
(screening baseline tissue) in paraffin blocks (preferred) or at least 20 unstained slides.
Patients with fewer than 20 unstained slides available at baseline may be eligible upon 
discussion with the medical monitor.
Tumor tissue should be of good quality based on total and viable tumor content and 
must be evaluated for PD-L1 expression prior to enrollment.  Patients whose tumor 
tissue is not evaluable for PD-L1 expression are not eligible for enrollment in the study.
If multiple screening baseline tumor specimens are submitted, patients may be eligible 
if at least one specimen is evaluable for PD-L1.  For the purpose of stratification, the 
PD-L1 score of the patient will be the maximum PD-L1 score among the samples.
Acceptable samples include tissue obtained from surgery or core needle 
biopsies (minimum three cores per paraffin block).
A paraffin block for FFPE tumor specimens is preferred.
FNA or cell pellets from ascites or pleural effusion are not acceptable.
Tumor tissue from bone metastases is not evaluable for PD-L1 expression and 
is not acceptable.

For patient enrolled in the extended China enrollment phase: residents in Mainland China, 
residents in Hong Kong and Taiwan of Chinese ancestry and enrolled at sites recognized 
by China’s National Products Administration (NMPA). 


Atezolizumab—F. Hoffmann-La Roche Ltd
38/Statistical Analysis Plan YO39523
Exclusion Criteria
Patients who meet any of the following criteria will be excluded from enrollment in the study:

Received a current diagnosis of borderline epithelial ovarian tumor (formerly tumors of low 
malignant potential)

Have recurrent invasive epithelial ovarian, fallopian tube, or primary peritoneal cancer that 
was treated only with surgery (e.g., patients with Stage IA or Stage IB epithelial ovarian or 
fallopian tube cancers)
Patients who received a prior diagnosis of a borderline tumor that was surgically 
resected and who subsequently developed an unrelated, new invasive epithelial 
ovarian, fallopian tube, or primary peritoneal cancer are eligible for enrollment, if they 
have never received prior chemotherapy for any ovarian tumor.

Have non-epithelial ovarian tumors (e.g., germ cell tumors, sex cord stromal tumors)

Received prior radiotherapy to any portion of the abdominal cavity or pelvis
Prior focal radiation for localized cancer of the breast, head and neck, or skin is 
permitted, if it was completed 5 years prior to initiation of study treatment, and the 
patient remains free of recurrent or metastatic disease.

Received prior chemotherapy for any abdominal or pelvic tumor that include NACT for 
ovarian, primary peritoneal or fallopian tube cancer
Patients may have received prior chemotherapy for localized breast cancer, if it was 
completed 5 years prior to initiation of study treatment, and the patient remains free of 
recurrent or metastatic disease.

Received any biological and/or targeted therapy (including but not limited to vaccines, 
antibodies, tyrosine kinase inhibitors) or hormonal therapy for management and/or 
treatment of epithelial ovarian or peritoneal primary cancer

Have synchronous primary endometrial cancer

Have a prior history of primary endometrial cancer, except for the following:
A prior diagnosis of endometrial cancer is allowed if all of the following conditions are 
met:
Stage IA cancer
Superficial myometrial invasion, without lymphovascular invasion
Grade 3 or not poorly differentiated subtypes, and this includes papillary serous, 
clear cell or other FIGO Grade 3 lesions

With the exception of non-melanoma skin cancer and other specific malignancies as noted 
above, other invasive malignancies within the last 5 years or previous cancer treatment that 
contraindicates this protocol therapy (e.g., previous chemotherapy treatment for breast 
cancer completed 5 years ago is permitted as per above).

Are pregnant, lactating, or intend to become pregnant during the study

Have a history of severe allergic, anaphylactic, or other hypersensitivity reactions 
to chimeric or humanized antibodies or fusion proteins

Have a known hypersensitivity or allergy to biopharmaceutical agents produced in Chinese 
hamster ovary cells or any component of the atezolizumab and/or bevacizumab 
formulations

Have an active or history of autoimmune disease or immune deficiency that includes but is 
not limited to myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus 
erythematosus, rheumatoid arthritis, inflammatory bowel disease, antiphospholipid antibody 
syndrome, Wegener’s granulomatosis, Sjögren’s syndrome, Guillain-Barré syndrome, or 
multiple sclerosis (see protocol for a more comprehensive list of autoimmune diseases).  

Exceptions include the following:
Patients with a history of autoimmune-related hypothyroidism on a stable dose of thyroid 
replacement hormone are eligible.


Atezolizumab—F. Hoffmann-La Roche Ltd
39/Statistical Analysis Plan YO39523
Patients with controlled Type 1 diabetes mellitus on a stable dose of insulin regimen are 
eligible.
Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with dermatologic 
manifestations only (e.g., patients with psoriatic arthritis would be excluded) are eligible 
for enrollment in the study provided that they meet all of the following conditions:
Rash must cover less than 10% of body surface area
Disease is well controlled at baseline and requires only low potency topical 
steroids
No acute exacerbations of underlying condition within the previous 12 months 
(i.e., does not require psoralen plus ultraviolet A radiation, methotrexate, 
retinoids, biologic agents, oral calcineurin inhibitors, high-potency or oral 
steroids)

Have a history of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis 
obliterans), drug-induced pneumonitis, idiopathic pneumonitis, or evidence of active 
pneumonitis based on a screening chest computed tomography (CT) scan, with the 
following exceptions
A history of radiation pneumonitis in the localized radiation field (fibrosis) is permitted.  
Patient must still meet all other radiotherapy exclusions listed above.

Have a positive test result for HIV

Have active tuberculosis

Have severe infections within 4 weeks prior to initiation of study treatment, including but not 
limited to hospitalization for complications of infection, bacteremia, or severe pneumonia

Have received therapeutic oral or IV antibiotic medication within 2 weeks prior to initiation of 
study treatment, with the following exceptions:
Patients who receive prophylactic antibiotic medication (e.g., urinary tract infection 
prophylaxis, prior to dental procedure) are eligible for enrollment.

Have significant cardiovascular disease, such as New York Heart Association cardiac 
disease (Class II or greater), myocardial infarction, or cerebrovascular accident within 
3 months prior to initiation of study treatment, unstable arrhythmias, or unstable angina
Patients with known coronary artery disease, congestive heart failure not meeting the 
above criteria, or 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.

Undergo major surgical procedure within 28 days prior to first bevacizumab dose, or 
anticipation of the need for a major surgical procedure during the course of the study except 
patients who receive NACT and will need interval surgery.  This may include but is not 
limited to laparotomy.  All incisions should be fully healed, as assessed clinically, prior to 
starting bevacizumab.
Consult with the Medical Monitor prior to patient entry for any questions related to the 
classification of surgical procedures.

Are administered treatment with a live attenuated vaccine within 4 weeks prior to initiation of 
study treatment, or anticipation of need for such a vaccine during the course of the study or 
within 5 months after the last dose of atezolizumab

Current treatment with anti-viral therapy for HBV

Have prior allogeneic bone marrow transplantation or solid organ transplant

Have 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

Have any approved or investigational anti-cancer therapy, including chemotherapy or 
hormonal therapy, with the following exceptions:
Hormone-replacement therapy or oral contraceptives are allowed.

Current or recent (within 10 days of initiation of study treatment) use of aspirin 
(325 mg/day) or clopidogrel 75 mg/day)


Atezolizumab—F. Hoffmann-La Roche Ltd
40/Statistical Analysis Plan YO39523

Are administered treatment with any other investigational agent or participation in another 
clinical study with anti-cancer therapeutic intent

Have prior treatment with CD137 agonists or immune checkpoint blockade therapies, 
antiPD-1, antiPD-L1, or anti-cytotoxic T-lymphocyte-associated protein 4 therapeutic 
antibodies

Have treatment with systemic immunostimulatory agents (including but not limited to 
interferons [IFNs], interleukin [IL]-2) within 4 weeks or 5 half-lives of the drug, whichever is 
longer, prior to initiation of study treatment

Have treatment with systemic immunosuppressive medications (including but not limited to 
prednisone, cyclophosphamide, azathioprine, methotrexate, thalidomide, and antitumor 
necrosis factor [TNF] agents) within 2 weeks prior to initiation of study treatment, with the 
following exceptions:
Patients who have received acute, low-dose, systemic immunosuppressant medications
or a one-time pulse dose of systemic immunosuppressant medication (e.g., 48 hours of
corticosteroids for a contrast allergy) are eligible for enrollment in the study.
The use of corticosteroids for chronic obstructive pulmonary disease and asthma, 
mineralocorticoids (e.g., fludrocortisone), or low-dose corticosteroids for patients with 
orthostatic hypotension or adrenocortical insufficiency is allowed.

Have inadequately-controlled hypertension (defined as systolic blood pressure 150 mmHg 
and/or diastolic blood pressure 100 mmHg)
Anti-hypertensive therapy to achieve these parameters is allowed.

Have prior history of hypertensive crisis or hypertensive encephalopathy

Have significant vascular disease (e.g., aortic aneurysm requiring surgical repair or recent 
peripheral arterial thrombosis) within 6 months prior to initiation of study treatment

Have a history of Grade 2 hemoptysis (2.5 mL of bright red blood per episode) within 
1 month prior to screening

Have evidence of active bleeding, bleeding diathesis, coagulopathy, tumor that involves 
major vessels (in the absence of therapeutic anticoagulation)

Have a history or evidence upon physical examination of any CNS disease, including 
primary brain tumor, CNS metastases, seizures not controlled with standard medical 
therapy, any brain metastases, or history of cerebrovascular accident (stroke), transient 
ischemic attack or subarachnoid hemorrhage within 6 months of the first date of treatment 
on this study.

History of leptomeningeal disease

History of Grade 4 venous thromboembolism

Have current use of full-dose oral or parenteral anticoagulants or thrombolytic agents for 
therapeutic purposes that has not been stable prior to initiation of study treatment, with the 
following exceptions:
The use of full-dose oral or parenteral anticoagulants is permitted as long as the INR or 
aPTT is within therapeutic limits according to the medical standard of the enrolling 
institution, and the patient has been receiving a stable dose of anticoagulants prior to 
initiation of study treatment.
Prophylactic anticoagulation for the patency of venous access devices is allowed, 
provided the activity of the agent results in an INR 1.5 ULN and aPTT is within 
normal limits prior to initiation of study treatment.
Deep venous thrombosis prophylaxis with low-molecular-weight heparin is permitted.

Have core biopsy or other minor surgical procedures within 7 days prior to the first dose of 
bevacizumab


Atezolizumab—F. Hoffmann-La Roche Ltd
41/Statistical Analysis Plan YO39523
The interval of time between placement of a central vascular access device (CVAD; 
e.g., Port-a-cath) and the first dose of bevacizumab must be no shorter than 2 days with 
a well-healed incision
If placing a CVAD between bevacizumab doses, placement must occur at least 14 days 
from the prior (i.e, pre-CVAD placement) bevacizumab dose, and at least 7 days from 
the following (i.e., post-CVAD placement) bevacizumab dose.

Have a history of abdominal fistula or gastrointestinal perforation within 6 months prior to 
initiation of study treatment, with the following exceptions:
Patients with granulating incisions healing by secondary intention with no evidence of 
fascial dehiscence or infection are eligible but require weekly wound examinations.

Have clinical signs of gastrointestinal obstruction that require routine parenteral hydration, 
parenteral nutrition, or tube feeding

Have evidence of abdominal free air not explained by paracentesis or recent surgical 
procedure

Have serious, non-healing wound, active ulcer, or untreated bone fracture

Have proteinuria, as demonstrated by urine dipstick or 1.0 of protein in a urine 
protein-to-creatinine ratio and/or 24-hour urine collection
All patients with 2 protein on dipstick urinalysis at baseline must undergo a urine 
protein-to-creatinine ratio and/or 24-hour urine collection and demonstrate 1.0 of 
protein.

Have known sensitivity to any component of bevacizumab

Have known sensitivity to any component of paclitaxel

Have Grade 2 peripheral neuropathy as defined by the National Cancer Institute Common 
Terminology Criteria for Adverse Events, Version 4.0 (NCI CTCAE v4.0)

Have known history of severe allergic reactions to platinum-containing compounds

Have known history of severe hypersensitivity reactions to products that contain 
CremophorEL (e.g., cyclosporine for injection concentrate and teniposide for injection 
concentrate)
End of Study
The end of the study is expected to be approximately 55 months after the first patient is enrolled, 
when the approximate preplanned numbers of deaths among the PD-L1positive patients and the 
intent-to-treat (ITT) population have been observed.  Deaths will be monitored throughout the
course of the study.  The sponsor has the right to close the study at any time if futility is observed 
(e.g., based on the predicted probability of success at the subsequent analysis).  The study 
timelines may be updated as needed.
Length of Study
The length of study is approximately 55 months from enrollment of the first patient to the “end of 
study” as described above
Investigational Medicinal Products
The investigational medicinal product (IMP) for this study is atezolizumab.
Atezolizumab
Atezolizumab will be supplied by the Sponsor as a sterile liquid in a single-use, 20-mL glass 
vial.  The vial contains approximately 20 mL (1200 mg) of atezolizumab solution.
Placebo
The placebo will be supplied by the Sponsor and will be identical in appearance to atezolizumab 
and comprise the same excipients but without atezolizumab drug product.
Non-Investigational Medicinal Products
Bevacizumab will be supplied by the Sponsor.  Paclitaxel and carboplatin will be used in 
commercially available formulations.  Bevacizumab will be considered an IMP by local 
regulations in some countries.


Atezolizumab—F. Hoffmann-La Roche Ltd
42/Statistical Analysis Plan YO39523
Statistical Methods
Primary Analysis
The primary analysis populations for efficacy are the ITT population, defined as all patients 
randomized in the study, and the PD-L1positive subgroup, defined as the patients in the ITT 
population whose PD-L1 status is IC1/2/3 at the time of randomization.  Patients will be grouped 
in accordance with the treatment assigned at randomization.
The primary analysis population for safety is the Safety Population, defined as all randomized 
patients who receive at least one dose of the study medication.  Patients will be grouped in 
accordance with the treatment they actually receive, and all patients who received any dose of 
atezolizumab will be included in the atezolizumab treatment arm for analysis.
If the China extension phase is initiated, data from this phase will not be included in the primary 
analysis of the main study.  A separate analysis will be performed for the China subgroup, 
where data from the China extension phase and from the patients in the global enrollment 
phase from China will be combined and summarized (refer to the protocol and the statistical 
analysis plan [SAP] for further details).  All analyses discussed in this section will be restricted 
to the patients recruited in the global study only, unless noted.
Determination of Sample Size
Approximately 1300 patients will be randomized in the global study in a 1:1 ratio to the 
two treatment arms.
There are two co-primary efficacy endpoints:  investigator-assessed PFS and OS.  The overall 
Type I error rate will be controlled at a two-sided level of 0.05 to test PFS and OS in the 
PD-L1positive subgroup and the ITT population.  PFS in both the ITT and PD-L1positive 
subgroup will be tested in parallel at the same significance level of 0.002 (two-sided).  To test 
OS in both these specified populations, a hierarchical testing approach will be applied.  The 
alpha allocated to OS will be used first to test OS in the PD-L1positive subgroup.  If the 
significance is reached, the same alpha as used for the PD-L1positive subgroup OS testing 
will be passed to OS in the ITT.  Note that the OS testing sequence of the populations may be 
inverted.  The OS test in the PD-L1positive subgroup is initially assigned with an alpha level of 
0.046 and the actual alpha level will be determined by the results of the PFS tests.  If the PFS 
test in either the ITT or PD-L1positive population reaches significance, its assigned alpha of 
0.002 will be additively passed to OS.

The alpha level for OS will be 0.046 if neither of the PFS tests (in the ITT and 
PD-L1positive subgroup) reaches significance.

The alpha level for OS will be 0.048 if only one PFS test (in either the ITT or the 
PD-L1positive subgroup) reaches significance.

The alpha level for OS will be 0.05 if both the PFS tests (in the ITT and the PD-L1positive 
subgroup) reach significance.
The sample size of the study is determined by the number of patient deaths required to 
demonstrate efficacy in terms of OS in the PD-L1positive subgroup and the ITT population.  To 
detect an improvement in OS with the use of a log-rank test at a two-sided significance level of 
0.046, approximately 311 deaths in the PD-L1positive subgroup will be required to achieve 
81% power with a target hazard ratio (HR) of 0.72, and approximately 534 deaths in the ITT 
population to achieve 80% power with a target HR of 0.78.
Interim Analyses
There will be no interim analysis for PFS.  The primary analysis of PFS will take place when 
approximately 601 PFS events in the ITT and 347 PFS events in the PD-L1positive subgroup 
have occurred (whichever is later), which is expected at approximately 36 months after the first 
patient is enrolled in the study.  This provides 90% power to detect a PFS improvement of 
HR 0.7 in the ITT, and 91% power in the PD-L1positive subgroup with HR 0.62, at a 
two-sided significance level of 0.002.
Two interim analyses of OS will be performed on patients who are in the ITT and 
PD-L1positive populations.  The timing of the two interim analyses and the final analysis for 
OS depends on the results from the primary analysis of the co-primary endpoint of PFS.


Atezolizumab—F. Hoffmann-La Roche Ltd
43/Statistical Analysis Plan YO39523
The calculation of the sample size and estimates of the analysis timelines are based on the 
following assumptions:

PFS and OS are exponentially distributed.

The median duration of PFS in the control arm is 18 months.

The median duration of OS in the control arm is 43 months.

The prevalence of PD-L1positive (IC1/2/3) patients is 60%.

The two interim and final analyses of OS use the Lan-DeMets alpha spending function to 
approximate the O’Brien-Fleming boundary.

The dropout rate is 5% over 12 months for PFS and OS.

The recruitment of 1300 patients will take place over 25 months


Atezolizumab—F. Hoffmann-La Roche Ltd
44/Statistical Analysis Plan YO39523
Appendix 2
Schedule of Assessments for Patients Who Underwent Primary Surgery
Screening
Concurrent Treatment
Maintenance Treatment
Treatment 
Completion/
Early Terminationa
Post-Treatment 
Follow-up a
Day
–28 
to –1
Day
14 
to –1
Cycle a
Cycle a
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
Within 30days of 
the last dose of the 
study treatment
Q3Mo for 2 yr 
after the treatment 
completion visit, 
then Q6Mo for 
3 yr, then annually
Signed informed 
consent b
x
Demographic data
x
Medical history and 
baseline conditions
x
Complete physical 
examination c
x
Limited physical 
examination d
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
ECOG PS
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Vital signs e
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Adverse events f
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Concomitant 
medications
x g
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Hematologyh
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Urinalysis i
x
Urine proteini
x
x
x
x
x
x
x
x
x
x
x


Atezolizumab—F. Hoffmann-La Roche Ltd
45/Statistical Analysis Plan YO39523
Screening
Concurrent Treatment
Maintenance Treatment
Treatment 
Completion/
Early Terminationa
Post-Treatment 
Follow-up a
Day
–28 
to –1
Day
14 
to –1
Cycle a
Cycle a
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
Within 30days of 
the last dose of the 
study treatment
Q3Mo for 2 yr 
after the treatment 
completion visit, 
then Q6Mo for 
3 yr, then annually
Serum chemistry j
x
x
x 
x
x
x
x
x
x j
x
x j
x
x j
x
x j
x
x j
x
x j
x
x j
x
x j
x j
TSH, free T3, free T4
x
x
x
x
x
x
x
HIV, HBV, HCV 
serology k
x
Urine pregnancy test 
(for patients of 
childbearing potential l
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
PT/INR, aPTT
x
12-lead ECG
x
Radiologic disease 
assessment   m, n, o
x
x
x
x
x
x
x
x
x
Serum CA-125 level p
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
EORTC QLQ-C30, 
QLQ-OV28, EQ-5D-5Lq
x
x
x
x
x
x
x
x
x q
FACT-G, GP5 single 
item r
x
x
x
x
x
x
x
x r
Samples for PK, ADA, 
and biomarkers
See Appendix 3 for Schedule of PK, ADA, and biomarker sampling
Optional whole blood 
sample for RBR s
x
Atezolizumab/
placebo administration
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Appendix 2 Schedule of Assessments for Patients Who Underwent Primary Surgery (cont.)


Atezolizumab—F. Hoffmann-La Roche Ltd
46/Statistical Analysis Plan YO39523
Screening
Concurrent Treatment
Maintenance Treatment
Treatment 
Completion/
Early Terminationa
Post-Treatment 
Follow-up a
Day
–28 
to –1
Day
14 
to –1
Cycle a
Cycle a
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
Within 30days of 
the last dose of the 
study treatment
Q3Mo for 2 yr 
after the treatment 
completion visit, 
then Q6Mo for 
3 yr, then annually
Bevacizumab 
administration
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Paclitaxel administration
x
x
x
x
x
x
Carboplatin 
administration
x
x
x
x
x
x
Screening baseline
FFPE tumor tissue 
block or 20 unstained 
slides t
x
Mandatory FFPE tumor 
tissue specimen at 
disease progression u
x
Appendix 2 Schedule of Assessments for Patients Who Underwent Primary Surgery (cont.)


Appendix 2 Schedule of Assessments for Patients Who Underwent Primary Surgery (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
47/Statistical Analysis Plan YO39523
ADAanti-drug antibody; CAcancer antigen; CRcomplete response; CT computed tomography; ECOG PSEastern Cooperative Oncology 
Group performance status; eCRFelectronic Case Report Form; EORTCEuropean Organisation for Research and Treatment of Cancer; 
FACT-GFunctional Assessment of Cancer Therapy-General; FFPEformalin-fixed, paraffin-embedded; HBVhepatitis B virus; HBcAbhepatitis 
B core antibody; HBsAghepatitis B surface antigen; HCVhepatitis C virus; MRImagnetic resonance imaging; PKpharmacokinetic; 
PRpartial response; PROpatient-reported outcome; Q3Moevery 3 months; Q6Moevery 6 months; QLQ-OV28Quality of Life Questionnaire 
Ovarian Cancer Module 28; RECIST Response Evaluation Criteria in Solid Tumors; UPCR urine protein-to-creatinine ratio; yryear.
Note:  Study assessments/cycles may be adjusted slightly to accommodate holidays, vacations, and unforeseen major life events.  Documentation 
to justify this decision should be provided.
a Each cycle is 21 days.  Study drug administration occurs on Day 1 (3 days) of each cycle.  All other events and assessments during the study 
treatment period (Cycle 1 through Cycle 22) must occur within 3 days prior to the administration (e.g., activities/assessments for Cycle 1, except 
the actual drug infusion, must be performed within 3 days before infusion of Cycle 1).  The end of the study treatment or early discontinuation 
visit should occur within 30 days after the last dose of the study treatment is administered.  The post-treatment follow-up visits will occur every 
3 months (21 days) for the first 2 years after the treatment completion visit, then every 6 months (21 days) for 3 years, and then annually 
(21 days). Post-treatment visits can be performed via telephone or clinic visit as indicated by assessment requirements.
b The Informed consent must be obtained prior to any study-specific procedure and within 28 days (7 days) before randomization.
c A complete physical examination should include an evaluation of the patient’s head, eyes, ears, nose, throat, and the cardiovascular, 
dermatological, musculoskeletal, respiratory, gastrointestinal, genitourinary, and neurological systems.  Any abnormality identified at the baseline 
should be recorded on the General Medical History and Baseline Conditions eCRF.
d Limited, symptom-directed physical examinations should be performed at specified visits and as clinically indicated.  Changes from baseline 
abnormalities should be recorded in the patient notes.  New or deteriorated clinically-significant abnormalities should be recorded as adverse 
events on the Adverse Event eCRF.
e Vital signs will include measurements of the respiratory rate, pulse rate, and systolic and diastolic blood pressure while the patient is in a seated 
position, and body temperature.  Vital signs should be measured prior to the first study treatment infusion of the cycle, as clinically indicated, and 
at other specified timepoints as outlined in the schedule of activities.


Appendix 2 Schedule of Assessments for Patients Who Underwent Primary Surgery (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
48/Statistical Analysis Plan YO39523
f
All serious adverse events and adverse events of special interest, regardless of their relationship to the study drug, will be reported until 90 days 
after the last dose of the study drug is administered or the initiation of new anti-cancer therapy, whichever occurs first.  All other adverse events, 
regardless of the relationship to the study drug, will be reported until 30 days after the last dose of the study drug is administered or the initiation 
of new anti-cancer therapy, whichever occurs first.  After this period, the investigator should report any serious adverse events that are believed 
to be related to prior study drug treatment.
g Concomitant medications need to be collected within 7 days prior to starting study treatment.
h Hematology consists of CBC, including hemoglobin, WBC count with differential (neutrophils, lymphocytes, eosinophils, monocytes, basophils, 
and other cells), and platelet count.
i
Patients must demonstrate negativity for proteinuria (see Section 4.1.2).  Urine protein is no longer required for patients who discontinue 
bevacizumab for reasons other than proteinuria.  However, for those who discontinue bevacizumab due to proteinuria, urine protein is required 
until proteinuria returns to baseline or until the end of the study, whichever occurs first.
j
Serum chemistry includes BUN, creatinine, sodium, potassium, magnesium, calcium, glucose, total bilirubin, ALT, AST, ALP, and albumin.  
Serum chemistry eligibility must be confirmed during the screening period before randomization.  After Cycle 1, serum magnesium may be 
performed as clinically indicated.  Serum chemistry samples performed during the maintenance phase and at treatment discontinuation may be 
performed at each cycle, instead of every other cycle, in accordance to country-specific health authority mandates (e.g., Spain).
k All patients will be tested for HIV infection prior to enrollment into the study, and HIV-positive patients will be excluded from the study.  All 
patients will be tested for HBsAg and total HBcAb at the baseline.  If a patient has a negative HBsAg test and a positive total HBcAb test at 
screening, an HBV DNA test must also be performed to determine if the patient has an HBV infection.  If a patient has a positive HCV antibody 
test at screening, an HCV RNA test must also be performed to determine if the patient has an HCV infection.
l
Urine pregnancy tests beyond Cycle 1 for Cycles 222, at treatment discontinuation, and at 3 and 6 months after treatment discontinuation must 
be performed in accordance to country-specific health authority mandates (e.g., Spain, Norway, Czech Republic, Poland, Germany, and 
Belgium).
m All radiographic assessments will be performed according to the time interval (e.g., 9 weeks, 12 weeks, etc.) with the corresponding windows per 
Section 4.5.5 regardless of the treatment cycle.  For patients who have had primary tumor reductive surgery, an initial CT scan or MRI of at least 
the chest, abdomen, and pelvis is required to establish postsurgical (i.e., primary cytoreductive surgery) baseline of the extent of residual 
disease within 28 days prior to randomization.  In the absence of disease progression, imaging that uses the same modality and encompasses 
the same field as in the initial pre-treatment evaluation should be repeated (1) every 9 weeks during the concurrent treatment phase, (2) every 
12 weeks in the maintenance phase (the first scan in the maintenance phase is performed 12 weeks after the last scan in the concurrent 
treatment phase), (3) every 3 months for the first 2 years after completion of all protocol therapy, (4) and then every 6 months for the next 
3 years, regardless of whether the patient showed measurable disease on the initial CT or MRI.  CT scans or MRIs after 5 years of survival 
follow-up may be done, as clinically indicated.  Head/neck imaging at screening is dictated by clinical judgment.  If a tumor assessment is 
performed within 30 days prior to the scan scheduled at the treatment completion/early termination visit, then a specific treatment 
completion/early termination tumor assessment does not need to be performed.


Appendix 2 Schedule of Assessments for Patients Who Underwent Primary Surgery (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
49/Statistical Analysis Plan YO39523
n A CT scan or MRI of at least the patient’s chest, abdomen, and pelvis is required to establish the postsurgical (i.e., primary cytoreductive 
surgery) baseline for the extent of residual disease within 28 days prior to the initiation of study treatment (Scan 1).
o Follow-Up Radiographic Assessment of Disease:  In the absence of disease progression and/or allergic reaction to IV contrast, imaging with the 
same modality and field as the initial pretreatment evaluation should be repeated at the following time intervals (i.e., 9 weeks, 12 weeks, etc.) 
with the corresponding windows per Section 4.5.5 regardless whether the patient had measurable disease on the initial CT or MRI and 
regardless of the treatment cycle.
Scans 2 and 3:  Every 9 weeks from randomization during the concurrent treatment phase (approximately after Cycle 3 and Cycle 6, but 
may vary).
Scans 4, 5, 6, and 7:  Every 12 weeks after the last scan during the concurrent treatment phase, which is now during the maintenance 
phase (approximately after Cycle 10, Cycle 14, Cycle 18, and Cycle 22).
After the treatment completion visit, every 3 months for 2 years, then every 6 months for 3 years.  CT scans or MRIs after 5 years of 
survival follow-up may be done, as clinically indicated.
p Baseline prechemotherapy value is required.  When available, also include the presurgical value.  CA-125 after 5 years may be done as clinically 
indicated.
q All PRO questionnaires must be completed in their entirety by the patient at the investigational site at the start of the clinic visit before discussion 
of the patient’s health state, laboratory test results, or health records, before the administration of the study treatment, and/or prior to the 
performance of any other study assessments (e.g., scans) that could bias the patient’s responses.
The EORTC QLQ-C30, QLQ-OV28, and EQ-5D-5L questionnaires must be administered and completed by patients in that order at the following 
assessment timepoints during each treatment and post-treatment period:
Concurrent treatment:  At baseline (Cycle 1, Day 1) (3 days), and on Day 1 (3 days) of every other cycle thereafter until 
Cycle 6 (i.e., every 6 weeks)
Maintenance treatment:  At Cycle 8, Day 1 (3 days) and on Day 1 (3 days) of each cycle every 12 weeks thereafter until Cycle 22
Treatment discontinuation or completion:  At the end of the treatment or discontinuation visit within 30 days of the administration of the last 
dose of the study treatment
Post-treatment follow-up:  Patients who discontinue study treatment for progressive disease or loss of clinical benefit or any other reason, 
regardless of receipt of subsequent anti-cancer therapy will complete the PROs after the treatment completion visit, every 3 months 
(21 days) for the first year of the survival follow-up period; every 6 months (21 days) for the second year of the survival follow-up period; 
and every year (21 days) for the final 3 years of the survival follow-up period.  Patients in the survival follow-up phase who are unable to 
visit the site in-person due to COVID-19 may complete the PRO questionnaires via phone interview by site staff.
r
The single-item GP5 from the FACT-G questionnaire will be the final measure to be administered and must be completed by patients at the 
following assessment timepoints during each treatment and post-treatment period:
Concurrent treatment:  At Cycle 3, Day 1 (3 days), and on Cycle 5, Day 1 (3 days)
Maintenance treatment:  At Cycle 8, Day 1 (3 days), and on Day 1 (3 days) of each cycle every 12 weeks thereafter until Cycle 22


Appendix 2 Schedule of Assessments for Patients Who Underwent Primary Surgery (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
50/Statistical Analysis Plan YO39523
Treatment discontinuation or completion:  At the end of the treatment or discontinuation visit within 30 days of the administration of the last 
dose of the study treatment
Post-treatment follow-up:  Patients who discontinue study treatment for progressive disease or loss of clinical benefit or any other reason, 
regardless of receipt of subsequent anti-cancer therapy will complete FACT-G GP5 after the treatment completion visit, every 3 months 
(21 days) for the first year of the survival follow-up period; every 6 months (21 days) for the second year of the survival follow-up period;
every year (21 days) for the final 3 years of the survival follow-up period. Patients in the survival follow-up phase who are unable to visit
the site in-person due to COVID-19 may complete the PRO questionnaires via phone interview by site staff.
s Whole blood for DNA isolation will be collected from patients who have consented to optional RBR sampling at Cycle 1, Day 1. If the RBR 
genetic blood sample is not collected during the scheduled visit, it may be collected after randomization during the clinical study.
t
Tumor tissue should be of good quality based on the total and viable tumor content (sites will be informed if the quality of the submitted 
specimen is inadequate to determine tumor PD-L1 status).  An FFPE block or at least 20 unstained slides should be provided.  Fine-needle 
aspiration, brushing, cell pellets from pleural effusion, lavage samples, and bone metastases are not acceptable.  For core needle biopsy 
specimens, at least three cores (18 gauge minimum) should be submitted for evaluation.  Submission of the screening tumor sample can occur 
outside the 28-day screening period in conjunction with obtaining the informed consent.  Primary surgery must be within 42 days of 
randomization.
u The collection of a sample at disease progression is mandatory if clinically feasible.  Preferably, samples collected at the time of radiographic 
progression should be collected from growing lesions.  An FFPE block or at least 15 unstained slides should be provided.  Fine-needle 
aspiration, brushing, cell pellets from pleural effusion, lavage samples, and bone metastases are not acceptable.  For core needle biopsy 
specimens, at no fewer than two cores (18 gauge minimum) should be submitted for evaluation.


Atezolizumab—F. Hoffmann-La Roche Ltd
51/Statistical Analysis Plan YO39523
Appendix 3
Schedule of Assessments for Patients Who Underwent Neoadjuvant Chemotherapy and 
Interval Surgery
Screening
Concurrent 
Neoadjuvant 
Treatment
Presurgical/
Surgery Visit
Concurrent 
Post-
neoadjuvant 
Treatment
Maintenance Treatment
Completion of 
Treatment/
Early 
Termination
Visit a
Post-
Treatment 
Follow-Up a
Cycle a
Cycle a
Cycle a
Day
–28 
to -1
Day
14 
to –1
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
Within 
30 days of 
last dose of 
study 
treatment
Q3Mo for 2 yr 
after the 
treatment 
completion 
visit, then 
Q6Mo for 3 yr, 
then annually
Written informed 
consent b
x
Demographic data
x
Medical history and 
baseline conditions
x
Complete physical 
examination c
x
Paclitaxel 
administration
x
x
x
x
x
x
Limited physical 
examination d
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
ECOG PS
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Vital signs e
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Adverse eventsf
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x


Atezolizumab—F. Hoffmann-La Roche Ltd
52/Statistical Analysis Plan YO39523
Screening
Concurrent 
Neoadjuvant 
Treatment
Presurgical/
Surgery Visit
Concurrent 
Post-
neoadjuvant 
Treatment
Maintenance Treatment
Completion of 
Treatment/
Early 
Termination
Visit a
Post-
Treatment 
Follow-Up a
Cycle a
Cycle a
Cycle a
Day
–28 
to -1
Day
14 
to –1
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
Within 
30 days of 
last dose of 
study 
treatment
Q3Mo for 2 yr 
after the 
treatment 
completion 
visit, then 
Q6Mo for 3 yr, 
then annually
Concomitant 
medicationsg
x f
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Hematologyh
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Urinalysis i
x
Urine protein i
x
x
x
x
x
x
x
x
x
x
x
Serum chemistry j
x
x
x
x
x
x
x
x
x j
x
x j
x
x j
x
x j
x
x j
x
x j
x
x j
x
x j
x j
TSH, free T3, and 
free T4
x
x
x
x
x
x
x
HIV, HBV, HCV 
serology k
x
Urine pregnancy test 
(if childbearing 
potential exists) l
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
PT/INR, aPTT
x
12-lead ECG
x
Radiographic disease 
assessment m, n
x
x
x
x
x
x
x
x
x
Serum CA-125 level o
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
                                                                           
Appendix 3  
Schedule of Assessments for Patients Who Underwent Neoadjuvant Chemotherapy and Interval Surgery (cont.)


Atezolizumab—F. Hoffmann-La Roche Ltd
53/Statistical Analysis Plan YO39523
Screening
Concurrent 
Neoadjuvant 
Treatment
Presurgical/
Surgery Visit
Concurrent 
Post-
neoadjuvant 
Treatment
Maintenance Treatment
Completion of 
Treatment/
Early 
Termination
Visit a
Post-
Treatment 
Follow-Up a
Cycle a
Cycle a
Cycle a
Day
–28 
to -1
Day
14 
to –1
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
Within 
30 days of 
last dose of 
study 
treatment
Q3Mo for 2 yr 
after the 
treatment 
completion 
visit, then 
Q6Mo for 3 yr, 
then annually
EORTC QLQ-C30, 
QLQ-OV28, 
EQ-5D-5L p
x
x
x
x
x
x
x
x
x
x p
FACT-G, GP5 single 
item q
x
x
x
x
x
x
x
x q
Blood samples for 
PK, ADA , and 
biomarkers
See Appendix 3 for schedule of PK, ADA, and biomarker sampling.
Optional whole blood 
sample for RBR
x r
Atezolizumab/
placebo 
administration
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Bevacizumab 
administration
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Paclitaxel 
administration
x
x
x
x
x
x
                                                                           
Appendix 3  
Schedule of Assessments for Patients Who Underwent Neoadjuvant Chemotherapy and Interval Surgery (cont.)


Atezolizumab—F. Hoffmann-La Roche Ltd
54/Statistical Analysis Plan YO39523
Screening
Concurrent 
Neoadjuvant 
Treatment
Presurgical/
Surgery Visit
Concurrent 
Post-
neoadjuvant 
Treatment
Maintenance Treatment
Completion of 
Treatment/
Early 
Termination
Visit a
Post-
Treatment 
Follow-Up a
Mandatory FFPE 
tumor tissue 
specimen at disease 
progression u
x
Carboplatin 
administration
x
x
x
x
x
x
Screening baseline
FFPE tumor tissue 
block or 20 unstained 
slides s
x
Biopsy t
x
FFPE tumor tissue 
sample from surgical 
material
x
Mandatory FFPE 
tumor tissue 
specimen at disease 
progression u
x
ADA anti-drug antibody; CAcancer antigen; CRcomplete response; CT computed tomography; ECOG PSEastern Cooperative Oncology 
Group performance status; eCRFelectronic Case Report Form; EORTCEuropean Organisation for Research and Treatment of Cancer; 
FACT-GFunctional Assessment of Cancer Therapy-General; FFPEformalin-fixed, paraffin-embedded; HBVhepatitis B virus; HBcAb hepatitis 
B core antibody; HBsAg hepatitis B surface antigen; HCVhepatitis C virus; MRImagnetic resonance imaging; PKpharmacokinetic; 
PRpartial response; PROpatient-reported outcome; Q3Mo every 3 months; Q6Moevery 6 months;; QLQ-OV28 Quality of Life 
Questionnaire Ovarian Cancer Module 28; RECIST Response Evaluation Criteria in Solid Tumors; UPCR urine protein-to-creatinine ratio; 
yr year.
Note:  Study assessments/cycles may be adjusted slightly to accommodate holidays, vacations, and unforeseen major life events.  Documentation 
to justify this decision should be provided.
a Each cycle is 21 days.  Study drug administration occurs on Day 1 (3 days) of each cycle.  All other events and assessments during the study 
treatment period (Cycle 1 through Cycle 22) must occur within 3 days prior to the administration (e.g., activities/assessments for Cycle 1, except 
the actual drug infusion, must be performed within 3 days before infusion of Cycle 1).  The end of the study treatment or early discontinuation 
                                                                           
Appendix 3  
Schedule of Assessments for Patients Who Underwent Neoadjuvant Chemotherapy and Interval Surgery (cont.)


Atezolizumab—F. Hoffmann-La Roche Ltd
55/Statistical Analysis Plan YO39523
visit should occur within 30 days after the last dose of the study treatment is administered.  The post-treatment follow-up visits will occur every 
3 months (21 days) for the first 2 years after the treatment completion visit, then every 6 months (21 days) for 3 years, and then annually 
(21 days). Post-treatment visits can be performed via telephone or clinic visit as indicated by assessment requirements.
b The Informed consent must be obtained prior to any study-specific procedure and within 28 days (7 days) before randomization.
c A complete physical examination should include an evaluation of the patient’s head, eyes, ears, nose, throat, and the cardiovascular, 
dermatological, musculoskeletal, respiratory, gastrointestinal, genitourinary, and neurological systems.  Any abnormality identified at the baseline 
should be recorded on the General Medical History and Baseline Conditions eCRF.
d Limited, symptom-directed physical examinations should be performed at specified visits and as clinically indicated.  Changes from baseline 
abnormalities should be recorded in the patient notes.  New or deteriorated clinically-significant abnormalities should be recorded as adverse 
events on the Adverse Event eCRF.
e Vital signs will include measurements of the respiratory rate, pulse rate, and systolic and diastolic blood pressure while the patient is in a seated 
position, and body temperature.  Vital signs should be measured prior to the first study treatment infusion of the cycle, as clinically indicated, and 
at other specified timepoints as outlined in the schedule of activities.
f
All serious adverse events and adverse events of special interest, regardless of their relationship to the study drug, will be reported until 90 days 
after the last dose of the study drug is administered or the initiation of new anti-cancer therapy, whichever occurs first.  All other adverse events, 
regardless of the relationship to the study drug, will be reported until 30 days after the last dose of the study drug is administered or the initiation 
of new anti-cancer therapy, whichever occurs first.  After this period, the investigator should report any serious adverse events that are believed 
to be related to prior study drug treatment.
g Concomitant medications need to be collected within 7 days prior to starting study treatment.
h Hematology consists of CBC, including hemoglobin, WBC count with differential (neutrophils, lymphocytes, eosinophils, monocytes, basophils, 
and other cells), and platelet count.i Patients must demonstrate negativity for proteinuria (see Section 4.12).  Urine protein is no longer required 
for patients who discontinue bevacizumab for reasons other than proteinuria.  However, for those who discontinue bevacizumab due to 
proteinuria, urine protein is required until proteinuria returns to baseline or until the end of the study, whichever occurs first.
j
Serum chemistry includes BUN, creatinine, sodium, potassium, magnesium, calcium, glucose, total bilirubin, ALT, AST, ALP, and albumin.  
Serum chemistry eligibility must be confirmed during the screening period before randomization.  After Cycle 1, serum magnesium may be 
performed as clinically indicated.  Serum chemistry samples performed during the maintenance phase and at treatment discontinuation may be 
performed at each cycle, instead of every other cycle, in accordance to country-specific health authority mandates (e.g., Spain).
k All patients will be tested for HIV infection prior to enrollment into the study, and HIV-positive patients will be excluded from the study.  All 
patients will be tested for HBsAg and total HBcAb at the baseline.  If a patient has a negative HBsAg test and a positive total HBcAb test at 
screening, an HBV DNA test must also be performed to determine if the patient has an HBV infection.  If a patient has a positive HCV antibody 
test at screening, an HCV RNA test must also be performed to determine if the patient has an HCV infection.
l
Urine pregnancy tests beyond Cycle 1 for Cycles 222, at treatment discontinuation, and at 3 and 6 months after treatment discontinuation must 
be performed in accordance to country-specific health authority mandates  (e.g., Spain, Norway, Czech Republic, Poland, Germany, and Belgium).
m All radiographic assessments will be performed according to the time interval (e.g., 9 weeks, 12 weeks, etc.) with the corresponding windows per 
Section 4.5.5 regardless of the treatment cycle.  The initial CT scan/MRI of at least the patient’s chest, abdomen, and pelvis is required within 
                                                                           
Appendix 3  
Schedule of Assessments for Patients Who Underwent Neoadjuvant Chemotherapy and Interval Surgery (cont.)


Atezolizumab—F. Hoffmann-La Roche Ltd
56/Statistical Analysis Plan YO39523
28 days of randomization to establish the first baseline prior to starting neoadjuvant therapy and interval cytoreductive surgery.  A CT scan or 
MRI of at least the patient’s chest, abdomen, and pelvis is required to establish the new baseline (i.e., postsurgical from interval cytoreductive 
surgery) for the extent of residual disease within 14 days prior to re-initiation of study treatment (Scan 3).  CT scans or MRIs after 5 years of 
survival follow-up may be done as clinically indicated.  Head/neck imaging at screening is dictated by clinical judgment.  If a tumor assessment is 
performed within 30 days prior to the scan scheduled at the treatment completion/early termination visit, then a specific treatment 
completion/early termination tumor assessment does not need to be performed.
n Follow-Up Radiographic Assessment of Disease:  In the absence of disease progression and/or allergic reaction to IV contrast, imaging with the 
same modality and field as the initial pretreatment evaluation should be repeated at the following time intervals (i.e., 9 weeks, 12 weeks, etc.) 
with the corresponding windows per Section 4.5.5 regardless whether the patient had measurable disease on the initial CT or MRI and 
regardless of the treatment cycle:
Concurrent treatment phase Scan 2: 9 weeks from randomization during the concurrent treatment phase (approximately end of Cycle 3).
Scan 3:  postsurgical scan done after interval cytoreductive surgery and as close as possible (within 14 days) to starting Cycle 4 during the 
concurrent treatment phase. 
Scan 4:  9 weeks from Scan 3 (i.e., postsurgical scan done after interval cytoreductive surgery) during the concurrent treatment phase 
(approximately end of Cycle 6).  Tumor assessment scans during the concurrent treatment phase must be done every 9 weeks, regardless 
of treatment cycle.
Maintenance phase Scans 5, 6, and 7:  Every 12 weeks after the last scan during the concurrent treatment phase, which is now during the 
maintenance phase (approximately after Cycle 10, Cycle 14, Cycle 18, and Cycle 22).
After the treatment completion visit, every 3 months for 2 years, then every 6 months for 3 years.  CT scans or MRIs after 5 years of 
survival follow-up may be done, as clinically indicated.
o Baseline prechemotherapy value is required.  When available, also include the presurgical value.  CA-125 after 5 years may be done as clinically 
indicated.
p All PRO questionnaires must be completed in their entirety by the patient at the investigational site at the start of the clinic visit before discussion 
of the patient’s health state, laboratory test results, or health records, before the administration of the study treatment, and/or prior to the 
performance of any other study assessments (e.g., scans) that could bias the patient’s responses.
The EORTC QLQ-C30, QLQ-OV28, and EQ-5D-5L questionnaires must be administered and completed by patients in that order at the following 
assessment timepoints during each treatment and post-treatment period:
Concurrent Treatment:  At baseline (Cycle 1, Day 1) (± 3 days); post Cycle 3/pre-Interval Surgery visit (± 3 days); post-Interval Surgery at 
Cycle 4, Day 1 (±3 days); Cycle 6, Day 1 (± 3 days)
Maintenance Treatment:  At Cycle 8, Day 1 (± 3 days) and on Day 1 (± 3 days) of each cycle every 12 weeks thereafter until Cycle 22
Treatment Discontinuation or completion: At the end of treatment or discontinuation visit within 30 days of the administration of the last 
dose of the study treatment
                                                                           
Appendix 3  
Schedule of Assessments for Patients Who Underwent Neoadjuvant Chemotherapy and Interval Surgery (cont.)


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Post-Treatment Follow-up:  Patients who discontinue study treatment for progressive disease or loss of clinical benefit or any other reason, 
regardless of receipt of subsequent anti-cancer therapy will complete the PROs after the treatment completion visit, every 3 months 
(21 days) for the first year of the survival follow-up period; every 6 months (21 days) for the second year of the survival follow-up period; 
and every year (21 days) for the final 3 years of the survival follow-up period. Patients in the survival follow-up phase who are unable to 
visit the site in-person due to COVID-19 may complete the PRO questionnaires via phone interview by site staff.
q The single-item GP5 from the FACT-G questionnaire will be the final measure to be administered and must be completed by patients at the 
following assessment timepoints during each treatment and post-treatment period:
Concurrent treatment:  At the post Cycle 3/pre-Interval Surgery visit (3 days), and on Cycle 6, Day 1 (3 days)
Maintenance treatment:  At Cycle 8, Day 1 (3 days), and on Day 1 (3 days) of each cycle every 12 weeks thereafter until Cycle 22
Treatment discontinuation or completion:  At the end of the treatment or discontinuation visit within 30 days of the administration of the last 
dose of the study treatment
Post-treatment follow-up:  Patients who discontinue study treatment for progressive disease or loss of clinical benefit or any other reason, 
regardless of receipt of subsequent anti-cancer therapy will complete FACT-G GP5 after the treatment completion visit, every 3 months 
(21 days) for the first year of the survival follow-up period; every 6 months (21 days) for the second year of the survival follow-up period; 
every year (21 days) for the final 3 years of the survival follow-up period. Patients in the survival follow-up phase who are unable to visit the 
site in-person due to COVID-19 may complete the PRO questionnaires via phone interview by site staff.
r
Whole blood for DNA isolation will be collected from patients who have consented to optional RBR sampling at Cycle 1, Day 1. If the RBR 
genetic blood sample is not collected during the scheduled visit, it may be collected after randomization during the clinical study.
s Tumor tissue should be of good quality based on the total and viable tumor content (sites will be informed if the quality of the submitted 
specimen is inadequate to determine tumor PD-L1 status).  An FFPE block or at least 20 unstained slides should be provided.  Fine-needle 
aspiration, brushing, cell pellets from pleural effusion, lavage samples, and bone metastases are not acceptable.  For core needle biopsy 
specimens, at least three cores (18 gauge minimum) should be submitted for evaluation.  Submission of the screening tumor sample from 
needle core biopsy or laparoscopy can occur outside the 28-day screening period in conjunction with obtaining the informed consent.
t
For patients who are enrolled in the biomarker cohort; tumor biopsy samples should be collected by core needle (18 gauge minimum) or 
excisional biopsy at Cycle 1, Day 15.  Three cores per paraffin block should be submitted for analysis.
u The collection of a sample at disease progression is mandatory if clinically feasible.  Preferably, samples collected at the time of radiographic 
progression should be collected from growing lesions.  An FFPE block or at least 15 unstained slides should be provided.  Fine-needle 
aspiration, brushing, cell pellets from pleural effusion, lavage samples, and bone metastases are not acceptable.  For core needle biopsy 
specimens, at no fewer than two cores (18 gauge minimum) should be submitted for evaluation.
                                                                           
Appendix 3  
Schedule of Assessments for Patients Who Underwent Neoadjuvant Chemotherapy and Interval Surgery (cont.)


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Appendix 4
Schedule of Pharmacokinetic, Immunogenicity, and Biomarker Samples a
Sample Type
Visit
Timepoint
Patients who undergo primary surgery
Patients who undergo NACT interval surgery
(and, where applicable, the biomarker
cohort only; n100)
Screening
(Day 28 to Day 
1)



Randomization

Atezolizumab/placebo biomarker (tissue)
Atezolizumab/placebo biomarker (tissue)
Cycle 1, Day 1
Prior to the first infusion (up to 
24 hours prior)
Atezolizumab/placebo pharmacokinetics 
(serum) b
Atezolizumab/placebo ADA (serum) b
Atezolizumab/placebo biomarker (blood, 
plasma c)
Atezolizumab/placebo pharmacokinetics 
(serum) b
Atezolizumab/placebo ADA (serum) b
Atezolizumab/placebo biomarker (blood, 
plasma c)
30 minutes (15 minutes) 
after end of infusion
Atezolizumab/placebo pharmacokinetics 
(serum) b
Atezolizumab/placebo pharmacokinetics 
(serum) b
Cycle 1, Day 15


Atezolizumab/placebo biomarker (tissue) 
(biomarker cohort only; n100) 
Atezolizumab/placebo biomarker (plasma c) 
(biomarker cohort only; n100) 
Cycle 2
Prior to the first infusion (up to 
24 hours prior)
Atezolizumab/placebo pharmacokinetics 
(serum) b
Atezolizumab/placebo ADA (serum) b
Atezolizumab/placebo biomarker (plasma c)
Atezolizumab/placebo pharmacokinetics 
(serum) b
Atezolizumab/placebo ADA (serum) b
Atezolizumab/placebo biomarker (plasma c)
Cycle 3
Prior to the first infusion (up to 
24 hours prior)
Atezolizumab/placebo pharmacokinetics 
(serum) b
Atezolizumab/placebo ADA (serum) b
Atezolizumab/placebo pharmacokinetics 
(serum) b
Atezolizumab/placebo ADA (serum) b
30 minutes (15 minutes) 
after the end of infusion
Atezolizumab/placebo pharmacokinetics 
(serum) b
Atezolizumab/placebo pharmacokinetics 
(serum) b


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Appendix 4
Schedule of Pharmacokinetic, Immunogenicity, and Biomarker Samples a (cont.)
Sample Type
Visit
Timepoint
Patients who undergo primary surgery
Patients who undergo NACT interval surgery
(and, where applicable, the biomarker
cohort only; n100)
Cycle 4
Prior to the first infusion (up 
to 24 hours prior)
Atezolizumab/placebo pharmacokinetics (serum) b
Atezolizumab/placebo ADA (serum) b
Atezolizumab/placebo biomarker (plasma c, d)
Atezolizumab/placebo pharmacokinetics (serum) b
Atezolizumab/placebo ADA (serum) b
Atezolizumab/placebo biomarker (plasma c, d)
Cycle 8 and 
Cycle 16
Prior to the first infusion (up 
to 24 hours prior)
Atezolizumab/placebo pharmacokinetics (serum) b
Atezolizumab/placebo ADA (serum) b

At surgical visit


Atezolizumab/placebo biomarker (tissue) 
Atezolizumab/placebo biomarker (plasma c, d) 
At disease 
progressione

Atezolizumab/placebo biomarker
(tissue, plasma c, d)
Atezolizumab/placebo biomarker
(tissue, plasma c, d)
Treatment
discontinuation/ 
completion visit f
(24 hours)
Atezolizumab/placebo pharmacokinetics (serum) b
Atezolizumab/placebo ADA (serum) b
Atezolizumab/placebo biomarker (plasma c, d)
Atezolizumab/placebo pharmacokinetics (serum) b
Atezolizumab/placebo ADA (serum) b
90 days after last 
dose of 
atezolizumabh
(1 weekg)
Atezolizumab/placebo pharmacokinetics (serum) b
Atezolizumab/placebo ADA (serum) b
Atezolizumab/placebo pharmacokinetics (serum) b
Atezolizumab/placebo ADA (serum) b


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Appendix 4
Schedule of Pharmacokinetic, Immunogenicity, and Biomarker Samples a (cont.)
ADA anti-drug antibody; NACT neoadjuvant chemotherapy.
Note:  Study assessments/cycles may be adjusted slightly to accommodate holidays, vacations, and unforeseen major life events.  Documentation to 
justify this decision should be provided.
a
Pharmacokinetic and ADA samples will not be collected for the patients enrolled in the sites in China.
b
Patients who discontinue atezolizumab/placebo no longer need to provide pharmacokinetics/ADA samples.
c
EDTA plasma.
d
This may include WGS and/or RBR samples.  Refer to the laboratory manual for details.
e
Samples should be collected from either RECIST progression or investigators-determined clinical progression
f
Patients who complete the study treatment period will return to the clinic for a treatment completion visit at 30 days from the administration of the 
last dose of the study drug.  Patients who discontinue the study drug prematurely will return to the clinic for a treatment discontinuation visit 30 days after 
the administration of the last dose of the study drug.  The visit at which the response assessment shows progressive disease may be designated as the 
treatment discontinuation visit.
g
Samples greater than one week are acceptable.
h
Can be combined with the Month 3 Survival Follow-Up visit when appropriate. 


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Appendix 5 Blinded Independent Central Review Audit Plan




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TABLE OF CONTENTS 
 
1. 
PURPOSE OF THE DOCUMENT ................................................................. 3 
2. 
BACKGROUND ............................................................................................ 3 
2.1 
Blinded Independent Central Review in 
Progression-Free Survival ....................................................... 3 
2.2 
Audit for Blinded Independent Central Review ........................ 3 
2.3 
Audit Methods .......................................................................... 5 
2.4 
Audit Methods Assessment ..................................................... 7 
3. 
CLINICAL TRIAL YO39523 ........................................................................... 8 
3.1 
Study Design ........................................................................... 8 
3.2 
Progresssion Free Survival ...................................................... 8 
4. 
AUDIT STRATEGY FOR YO39523 .............................................................. 9 
5. 
AUDIT METHODOLOGY FOR YO39523 ....................................................10 
5.1 
Model Free Audit Approach ................................................... 10 
5.2 
Statistical Properties .............................................................. 10 
5.3 
Threshold Determination ....................................................... 11 
5.4 
Operational Characteristics ................................................... 13 
5.5 
Decision Rule ........................................................................ 14 
5.6 
Implementation ...................................................................... 14 
6. 
REFERENCES ............................................................................................15 
 
 
LIST OF TABLES 
Table 1 
The Operational Characteristics of Audit from Interim 
Sampling ..................................................................................... 13 
 
 
LIST OF APPENDICES 
Appendix 1 
Simulation to Compare PFS Audit Stratigies............................... 17 
 
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1. 
PURPOSE OF DOCUMENT 
The purpose of this document is to describe the audit plan related to the blinded 
independent central review (BICR)-determined progression-free survival which 
will be conducted in support of clinical trial protocol YO39523 [11].  
 
In addition to the audit strategy and methodology, this document also describes 
the roles and responsibilities of participating parties, and some implementation 
details. Revisions or amendments to the protocol will not require an amendment 
to this document unless substantive changes impact the blinded independent 
central review (BICR). 
 
 
2. 
BACKGROUND 
 
2.1 
BLINDED INDEPENDENT CENTRAL REVIEW FOR 
PROGRESSION-FREE SURVIVAL 
Progression-free survival is commonly used as a primary endpoint for evaluating efficacy 
of cancer products in clinical trials pursuing marketing approval. When progression-free 
survival is the primary efficacy endpoint of a clinical trial, a blinded independent central 
review is usually required in addition to local-evaluated (LE) progression-free survival. 
Local-evaluated progression-free survival could potentially be biased in favor of the IMP 
treatment especially in open-label studies when investigators know their patients’ 
treatment assignment. Blinded independent central review is implemented to reduce the 
potential bias from the local assessments. For blinded studies, there is usually less 
concern on potential bias from LE. Blinded independent central review-assessed 
progression-free survival is particularly relevant for cancers with diffuse intraperitoneal 
spread patterns and/or frequent non-target lesions, such as ovarian cancer. Indeed, 
variation between evaluators' assessments may be particularly germane in ovarian 
cancer, where diffuse peritoneal implantation and frequent non-target lesions, including 
ascites, can complicate radiologic assessments. 
 
2.2 
AUDIT FOR BLINDED INDEPENDENT CENTRAL REVIEW 
The use of blinded independent central review (BICR) increases trial complexity and 
cost, and it is an added burden to both investigators and sponsors. Subjectivity in 
disease progression assessments and differences in evaluations between LE and BICR 
at the individual patient level exist. However, some publications [1] and FDA [2,3] 
analyses have suggested that there is high correlation between LE and BICR 
assessments with respect to the relative treatment effect measure (hazard ratio). A 
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meta-analysis conducted by the Pharmaceutical Research and Manufacturers of 
America (PhRMA) and FDA showed that some degree of discordance between local and 
central readers may not affect the conclusions about the efficacy of a study as measured 
by the HR. This high correlation raises the question whether complete case BICR 
evaluation is needed. 
Dodd (2008) [4] and Amit (2011) [5] suggest using BICR as an auditing tool to assess 
the reliability of marginally positive results or to use a sample-based BICR in not 
adequately blinded studies. In their view, a full BICR would only be required for smaller 
trials or in situations, in which confidence in the local evaluation results needs to be 
increased. Retrospective analyses of 27 randomized clinical trials in various indications 
from Zhang (2012) [1] suggest that an audit strategy is also feasible. 
An oncologic advisory committee discussion (ODAC) meeting was held in July 2012 to 
discuss whether the current practice of complete-case BICR should be replaced by a 
random sample-based BICR audit, based on the information and analyses presented 
herein [2].In the ODAC, focusing on a general discussion of oncologic products seeking 
marketing approval in the United States for the treatment of non-hematologic 
malignancies, members felt that the available data support a sample-based BICR [3]. 
Committee members agreed that a random sample-based BICR audit should be 
considered: BICR audit on a random sample of clinical trial patients may streamline the 
process and reduce the drug development burden. However, the potential merits must 
be viewed in tandem with the potential limitations and challenges:  no definite 
conclusions were drawn. They also advised against the complete elimination of BICR, 
which could jeopardize the integrity of the local site evaluation. Concerns were raised 
that in small sized trials, studies with a moderate PFS improvement, and certain difficult-
to-assess tumor types, this sample approach would not be adequate. 
Although analyses [Dodd (2008) [4], Amit (2011) [5], and Zhang (2012) [1] have showed 
that a BICR audit to assess potential bias in the local site evaluation is a feasible 
approach, the logistics of how the audit should proceed need further discussion and 
consideration. The method of selecting the random sample audit needs to be determined; 
a simple random sample audit may not be sufficient, for example, to ensure 
representation of all study sites. Efforts should also be made to minimize any additional 
burden that the audit may cause the investigator or sponsor without compromising the 
integrity of the study. Selection of the actual audit strategy to implement within a trial 
may need to be determined on a case-by-case basis. At the ODAC meeting held on July 
2012, examples of two methods have been proposed to use a random sample-based 
IRC audit to examine potential systematic bias. 
 
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2.3 
AUDIT METHODS 
Although measurement error is inherent in the reading of radiographic scans, regulatory 
considerations for drug approval are based on the relative treatment effect at the 
population level. Given that multiple publications have corroborated the strong 
correlation between local site evaluation– and BICR-assessed PFS treatment effect 
estimates, there is a need for the exploration of alternative strategies to detect bias in 
the local site evaluation. The results of the analyses presented in Zhang (2013) [1] 
support that a random sample-based BICR audit is a viable alternative to a complete-
case BICR and may be a more efficient strategy for bias evaluation of the local site 
evaluation. In Zhang (2013) [8], the performance characteristics of the two audit 
methods proposed in the literature are evaluated on 26 prospective, randomized phase 
III registration trials in non-hematologic malignancies. The results support that a BICR 
audit to assess potential bias in the local site evaluation is a feasible approach. Note that, 
although there is general agreement, in one study reported in Zhang (2013), there were 
divergent conclusions depending on the choice of local site evaluation and BICR, 
justifying a continued need for BICR to provide assurance about the local site 
evaluation–based treatment effect. 
Originally, two methods have been proposed for this type of audit.  [Dodd (2011) [6] and 
Amit (2011)] Dodd uses the HRs directly and is about early testing of the statistical 
significance of the BICR based on a sample – so it may, in the case of a large treatment 
effect, accept the sample even if the HRs estimated are quite different. In Dodd’s 
method, the treatment effect based on the full BICR evaluation can be estimated on the 
basis of investigator evaluation and the correlation between investigator assessment and 
BICR assessment of the audit sample. A full BICR evaluation is only needed to confirm 
the investigator assessed treatment effect is reliable when the upper limit of the 
confidence interval (CI) of the HR estimate based on the BICR and investigator 
assessment of the audit sample exceeds a pre-specified clinical irrelevance factor (CIF). 
The CIF is a factor reflecting the smallest treatment effect that is clinically meaningful. 
The size of the audit sample required depends on the number of PFS events, the 
magnitude of the effect, the CIF, and the correlation between the BICR and investigator 
assessment. More details about calculating the audit sample size can be found in Dodd 
et al. (2011). Amit et al. (2011) proposed using differential discordance as a measure to 
detect potential systematic evaluation bias in investigator-assessed tumor data (the 
PhRMA approach). Two types of discrepancy measure can be calculated for each 
treatment arm: early discrepancy rate (EDR) is defined as the frequency with which the 
investigator declares progression early relative to BICR as a proportion of the total 
number of investigator-assessed progression events; late discrepancy rate (LDR) is 
defined as the frequency with which the investigator declares progression later than 
BICR as a proportion of the total number of discrepancies within the arm. Differential 
discordance for each type of measure can be defined as the LDR/EDR in the 
experimental arm minus the rate in the control arm. The former was undertaken by the 
national cancer institute (NCI), while the latter was undertaken by the PhRMA PFS 
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working group. Both the PhRMA and NCI approaches aim to provide a decision rule as 
to whether a full BICR is needed by comparing LE and BICR data in the audit sample. 
However, the philosophy of both approaches does somewhat differ.  The NCI approach 
uses the LE and BICR hazard ratio (HR) directly and tests whether the sample BICR is 
sufficient to already conclude that the full sample BICR would likely be statistically 
significant.  Whereas, the PhRMA approach focuses on whether there is evidence of 
bias in the assessment of investigators by a between arm comparison of carefully 
chosen discordance metrics. These two approaches may come to different 
recommendations for the same trial or pick out different trials for complete BICR. 
Challenge of selection of sample size and threshold exists.  
Dodd (2011) method seems to perform well in most situations; that is, it seems able to 
distinguish between trials with and without bias present. The savings with respect to 
audit size varies from case to case, depending on the study size and magnitude of the 
observed local site evaluation PFS treatment effect; larger effect sizes and/or studies 
typically require smaller audit proportions. Method from Amit (2011) is intuitively 
appealing, but needs further evaluation, particularly with respect to determination of the 
appropriate threshold value. Potential reasons for its variable performance that need 
further evaluation include loss of important information due to dichotomization and 
ignoring patients who were censored by both the local site evaluation and BICR in the 
definition of EDR and LDR. This method counts discordances but not how far apart they 
are. For example, with the LDR, the local site evaluation could call progressive disease 
right after BICR or a long time after. If the late discrepancies occurred in the control arm 
many visits after BICR, this would produce more significant bias in the HR estimate. On 
a similar note, we could have a relatively small number of late discrepancies, but if they 
occur very late, then this would produce greater bias in the HR estimate. 
In 2015, to deepen the understanding of the two proposed audit methods, the PhRMA 
approach (i.e., Amit (2011)) and the NCI approach (i.e., Dodd (2011)), as described 
above and to collect first-hand operational experience, Roche retrospectively performed 
PFS audit for study TH3RESA after its primary analysis of PFS by LE.[7] Roche 
implemented the PhRMA approach (i.e., Amit (2011)) as the primary audit approach and 
the strategy proposed by Dodd (2011) (i.e., the NCI approach) as a secondary approach 
for TH3REASA study. It was not clear which audit strategy was more superior and more 
appropriate for this study, because it was noted that the statistical properties of the audit 
strategies and the proper selection of audit sample size and threshold require further 
investigation to be better understood. For the PhRMA approach, the difficulty lies in the 
challenge of translating differential discordance rate for a specific study between two 
arms to bias in PFS, which is the real objective we are interested in, and the selection of 
threshold in terms of discordance rates.  For the NCI approach, the selection of the 
threshold (i.e., CIF) is somewhat subjective. 
Later, a third method [4], developed by Andrew Stone, which shares some key features 
with both the Dodd and Amit methods, was published, see section 5.1 for more details. 
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The authors labelled their method model-free.  Whilst asymptotic assumptions of 
normality are made there is no requirement, as per the Amit method, for the construction 
of an underlying, study-specific error model.   The method was labelled as model-free as 
it is an extension of the approach, described as parameter-free by Jennison and 
Turnbull[14], that can be used in group sequential trials for the construction of futility 
analyses. In common with the Dodd method, it utilizes the HRs directly, and in common 
with the Amit method, it aims to detect bias in terms of differences in treatment effect 
estimates rather than to retest statistical significance. A key advantage of this approach 
is that the sensitivity and specificity of using the audit sample to detect if there is any 
assessment bias by LE can be mostly mathematically computed.    
 
 
 
2.4 
AUDIT METHODS ASSESSMENTS 
Roche ran a few simulations based on similar error models described in Dodd (2011) 
and Amit (2011) to compare the 3 methods described above. Across the simulations with 
assumptions of various magnitudes of bias between LE and BCIR and various audit 
samples sizes, it consistently shown that test statistics HRR gave the optimal 
performance in the sense of specificity and sensitivity based on the ROC curves 
compared to test statistics DD of LDR did.  Details are provided in Appendix 1. Thus, 
HRR will be used as the test statistics for study YO39523 PFS audit, and the threshold 
for the HRR test statistics will be determined based on the approach introduced in Stone 
(2015) and will be described in details in section 5.  
Simulation was also ran to assess the performance of two sampling strategies: the 
simple random sampling and interim sampling. Simple random sampling includes all 
images of patients who are randomly sampled from the ITT population for audit by BICR 
review. Interim sampling includes all images of all patients up to an interim time point for 
audit. The simulation shows comparable performance in the sense of sensitivity and 
specificity, when the numbers of images included for audit are about the same. More 
details are included in Appendix 1. One challenge implementing the “simple random 
sampling” strategy is that the audit can be performed only after all images are available 
(i.e. after database lock). This may potentially elongate timeline of the primary analysis 
of PFS, especially if the pre-specified threshold is crossed and a full BICR is needed. 
Interim sampling can avoid this aforementioned challenge, since the audit can be 
performed at the interim time points and the audit results will be available at that time as 
well. If the audit at interim is passed, then BICR of future images won’t be needed any 
more. If the audit at interim failed to rule out potential bias, the BICR will be continued. 
Neither case will elongate the post database lock timeline. Thus, interim sampling will be 
used for study YO39523 PFS audit. Details are described in section 4. 
 
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3. 
CLINICAL TRIAL YO39523 
 
3.1 
STUDY DESIGN  
Clinical trial YO39523 is a Phase III randomized double-blind, placebo-controlled study 
evaluating the efficacy and safety of paclitaxel+carboplatin+bevacizumab with 
atezolizumab (vs. placebo) followed by maintenance bevacizumab and atezolizumab 
(vs. placebo) for patients with previously untreated advanced-stage epithelial ovarian-, 
fallopian tube-, and peritoneal cancer.  This global study will enroll approximately 
1300 patients both after primary cytoreductive surgery and prior to neoadjuvant therapy 
per the patient’s treatment plan.  The co-primary endpoints will be local-assessed 
progression-free survival (INV-PFS) and overall survival (OS). 
 
3.2 
PROGRESSION-FREE SURVIVAL 
PFS is defined as the time from randomization to the occurrence of disease progression, 
as determined by investigators from tumor assessments, per RECIST v1.1, or death 
from any cause, whichever occurs first. Patients who have not experienced disease 
progression or death at the time of analysis will be censored at the time of the last tumor 
assessment. Patients with no post-baseline tumor assessment will be censored on the 
date of randomization plus 1 day. 
INV-PFS will be analyzed using the intent-to-treat population (ITT) population, defined as 
all randomized patients with patients assigned to treatment groups as per the 
randomization. 
INV-PFS will be tested with the overall Type I error controlled at a two-sided level of 0.05.  
The null and alternative hypotheses regarding INV-PFS in the ITT population can be 
phrased in terms of the survival functions SA(t) and SB(t) for Arm A (atezolizumab + 
paclitaxel+carboplatin+bevacizumab) and Arm B (placebo + 
paclitaxel+carboplatin+bevacizumab), respectively: 
H0: SA(t) = SB(t) versus H1: SA(t) ≠ SB(t). 
INV-PFS will be compared between treatment arms with use of the stratified log-rank 
test, and the hazard ratio (HRA/B) for INV-PFS (with 95% CI) will be estimated using the 
stratified Cox proportional hazards model. The stratification factors will be those defined 
by the protocol, and will be based on data collected by the Interactive Voice/Web 
Response System (IxRS) at the time of randomization [12]. 
In this study, the co-primary efficacy endpoints are local-assessed progression-free 
survival (PFS) & overall survival (OS). Therefore, a blinded independent central review is 
recommended to confirm the local assessment of progression-free survival. The concept 
of sample-based independent review (i.e., the independent review amongst a sample of 
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patients) is considered instead of a full review by blinded independent central review 
(BICR) using the Stone method as described in section 5. 
 
4. 
AUDIT STRATEGY FOR YO39523  
A sample of centrally reviewed cases will be used to decide if a full review of local 
assessments of progression free survival is needed. The sample will be initiated 
approximately 24 months after the first patient randomized in the study, 12 months 
ahead of pre-specified primary analysis of PFS in study protocol, to allow a rapid 
decision on whether full study review is required. The idea of choosing 24 month from 
FPI is for implementation consideration, in which the conduct of this sample-based BICR 
is attached to one of the pre-specified iDMC reviews for safety, eg: every 6 month from 
FPI. In addition, sufficient time has to be left after this sample-based BICR in any case 
that a complete full BICR review has to be implemented. Based on the current 
assumption of enrollment duration of 25 months in total and the yearly dropout rate of 
5%, there will be approximately 1248 patients, whose scans will be available for reading. 
According to the tumor assessment in the protocol, approximately 5720 scans 
(composite of 40% of total number of scans if patients all finish their scheduled tumor 
assessments) will be available for BICR. 24 months time point is supported by the 
operational characteristics (OC) described in section 5.3. 
Parexel was contracted by the sponsor to perform the BICR based on a uniform 
interpretation of radiographic image data for study YO39523. The independent review 
charter describes the processes, services, and issues related to procedures directed by 
Parexel for the independent assessment of the radiographic endpoint. In the context of 
the interim audit strategy, images up to 24 months after the first patient randomized will 
be collected and analyzed according to Sponsor/Parexel standard procedures. 
The essential data of the BICR will be provided by the sponsor to the independent data 
coordinating center (iDCC) for analysis. The evaluation of the interim audit data will be 
submitted to the independent data monitoring committee (iDMC) to indicate to the 
sponsor whether the BICR-assessed progression-free survival interim sample had been 
accepted according to an approach that adapts a method originally created for defining 
futility bounds in group sequential designs presented by Stone (2015) [13] where the 
hazard ratio ratio, the ratio of the hazard ratio of PFS for the treatment effect estimated 
from the blinded independent central review (BICR) to the corresponding hazard ratio for 
the local assessments, is used as the metric to define bias (Section 4) without unblinding 
the treatment assignments or revealing any efficacy results to sponsor. 
As to be defined in the independent data monitoring committee charter, when the iDMC 
issues its recommendation, the Sponsor’s data review board makes the final decision as 
to whether to accept the iDMC’s recommendations. 
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5. 
AUDIT METHODOLOGY FOR YO39523 
5.1 
MODEL FREE AUDIT APPROACH 
The model free audit approach presented in Stone (2015) is based on an approach to 
futility analyses developed to be used in group sequential designs, specifically the 
parameter-free approach as described in Chapter 10 of Jennison and Turnbull. [14]The 
primary inference of the model-free audit procedure concerns the point estimate for the 
hazard ratio (HRR) in the full data set, which is equal to the point estimate of BICR-
assessed hazard ratio (HR)  divided by the point estimate of the local-assessed hazard 
ratio (HR) .  In the model-free audit approach, inference is made about the point-
estimates, as opposed to population parameters, as an assessment of bias in the LE in 
individual studies is made by a comparison of point estimates and not of a statistical 
comparison of true population HRs between local and BICR for example.  
In the model-free approach, absence of bias, or more precisely lack of evidence of 
meaningful bias, is concluded if there is a low conditional probability that the HRR seen 
in the random sample of patients would have been observed if, in fact, the point estimate 
of the HRR in the full trial were unacceptably high. 
When applied to this study, the probability of falsely accepting the sample (sensitivity, 
see section 5.4) will always be 10% if the true HRR in the full study is as small as 1.14.  
A HRR of 1.14 would occur if the BICR HR was 0.8 and LE HR was 0.7 in the full trial.   
The size of the sample has then been determined to ensure there is also a high 
probability (specificity, see section 5.4,) ~90%, of accepting the sample when in fact 
there is no bias (HRR=1).If the size of the sample changes, the specificity will change 
accordingly but the sensitivity will stay the same as 90%, which could make sure the 
regulatory risk is well controlled.  
5.2 
STATISTICAL PROPERTIES 
In the model-free approach, the estimated HRR based on full dataset, HRRF  is defined 
as: 
HRRF =HRB,F/HRL,F 
Based on its large sample distribution, it could be expressed on the log scale as: 
ln(HRRF)~N(ln(HRRF), IF
-1) 
where IF denotes the Fisher information for ln(HRR). 
Similarly, after assessment of the sample of the data, we could estimate the HRs based 
on local evaluations of sampled subjects.  
ln(HRRS)~N(ln(HRRS), IS
-1) 
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Specifically, the two estimates are bivariate normal with means and variance as stated 
above, and their covariance is IF
-1
.
 It follows that the conditional distribution of ln(HRRS) 
given HRRF is  
ln(HRRS)| HRRF~N(ln(HRRS), IS
-1 -IF
-1) 
Standardized test statistics are defined as  
ZF= ln(HRRF) √IF  and ZS= ln(HRRS) √IS 
Therefore, the conditional distribution of ZS  given ZF is  
ZS|ZF~N(ZF√IS √IF
⁄
 , (IF –IS)/ IF) 
 
Based on those statistical properties, the threshold for decision making is discussed in 
the section below.  
5.3 
THRESHOLD DETERMINATION 
When analyzing the sampled data, the following hypothesis testing is specified 
H0 (null hypothesis): HRRF ≥ HRRU 
Against 
H1 (alternative hypothesis): HRRF < HRRU 
where 
• 
HRRF, the estimated hazard ratio ratio based on the full data, 
• 
HRRU, a maximum acceptable value of the hazard ratio ratio (HRR) on the full data. 
The null hypothesis is defined under which the level of bias in local evaluations is 
unacceptable. If the audit sample leads to rejection of this null hypothesis, we 
conclude that local evaluations are sufficiently close to BICR (or biased against 
the experimental treatment) and a full BICR is unnecessary. Please note that 
these hypotheses concern the final estimate of HRR and compare it with a pre-
specified HRRU. The determination of HRR comes from clinical judgement of bias, 
eg: how difference the local assessments vary from BICR’s review. In this study, 
we define the HR in BICR review as 0.8, which preserves two-thirds of the pre-
specified HR of local assessments in protocol. Therefore, the HRRU is 
0.8/0.7=1.14. 
 
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With the model-free approach closed form solutions exist that can be pre-determined 
prior to data being analyzed so that the properties of the approach are transparent. As 
specified in [13] and section 5.1, for a 1-sided level α test, we stop and reject H0 based 
on the sample of data if: 
ZS<ln(HRRU) √IS-φ-1(1-α)√(IF-IS)/IF] 
This criterion can be expressed as a bound on the estimate of HRRS from the data 
sample 
HRRS < exp[ln(HRRU)-φ-1(1-α)√(IF-IS)/ISIF]=HRRAT 
where 
• 
HRRS, the estimated hazard ratio based on the sample data, 
• 
HRRAT, the ‘acceptance threshold’ for the hazard ratio ratio observed in the sample 
data, 
• 
IF denotes the Fisher information for logarithm(hazard ratio ratio) in the full data set, 
• 
IS denotes the information for logarithm (hazard ratio ratio) in the sample data. 
Both IF and IS are functions of number of events in both full and sample data from 
local assessments, the number of events in BICR, and the correlation between 
BICR and local assessments as given by equations (5) and (6) of Stone et al. 
• 
α is the total type I error for testing H0, the probability of accepting the sample if bias 
exist.  
Assuming, 
• 
k, the randomization ratio of 1, 
• 
nL,F=601, the number of events in full sample size, 
• 
nL,S=374, the number of events in audited sampler, based on the current estimation 
of mPFS and enrollment , and it might come from 1248 enrolled patients 
• 
r=nB,F/nL,F=0.782, the ratio of number of events in full sample by the independent 
committee and local assessments respectively, the ratio is usually less than 1 given 
the informative censoring 
• 
ρ=0.7, the correlation between BICR and local assessments,  
• 
HRRu defined as 1.14 to preserve two-thirds of the local-assessed hazard ratio of 0.7 
in study YO39523, as stated above 
the threshold is calculated as HRRAT=1.06. 
Based on the information from three conducted Phase III studies conducted by 
Genentech/ Roche in ovarian cancers [13,15,16], r is calculated via dividing the number 
of events reported from BICR by the number of events reported from local assessment. 
The numeric average of r from those three studies is 0.782. 
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ρ=0.7, the correlation between BICR and local assessments, is calculated via bootstrap 
using data from three studies as mentioned above (OCEANS, AURELIA, GOG0218). 
Please note that when doing the interim sampling, ρ and r will be adjusted according to 
calculation from real sample. Therefore, the threshold might be changed as well, so as 
the specificity. Sensitivity won’t change as it does not depend on either the numerical 
value of threshold nor ρ and r.  
 
5.4 
OPERATIONAL CHARACTERISTICS 
In the model-free approach, sensitivity and specificity are defined as following: 
• 
Sensitivity - Probability to conclude bias (i.e. observing HRR in the audit sample is 
greater than the threshold), or more specifically the probability of accepting H0 when 
the true HRR=1.14, where H0 is the presence of bias. 
• 
Specificity - Probability to conclude no bias (i.e. observing HRR in the audit sample 
smaller than the threshold) , or more specifically the probability of rejecting H0 when 
the true HRR = 1.  
 
In all applications of the model-free approach sensitivity is set at 90%, this guarantees 
that the probability of falsely accepting the sample is 10% in all cases.   This then 
determines the acceptance threshold and specificity for any particular design. The 
operation characteristics are provided in Table 1, given the determined threshold as 1.06. 
For example, taking all images up to 24 months after FPI for audit, it’s estimated that 
approximately 1248 patients will be enrolled with approximately 374 events occurred by 
that time. With 90% sensitivity, , we could make sure that there is only 10% chance to 
make a wrong call to accept the sample when there is some bias such that the true 
value of HRR is 1.14.  Applying the threshold of 1.06 will give a specificity of 88.3%, i.e. 
11.7% chance making a wrong call when there is no bias as the true ratio of BCIR HR to 
LE HR is 1.  
 
Table 1. The Operational Characteristics of Audit from Interim Sampling 
Time-point 
Predicted 
# 
of 
enrolled 
patients 
Predicted 
# 
of 
events 
Threshold 
from 
interim 
sampling 
Sensitivity 
Specificity 
24 
month 
from FPI 
1248 
374 
1.06 
90% 
88.3% 
1080 
320 
1.05 
90% 
78% 
30 
month 
from FPI 
1300 
469 
1.09 
90% 
99% 
 
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5.5 
DECISION RULE 
If the aforementioned test does not reject H0 (i.e., HRRS ≥ HRRAT), blinded independent 
central review is conducted for the full set of data. However, if H0 is rejected (i.e., 
HRRS < HRRAT), a full blinded independent central review (BICR) will not be conducted 
is not required. 
5.6 
IMPLEMENTATION 
The sponsor will work with Paraxel in developing a separate document of BICR charter, 
which defines the scope of logistics activities.  
In addition, sponsor will update working order to iDCC vendor (Cytel), who will calculate 
the statistics HRR at month 24 after first patient in, with the scan reading data sent 
directly from Paraxel and treatment assignments information from IxRSsystem. After that, 
iDMC will calculate the statistics and make assessment respect to the threshold 
accordingly, and send their recommendation to sponsor without revealing the numeric 
value of HRR. The details could be found in the updated working contract with iDCC 
vendor and iDMC charter.  
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6. 
REFERENCES 
1. Zhang JJ et al. Evaluation of blinded independent central review of tumor 
progression in oncology clinical trials: a meta-analysis. Therapeutic 
Innovation & Regulatory Science September 7, 2012 and March 2013 vol. 
47 no. 2 167-174. 
2. Oncologic Drug Advisory Committee—evaluation of radiologic review of PFS 
in 
non-hematologic 
malignancies. cited 
2012 
Jul 
24. 
Available 
from: http://www.fda.gov/AdvisoryCommittees/CommitteesMeetingMaterials/
Drugs/OncologicDrugsAdvisoryCommittee/ucm285400.htm 
3. Food and Drug Administration (FDA). Summary minutes of the Oncologic 
Drugs 
Advisory 
Committee 
Meeting, 
July 
24, 
2012. 
http://www.fda.gov/downloads/AdvisoryCommittees/Committees 
MeetingMaterials/Drugs/OncologicDrugsAdvisoryCommittee/ 
UCM316323.pdf 
4. Dodd et al. Blinded independent central review of progression-free survival in 
phase III clinical trials: important design element or unnecessary expense? J 
Clin Oncol 2008;26:3791–6. 
5. Amit O et al. Blinded independent central review of progression in cancer 
clinical trials: results from a meta-analysis. Eur J Cancer 2011;47:1772–8. 
6. Dodd et al. An audit strategy for progression-free survival. Biometrics. 2011 
September; 67(3): 1092–1099. 
7. F. Hoffmann-La Roche Ltd./Genentech, Inc. BLINDED INDEPENDENT 
CENTRAL REVIEW AUDIT PLAN FOR THE TH3RESA STUDY. 09-April-
2013. 
8. Zhang et al. Assessment of Audit Methodologies for Bias Evaluation of 
Tumor Progression in Oncology Clinical Trials. Clin Cancer Res; 2013 May 
15;19(10):2637-45. 
9. Stone et al. Model free audit methodology for bias evaluation of tumour 
progression in oncology. Pharmaceutical Statistics, Volume 14, Issue 6 
November/December 2015, 455–463. 
10. Sun et al. Testing of evaluation bias for progression free survival endpoint in 
oncology clinical trials. Statist. Med. 2016, 35 3923–3932. 
11. F. Hoffmann-La Roche Ltd./Genentech, Inc. Protocol YO39523: A PHASE III, 
MULTICENTER, RANDOMIZED, STUDY OF ATEZOLIZUMAB VERSUS 
PLACEBO ADMINISTERED IN COMBINATION WITH PACLITAXEL, 
CARBOPLATIN, AND BEVACIZUMAB TO PATIENTS WITH NEWLY-
DIAGNOSED STAGE III OR STAGE IV OVARIAN, FALLOPIAN TUBE, OR 
PRIMARY PERITONEAL CANCER. Version 1.0. 12-Sep-2016. 
12. Ruikar 2016 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4763512/ 
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13. Aghajanian et al. OCEANS: A Randomized, Double-Blind, Placebo-
Controlled Phase III Trial of Chemotherapy With or Without Bevacizumab in 
Patients With Platinum-Sensitive Recurrent Epithelial Ovarian, Primary 
Peritoneal, or Fallopian Tube Cancer. Journal of Clinical Oncology 30, no. 17 
(June 2012) 2039-2045. 
14. Group Sequential Methods:  Application to Clinical Trials.  Jennison C, 
Turnbull BW Chapman&Hall 
15. Husain et al. Independent radiologic review of AURELIA, a phase 3 trial of 
bevacizumab plus chemotherapy for platinum-resistant recurrent ovarian 
cancer. Gynecol Oncol. 2016 Sep;142(3):465-70. 
16. Burger et al. Independent radiologic review of the Gynecologic Oncology 
Group Study 0218, a phase III trial of bevacizumab in the primary treatment 
of advanced epithelial ovarian, primary peritoneal, or fallopian tube cancer. 
Gynecol Oncol. 2013 Oct;131(1):21-6. 
17. Stone et al. Model free audit methodology for bias evaluation of tumour 
progression in oncology. Pharmaceutical Statistics, Volume 14, Issue 6 
November/December 2015, 455–463. 
 
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Appendix 1  
Simulation to Compare PFS Audit Strategies 
 
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APPENDIX 1: 
SIMULATION TO COMPARE PFS AUDIT STRATIGIES 
To compare the performance of various PFS audit strategies (including the sampling 
strategies and the testing methods), we conducted serval simulation studies as 
presented below.  
1.1 
SIMULATION SETUP 
1.1.1 
ERROR MODEL TO SIMULATE PFS DATA 
PFS data points in simulated clinical trials were generated as illustrated in Figure A1. 
This is similar to the simulation procedure used in Amit (2013) and Dodd (2010). We 
assumed that actual PFS (shown as T in Figure A1) is a continuous variable having an 
underlying exponential distribution, but they are not directly observed in clinical trials. 
Instead, disease progression is measured at scheduled assessments. The set of 
parameters (p1, p2, p3), also referred as error rates, characterizes the probability 
reporting the PD event earlier than, exactly at, or later than the actual event time (by 
BICR or LE, in ctrl or trt arm).  
 
Figure A1: Error Model for Simulation of PFS data 
Four sets of parameters (p1, p2, p3), each for (BICR for control arm, BICR for treatment 
arm, LE for control arm, and LE treatment arm) respectively, introduce the 
measurement error/variation and potential bias by LE favoring treatment. Magnitude of 
bias is controlled through setting different error rates between the two arms. In contrast, 
an unbiased error model will purely characterize measurement error by assigning the 
same set of error rates to both of the arms. In our simulations, we set error model 
parameters as below.  
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Set p1 = p3 = 0.15, and p2 = 0.7 for BICR, which has no bias and relatively high 
accuracy 70%. Set p1 = p3 = 0.2, and p2 = 0.6 for LE when there is no bias, but slightly 
less accuracy. This unbiased LE simulation is used to calculate specificity when 
comparing various audit strategies. 
To introduce evaluation bias, we changed the parameters in the error model for LE to 
be p1 = p.bias in the control arm and p3 = p.bias in the treatment arm, assuming that LE 
tend to call progression early in the control arm and late in the treatment arm at the 
same time. The rest of the error rates remain the same on both arms. Two biased 
scenarios were simulated: the median biased scenario with p.bias = 0.35, and the high 
biased scenario with p.bias = 0.65. These two scenarios were used to calculate the 
sensitivity when comparing various audit strategies. 
1.1.2 
TRIAL DESIGN PARAMETERS FOR SIMULATION 
The true progression time was simulated with a median PFS of 3 months in the control 
arm, and with a hazard ratio of 0.7 for the treatment arm. Tumor assessment by imaging 
was equally spaced by every 1.5 month. In addition, we added an optional feature in our 
simulation to reflect that when a progression is called by LE, there will be no further 
tumor assessment call that can be made by BICR. This is to mimic the reality that in 
most clinical trials, tumor image data collection is stopped after a disease progression is 
called by LE. 
1.1.3 
SENSITIVITY, SPECIFICITY, AND ROC CURVE FOR STRATEGY 
COMPARISON 
The performance of various audit strategies was evaluated by examining each 
strategy’s Specificity, Sensitivity, and ROC (receiver operating characteristic) curve. 
Specificity (Sp) is defined as the probability of declaring LE is reliable when truly there is 
no bias. It was calculated by the simulation with the error model being set to with no 
bias for both LE and BICR as described in section 1.1.1. For each audit strategy, there 
is a test statistics and a threshold. The Sp for the audit strategy was computed as the 
proportion that the test statistic does not exceed the specific threshold when there is no 
bias, over one thousand simulated datasets. The higher the Sp is, the better the 
strategy is.  
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Sensitivity (Sn) is defined as the probability of detecting evaluation bias (between LE 
and BICR) when the bias is truly present. It was calculated under two scenarios by 
simulation with the error model being set to with median or high bias respectively, as 
described in section 1.1.1. For each audit strategy, the Sn was computed as the 
proportion that this strategy’s test statistic does exceed the specific threshold when 
there is bias, over one thousand simulated datasets. The higher the Sn is, the better the 
strategy is. 
ROC curve showing Sn as the y-axis vs Sp as the x-axis for each audit strategy was 
plotted as well. The closer the curve is to the top-right corner, the better the strategy is. 
1.2 
COMPARING SAMPLING STRATEGY 
One challenge for the audit strategies is that when a simple random sample is selected 
for audit, the audit can only be performed when all image data for the audit patients are 
available, i.e. after or around databased lock. The Sponsor usually would like to shorten 
the filing timeline after database lock. In the case of the audit doesn’t pass the 
consistency check between LE and BICR, a full BICR will be needed resulting in a 
longer timeline and higher cost. To overcome this challenge, an interim sampling 
strategy is proposed and illustrated in Figure A2. With the interim sampling strategy, if 
the audit passes the LE-BICR consistence check, further BCIR assessment won’t be 
needed anymore which will save the future work and cost; if the audit doesn’t pass the 
check, BICR can continue as planned, and there is no impact on the original timeline 
and cost. 
 
Figure A2. Comparison of interim and random audit samples in terms of timeline denotes number of 
subjects in the audit sample. 
To understand how interim sampling performs compared to the usual random sampling, 
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we set the time of analysis when using the interim audit sample and size of subsample 
when using the random audit sample in a way such that the total amount of imaging 
assessments are similar for the two sampling methods. This is to ensure a fair 
comparison between the two sampling methods by checking their performance based 
on similar amount of information available. 
Figure A3 shows the receiver operating characteristic (ROC) curves using interim and 
random audit samples, which plots the sensitivity and specificity of the test statistics 
being compared to a sequence of thresholds as the decision rules. The performance of 
the testing methods under the median bias scenario was shown is this figure. The left 
panel applied the PhRMA audit procedure to the interim and random sample, and the 
right panel used the HRR test statistic. Note that, even though the interim sample has 
more subjects than the random sample, the number of imaging assessments is similar 
between the two audit samples. Using either PhRMA or HRR, we see that interim 
sample performs as well as a random sample with very similar operating characteristics. 
For scenarios not shown in the figure such as LE evaluation with high bias or with 
treatment giving larger treatment benefit (i.e. smaller HR), we came to the same 
conclusion that the operating characteristics are similar for these two sampling 
procedures for PFS audit. Considering the advantage of no risk of additional cost and 
timeline delay post database lock but only possible saving of work and cost before 
database lock, the interim sampling is a generally recommended. 
 
Figure A3. Comparison of interim and random audit samples in terms of operational characteristics under 
median bias, using PhRMA and HRR methods. The number of imaging assessments for the two types of 
audit samples are similar. (N.image is similar). 
 
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1.3 
COMPARING TEST STATISTICS 
Performance of the three test statistics PhRMA (using the LDR), NCI and HRR, as well 
as the random and interim sampling methods, was also evaluated in terms of the 
operational characteristics, i.e., sensitivity and specificity, in both the median and high 
bias scenarios. 
Figure 4A shows the ROC curves of the PhRMA (using LDR), NCI and HRR test 
statistics in the median bias scenario, using either a random sample presented in the 
left panel, or an interim sample in the right panel. For the random audit sample, we 
consider a sample size of either 120 or 240. For the interim sample, 356 patients are 
audited, with a similar number of imaging assessments as 240 patients in the random 
sample. The HRR method consistently outperforms the PhRMA and NCI methods for 
both audit sampling mechanisms and for both audit sample sizes 120 and 240. 
Additional scenarios not shown in Figure 4A such as with high bias, or with treatment 
giving larger treatment benefit (i.e. smaller HR), or with other different audit sample 
sizes, the same pattern is consistently observed. Thus, HRR is generally recommended. 
Of note, when using the random sampling mechanism for audit, increasing audit sample 
size does improve the performance substantially.  
 
Figure A4. Comparison of PhRMA, NCI and HRR methods in terms of operational characteristics under 
median bias, using interim and random audit sample. N denotes number of subjects in the audit sample. 
Sample sizes of 120 and 240 are considered for random sample, and simple size of 356 is implemented 
in the interim sample. 
1.4 
SUMMARY 
Comprehensive simulations based on similar error model used in Amit (2013) and Dodd 
(2010) were ran to compare the performance of the three test statistics PhRMA (using 
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the LDR), NCI and HRR, as well as the random vs interim sampling methods. The 
performance was evaluated based on ROC curve, i.e. sensitivity and specificity along 
various thresholds for testing. Across various scenarios including when LE with medium 
or high bias, or with treatment giving larger treatment benefit (i.e. smaller HR), or with 
different audit sample sizes, consistently we observed the following: 
• the interim sampling approach performs as well as the random sampling does 
• comparing the PhRMA, NCI, and HRR test statistics, the HRR statistics 
outperforms the others  
Compared to the random sampling approach, the interim sampling has the attractive 
advantage of no risk of additional cost and timeline delay post database lock but only 
possible saving of work and cost before database lock.  
 
Therefore, in general, an interim sample-based PFS audit using the HRR method for 
bias detection is recommended over other options. 
 
 
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