Clinical trial NCT03197935
Conditions: Triple-negative Breast Cancer
Sponsor: Hoffmann-La Roche
Start date: 2017-07-24; Completion date: 2022-09-28
Enrollment: 333 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a global Phase III, double-blind, randomized, placebo-controlled study designed to evaluate the efficacy and safety of neoadjuvant treatment with atezolizumab (anti-programmed death-ligand 1 \[anti-PD-L1\] antibody) and nab-paclitaxel followed by doxorubicin and cyclophosphamide (nab-pac-AC), or placebo and nab-pac-AC in participants eligible for surgery with initial clinically assessed triple-negative breast cancer (TNBC).

Detailed description:

Arms: arm 1: Participants received atezolizumab (840 milligrams \[mg\]) via intravenous (IV) infusion every 2 weeks in combination with nab-paclitaxel (125 milligrams per square meter \[mg/m\^2\]) via IV infusion every week for 12 weeks, followed by atezolizumab (840 mg) every 2 weeks in combination with doxorubicin (60 mg/m\^2) and cyclophosphamide (600 mg/m\^2) every 2 weeks via IV infusions with filgrastim/pegfilgrastim support for 4 doses. Participants continued to receive unblinded atezolizumab post-surgery at a fixed dose of 1200 mg by IV infusion every 3 weeks for 11 doses, for a total of approximately 12 months of atezolizumab therapy. arm 2: Participants received placebo matched to atezolizumab via IV infusion every 2 weeks in combination with nab-paclitaxel (125 mg/m\^2) via IV infusion every week for 12 weeks, followed by placebo matched to atezolizumab every 2 weeks in combination with doxorubicin (60 mg/m\^2) and cyclophosphamide (600 mg/m\^2) every 2 weeks via IV infusions with filgrastim/pegfilgrastim support for 4 doses. Participants will be unblinded post-surgery and will continue to be followed.
Interventions: intervention 1: Atezolizumab (MPDL3280A), an engineered anti-PDL1 antibody intervention 2: Placebo intervention 3: Nab-paclitaxel intervention 4: Doxorubicin intervention 5: Cyclophosphamide intervention 6: Filgrastim intervention 7: Pegfilgrastim
Intervention descriptions: intervention 1: Atezolizumab was administered as per schedule described in respective arm. intervention 2: Placebo matched to atezolizumab was administered as per schedule described in respective arm. intervention 3: Nab-paclitaxel was administered as per schedule described in the arms. intervention 4: Doxorubicin was administered as per schedule described in the arms. intervention 5: Cyclophosphamide was administered as per schedule described in the arms. intervention 6: Filgrastim was administered according to local prescribing information as determined by the Investigator for 4 doses after completion of initial 12 weeks. intervention 7: Pegfilgrastim was administered according to local prescribing information as determined by the Investigator for 4 doses after completion of initial 12 weeks.

Protocol documents:
Prot_002.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 WO39392, Version 9
PROTOCOL
TITLE:
A PHASE III RANDOMIZED STUDY TO 
INVESTIGATE THE EFFICACY AND SAFETY OF 
ATEZOLIZUMAB (ANTI–PD-L1 ANTIBODY) IN 
COMBINATION WITH NEOADJUVANT 
ANTHRACYCLINE/NAB-PACLITAXEL-BASED 
CHEMOTHERAPY COMPARED WITH PLACEBO 
AND CHEMOTHERAPY IN PATIENTS WITH 
PRIMARY INVASIVE TRIPLE-NEGATIVE 
BREAST CANCER
PROTOCOL NUMBER: WO39392
VERSION NUMBER:
9
EUDRACT NUMBER:
2016-004734-22
IND NUMBER:
123277
NCT NUMBER:
NCT03197935
TEST PRODUCT:
Atezolizumab (RO5541267)
MEDICAL MONITOR:
 M.D., Ph.D.
SPONSOR:
F. Hoffmann-La Roche Ltd
APPROVAL DATE:
See electronic date stamp below.
 
Company Signatory
Approver's Name
Title
Date and Time (UTC)
24-Feb-2022 14:49:20


AtezolizumabF. Hoffmann-La Roche Ltd
2/Protocol WO39392, Version 9
PROTOCOL HISTORY
Protocol
Associated Country-Specific Protocols
Version
Date Final
Country
Version
Date Final
9
See electronic date 
stamp on title page.

8
9 February 2021
VHP adopted Version 8.
7
11 February 2020
VHP adopted Version 7.
6
7 June 2019
VHP adopted Version 6.
5
10 October 2018
VHP
5
10 December 2018
4
11 May 2018
VHP adopted Version 4.
3
4 May 2017
VHP adopted Version 3.
VHP (only)
2
17 April 2017
1
14 December 2016
VHP adopted Version 1.


AtezolizumabF. Hoffmann-La Roche Ltd
3/Protocol WO39392, Version 9
PROTOCOL AMENDMENT, VERSION 9:
RATIONALE
Protocol WO39392 has primarily been amended to update risks and management 
guidelines for atezolizumab to align with the latest Atezolizumab Investigator's Brochure
(Version 18).  Changes to the protocol, along with a rationale for each change, are 
summarized below:

A benefitrisk assessment and guidance on concomitant administration of 
coronavirus disease 2019 (COVID-19) vaccines with atezolizumab has been added 
(Section 1.4), and COVID-19 vaccines have been added as a permitted therapy 
(Section 4.4.1).

The responsibilities of the investigator and the role of the Medical Monitor have 
been clarified in determining patient eligibility and decision-making to re-challenging 
patients with atezolizumab after treatment interruption based on the investigator’s 
assessment of the benefits and risks (Sections 3.1.1, 4.1.2, 5.1.5, Appendix 8 and
Appendix 13).

The Medical Monitor name and associated contact information have been updated 
(Section 5.4.1).

References have been updated based on changes made to the protocol 
(Section 10).

The medical term “primary biliary cirrhosis” has been replaced by the term “primary 
biliary cholangitis” to align with the updated preferred term in Medical Dictionary for 
Regulatory Activities (Appendix 8).

The adverse event management guidelines have been updated to align with the 
Atezolizumab Investigator’s Brochure, Version 18 (Appendix 13).
Additional minor changes have been made to improve clarity and consistency.  
Substantive new information appears in italics.  This amendment represents cumulative 
changes to the original protocol.


AtezolizumabF. Hoffmann-La Roche Ltd
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TABLE OF CONTENTS
PROTOCOL AMENDMENT ACCEPTANCE FORM .......................................... 12
PROTOCOL SYNOPSIS .................................................................................... 13
1.
BACKGROUND .......................................................................................... 26
1.1
Background on Breast Cancer............................................... 26
1.2
Treatment for Early Triple-Negative Breast 
Cancer................................................................................... 27
1.3
Background on Atezolizumab................................................ 27
1.4
Study Rationale and Benefit-Risk Assessment...................... 29
2.
OBJECTIVES AND ENDPOINTS ............................................................... 32
3.
STUDY DESIGN......................................................................................... 35
3.1
Description of the Study......................................................... 35
3.1.1
Overview of Study Design ..................................................... 35
3.1.2
Independent Data Monitoring Committee .............................. 40
3.2
End of Study and Length of Study......................................... 41
3.3
Rationale for Study Design.................................................... 41
3.3.1
Rationale for Atezolizumab Dose and Schedule.................... 41
3.3.2
Rationale for Patient Population and Analysis 
Groups................................................................................... 42
3.3.3
Rationale for Comparator of Nab-Paclitaxel 
followed by Doxorubicin and Cyclophosphamide .................. 42
3.3.4
Rationale for Pathologic Complete Response as 
Primary Endpoint................................................................... 45
3.3.5
Rationale for Biomarker Assessments................................... 45
3.3.6
Rationale for Patient-Reported Outcome 
Assessments ......................................................................... 47
4.
MATERIALS AND METHODS .................................................................... 48
4.1
Patients.................................................................................. 48
4.1.1
Inclusion Criteria.................................................................... 48
4.1.2
Exclusion Criteria................................................................... 51
4.2
Method of Treatment Assignment and Blinding..................... 55
4.3
Study Treatment.................................................................... 57


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4.3.1
Formulation, Packaging, and Handling.................................. 57
4.3.1.1
Atezolizumab and Placebo .................................................... 57
4.3.1.2
Background Treatment .......................................................... 57
4.3.2
Dosage, Administration, and Compliance.............................. 57
4.3.2.1
Atezolizumab or Placebo....................................................... 57
4.3.2.2
Background Treatment .......................................................... 59
4.3.3
Investigational Medicinal Product Accountability ................... 60
4.3.4
Post-Trial Access to Atezolizumab ........................................ 61
4.4
Concomitant Therapy and Additional Restrictions................. 61
4.4.1
Permitted Therapy................................................................. 61
4.4.2
Cautionary Therapy ............................................................... 62
4.4.3
Potential Drug Interactions with Chemotherapy..................... 62
4.4.4
Prohibited Therapy ................................................................ 63
4.5
Study Assessments ............................................................... 64
4.5.1
Informed Consent Forms and Screening Log........................ 64
4.5.2
Medical History, Concomitant Medication, and 
Demographic Data................................................................. 65
4.5.3
Physical Examinations........................................................... 65
4.5.4
Vital Signs.............................................................................. 65
4.5.5
Locoregional Tumor Status.................................................... 66
4.5.6
Distant Sites Tumor Assessment........................................... 67
4.5.7
Disease Follow-Up and Confirmation of Disease 
Progression or Recurrence.................................................... 67
4.5.8
Surgical Specimen Pathology................................................ 71
4.5.9
Laboratory, Biomarker, and Other Biological 
Samples................................................................................. 71
4.5.10
Electrocardiograms................................................................ 74
4.5.11
Echocardiograms or Multiple-Gated Acquisition 
Scans..................................................................................... 74
4.5.12
Pulmonary Function Tests (Spirometry) ................................ 75
4.5.13
Patient-Reported Outcomes .................................................. 75
4.5.13.1
EORTC QLQ-C30.................................................................. 75
4.5.13.2
FACT-G Single Item GP5 ...................................................... 76
4.5.13.3
EQ-5D-5L .............................................................................. 76


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4.5.14
Mandatory Samples for Whole Genome 
Sequencing............................................................................ 76
4.5.15
Optional Samples for Research Biosample 
Repository ............................................................................. 77
4.5.15.1
Overview of the Research Biosample Repository.................. 77
4.5.15.2
Approval by the Institutional Review Board or 
Ethics Committee .................................................................. 78
4.5.15.3
Sample Collection.................................................................. 78
4.5.15.4
Confidentiality........................................................................ 79
4.5.15.5
Consent to Participate in the Research 
Biosample Repository............................................................ 79
4.5.15.6
Withdrawal from the Research Biosample 
Repository ............................................................................. 80
4.5.15.7
Monitoring and Oversight....................................................... 80
4.6
Treatment, Patient, Study, and Site 
Discontinuation...................................................................... 80
4.6.1
Study Treatment Discontinuation........................................... 80
4.6.2
Patient Discontinuation from Study........................................ 81
4.6.3
Study Discontinuation............................................................ 81
4.6.4
Site Discontinuation............................................................... 82
5.
ASSESSMENT OF SAFETY....................................................................... 82
5.1
Safety Plan ............................................................................ 82
5.1.1
Risks Associated with Atezolizumab ..................................... 83
5.1.2
Risks Associated with Nab-Paclitaxel.................................... 83
5.1.3
Risks Associated with Doxorubicin ........................................ 84
5.1.3.1
Cardiomyopathy .................................................................... 84
5.1.4
Risks Associated with Cyclophosphamide............................. 84
5.1.5
Management of Patients Who Experience 
Specific Adverse Events........................................................ 85
5.2
Safety Parameters and Definitions ........................................ 87
5.2.1
Adverse Events ..................................................................... 87
5.2.2
Serious Adverse Events (Immediately Reportable 
to the Sponsor)...................................................................... 88
5.2.3
Adverse Events of Special Interest (Immediately 
Reportable to the Sponsor).................................................... 89


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5.2.4
Selected Adverse Events....................................................... 90
5.2.4.1
Cardiac, General ................................................................... 90
5.2.4.2
Asymptomatic Left Ventricular Systolic 
Dysfunction............................................................................ 90
5.3
Methods and Timing for Capturing and 
Assessing Safety Parameters................................................ 90
5.3.1
Adverse Event Reporting Period ........................................... 90
5.3.2
Eliciting Adverse Event Information....................................... 91
5.3.3
Assessment of Severity of Adverse Events ........................... 91
5.3.4
Assessment of Causality of Adverse Events ......................... 92
5.3.5
Procedures for Recording Adverse Events............................ 93
5.3.5.1
Infusion-Related Reactions.................................................... 93
5.3.5.2
Diagnosis versus Signs and Symptoms................................. 93
5.3.5.3
Adverse Events That Are Secondary to Other 
Events.................................................................................... 94
5.3.5.4
Persistent or Recurrent Adverse Events................................ 94
5.3.5.5
Abnormal Laboratory Values ................................................. 95
5.3.5.6
Abnormal Vital Sign Values ................................................... 95
5.3.5.7
Abnormal Liver Function Tests.............................................. 96
5.3.5.8
Deaths ................................................................................... 96
5.3.5.9
Preexisting Medical Conditions.............................................. 97
5.3.5.10
Lack of Efficacy or Worsening of TNBC................................. 97
5.3.5.11
Hospitalization or Prolonged Hospitalization.......................... 97
5.3.5.12
Cases of Accidental Overdose or Medication 
Error....................................................................................... 98
5.3.5.13
Patient-Reported Outcome Data ........................................... 99
5.4
Immediate Reporting Requirements from 
Investigator to Sponsor.......................................................... 99
5.4.1
Emergency Medical Contacts.............................................. 100
5.4.2
Reporting Requirements for Serious Adverse 
Events and Adverse Events of Special Interest................... 100
5.4.2.1
Events That Occur prior to Study Treatment 
Initiation ............................................................................... 100
5.4.2.2
Events That Occur after Study Treatment 
Initiation ............................................................................... 101


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5.4.3
Reporting Requirements for Pregnancies............................ 101
5.4.3.1
Pregnancies in Female Patients.......................................... 101
5.4.3.2
Pregnancies in Female Partners of Male Patients............... 101
5.4.3.3
Abortions ............................................................................. 102
5.4.3.4
Congenital Anomalies/Birth Defects .................................... 102
5.5
Follow-Up of Patients after Adverse Events ........................ 102
5.5.1
Investigator Follow-Up......................................................... 102
5.5.2
Sponsor Follow-Up .............................................................. 103
5.6
Adverse Events That Occur after the Adverse 
Event Reporting Period........................................................ 103
5.7
Expedited Reporting to Health Authorities, 
Investigators, Institutional Review Boards, and 
Ethics Committees............................................................... 103
6.
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN..................... 104
6.1
Determination of Sample Size ............................................. 104
6.1.1
Adaptive Design .................................................................. 104
6.1.2
Type I Error Control............................................................. 105
6.2
Summaries of Conduct of Study.......................................... 106
6.3
Summaries of Treatment Group Comparability ................... 106
6.4
Efficacy Analyses ................................................................ 106
6.4.1
Primary Efficacy Endpoint:  Pathologic Complete 
Response ............................................................................ 106
6.4.2
Secondary Efficacy Endpoints............................................. 107
6.4.2.1
Event-Free Survival ............................................................. 107
6.4.2.2
Disease-Free Survival ......................................................... 107
6.4.2.3
Overall Survival ................................................................... 108
6.4.2.4
Patient-Reported Outcomes of Role and Physical 
Function and GHS/HRQoL―EORTC Data.......................... 108
6.4.3
Exploratory Efficacy Endpoints............................................ 108
6.4.3.1
Patient-Reported Outcomes of 
Disease/Treatment-Related Symptoms, 
Emotional and Social Function―EORTC Data.................... 108
6.4.3.2
Patient-Reported Outcome of Treatment 
Bother―FACT-G, GP5 Single Item Data............................. 109
6.4.3.3
Health Economic EQ-5D-5L Data........................................ 109


AtezolizumabF. Hoffmann-La Roche Ltd
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6.5
Safety Analyses................................................................... 109
6.6
Pharmacokinetic Analyses................................................... 110
6.7
Immunogenicity Analyses.................................................... 110
6.8
Biomarker Analyses............................................................. 110
6.9
Interim Analyses .................................................................. 110
6.9.1
Planned Interim Analysis ..................................................... 110
6.9.2
Optional Interim Analysis..................................................... 111
7.
DATA COLLECTION AND MANAGEMENT ............................................. 111
7.1
Data Quality Assurance....................................................... 111
7.2
Electronic Case Report Forms............................................. 112
7.3
Source Data Documentation................................................ 112
7.4
Use of Computerized Systems ............................................ 113
7.5
Retention of Records........................................................... 113
8.
ETHICAL CONSIDERATIONS.................................................................. 113
8.1
Compliance with Laws and Regulations .............................. 113
8.2
Informed Consent................................................................ 114
8.3
Institutional Review Board or Ethics Committee.................. 115
8.4
Confidentiality...................................................................... 115
8.5
Financial Disclosure ............................................................ 116
9.
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION ................................................................................... 116
9.1
Study Documentation .......................................................... 116
9.2
Protocol Deviations.............................................................. 116
9.3
Management of Study Quality ............................................. 116
9.4
Site Inspections ................................................................... 117
9.5
Administrative Structure....................................................... 117
9.6
Publication of Data and Protection of Trade 
Secrets ................................................................................ 117
9.7
Protocol Amendments ......................................................... 118
10. REFERENCES ......................................................................................... 119


AtezolizumabF. Hoffmann-La Roche Ltd
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LIST OF TABLES
Table 1
Objectives and Corresponding Endpoints................................... 33
Table 2
Definitions of and Procedures for Confirming Disease 
Recurrence, Death, and Other Noteworthy Events on 
Follow-Up.................................................................................... 69
Table 3
Dose Levels for Nab-Paclitaxel (Weekly Dose)........................... 86
Table 4
Guidelines for Management of Patients Who Experience 
Nab-PaclitaxelSpecific Adverse Events .................................... 86
Table 5
Adverse Event Severity Grading Scale for Events Not 
Specifically Listed in NCI CTCAE ............................................... 92
Table 6
Causal Attribution Guidance ....................................................... 93
LIST OF FIGURES
Figure 1
Study Schema............................................................................. 37
Figure 2
Documenting Treatment Burden in Early Breast Cancer 
Patients....................................................................................... 48
LIST OF APPENDICES
Appendix 1
Schedule of Activities (for Both Stage 1 and Stage 2) .............. 127
Appendix 2
Schedule of Pharmacokinetic, Immunogenicity, and Fluid 
Biomarker Samples................................................................... 136
Appendix 3
Tumor Tissue Requirements..................................................... 138
Appendix 4
Cardiac Safety Cohort Cardiac Assessments ........................... 139
Appendix 5
European Organisation for Research and Treatment of 
Cancer Quality of Life Questionnaire Core 30........................... 141
Appendix 6
FACT-G Single Item GP5.......................................................... 143
Appendix 7
EuroQol 5-Dimension, 5-Level Questionnaire:  EQ-5D-5L........ 144
Appendix 8
Preexisting Autoimmune Diseases ........................................... 147
Appendix 9
Anaphylaxis Precautions........................................................... 148
Appendix 10
Eastern Cooperative Oncology Group Scale of Performance 
Status........................................................................................ 149
Appendix 11
Guideline on the Management of Axillary Lymph Nodes for 
Study WO39392 (IMpassion031).............................................. 150
Appendix 12
Criteria for Baseline Nodal Staging and Implications on Post-
Neoadjuvant Axillary Lymph Node Management for 
Study WO39392 (IMpassion031).............................................. 151
Appendix 13
Risks Associated with Atezolizumab and Guidelines for 
Management of Adverse Events Associated with 
Atezolizumab ............................................................................ 153
Appendix 14
Statistical Detail of the Adaptive Design for Study WO39392 
(IMpassion031) ......................................................................... 182


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Appendix 15
Statistical Performance of the Adaptive Design ........................ 185


AtezolizumabF. Hoffmann-La Roche Ltd
12/Protocol WO39392, Version 9
PROTOCOL AMENDMENT ACCEPTANCE FORM
TITLE:
A PHASE III RANDOMIZED STUDY TO 
INVESTIGATE THE EFFICACY AND SAFETY OF 
ATEZOLIZUMAB (ANTI–PD-L1 ANTIBODY) IN 
COMBINATION WITH NEOADJUVANT 
ANTHRACYCLINE/NAB-PACLITAXEL-BASED 
CHEMOTHERAPY COMPARED WITH PLACEBO 
AND CHEMOTHERAPY IN PATIENTS WITH 
PRIMARY INVASIVE TRIPLE-NEGATIVE 
BREAST CANCER
PROTOCOL NUMBER:
WO39392
VERSION NUMBER:
9
EUDRACT NUMBER:
2016-004734-22
IND NUMBER:
123277
NCT NUMBER:
NCT03197935
TEST PRODUCT:
Atezolizumab (RO5541267)
MEDICAL MONITOR:
 M.D., Ph.D.
SPONSOR:
F. Hoffmann-La Roche Ltd
I agree to conduct the study in accordance with the current protocol.
Principal Investigator’s Name  (print)
Principal Investigator’s Signature
Date
Please retain the signed original of this form for your study files. Please return a copy of 
this form to the Sponsors or their designee.  Contact details will be provided to the 
investigator prior to study start.


AtezolizumabF. Hoffmann-La Roche Ltd
13/Protocol WO39392, Version 9
PROTOCOL SYNOPSIS
TITLE:
A PHASE III RANDOMIZED STUDY TO INVESTIGATE THE 
EFFICACY AND SAFETY OF ATEZOLIZUMAB (ANTI–PD-L1 
ANTIBODY) IN COMBINATION WITH NEOADJUVANT 
ANTHRACYCLINE/NAB-PACLITAXEL-BASED CHEMOTHERAPY 
COMPARED WITH PLACEBO AND CHEMOTHERAPY IN 
PATIENTS WITH PRIMARY INVASIVE TRIPLE-NEGATIVE 
BREAST CANCER
PROTOCOL NUMBER:
WO39392
VERSION NUMBER:
9
EUDRACT NUMBER:
2016-004734-22
IND NUMBER:
123277
NCT NUMBER:
NCT03197935
TEST PRODUCT:
Atezolizumab (RO5541267)
PHASE:
III
INDICATION:
Triple-negative breast cancer
SPONSOR:
F. Hoffmann-La Roche Ltd
Objectives and Endpoints
Study WO39392 (also known as IMpassion031) will evaluate the efficacy, safety, and 
pharmacokinetics of neoadjuvant nab-paclitaxel and atezolizumab followed by doxorubicin and 
cyclophosphamide with atezolizumab (referred to as atezolizumab nab-pacAC) or 
neoadjuvant nab-paclitaxel and placebo followed by doxorubicin and cyclophosphamide with 
placebo (referred to as placebo nab-pacAC) in patients with T24d triple-negative breast 
cancer (TNBC).  Specific objectives and corresponding endpoints for the study are as follows:
Objectives
Corresponding Endpoints
Primary Efficacy Objective:
To evaluate the efficacy of 
atezolizumabnab-pacAC compared 
with placebonab-pacAC in the 
neoadjuvant setting 
pCR defined as eradication of tumor from both breast 
and lymph nodes (ypT0/is ypN0) in the following:
All patients (ITT population)
Subpopulation of patients with PD-L1positive 
tumor status (IC1/2/3)


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Objectives
Corresponding Endpoints
Secondary Efficacy Objectives:
To evaluate the efficacy of 
atezolizumabnab-pacAC compared 
with placebonab-pacAC in the 
neoadjuvant setting
EFS defined as the time from randomization until 
documented disease recurrence, progression, or 
death from any cause in all patients (ITT population)
and in the subpopulation with PD-L1positive tumor 
status
DFS defined as the time from surgery until 
documented disease recurrence or death from any 
cause in all patients (ITT population) who undergo 
surgery and in the subpopulation of patients with 
PD-1positive tumor status who undergo surgery
OS defined as the time from randomization to the 
date of death from any cause in all patients
(ITT population) and in the subpopulation with 
PD-L1positive tumor status
To evaluate PROs of function and 
HRQoL associated with 
atezolizumabnab-pacAC compared 
with placebonab-pacAC, measured 
by the functional and HRQoL scales of 
the EORTC QLQ-C30
Mean and mean changes from baseline score in 
function (role, physical) and GHS/HRQoL by cycle 
and between treatment arms as assessed by the 
functional and HRQoL scales of the EORTC 
QLQ-C30
Exploratory Efficacy Objectives:
To evaluate the efficacy of 
atezolizumabnab-pacAC compared 
with placebonab-pacAC in the 
neoadjuvant setting
Proportion of patients undergoing breast-conserving 
surgery
RCB index
Correlation of RCB with other clinical endpoints 
(if deemed appropriate)
To evaluate PROs of 
disease/treatment-related symptoms 
associated with 
atezolizumabnab-pacAC compared 
with placebonab-pacAC, as 
measured by the EORTC QLQ-C30
Mean and mean changes from baseline score in 
disease/treatment-related symptoms by cycle and 
between treatment arms as assessed by all symptom 
items/scales of the EORTC QLQ-C30
To evaluate any treatment burden 
patients may experience associated 
with the addition of atezolizumab 
tonab-pacAC compared with 
placebonab-pacAC, as measured by 
a single item (GP5: “I am bothered by 
side effects of treatment”) from the 
physical well-being 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 patient’s health utility as 
measured by the EQ-5D-5L 
questionnaire to generate utility scores 
for use in economic models
Utility scores of the EQ-5D-5L questionnaire
Safety Objective:
To evaluate the safety and tolerability 
of atezolizumabnab-pacAC
compared with placebonab-pacAC 
Occurrence and severity of adverse events as 
defined by NCI CTCAE v4.0 


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Objectives
Corresponding Endpoints
Pharmacokinetic Objectives:
To characterize the pharmacokinetics 
of atezolizumab when administered in 
combination with nab-pacAC 
chemotherapy
Serum concentration of atezolizumab at specified 
timepoints
Immunogenicity Objective:
To evaluate the immune response to 
atezolizumab
Incidence of ADAs during the study and the 
prevalence of ADAs at baseline
Exploratory Immunogenicity Objective:
To evaluate potential effects of ADAs
Relationship between ADA status and efficacy, 
safety, and PK endpoints
Exploratory Biomarker Objective:
To assess predictive, prognostic, and 
pharmacodynamic exploratory 
biomarkers in archival and/or fresh 
tumor tissue and blood and their 
association with efficacy endpoints 
including but not limited to pCR
Relationship between PD-L1 IHC and efficacy 
endpoints other than pCR
Relationship between tumor derived RNA-based 
immune gene signatures and efficacy endpoints,
including but not limited to pCR
Relationship between tumor-based tumor infiltrating 
lymphocytes and/or CD8 IHC and efficacy 
endpoints, including but not limited to pCR
Pharmacodynamic changes in cancer-related 
immune, stroma and tumor immune biology 
parameters on-treatment by, but not limited to, gene 
expression and IHC in baseline, on-treatment, and 
residual disease tumor tissues 
Relationship of baseline and on-treatment plasma 
biomarkers and efficacy endpoints, including but not 
limited to pCR
ADA anti-drug antibody; atezolizumab nab-pacAC nab-paclitaxel and atezolizumab 
followed by doxorubicin and cyclophosphamide with atezolizumab; DFSdisease-free survival; 
EFSevent-free survival; EORTCEuropean Organisation for Research and Treatment of 
Cancer; EQ-5D-5LEuroQoL 5-Dimension, 5-Level; FACTG Functional Assessment of 
Cancer TherapyGeneral; GHSglobal health status; HRQoLhealth-related quality of life; 
ICtumor-infiltrating immune cell; IHCimmunohistochemistry; ITTintent to treat; NCI
CTCAENational Cancer Institute Common Terminology Criteria for Adverse Events;
OSoverall survival; pCRpathologic complete response; PDL1 programmed deathligand 1; 
PK pharmacokinetics; placebo nab-pacACneoadjuvant nab-paclitaxel and placebo followed 
by doxorubicin and cyclophosphamide with placebo; PRO patient-reported outcome; QLQ-
C30Quality of Life Questionnaire Core 30; RCB residual cancer burden. 
Study Design
Description of Study
This is a global Phase III, double-blind, randomized, placebo-controlled study designed to 
evaluate the efficacy and safety of neoadjuvant treatment with atezolizumab nab-pac-AC, or 
placebo nab-pacAC in patients eligible for surgery with initial clinically assessed T2-4d TNBC.
Female and male patients aged 18 years with an Eastern Cooperative Oncology Group 
(ECOG) performance status of 0 or 1 who have histologically confirmed invasive TNBC with a 
primary tumor size of 2 cm are eligible.


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Human epidermal growth factor receptor 2 (HER2) and estrogen/progesterone receptor 
(ER/PR) status will be used to define TNBC.  HER2 negativity will be defined by central 
laboratory assessment using in situ hybridization (ISH) or immunohistochemistry (IHC) assays 
per American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) 
criteria, and ER/PgR negativity will be defined by using IHC per ASCO/CAP criteria.  Central 
laboratory assessment will occur prior to randomization.  Patients whose tumors are not 
confirmed to be triple negative will not be eligible.  Patients whose tumor tissue is not evaluable 
for PD-L1 will not be eligible.
Patients who do not initially meet all eligibility criteria, other than TNBC status, may be 
rescreened once.
This study has an adaptive design consisting of two stages.  Stage 1 is the randomization and 
treatment of approximately 204 patients.  At the end of Stage 1, an interim analysis for efficacy 
will be done by an iDMC.  Then, a recommendation will be made to either continue the study 
unchanged or to expand the patient population (Stage 2; approximately 120 additional patients).  
If the recommendation is to expand the patient population into Stage 2, the Sponsor will remain 
blinded to the results of the interim analysis performed at the end of Stage 1.
Patients who have consented and are eligible will be randomized in a 1:1 ratio to either of the 
following treatment groups:

Arm A:  atezolizumab (840 mg) administered via intravenous (IV) infusion Q2W in 
combination with nab-paclitaxel (125 mg/m2) administered via IV infusion QW for 12 weeks 
followed by atezolizumab (840 mg) administered Q2W in combination with doxorubicin 
(60 mg/m2)cyclophosphamide (600 mg/m2) administered Q2W via IV infusions with 
filgrastim/pegfilgrastim support for 4 cycles.  Patients randomized to the atezolizumab arm 
will continue to receive unblinded atezolizumab post-surgery at a fixed dose of 1200 mg by 
IV infusion every 3 weeks (Q3W) for 11 cycles, for a total of approximately 12 months of 
atezolizumab therapy.  

Arm B: placebo administered Q2W via IV infusion in combination with nab-paclitaxel 
(125 mg/m2) administered QW via IV infusion for 12 weeks followed by placebo 
administered Q2W in combination with doxorubicin (60 mg/m2) cyclophosphamide 
(600 mg/m2) administered Q2W via IV infusions with filgrastim/pegfilgrastim support for 
4 cycles.  Patients randomized to the placebo arm will be unblinded post-surgery and will 
continue to be followed.
For patients in Stage 1 of the study, randomization will be stratified by the following factors:

American Joint Committee on Cancer (AJCC) stage at diagnosis (II vs. III; see below for 
evaluation and classification of lymph nodes)

Tumor PD-L1 status (tumor-infiltrating immune cell [IC] IC0 [<1% PD-L1 expressing IC per 
tumor area] vs. IC1/2/3 [1% PD-L1 expressing IC per tumor area])
Depending on the iDMC recommendation, Stage 2 could follow either an all-comer or PD-L1 
enrichment design.  If an all-comer design is recommended, the patients enrolled in Stage 2 will 
be stratified the same as patients enrolled in Stage 1.  If an enrichment design is recommended, 
only PD-L1positive patients will be enrolled, and the AJCC stage at diagnosis will be used as 
the sole randomization stratification factor.
Patients who discontinue neoadjuvant therapy early as a result of disease progression must 
be discontinued from all study treatment, will be managed as per local practice, and will be 
followed for survival only.  Patients who discontinue prematurely from the study will not 
be replaced.
Any patient who receives non-protocol therapy prior to surgery will be discontinued from study 
treatment and will be managed as per local practice; these patients will remain on study for 
survival follow-up.
The primary efficacy endpoint (pathologic complete response [pCR]; ypT0/is ypN0) will be 
established via local review following completion of neoadjuvant therapy and surgery.  
Pathologists who review study specimens must utilize the evaluations and assessments 
outlined in the Pathology Manual.  Investigator/individual patient unblinding will occur after pCR 
assessment.  Surgery should be performed at least 14 days after the last dose of neoadjuvant 


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therapy but no later than 6 weeks after the last infusion.  Platelet counts should be checked 
prior to surgery and should be 75,000 cells/L. 
Patients with clinically positive axillary nodes by physical examination or by any radiographic 
imaging at baseline should undergo fine-needle aspiration or core-needle biopsy prior to 
randomization followed by axillary lymph node dissection (ALND) at time of definitive surgery.  
The results of the baseline fine-needle aspiration or core-needle biopsy will determine the nodal 
staging, so that patients with a positive biopsy result should be staged as lymph-node-positive 
(N1-N3c) whereas patients with a negative or equivocal biopsy result should be staged as 
lymph-node-negative (N0) regardless of any other clinical measurements.
Baseline fine-needle aspiration (FNA) or core-needle biopsy is not mandatory for 
clinically/radiologically enlarged/suspicious internal mammary, subpectoral, infraclavicular, or 
supraclavicular lymph nodes.  Investigators are advised to follow local practice guidelines 
regarding assessment of internal mammary, subpectoral, infraclavicular, or supraclavicular 
lymph nodes.  Management of internal mammary, subpectoral, infraclavicular, or 
supraclavicular lymph nodes at the time of definitive surgery will be based on local practice
guidelines.  Patients with baseline axillary lymph nodes involvement who may also have 
clinically/radiologically enlarged internal mammary, subpectoral, infraclavicular, or 
supraclavicular lymph nodes must still undergo ALND as described earlier.
For patients with baseline clinically/radiologically enlarged/suspicious internal mammary, 
subpectoral, infraclavicular, or supraclavicular lymph nodes, pCR may be reported only if all the 
following conditions are met:

Presurgical imaging assessment of internal mammary, subpectoral, infraclavicular, or 
supraclavicular lymph nodes does not show any enlarged/suspicious lymph node(s) after 
neoadjuvant study treatment.
AND

Pathological evaluation of the breast and all resected lymph node(s) shows no residual 
invasive disease (i.e., pCR; ypT0/is ypN0).
Postoperative radiotherapy may be administered based on local practice guidelines.  The
Medical Monitor is available to advise as needed. 
In patients with clinically or fine-needle biopsy (FNA)/core needle biopsy-proven negative 
axillary nodes at baseline, axillary surgical management after completion of neoadjuvant 
therapy should include sentinel lymph node biopsy (SLNB) or ALND.  If SLNB is conducted, it is 
strongly recommended that more than one lymph node (two to three minimum) be removed and 
all patients with positive macrometastases in sentinel nodes should undergo ALND regardless 
of the number of positive nodes.  All patients with T4 tumors should undergo ALND or current 
standard of care as described in international or national guidelines.
Postoperative patient management for those in either treatment arm should include 
radiotherapy as clinically indicated, and management of patients who do not achieve a pCR
should follow current standard-of-care guidelines.  For those randomized to receive 
atezolizumab, patients may receive this therapy simultaneously with atezolizumab.
For those randomized to receive atezolizumab, the first dose of postoperative atezolizumab 
should be administered within 45 days of surgery.
Efficacy, safety, laboratory measurements, patient-reported outcomes (PROs), and 
pharmacokinetics will be assessed throughout the study.  The first 26 patients enrolled 
(approximately 13 patients in the control arm and approximately 13 patients in the atezolizumab 
containing arm) will undergo additional cardiac safety monitoring as part of a cardiac safety 
cohort.  Following completion of study treatment and surgery, all patients will continue to be 
followed for efficacy, safety, and PRO objectives until the end of the study.  No interim efficacy 
analyses for early stopping are planned.
Safety assessments will include the occurrence and severity of adverse events and laboratory 
abnormalities graded per National Cancer Institute Common Terminology Criteria for Adverse 
Events, Version 4.0 (NCI CTCAE v4.0).  Laboratory safety assessments will include the 
regular monitoring of hematology and blood chemistry.  Serum samples will be collected to 
monitor chemotherapy and atezolizumab pharmacokinetics and to detect the presence of 


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antibodies to atezolizumab.  Patient samples, including tumor tissues, as well as plasma and 
blood, will be collected for exploratory biomarker assessments.
An iDMC will evaluate the primary efficacy endpoint of pCR in the intent-to-treat (ITT) population 
(defined as all randomized patients) and in the PD-L1positive subpopulation based on an 
interim analysis of efficacy data from the Stage 1 patients (approximately 204 enrolled patients).  
The iDMC will make a recommendation either to continue the study unchanged or to enroll an 
additional 120 patients (Stage 2).  The decision rules to be applied at the interim analysis will be 
clearly expressed to the iDMC and documented in the iDMC charter so that the study can be 
conducted with the Sponsor remaining completely blinded to all results at this stage.
The iDMC will evaluate safety data and study conduct on a regular basis during the study until 
the primary analysis of pCR, which is performed at Stage 1 (approximately 204 patients) or 
Stage 2 (approximately 324 patients), if the iDMC recommends extending the target population.  
After which, iDMC review of the study data will be discontinued.
Sponsor affiliates will be excluded from iDMC membership.  The iDMC will follow a charter that 
outlines the iDMC roles and responsibilities.
Number of Patients
Approximately 204 patients will be enrolled in this study during Stage 1 and approximately 
120 additional patients will be enrolled if the iDMC recommends to expand to Stage 2.  
Enrollment will take place at approximately 75 global sites.
Target Population
Inclusion Criteria
Patients must meet the following criteria for study entry:

Signed Informed Consent Form

Ability to comply with protocol, in the investigator’s judgment

Women or men aged 18 years

ECOG performance status of 0 or 1

Histologically documented TNBC (negative HER2, ER, and PgR status); HER2 negativity 
will be defined by central laboratory assessment using ISH or IHC assays per ASCO/CAP 
criteria and ER/PgR negativity will be defined by central laboratory assessment using IHC 
per ASCO/CAP criteria.  Central laboratory assessment will occur prior to randomization.
Patients with multifocal tumors (more than one tumor confined to the same quadrant as 
the primary tumor) are eligible provided all discrete lesions are sampled and centrally 
confirmed as TNBC.

Confirmed tumor PD-L1 evaluation as documented through central testing of a 
representative tumor tissue specimen
In Stage 2, if the iDMC recommendation is to expand to a PD-L1positive population, 
only patients with confirmed tumor PD-L1 positive (IC1/2/3) will be considered eligible.

Primary breast tumor size of 2 cm by at least one radiographic or clinical measurement

Stage at presentation:  cT2cT4, cN0cN3, cM0

Patient agreement to undergo appropriate surgical management including axillary lymph 
node surgery and partial or total mastectomy after completion of neoadjuvant treatment

Baseline LVEF 53% measured by echocardiogram (ECHO) or multiple-gated acquisition 
(MUGA) scans

Adequate hematologic and end-organ function, as defined by the following laboratory 
results obtained within 14 days prior to the first study treatment:

ANC 1500 cells/L (without granulocyte colonystimulating factor [G-CSF] support 
within 2 weeks prior to Cycle 1, Day 1)

Lymphocyte count 500 cells/L

Platelet count 100,000 cells/L (without transfusion within 2 weeks prior to Cycle 1, 
Day 1)

Hemoglobin 9.0 g/dL


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
AST, ALT, and alkaline phosphatase 2.5 the upper limit of normal (ULN)

Serum bilirubin 1.0 ULN
Patients with known Gilbert syndrome who have serum bilirubin level 3 ULN 
may be enrolled.

For patients not receiving therapeutic anticoagulation: INR or aPTT 1.5 ULN within 
14 days prior to initiation of study treatment

For patients receiving therapeutic anticoagulation:  stable anticoagulant regimen and 
stable INR during the 14 days immediately preceding initiation of study treatment

Creatinine clearance 30 mL/min (calculated using the Cockcroft-Gault formula)

Serum albumin 25 g/L (2.5 g/dL)

Representative formalin-fixed, paraffin-embedded (FFPE) tumor specimen in paraffin blocks 
(preferred) or at least 20 unstained slides, with an associated pathology report documenting 
ER, PgR, and HER2 negativity 
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.
If multiple 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.
In Stage 2, if the recommendation from the iDMC is to expand to a PD-L1positive 
population, no further stratification based on PD-L1 status will be conducted.
Acceptable samples include core-needle biopsies for deep tumor tissue (minimum 
three cores) or excisional, incisional, punch, or forceps biopsies for cutaneous, 
subcutaneous, or mucosal lesions.
Fine-needle aspiration, brushing, and cell pellet from cytology specimens are not 
acceptable.

For women of childbearing potential:  agreement to remain abstinent (refrain from 
heterosexual intercourse) or use contraceptive methods, and agreement to refrain from 
donating eggs, as defined below:
Women must remain abstinent or use contraceptive methods that result in a failure rate 
of 1% per year during the treatment period and for at least 5 months after the last 
dose of atezolizumab, or 1 month after the last dose of nab-paclitaxel, or 6 months after 
the last dose of doxorubicin, or 12 months after the last dose of cyclophosphamide, 
whichever is later.  Women must refrain from donating eggs during this same period.
A woman is considered to be of childbearing potential if she is postmenarcheal, has not 
reached a postmenopausal state (12 continuous months of amenorrhea with no 
identified cause other than menopause), and has not undergone surgical sterilization 
(removal of ovaries and/or uterus).
Examples of contraceptive methods with a failure rate of 1% per year when used 
consistently and correctly, include combined (estrogen and progestogen containing) 
hormonal contraception associated with inhibition of ovulation, progestogen-only
hormonal contraception associated with inhibition of ovulation, bilateral tubal occlusion;
male sterilization; intrauterine devices; intrauterine hormone-releasing system; and 
sexual abstinence.
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. 


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
For men:  agreement to remain abstinent (refrain from heterosexual intercourse) or use 
contraceptive measures and agreement to refrain from donating sperm, as defined below:
With female partners of childbearing potential, men must remain abstinent or use a 
condom plus an additional contraceptive method that together result in a failure rate of 
1% per year during the treatment period and for 6 months after the last dose of 
nab-paclitaxel, cyclophosphamide, or doxorubicin.  Men must refrain from donating 
sperm during this same period.
With pregnant female partners, men must remain abstinent or use a condom during the 
treatment period and for 6 months after the last dose of nab-paclitaxel, 
cyclophosphamide, or doxorubicin to avoid exposing the embryo.
The reliability of sexual abstinence should be evaluated in relation to the duration of the 
clinical trial and the preferred and usual lifestyle of the patient.  Periodic abstinence 
(e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal 
are not acceptable methods of contraception.

Women who are not postmenopausal (12 months of nontherapy-induced amenorrhea) or 
have undergone a sterilization procedure must have a negative serum pregnancy test result 
within 14 days prior to initiation of study drug

Willingness and ability to comply with scheduled visits, treatment plans, laboratory tests, 
and other study procedures, including the completion of PRO questionnaires
Exclusion Criteria
Patients who meet any of the following criteria will be excluded from study entry:

Prior history of invasive breast cancer

Stage IV (metastatic) breast cancer

Prior systemic therapy for treatment and prevention of breast cancer 

Previous therapy with anthracyclines or taxanes for any malignancy

History of ductal carcinoma in situ (DCIS), except for patients treated exclusively with 
mastectomy 5 years prior to diagnosis of current breast cancer 

History of pleomorphic lobular carcinoma in situ (LCIS), except for patients surgically 
managed 5 years prior to diagnosis of current breast cancer (note that patients with non-
pleomorphic LCIS [either untreated or treated with surgery] are allowed)

Bilateral breast cancer 

Undergone incisional and/or excisional biopsy of primary tumor and/or axillary lymph nodes.  
Patients who have undergone SLNB at the baseline may be eligible only if the SLNB was 
free of invasive carcinoma.  Any patient with a positive SLN (involved with invasive 
carcinoma) is ineligible to participate in this study.

Axillary lymph node dissection prior to initiation of neoadjuvant therapy 

History of other malignancy within 5 years prior to screening, with the exception of those 
with a negligible risk of metastasis or death (e.g., 5-year OS of 90%), such as adequately 
treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, localized prostate 
cancer, or Stage I uterine cancer

History of cerebrovascular accident within 12 months prior to randomization

Cardiopulmonary dysfunction as defined by any of the following prior to randomization:

History of NCI CTCAE v4.0 Grade 3 symptomatic congestive heart failure or New 
York Heart Association (NYHA) criteria Class II

Angina pectoris requiring anti-anginal medication, serious cardiac arrhythmia not 
controlled by adequate medication, severe conduction abnormality, or clinically 
significant valvular disease

High-risk uncontrolled arrhythmias (i.e., atrial tachycardia with a heart rate 100/min at 
rest, significant ventricular arrhythmia [ventricular tachycardia], or higher-grade 
atrioventricular [AV]-block [second-degree AV-block Type 2 [Mobitz 2] or third degree 
AV-block])


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
Significant symptoms (Grade 2) relating to left ventricular dysfunction, cardiac 
arrhythmia, or cardiac ischemia

Myocardial infarction within 12 months prior to randomization

Uncontrolled hypertension (systolic blood pressure 180 mmHg and/or diastolic blood 
pressure 100 mmHg)

Evidence of transmural infarction on ECG

Requirement for oxygen therapy

History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or 
humanized antibodies or fusion proteins

Known hypersensitivity to biopharmaceuticals produced in Chinese hamster ovary cells

Known allergy or hypersensitivity to the components of the atezolizumab formulation

Known allergy or hypersensitivity to the components of the nab-paclitaxel, 
cyclophosphamide, or doxorubicin formulations

Known allergy or hypersensitivity to filgrastim or pegfilgrastim formulations

Active or history of autoimmune disease or immune deficiency, including but not limited to 
myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, 
rheumatoid arthritis, inflammatory bowel disease, antiphospholipid syndrome, Wegener 
granulomatosis, Sjögren syndrome, Guillain-Barré syndrome, or multiple sclerosis with the 
following exceptions:
Patients with a history of autoimmune-related hypothyroidism on a stable dose of 
thyroid replacement hormone may be eligible for this study.
Patients with controlled Type I diabetes mellitus on a stable dose of insulin regimen 
may be eligible for this study.
Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with dermatologic 
manifestations only (e.g., patients with psoriatic arthritis are excluded) are permitted 
provided all of following conditions are met:

Rash must cover 10% of body surface area

Disease is well controlled at baseline and requires only low-potency topical 
corticosteroids

No occurrence of acute exacerbations of the underlying condition requiring 
psoralen plus ultraviolet A radiation, methotrexate, retinoids, biologic agents, oral 
calcineurin inhibitors, or high-potency or oral corticosteroids within the previous 
12 months

History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis 
obliterans), drug-induced pneumonitis, idiopathic pneumonitis, or evidence of active 
pneumonitis on screening chest computed tomography (CT) scan
History of radiation pneumonitis in the radiation field (fibrosis) is permitted.

Positive HIV test at screening

Active hepatitis B virus (HBV) infection, defined as having a positive hepatitis B surface 
antigen (HBsAg) test at screening
Patients with a past or resolved HBV infection, defined as having a negative HBsAg 
test and a positive total hepatitis B core antibody (HBcAb) test at screening, are eligible 
for the study if active HBV infection is ruled out on the basis of HBV DNA viral load per 
local guidelines.

Active hepatitis C virus (HCV) infection, defined as having a positive HCV antibody test at 
screening
Patients who have a positive HCV antibody test are eligible for the study if a 
polymerase chain reaction (PCR) assay is negative for HCV RNA.

Active tuberculosis

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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
Treatment with therapeutic oral or IV antibiotics within 2 weeks prior to initiation of study 
treatment
Patients receiving prophylactic antibiotics (e.g., for prevention of a urinary tract infection 
or to prevent chronic obstructive pulmonary disease exacerbation) are eligible for the 
study.

Major surgical procedure within 4 weeks prior to initiation of study treatment or anticipation 
of need for a major surgical procedure (other than anticipated breast surgery) during the 
course of the study

Prior allogeneic stem cell or solid organ transplantation

Administration of a live attenuated vaccine within 4 weeks prior to initiation of study 
treatment or anticipation of need for such a vaccine during the atezolizumab/placebo 
treatment or within 5 months after the last dose of atezolizumab/placebo
Patients must agree not to receive live, attenuated influenza vaccine (e.g., FluMist®) 
within 4 weeks prior to randomization, during treatment or within 5 months following the 
last dose of atezolizumab (for patients randomized to atezolizumab).

Any other disease, metabolic dysfunction, physical examination finding, or clinical 
laboratory finding giving reasonable suspicion of a disease or condition that contraindicates 
the use of an investigational drug or that may affect the interpretation of the results or 
render the patient at high risk from treatment complications

Prior treatment with CD137 agonists or immune checkpointblockade therapies, including 
anti-CD40, antiCTLA-4, antiPD-1, and antiPD-L1 therapeutic antibodies

Treatment with systemic immunostimulatory agents (including but not limited to interferons, 
IL-2) within 4 weeks or 5 half-lives of the drug, whichever is longer, prior to initiation of study 
treatment

Treatment with systemic immunosuppressive medications (including but not limited to 
prednisone, cyclophosphamide, azathioprine, methotrexate, thalidomide, and antitumor 
necrosis [anti-TNF] factor agents) within 2 weeks prior to initiation of study treatment or 
anticipation of need for systemic immunosuppressive medications during the study
Patients who have received acute, low-dose, systemic immunosuppressant 
medications (e.g., a one-time dose of dexamethasone for nausea) are eligible for the 
study.
The use of inhaled corticosteroids and mineralocorticoids (e.g., fludrocortisone for 
adrenal insufficiency) is allowed.

Pregnant or lactating, or intending to become pregnant during the study
Women of childbearing potential must have a negative serum pregnancy test result 
within 14 days prior to initiation of study treatment.
End of Study
The end of the study is defined as the date when the last patient, last visit (LPLV) occurs for 
evaluation of secondary endpoints, or the date of Sponsor decision to end the study, whichever 
is earlier.  
Length of Study
The total duration of the study for Stage 1 is expected to be approximately 51 months.  If the 
iDMC recommends to expand enrollment (Stage 2), the duration of the study may increase to 
approximately 74 months.
Investigational Medicinal Products
The investigational medicinal products (IMPs) for this study are atezolizumab, its placebo, and 
nab-paclitaxel.  
Atezolizumab and Placebo
Patients will receive 840 mg atezolizumab or placebo administered by IV infusion Q2W
(14 [3] days) for 20 weeks (i.e., 10 doses) in combination with nab-paclitaxel, doxorubicin, and 
cyclophosphamide chemotherapy (see below).  Postoperatively, patients randomized to the 


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atezolizumab arm will continue to receive unblinded atezolizumab post-surgery at a fixed dose 
of 1200 mg by IV infusion every 3 weeks (Q3W) for 11 cycles, for a total of approximately 
12 months of atezolizumab therapy; patients randomized to the placebo arm will stop 
receiving placebo.
Nab-Paclitaxel
Nab-paclitaxel will be administered as background treatment along with the non-IMPs
doxorubicin, cyclophosphamide, and filgrastim/pegfilgrastim as specified below.
Non-Investigational Medicinal Products
Patients will receive nab-paclitaxel (125 mg/m2) administered via IV infusion given over 
30 minutes weekly for 12 weeks followed by doxorubicin (60 mg/m2) cyclophosphamide
(600 mg/m2) administered via IV infusion Q2W with filgrastim/pegfilgrastim support for 4 cycles 
(i.e., a total of 4 doses of doxorubicin and cyclophosphamide).  The dose of cyclophosphamide 
should be capped at 1200 mg.
Statistical Methods
Primary Analysis
The primary efficacy objective for this study is to evaluate the efficacy of neoadjuvant 
atezolizumab nab-pacAC compared with placebo nab-pacAC in patients with T2-4d TNBC, 
as measured by pCR defined as eradication of tumor from both breast and lymph nodes 
(ypT0/is ypN0).  The primary efficacy endpoint will be established following completion of 
neoadjuvant therapy and surgery. 
The ITT as well as PD-L1positive populations will be used for the primary analysis of pCR.  
In the primary analysis, patients whose pCR assessment was missing will be counted as not 
achieving a pCR.  An estimate of the pCR rate and its 95% CI (Clopper and Pearson 1934) will 
be calculated for each treatment arm.  The difference in pCR rates will be provided with 95% CI, 
using the normal approximation to the binomial distribution.  For the ITT population, the 
Cochran-Mantel-Haenszel 2 test stratified according to tumor PD-L1 status (IC0 vs. IC1/2/3) 
and clinical stage at presentation (Stage II vs. III) will be used to test pCR rates between 
treatment groups at a two-sided significance level of 5%.  For the PD-L1positive population, 
similar test will be used with stratification only for clinical stage at presentation. An unstratified 2
versions of these tests will also be provided as a sensitivity analysis.
Determination of Sample Size
The study will first randomize approximately N1204 patients in Stage 1 (1:1 randomization 
ratio).  Based on information from these patients and a pre-specified adaptive rule, the decision 
will be made regarding whether or not to randomize approximately N2120 patients in Stage 2 
(1:1 randomization ratio).
The pre-defined one-sided type I error for the interim analysis at Stage 1 is α 0.0125 
(i.e., 50% of the total type I error).  The co-primary endpoints in the ITT and PD-L1-positive 
populations at Stage 1 will be tested using a closed testing procedure using Simes’ test for the 
intersection hypothesis.  Test statistics in ITT and PD-L1-positive populations are always 
positively correlated, hence type I error rate control of the Simes test can be guaranteed in 
general.
Importantly, the p-value p based on Stage 1 data only and the combination p-value p	
 have 
the same joint distribution under the null hypothesis as the p-values from a group-sequential 
test with two stages at information times t = w and t = 1.  Thus standard statistical software 
for group sequential designs can be used for the determination of critical values for the adaptive 
design.  As the study design uses a critical value of α 0.0125 (i.e., 50% of the total type I 
error) for Stage 1, this implies that a critical value of α	
 0.0184 can be applied to the 
combination p-values.


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Definition
AC
doxorubicincyclophosphamide
ADA
anti-drug antibody, also known as an anti-therapeutic 
antibody (ATA)
AE
adverse event
AJCC
American Joint Committee on Cancer
ALND
axillary lymph node dissection
ASCO
American Society of Clinical Oncology
AV
atrioventricular
CAP
College of American Pathologists
COVID-19
coronavirus disease 2019
CT
computed tomography
CV
coefficient of variation
CYP
cytochrome P450
DCIS
ductal carcinoma in situ
DFS
disease-free survival
EBC
early breast cancer
EC
Ethics Committee
ECHO
echocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic Case Report Form
EDC
electronic data capture
EFS
event-free survival
EORTC
European Organisation for Research and Treatment of 
Cancer
EQ-5D-5L
EuroQoL 5-Dimension, 5-Level
ER
estrogen receptor
ESMO
European Society for Medical Oncology
FACT-G
Functional Assessment of Cancer Therapy-General
FDA
Food and Drug Administration
FFPE
formalin-fixed paraffin embedded
G-CSF
granulocyte colonystimulating factor
GHS
global health status
HBcAb
hepatitis B core antibody
HBsAg
hepatitis B surface antigen
HBV
hepatitis B virus
HCV
hepatitis C virus


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Abbreviation
Definition
HER2
human epidermal growth factor receptor 2
HIPAA
Health Insurance Portability and Accountability Act
HR
hazard ratio
HRQoL
health-related quality of life
IC
tumor-infiltrating immune cell
ICH
International Council for Harmonisation
iDMC
independent Data Monitoring Committee
Ig
immunoglobulin
IHC
immunohistochemistry
IMP
investigational medicinal product
IND
Investigational New Drug
IFN
interferon
IRB
Institutional Review Board
IRR
infusion-related reaction
ISH
in situ hybridization
ITT
intent to treat
IV
intravenous
IxRS
interactive voice or web-based response system
LCIS
lobular carcinoma in situ
LPLV
last patient, last visit
LVEF
left ventricular ejection fraction
MRI
magnetic resonance imaging
MUGA
multiple-gated acquisition
nab-pacAC
nab-paclitaxel followed by doxorubicin and 
cyclophosphamide 
NAST
neoadjuvant systemic therapy
NCCN
National Comprehensive Cancer Network
NCI CTCAE
National Cancer Institute Common Terminology Criteria 
for Adverse Events
NGS
next-generation sequencing
NYHA
New York Heart Association
OS
overall survival
pCR
pathologic complete response
PCR
polymerase chain reaction
PD
pharmacodynamic
PD-1
programmed death1
PD-L1
programmed deathligand 1


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Abbreviation
Definition
PET
positron emission tomography
P-gp
P-glycoprotein
PgR
progesterone receptor
PK
pharmacokinetic
PRO
patient-reported outcome
PVC
polyvinyl chloride
Q
question
QW
weekly
Q2W
every 2 weeks
Q3W
every 3 weeks
QLQ-C30
Quality of Life Questionnaire Core 30
RBR
Research Biosample Repository
SAE
serious adverse event
SAP
Statistical Analysis Plan
SARS-CoV-2
severe acute respiratory syndrome coronavirus 2
SITC
Society for Immunotherapy of Cancer 
SLNB
sentinel lymph node biopsy
T3
triiodothyronine
TLS
tumor lysis syndrome
TNBC
triple-negative breast cancer
TNF
tumor necrosis factor
ULN
upper limit of normal
WGS
whole genome sequencing
1.
BACKGROUND
1.1
BACKGROUND ON BREAST CANCER
Globally, breast cancer is the second most common invasive malignancy and the most 
common cause of cancer-related mortality in women.  The majority of breast cancers in 
the Western world are diagnosed when the cancer is still confined to the breast, with or 
without locoregional lymph node spread (Sant et al. 2003; Jemal et al. 2011; Ferlay et al. 
2013; Howlader et al. 2016).  At these early stages (IIII, early breast cancer [EBC]), the 
largely asymptomatic disease is usually operable and can be treated with curative intent.
Triple-negative breast cancer (TNBC) is defined by the absence of immunostaining for 
estrogen receptor (ER), progesterone receptor (PgR), and human epidermal growth 
factor receptor 2 (HER2).  Overall, approximately 15%–20% of all breast cancers are 
classified as TNBC.  Large-scale comprehensive genomic analyses have characterized 


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the heterogeneous nature of TNBCs and their diverse gene expression patterns and 
underlying genomic changes, but these insights have not yet provided clear guidance for 
the identification of clinically effective targeted therapies currently under laboratory and 
clinical investigation.  Unfortunately, TNBCs are more likely to have aggressive features, 
such as a high proliferative rate, and exhibit an invasive phenotype. Patients with 
TNBCs exhibit a poor clinical outcome, generally with rapid progression and a shorter 
time to local and distant relapse (Dent et al. 2007).
Early-stage TNBC comprises 10%20% of all new diagnoses of EBC defined as 
Stages IIII (Lehmann et al. 2011; Howlader et al. 2016).  Three-year event-free survival 
(EFS) rates between 74% and 76% have been reported for patients with TNBC who 
have received neoadjuvant anthracycline/taxane therapy (Sikov et al. 2015).  Upon 
relapse, patients with metastatic TNBC have poor outcomes, with rapid progression and 
decreased overall survival (OS) (Kassam et al. 2009).
1.2
TREATMENT FOR EARLY TRIPLE-NEGATIVE BREAST 
CANCER
Multi-agent chemotherapy regimens have proven benefit as neoadjuvant/adjuvant 
therapy for early-stage TNBC, improving both disease-specific and OS outcomes 
(Berry et al. 2006; Senkus et al. 2015; NCCN 2016).  Chemotherapy intended to reduce 
the risk of relapse may be given preoperatively (neoadjuvant) or postoperatively 
(adjuvant) to patients with EBC and is currently recommended for TNBC patients with 
Stage IIII disease.  Globally, chemotherapy is most often administered as adjuvant 
therapy; however, rates of neoadjuvant treatment use are increasing.
The most effective chemotherapy combinations used for early-stage TNBC include 
anthracyclines, topoisomerase II inhibitors, platinum agents, cyclophosphamide, and/or 
taxanes (Early Breast Cancer Trialists’ Collaborative Group 2005; Peto et al. 2012).
Studies looking at optimizing the dose and schedule of EBC chemotherapy regimens 
(Citron et al. 2003; Sparano et al. 2008; Budd et al. 2015) have established one of the 
optimal regimens with respect to maximizing efficacy as doxorubicin 60 mg/m2 and 
cyclophosphamide 600 mg/m2 administered every 2 weeks (Q2W) for 4 cycles, followed 
by weekly (QW) paclitaxel 80 mg/m2 for 12 weeks; the regimen is included as a 
preferred option in international guidelines (Senkus et al. 2015; NCCN 2016).
However, despite having received standard anthracycline-taxanebased therapy, 
approximately 30%40% of patients with clinically localized disease at diagnosis 
develop metastatic disease and die of the cancer (Haffty et al. 2006; Tan et al. 2008; 
Budd et al. 2015).  Thus, there is a substantial need to improve long-term treatment 
outcomes for patients with early-stage TNBC.
1.3
BACKGROUND ON ATEZOLIZUMAB
Atezolizumab is a humanized immunoglobulin (Ig) G1 monoclonal antibody that targets 
programmed deathligand 1 (PD-L1) and inhibits the interaction between PD-L1 and its 


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receptors, programmed death1(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 approved for the treatment of urothelial carcinoma, nonsmall cell lung 
cancer, small-cell lung cancer, triple-negative breast cancer, hepatocellular carcinoma, 
and melanoma.  Atezolizumab is being studied as a single agent as well as in 
combination with chemotherapy, targeted therapy, and cancer immunotherapy.
Refer to the Atezolizumab Investigator's Brochure for additional details on nonclinical 
and clinical studies.
Clinical Experience with Atezolizumab in Triple-Negative Breast Cancer
Atezolizumab is currently being tested in multiple Phase I, II, and III studies, both as
monotherapy and in combination with several anti-cancer therapies in multiple 
indications (see the Atezolizumab Investigator’s Brochure for full study descriptions and 
available data). 
Much of the available safety and efficacy data in TNBC are from two studies:

Study PCD4989g, a Phase Ia, multicenter, first-in-human, open-label, 
dose-escalation trial evaluating the safety, tolerability, immunogenicity, 
pharmacokinetics, exploratory pharmacodynamics, and preliminary evidence of 
biologic activity of atezolizumab monotherapy in patients with locally advanced or 
metastatic solid malignancies or hematologic malignancies.  Data from the TNBC 
cohort have been reported and demonstrate promising safety and efficacy results 
mainly in 1L and PD-L1positive patients (Emens et al. 2018).

Study GP28328, a Phase Ib multi-cohort trial of the safety and pharmacology of 
atezolizumab administered with bevacizumab and/or chemotherapy in patients with 
advanced solid tumors. Arm F of the trial is evaluating atezolizumab administered in 
combination with weekly nab-paclitaxel in patients with TNBC. Data from Arm F 
have been reported and support the use of atezolizumab in combination with 
chemotherapy in TNBC patients.  Confirmed responses were seen in 46%
(95% CI: 19%, 75%) of patients with first-line metastatic TNBC and 38% 
(95% CI: 21%, 56%) of patients regardless of line of therapy and PD-L1 expression.  
No new safety signals were seen (Adams et al. 2016).  Results from Study 
GP28328 support the hypothesis that tumor-cell killing by cytotoxic chemotherapy 
may expose the immune system to high levels of tumor antigens.  Boosting 
tumor-specific T-cell immunity in this setting by blocking the PD-L1 pathway may 


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result in deeper and more durable responses than those observed with standard 
chemotherapy alone (Merritt et al. 2003; Apetoh et al. 2007), and these responses
may reasonably occur in tumors regardless of PD-L1 expression.  The inclusion of 
patients with all levels of PD-L1 expression in this study will enable a robust 
assessment of this hypothesis.
A third study (WO29522, IMpassion130) has read out for progression-free survival
(Schmid et al. 2018). This is a global, multicenter, double-blind, two-arm, randomized, 
placebo-controlled study designed to evaluate the efficacy and safety of atezolizumab 
administered with nab-paclitaxel in patients with metastatic or unresectable locally 
advanced TNBC who have not received prior systemic therapy for metastatic 
breast cancer.
Refer to the Atezolizumab Investigator's Brochure for details on the clinical studies 
involving atezolizumab as well as updated detailed safety and efficacy results.
1.4
STUDY RATIONALE AND BENEFIT-RISK ASSESSMENT
Encouraging clinical data emerging in the field of tumor immunotherapy have 
demonstrated that therapies focused on enhancing T-cell responses against cancer can 
result in a significant survival benefit in patients with Stage IV cancer (Hodi et al. 2010; 
Kantoff et al. 2010; Chen et al. 2012).
The PD-L1 pathway serves as an immune checkpoint to temporarily dampen immune 
responses in states of chronic antigen stimulation, such as chronic infection or cancer.  
PD-L1 is an extracellular protein that downregulates immune responses through binding 
to its two receptors, PD-1 and B7.1.  PD-1 is an inhibitory receptor expressed on T cells 
following T-cell activation, and expression is sustained in states of chronic stimulation 
(Blank et al. 2005; Keir et al. 2008).  B7.1 is a molecule expressed on antigen-presenting 
cells and activated T cells.  Binding of PD-L1 to PD-1 and B7.1 inhibits T-cell 
proliferation and activation, cytokine production, and cytolytic activity, leading to the 
functional inactivation or exhaustion of T cells (Butte et al. 2007; Yang et al. 2011).  
Overexpression of PD-L1 on tumor and tumor-infiltrating immune cells has been 
reported to impede anti-tumor immunity, resulting in immune evasion (Blank and 
Mackensen 2007).  Therefore, interruption of the PD-L1 pathway represents an 
attractive strategy for restoring tumor-specific T-cell immunity.
Targeting the PD-L1 pathway with atezolizumab has demonstrated activity in patients 
with advanced malignancies.  Objective responses have been observed across a broad 
range of malignancies, including nonsmall-cell lung cancer, urothelial carcinoma, renal 
cell carcinoma, melanoma, colorectal cancer, head and neck cancer, gastric cancer, 
breast cancer, and sarcoma. In particular, available data from the TNBC cohorts in 
Studies PCD4989g and GP28328 have demonstrated activity and durable responses in 
patients receiving atezolizumab as monotherapy or in combination with nab-paclitaxel 
(see the Atezolizumab Investigator's Brochure for detailed efficacy results).


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Atezolizumab has been generally well tolerated.  Immune-mediated adverse events are 
consistent with the role of the PD-L1/PD-1 pathway in regulating peripheral tolerance.  
Given the mechanism of action of atezolizumab, events associated with inflammation 
and/or immune-mediated adverse events are closely monitored in the atezolizumab 
clinical program.  Immune-mediated adverse events associated with atezolizumab 
include dermatologic, hepatic, endocrine, gastrointestinal, respiratory, and neurological 
events. To date, the majority of these events have been manageable without requiring 
treatment discontinuation. Refer to the Atezolizumab Investigator’s Brochure for 
additional details regarding immune-mediated adverse events observed in patients 
treated with atezolizumab.
Atezolizumab in combination with taxanes (including paclitaxel and nab-paclitaxel) has
also been investigated or is currently being investigated as part of several studies 
including Studies GP28328, GO29436 (IMpower150), GO29537 (IMpower130), 
GO30140, and WO29522 (IMpassion130).  Atezolizumab in combination with 
chemotherapeutic regimens including anthracyclines and cyclophosphamide is currently 
being investigated as part of Studies BO29563 and GO29831. Thus far, reported 
adverse events observed were similar to those experienced with the individual 
components of the study treatment and have generally been manageable. According to 
data available from the TNBC cohort in Study GP28328 (atezolizumab in combination 
with nab-paclitaxel), the most commonly occurring adverse events (30% incidence) 
were fatigue (65.6%); diarrhea (50%); nausea, constipation, and alopecia (40.6% each);
peripheral sensory neuropathy (37.5%); pyrexia, cough, and decreased neutrophil count 
(34.4% each); and peripheral neuropathy and neutropenia (31.3% each).  Three TNBC 
patients (9.4%) had serious adverse events assessed as related to study treatment; 
these serious adverse events were pyrexia, anemia, and mycoplasmal pneumonia. 
Refer to the Atezolizumab Investigator’s Brochure for additional details.
The risk of overlapping toxicities between atezolizumab and nab-paclitaxel, doxorubicin, 
and cyclophosphamide is thought to be minimal based on the mechanism of action of 
each product. Known serious risks associated with nab-paclitaxel include bone marrow 
suppression (neutropenia, anemia, and thrombocytopenia), elevation of liver enzymes, 
alopecia, peripheral neuropathy, infection, and pneumonitis. Known serious risks of 
doxorubicin include bone marrow suppression (neutropenia, anemia, and 
thrombocytopenia), alopecia, nausea and vomiting, skin reactions, and cardiotoxicity.  
Known serious risks associated with cyclophosphamide include bone marrow 
suppression (neutropenia, anemia, and thrombocytopenia), infection, renal toxicity, 
cystitis, cardiotoxicity, and pneumonitis.  In order to mitigate any potential risks 
associated with this combination regimen, patients with cardiopulmonary dysfunction will 
be excluded from the study (see Section 4.1.2), and an independent Data Monitoring 
Committee (iDMC) will regularly review unblinded safety data (see Section 3.1.2).  
Cardiac function will also be closely monitored, including regular measurements of left 
ventricular ejection fraction (LVEF) throughout the study.


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This study will enroll patients with cT2cT4d TNBC tumors who will receive neoadjuvant 
therapy prior to surgery.  Given the relatively poor prognosis for these patients
(see Section 3.3.2), the limited availability of targeted agents, and the ability to assess 
the benefitrisk profile in the neoadjuvant setting (see Section 3.3.4), this population 
and setting are considered appropriate for trials of novel therapeutic candidates.  
The benefit-risk ratio for atezolizumab in combination with nab-paclitaxel followed by
cyclophosphamide and doxorubicin is expected to be acceptable in this setting.
In the setting of the coronavirus disease 2019 (COVID-19) pandemic, patients with 
comorbidities, including those with cancer, are considered a more vulnerable population, 
with the potential for more severe clinical outcomes from severe acute respiratory 
syndrome coronavirus 2 (SARS-CoV-2) infection.  However, it is unclear whether or 
how systemic cancer therapies such as chemotherapy, targeted therapy, or 
immunotherapy impact the incidence or severity of SARS-CoV-2 infection.
A possible consequence of 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 SARS-CoV-2 infection is altered by cancer 
immunotherapy.
Severe SARS-CoV-2 infection appears to be associated with a cytokine-release 
syndrome (CRS) involving the inflammatory cytokines interleukin (IL)-6, IL-10, IL-2, and 
interferon (IFN)-(Merad and Martin 2020).  While it is not known, there may be a 
potential for an increased risk of an enhanced inflammatory response if a patient 
develops acute SARS-CoV-2 infection while receiving atezolizumab.  At this time, there 
is insufficient evidence for causal association between atezolizumab and an increased 
risk of severe outcomes from SARS-CoV-2 infection.
There may be potential synergy or overlap in clinical and radiologic features for 
immune-mediated pulmonary toxicity with atezolizumab and clinical and radiologic 
features for SARS-CoV-2related interstitial pneumonia.  Thus, investigators should use 
their clinical judgment when evaluating and managing patients with pulmonary 
symptoms.
Neutropenia and lymphopenia associated with chemotherapy may increase the risk for 
developing an infection in patients receiving atezolizumab in combination with 
chemotherapy.
There are limited data concerning the possible interactions between cancer 
immunotherapy treatment and COVID-19 vaccination, and it is recognized that human 


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immune responses are highly regulated and that immune-modifying therapies may 
positively or negatively impact the efficacy and safety of COVID-19 vaccination 
(Society for Immunotherapy of Cancer [SITC] 2020).
Per recommendations of the National Comprehensive Cancer Network (NCCN) 
COVID-19 Vaccination Advisory Committee, COVID-19 vaccination is recommended 
for all patients with cancer receiving active therapy (including immune checkpoint 
inhibitors), with the understanding that there are limited safety and efficacy data in 
such patients (NCCN 2021).  Given the lack of clinical data, currently no 
recommendations can be made regarding the optimal sequence of COVID-19
vaccination in patients who are receiving cancer immunotherapy (SITC 2020).  For 
patients enrolling in this study and receiving atezolizumab treatment, a decision to 
administer the vaccine to a patient should be made on an individual basis by the 
investigator in consultation with the patient.
In alignment with clinical practice procedures, factors to consider when making the 
individualized decision for patients receiving atezolizumab treatment to receive 
COVID-19 vaccination include the following:  the risk of SARS-CoV-2 infection and 
potential benefit from the vaccine, the general condition of the patient and potential 
complications associated with SARS-CoV-2 infection, underlying disease, and the 
severity of COVID-19 outbreak in a given area or region.  
SITC and NCCN recommendations along with institutional guidelines should be used 
by the investigator when deciding on administering COVID-19 vaccines.  When 
administered,  COVID-19 vaccines must be given in accordance with the approved or 
authorized vaccine label.  Receipt of the COVID-19 vaccine is considered a concomitant 
medication and should be documented as such (see Section 4.4). 
2.
OBJECTIVES AND ENDPOINTS
This study (Study WO39392, also known as IMpassion031) will evaluate the efficacy, 
safety, and pharmacokinetics of neoadjuvant nab-paclitaxel and atezolizumab followed 
by doxorubicin and cyclophosphamide with atezolizumab (referred to as 
atezolizumabnab-pacAC) or neoadjuvant nab-paclitaxel and placebo followed by 
doxorubicin and cyclophosphamide with placebo (referred to as placebonab-pacAC) 
in patients with T2-4d TNBC.  Specific objectives and corresponding endpoints for the 
study are outlined in Table 1.


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Table 1
Objectives and Corresponding Endpoints
Objectives
Corresponding Endpoints
Primary Efficacy Objective:
To evaluate the efficacy of 
atezolizumabnab-pacAC compared 
with placebonab-pacAC in the 
neoadjuvant setting 
pCR defined as eradication of tumor from both breast 
and lymph nodes (ypT0/is ypN0) in the following:
All patients (ITT population)
Subpopulation of patients with PD-L1positive 
tumor status (IC1/2/3)
Secondary Efficacy Objectives:
To evaluate the efficacy of 
atezolizumabnab-pacAC compared 
with placebonab-pacAC in the 
neoadjuvant setting
EFS defined as the time from randomization until 
documented disease recurrence, progression, or 
death from any cause in all patients (ITT population)
and in the subpopulation with PD-L1positive tumor 
status
DFS defined as the time from surgery until 
documented disease recurrence or death from any 
cause in all patients (ITT population) who undergo 
surgery and in the subpopulation of patients with 
PD-L1positive tumor status who undergo surgery
OS defined as the time from randomization to the 
date of death from any cause in all patients
(ITT population) and in the subpopulation with 
PD-L1positive tumor status
To evaluate PROs of function and 
HRQoL associated with 
atezolizumabnab-pacAC compared 
with placebonab-pacAC, measured 
by the functional and HRQoL scales of 
the EORTC QLQ-C30
Mean and mean changes from baseline score in 
function (role, physical) and GHS/HRQoL by cycle 
and between treatment arms as assessed by the 
functional and HRQoL scales of the EORTC 
QLQ-C30


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Table 1
Objectives and Corresponding Endpoints (cont.)
Objectives
Corresponding Endpoints
Exploratory Efficacy Objectives:
To evaluate the efficacy of 
atezolizumabnab-pacAC compared 
with placebonab-pacAC in the 
neoadjuvant setting
Proportion of patients undergoing breast-conserving 
surgery
RCB index
Correlation of RCB with other clinical endpoints 
(if deemed appropriate)
To evaluate PROs of 
disease/treatment-related symptoms 
associated with 
atezolizumabnab-pacAC compared 
with placebonab-pacAC, as 
measured by the EORTC QLQ-C30
Mean and mean changes from baseline score in 
disease/treatment-related symptoms by cycle and 
between treatment arms as assessed by all symptom 
items/scales of the EORTC QLQ-C30
To evaluate any treatment burden 
patients may experience associated 
with the addition of atezolizumab 
tonab-pacAC compared with 
placebonab-pacAC, as measured by 
a single item (GP5: “I am bothered by 
side effects of treatment”) from the 
physical well-being 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 patient’s health utility as 
measured by the EQ-5D-5L 
questionnaire to generate utility scores 
for use in economic models
Utility scores of the EQ-5D-5L questionnaire
Safety Objective:
To evaluate the safety and tolerability 
of atezolizumabnab-pacAC
compared with placebonab-pacAC 
Occurrence and severity of adverse events as 
defined by NCI CTCAE v4.0 
Pharmacokinetic Objectives:
To characterize the pharmacokinetics 
of atezolizumab when administered in 
combination with nab-pacAC 
chemotherapy
Serum concentration of atezolizumab at specified 
timepoints
Immunogenicity Objective:
To evaluate the immune response to 
atezolizumab
Incidence of ADAs during the study and the 
prevalence of ADAs at baseline
Exploratory Immunogenicity Objective:
To evaluate potential effects of ADAs
Relationship between ADA status and efficacy, 
safety, and PK endpoints


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Table 1
Objectives and Corresponding Endpoints (cont.)
Objectives
Corresponding Endpoints
Exploratory Biomarker Objective:
To assess predictive, prognostic, and 
pharmacodynamic exploratory 
biomarkers in archival and/or fresh 
tumor tissue and blood and their 
association with efficacy endpoints 
including but not limited to pCR
Relationship between PD-L1 IHC and efficacy 
endpoints other than pCR
Relationship between tumor derived RNA-based 
immune gene signatures and efficacy endpoints,
including but not limited to pCR
Relationship between tumor-based tumor infiltrating 
lymphocytes and/or CD8 IHC and efficacy 
endpoints, including but not limited to pCR
Pharmacodynamic changes in cancer-related 
immune, stroma and tumor immune biology 
parameters on-treatment by, but not limited to, gene 
expression and IHC in baseline, on-treatment, and 
residual disease tumor tissues 
Relationship of baseline and on-treatment plasma 
biomarkers and efficacy endpoints, including, but not 
limited to pCR
ADA anti-drug antibody; atezolizumab nab-pacAC nab-paclitaxel and atezolizumab 
followed by doxorubicin and cyclophosphamide with atezolizumab; DFSdisease-free survival; 
EFS event-free survival; EORTC European Organisation for Research and Treatment of 
Cancer; EQ-5D-5LEuroQoL 5-Dimension, 5-Level; FACTG Functional Assessment of 
Cancer TherapyGeneral; GHSglobal health status; HRQoLhealth-related quality of life; 
ICtumor-infiltrating immune cell; IHCimmunohistochemistry; ITTintent to treat; NCI
CTCAENational Cancer Institute Common Terminology Criteria for Adverse Events;
OSoverall survival; pCRpathologic complete response; PDL1 programmed deathligand 1; 
PK pharmacokinetics; placebo nab-pacACneoadjuvant nab-paclitaxel and placebo followed 
by doxorubicin and cyclophosphamide with placebo; PRO patient-reported outcome; 
QLQ-C30Quality of Life Questionnaire Core 30; RCB residual cancer burden. 
3.
STUDY DESIGN
3.1
DESCRIPTION OF THE STUDY
3.1.1
Overview of Study Design
This is a global Phase III, double-blind, randomized, placebo-controlled study designed 
to evaluate the efficacy and safety of neoadjuvant treatment with 
atezolizumabnab-pac-AC, or placebonab-pacAC in patients eligible for surgery with 
initial clinically assessed T2-4d TNBC.
Female and male patients aged 18 years with an Eastern Cooperative Oncology Group 
(ECOG) performance status of 0 or 1 who have histologically confirmed invasive TNBC 
with a primary tumor size of 2 cm are eligible (see Appendix 10).
HER2 and ER/PgR status will be used to define TNBC.  HER2 negativity will be defined 
by central laboratory assessment using in situ hybridization (ISH) or 
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of American Pathologists (ASCO/CAP) criteria (Wolff et al. 2013), and ER/PgR negativity 
will be defined by using IHC per ASCO/CAP criteria (Hammond et al. 2010).  Central 
laboratory assessment will occur prior to randomization.  Patients whose tumors are not 
confirmed to be triple negative will not be eligible.  Patients whose tumor tissue is not 
evaluable for PD-L1 will not be eligible.
Patients who do not initially meet all eligibility criteria, other than TNBC status, may be 
rescreened once.
This study has an adaptive design consisting of two stages. Stage 1 is the 
randomization and treatment of approximately 204 patients.  At the end of Stage 1, an 
interim analysis for efficacy will be done by an iDMC. Then, a recommendation will be 
made to either continue the study unchanged or to expand the patient population 
(Stage 2; approximately 120 additional patients). If the recommendation is to expand 
the patient population into Stage 2, the Sponsor will remain blinded to the results of the 
interim analysis performed at the end of Stage 1.
Patients who have consented and are eligible will be randomized in a 1:1 ratio to receive
either of the following treatment groups:

Arm A: atezolizumab (840 mg) administered via intravenous (IV) infusion Q2W in 
combination with nab-paclitaxel (125 mg/m2) administered via IV infusion QW for 
12 weeks followed by atezolizumab (840 mg) administered Q2W in combination with 
doxorubicin (60 mg/m2)cyclophosphamide (600 mg/m2) administered Q2W via IV 
infusions with filgrastim/pegfilgrastim support for 4 cycles.  Patients randomized to 
the atezolizumab arm will continue to receive unblinded atezolizumab post-surgery 
at a fixed dose of 1200 mg by IV infusion every 3 weeks (Q3W) for 11 cycles, for a 
total of approximately 12 months of atezolizumab therapy.  

Arm B: placebo administered Q2W via IV infusion in combination with 
nab-paclitaxel (125 mg/m2) administered QW via IV infusion for 12 weeks 
followed by placebo administered Q2W in combination with doxorubicin 
(60 mg/m2) cyclophosphamide (600 mg/m2) administered Q2W via IV infusions 
with filgrastim/pegfilgrastim support for 4 cycles.  Patients randomized to the 
placebo arm will be unblinded post-surgery and will continue to be followed.
The study schema is presented in Figure 1. 




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For patients in Stage 1 of the study, randomization will be stratified by the 
following factors:

American Joint Committee on Cancer (AJCC) stage at diagnosis (II vs. III; 
see below for evaluation and classification of lymph nodes)

Tumor PD-L1 status (tumor-infiltrating immune cell [IC] IC0 [<1% PD-L1 expressing 
IC per tumor area] vs. IC1/2/3 [1% PD-L1 expressing IC per tumor area])
Depending on the iDMC recommendation, Stage 2 could follow either an all-comer or 
PD-L1 enrichment design.  If an all-comer design is recommended, the patients enrolled 
in Stage 2 will be stratified the same as patients enrolled in Stage 1.  If an enrichment 
design is recommended, only PD-L1positive patients will be enrolled, and the AJCC 
stage at diagnosis will be used as the sole randomization stratification factor.
Patients who discontinue neoadjuvant therapy early as a result of disease progression 
must be discontinued from all study treatment, will be managed as per local practice,
and will be followed for survival only.  Patients who discontinue prematurely from the 
study will not be replaced.
Any patient who receives non-protocol therapy prior to surgery will be discontinued from 
study treatment and will be managed as per local practice; these patients will remain on 
study for survival follow-up.
The primary efficacy endpoint (pathologic complete response [pCR]; ypT0/is ypN0) will 
be established via local review following completion of neoadjuvant therapy and surgery.  
Pathologists who review study specimens must utilize the evaluations and assessments 
outlined in the Pathology Manual. Investigator/individual patient and Sponsor unblinding 
will occur after pCR assessment as detailed in Section 4.2.  Surgery should be 
performed at least 14 days after the last dose of neoadjuvant therapy but no later than 
6 weeks after the last infusion.  Platelet counts should be checked prior to surgery and 
should be 75,000 cells/L. 
Patients with clinically positive axillary nodes by physical examination or by any 
radiographic imaging at baseline should undergo fine-needle aspiration or core-needle 
biopsy prior to randomization followed by axillary lymph node dissection (ALND) at time 
of definitive surgery. The results of the baseline fine-needle aspiration or core-needle 
biopsy will determine the nodal staging, so that patients with a positive biopsy result 
should be staged as lymph-node-positive (N1-N3c) whereas patients with a negative or 
equivocal biopsy result should be staged as lymph-node-negative (N0) regardless of any 
other clinical measurements (see Appendix 12).
Baseline fine-needle aspiration (FNA) or core-needle biopsy is not mandatory for 
clinically/radiologically enlarged/suspicious internal mammary, subpectoral,
infraclavicular, or supraclavicular lymph nodes.  Investigators are advised to follow local 
practice guidelines regarding assessment of internal mammary, subpectoral, 


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infraclavicular, or supraclavicular lymph nodes. Management of internal mammary,
subpectoral, infraclavicular, or supraclavicular lymph nodes at the time of definitive 
surgery will be based on local practice guidelines. Patients with baseline axillary lymph 
nodes involvement who may also have clinically/radiologically enlarged internal 
mammary, subpectoral, infraclavicular, or supraclavicular lymph nodes must still 
undergo ALND as described earlier and in Appendix 11 and 12.
For patients with baseline clinically/radiologically enlarged/suspicious internal mammary,
subpectoral, infraclavicular, or supraclavicular lymph nodes, pCR may be reported only 
if all the following conditions are met:
1) Presurgical imaging assessment of internal mammary, subpectoral, infraclavicular, or 
supraclavicular lymph nodes does not show any enlarged/suspicious lymph node(s) 
after neoadjuvant study treatment.
AND
2) Pathological evaluation of the breast and all resected lymph node(s) shows no 
residual invasive disease (i.e., pCR; ypT0/is ypN0).
Postoperative radiotherapy may be administered based on local practice guidelines.  
The Medical Monitor is available to advise as needed. 
In patients with clinically or fine-needle biopsy (FNA)/core needle biopsy-proven
negative axillary nodes at baseline, axillary surgical management after completion of 
neoadjuvant therapy should include sentinel lymph node biopsy (SLNB) or ALND.  
If SLNB is conducted, it is strongly recommended that more than one lymph node (two to 
three minimum) be removed and all patients with positive macrometastases in sentinel 
nodes should undergo ALND regardless of the number of positive nodes.  All patients 
with T4 tumors should undergo ALND or current standard of care as described in 
international or national guidelines (see Appendix 11).
Postoperative patient management for those in either treatment arm may include 
radiotherapy as clinically indicated, and management of patients who do not achieve a 
pCR should follow current standard-of-care guidelines. For those randomized to receive 
atezolizumab, patients may receive this therapy simultaneously with atezolizumab.
For those randomized to receive atezolizumab, the first dose of postoperative 
atezolizumab should be administered within 45 days of surgery.
Efficacy, safety, laboratory measurements, patient-reported outcomes (PROs), and 
pharmacokinetics will be assessed throughout the study.  The first 26 patients enrolled 
(approximately 13 patients in the control arm and approximately 13 patients in the 
atezolizumab containing arm) will undergo additional cardiac safety monitoring as part of 
a cardiac safety cohort.  Following completion of study treatment and surgery, all 


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patients will continue to be followed for efficacy, safety, and PRO objectives until the end 
of the study.  No interim efficacy analyses for early stopping are planned.  
Safety assessments will include the occurrence and severity of adverse events and 
laboratory abnormalities graded per National Cancer Institute Common Terminology 
Criteria for Adverse Events (NCI CTCAE) Version 4.0.  Laboratory safety assessments 
will include the regular monitoring of hematology and blood chemistry.  Serum samples 
will be collected to monitor chemotherapy and atezolizumab pharmacokinetics and to 
detect the presence of antibodies to atezolizumab.  Patient samples, including tumor 
tissues, as well as plasma and blood, will be collected for exploratory biomarker 
assessments.  
3.1.2
Independent Data Monitoring Committee
An iDMC will evaluate the primary efficacy endpoint of pCR in the intent-to-treat (ITT) 
population (defined as all randomized patients) and in the PD-L1positive subpopulation 
based on an interim analysis of efficacy data from the Stage 1 patients (approximately 
204 enrolled patients). The iDMC will make a recommendation either to continue the 
study unchanged or to enroll an additional 120 patients (Stage 2).  The decision rules to 
be applied at the interim analysis will be clearly expressed to the iDMC and documented 
in the iDMC charter so that the study can be conducted with the Sponsor remaining 
completely blinded to all results at this stage.
The iDMC will evaluate safety data and study conduct on a regular basis during the 
study until the primary analysis of pCR, which is performed at Stage 1 (approximately 
204 patients) or Stage 2 (approximately 324 patients), if the iDMC recommends 
extending the target population. After which, iDMC review of the study data will be 
discontinued.
Sponsor affiliates will be excluded from iDMC membership.  The iDMC will follow a 
charter that outlines the iDMC roles and responsibilities.
Unblinded safety data will be reviewed on a regular basis by the iDMC.  To assess the 
potential cardiac toxicity of the combination of anthracyclines and atezolizumab, the 
iDMC will review data from a cardiac safety cohort involving additional cardiac 
monitoring in the first 26 patients enrolled (approximately 13 patients in the control arm 
and approximately 13 patients in the atezolizumab containing arm) after all 26 patients
have completed or have discontinued the neoadjuvant portion of the study.  A safety 
data review will also occur when at least 50 patients have received at least 2 cycles 
of atezolizumab/placebo and doxorubicin and cyclophosphamide (approximately 
25 patients in each treatment arm).  Subsequent safety reviews will occur approximately 
once every 6 months during the study until analysis of the primary endpoint.
All summaries and analyses for the iDMC review will be prepared by an independent 
Data Coordinating Center.  


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After reviewing the data, the iDMC will provide a recommendation to the Sponsor as 
described in the iDMC Charter.  Final decisions will rest with the Sponsor.
Any outcomes of these data reviews that affect study conduct will be communicated in a 
timely manner to the investigators for notification of their respective Institutional Review 
Boards/Ethics Committees (IRBs/ECs).
3.2
END OF STUDY AND LENGTH OF STUDY
The end of the study is defined as the date when the last patient, last visit (LPLV) occurs 
for evaluation of secondary endpoints. Thirty-six months after randomization of the last 
patient, all patients will be contacted for final evaluation of the secondary endpoints of 
EFS, DFS, OS, and PROs.  LPLV for Stage 1 is expected to occur approximately 
51 months after the first patient is randomized.  If the study expands to Stage 2, LPLV 
may occur at approximately 74 months after the first patient is randomized.
Recruitment for Stage 1 has stopped and was approximately 15 months. The 
recruitment period may increase to approximately 38 months if the iDMC recommends to 
expand to Stage 2.
The primary efficacy endpoint, pCR, will be analyzed at the interim analysis once 
approximately 204 patients enrolled in Stage 1 have received surgery, approximately 
6 months after the last of these patients has been randomized.  This interim analysis
is expected to take place approximately 21 months after the first patient is randomized.
If the iDMC recommends to expand to Stage 2, a second (final) pCR analysis will be 
performed at approximately 44 months after the first patient has been randomized, 
depending on the selected patient population.
Secondary efficacy endpoints of EFS, DFS, and OS will be analyzed approximately 
36 months after randomization of the last patient.  The total duration of the study for 
Stage 1 is expected to be approximately 51 months.  If the iDMC recommends to 
expand enrollment (Stage 2), the duration of the study may increase to approximately 
74 months.
The Sponsor has the right to terminate this study, including long-term follow-up, at any 
time (e.g., if emerging safety signals indicate a potential health hazard to patients).
3.3
RATIONALE FOR STUDY DESIGN
3.3.1
Rationale for Atezolizumab Dose and Schedule
Atezolizumab will be administered at a fixed dose of 840 mg Q2W by IV infusion in 
combination with nab-pacAC chemotherapy to align with the chemotherapy schedule 
(Weeks 120).  For patients randomized to receive atezolizumab, the atezolizumab 
dosing regimen will be switched to 1200 mg Q3W for 11 doses after the completion of 
chemotherapy and surgery; the total duration of atezolizumab treatment will be 
approximately 12 months.  


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The average atezolizumab exposure following the 840 mg Q2W dosage is expected to 
be similar to that of 1200 mg Q3W, the approved dosage for atezolizumab (Tecentriq™ 
U.S. Package Insert).  Anti-tumor activity has been observed across doses ranging from 
1 mg/kg to 20 mg/kg Q3W.  In Study PCD4989g, the maximum tolerated dose of 
atezolizumab was not reached and no dose-limiting toxicities were observed at any 
dose.  The fixed dose of 1200 mg Q3W (equivalent to an average body weightbased 
dose of 15 mg/kg Q3W) was selected on the basis of both nonclinical studies (Deng et 
al. 2016) and available clinical pharmacokinetic, efficacy, and safety data (refer to the 
Atezolizumab Investigator's Brochure for details).  Based on the understanding of 
population pharmacokinetic variability and atezolizumab concentrationtumor dynamic 
relationship, 840 mg Q2W and 1200 mg Q3W are expected to have comparable efficacy 
and safety profiles.  
3.3.2
Rationale for Patient Population and Analysis Groups
Stage 1 of this study will enroll patients with cT2cT4d operable TNBC, regardless of 
PD-L1 expression (Sections 4.1.1 and 4.1.2).
TNBC will be defined by prospective central laboratory assessment using ISH or IHC 
assays for HER2 assessment and IHC assays for ER/PgR assessment per ASCO-CAP 
guidelines (Hammond et al. 2010; Wolff et al. 2013).
Patients with cT2cT4d TNBC were selected for this study because increased primary 
tumor size has been identified as poor prognostic variables and has been associated 
with decreased disease-free survival (DFS) and increased likelihood of early 
metastatic disease in patients with TNBC (Pistelli et al. 2013; Rosa Mendoza et al. 
2013).  Not-yet-published internal analyses from the California Cancer Registry found 
survival rates in patients with Stage II or III disease to be significantly lower than those of 
patients diagnosed with Stage I disease (3-year OS rate of 94.2% [95% CI: 93.3, 95.0]
for Stage I; 86.2% [95%CI: 85.1, 87.2] for Stage II; and 58.8% [95%CI: 56.3, 61.2] for 
Stage III; data on file).  By selecting a patient population that has an increased rate of 
disease recurrence (larger tumor size) and poorer clinical outcomes and by further 
enriching this with patients with node-positive disease, the study will enroll patients with 
TNBC who have the highest unmet medical need. 
3.3.3
Rationale for Comparator of Nab-Paclitaxel followed by 
Doxorubicin and Cyclophosphamide
Multi-agent chemotherapy regimens have proven beneficial as neoadjuvant/adjuvant 
therapy for early stage breast cancer, improving both disease-specific and OS outcomes 
(Berry et al. 2006; NCCN 2016).  The most effective combination regimens include 
anthracyclines, topoisomerase II inhibitors, cyclophosphamide, and taxanes (Peto et al. 
2012; Early Breast Cancer Trialists’ Collaborative Group 2005). Studies looking at 
optimizing the dose and schedule of early breast cancer chemotherapy regimens 
(Citron et al. 2003; Sparano et al. 2008) have established one of the optimal adjuvant 
regimens as doxorubicin 60 mg/m2 and cyclophosphamide 600 mg/m2 administered 


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Q2W for 4 cycles, followed by QW paclitaxel 80 mg/m2 for 12 weeks with respect to 
maximizing efficacy and is included as a preferred option in international guidelines 
(Senkus et al. 2015; NCCN 2016).
Specifically, in the neoadjuvant setting, anthracycline/taxane chemotherapy-based 
regimens have routinely been used in TNBC, resulting in reported pCR rates of 
41%48% (Sparano et al. 2008; Sikov et al. 2015; Untch et al. 2016).  Three-year EFS 
rates of 74%76% have been reported for patients with TNBC who have received 
neoadjuvant anthracycline/taxane therapy (von Minckwitz et al. 2014; Sikov et al. 2015),
leaving room for improvement in outcomes. 
The safety of atezolizumab in combination with anthracyclines, cyclophosphamide, and 
other chemotherapeutic agents is being explored in Study BO29563, a Phase Ib/II study 
evaluating atezolizumab in combination with either obinutuzumab (G) + bendamustine or 
obinutuzumab (G) + cyclophosphamide, doxorubicin, vincristine, and prednisone 
(CHOP) in patients with follicular lymphoma or rituximab + CHOP in patients with diffuse 
large B-cell lymphoma. The CHOP regimen consists of cyclophosphamide 750 mg/m2
on Day 1, doxorubicin 50 mg/m2 on Day 1, vincristine 1.4 mg/m2 (max. 2 mg) on Day 1, 
and prednisone 40 mg/m2 on Days 15. During the safety run-in phase, patients 
received 6 cycles of induction treatment with either Atezo-G-benda or Atezo-G-CHOP. 
As of 19 July 2016, preliminary data from 7 patients who completed at least 3 cycles of 
induction treatment indicated that the combination of atezolizumab with G-CHOP was 
well tolerated. None of the stopping criteria defined for the safety run-in phase of the 
study were met. Two events of Grade 1 palpitation (1 related, 1 unrelated) were 
reported; no other cardiac events were reported. There were no treatment-related 
Grade 3 and Grade 4 adverse events during Cycles 2 and 3 (i.e., the safety observation 
window). No treatment delays or treatment discontinuations due to adverse events 
were observed.
For additional information on the safety of atezolizumab in combination with other 
agents, please refer to the Atezolizumab Investigator’s Brochure.
Nab-Paclitaxel as Neoadjuvant Treatment of Early TNBC
Nab-paclitaxel represents the preferred chemotherapy for combination with 
immunomodulatory drugs such as atezolizumab because of both 1) the opportunity to 
avoid immunosuppressive effects from the concurrent steroid use required with other 
taxanes (Gradishar et al. 2005) and 2) the high rate of tumor cell death achieved by 
nab-paclitaxel, which can be expected to expose the immune system to high levels of 
tumor antigens, thereby enhancing the degree and duration of cancer-specific T-cell 
immunity by inhibition of PD-L1mediated immune suppression by atezolizumab.  
Nab-paclitaxel appears to be at least as active as the commonly used paclitaxel in early 
breast cancer (Untch et al. 2016; Gianni et al. 2016), and data from Study GP28328 
suggests that the combination of nab-paclitaxel and atezolizumab is safe and efficacious 
(Section 1.3 and Adams et al. 2016). Identical chemotherapy backbone treatments were 


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selected for both the investigational and control arms of the study in order to isolate the 
effect of atezolizumab upon study endpoints.
The use of nab-paclitaxel in the neoadjuvant setting is supported by two randomized 
Phase III trials.
The Phase III GeparSepto study (n1206) compared the efficacy of a regimen of weekly 
nab-paclitaxel versus paclitaxel followed by epirubicin and cyclophosphamide as 
neoadjuvant therapy for EBC (Untch et al. 2016). The pCR rate among the cohort of 
patients with TNBC (n276) who received nab-paclitaxel was twice that of the women 
who received paclitaxel (48% vs. 26%; p0.00027). In the overall patient population, 
the incidence of Grade 3 or 4 anemia (2% nab-paclitaxel vs. 1% paclitaxel; p0.048) 
and peripheral sensory neuropathy Grade 3 or 4 (10% nab-paclitaxel [8% in those 
receiving 125 mg/m2 dose] vs. 3% paclitaxel, p0.001) was significantly higher for 
nab-paclitaxel.  Overall, 26% of patients had 1 or more serious adverse events in the 
nab-paclitaxel group compared with 21% of patients in the paclitaxel group (p0.057).  
The taxane dose was reduced in 30% of patients in the nab-paclitaxel group versus 
12% in the paclitaxel group (p0.0001).
Results were also reported from a separate Phase III study comparing the efficacy of 
neoadjuvant nab-paclitaxel versus paclitaxel, both followed by anthracycline regimens
in 695 women with HER2-negative high-risk breast cancer (Gianni et al. 2016).  
In the TNBC cohort (n219), 41.3% (95% CI: 31.9, 51.1) of patients who received 
the nab-paclitaxelcontaining regimen achieved a pCR compared with 35% 
(95% CI: 26.6, 45.1) of patients who received the paclitaxel-containing regimen 
(p0.376; Gianni et al. 2016). The incidence of peripheral neuropathy was 62.6% in the 
nab-paclitaxel arm versus 53.7% in the paclitaxel arm. Neutrophil count decrease was 
41.8% in the nab-paclitaxel arm versus 36.4% in the paclitaxel arm.
When combined, these studies suggest that nab-paclitaxel is at least as effective as 
paclitaxel; however, long term outcomes from these studies have not yet been reported.
Sequence of Neoadjuvant Chemotherapy
In Study WO39392, neoadjuvant nab-paclitaxel will be administered prior to 
doxorubicincyclophosphamide (AC) chemotherapy.  This sequence of chemotherapy 
agents was selected in order to maximize the potential for a robust, initial 
immune-response as there are less reports of neutropenia and lower usage of steroids 
with a nab-paclitaxel compared to AC.  In addition, biomarker analyses from Phase I 
atezolizumab studies have demonstrated activated CD8+ T cell proliferation and 
the presence of IL-18 peaks three weeks after the first-dose of atezolizumab 
(Herbst et al. 2014).  The combination with nab-paclitaxel, as assessed in 
Study GP28328 (Adams et al. 2016) has a similar effect, suggesting nab-paclitaxel does 
not hamper atezolizumab activity and, therefore, may not negatively impact efficacy.  
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yet been investigated and the net impact on immune-response is unknown.  
Data supporting the chemotherapy sequence come from several small prospective and 
retrospective studies that have evaluated the impact of changing the sequence of 
administration for anthracyclines and taxanes in the neoadjuvant setting for TNBC.  
While the endpoints measured have varied, these studies demonstrated that reversing 
the sequence of neoadjuvant breast cancer chemotherapy by starting with the taxane,
followed by an anthracycline-containing regimen, is at least as effective as the 
conventional sequence, with the majority of studies demonstrating no statistically 
significant differences in clinical outcomes between the two sequences 
(Sledge et al. 2003; Bines et al. 2014; Earl et al. 2014).
Dose and Schedule of Nab-Paclitaxel
The dose and schedule of nab-paclitaxel (125mg/m2 QW 12 cycles) was selected 
based upon the dosing regimen used in the Phase III GeparSepto study where weekly 
nab-paclitaxel was found to be superior to weekly paclitaxel in the neoadjuvant setting 
(described above; Untch et al. 2016)
3.3.4
Rationale for Pathologic Complete Response as Primary 
Endpoint
The primary objective of Study WO39392 is to evaluate the efficacy of neoadjuvant 
treatment with atezolizumabnab-pacAC compared with placebonab-pacAC in 
patients with newly diagnosed TNBC as measured by pCR.
pCR was selected as the primary efficacy endpoint; it is a validated, meaningful measure 
of response to therapy, and on the basis of data from several analyses and clinical trials 
and meta-analyses, there is an association between the pCR status of a patient and 
long-term outcomes (Cortazar et al. 2014; Liedtke et al. 2008; von Minckwitz et al. 
2012).  This association was especially strong in patients with TNBC (EFS hazard ratio 
[HR] 0.24 [95% CI: 0.18, 0.33]; OS HR 0.16 [95% CI: 0.11, 0.25]) (Cortazar et al. 2014). 
pCR will be defined as the absence of residual invasive cancer on hematoxylin and 
eosin evaluation of the complete resected breast specimen and all sampled regional 
lymph nodes following completion of neoadjuvant systemic therapy (NAST), in line with 
the U.S. Food and Drug Administration (FDA) and European Medicines Agency 
guidance for industry on pCR endpoints (i.e., ypT0/Tis ypN0 in the current AJCC 
staging system). 
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, baseline tumor specimens will be collected from patients 
and tested for PD-L1 expression by a central laboratory during the screening period.  
Randomization for patients enrolled in Stage 1, (as well as Stage 2 only if all-comer 


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patients are enrolled), will be stratified by PD-L1 expression as assessed by IHC.  
In addition to the assessment of PD-L1 status, other exploratory biomarkers potentially 
related to clinical benefit of atezolizumab, tumor immunobiology, mechanisms of 
resistance, or tumor type, may be analyzed.
Certain chemotherapies have been shown to be immunomodulatory (Pfirschke et al. 
2016). To evaluate the impact of nab-paclitaxel and atezolizumab in the tumor immune 
microenvironment, optional on-treatment biopsies will be collected 2 weeks after 
treatment initiation (Day 15). The pharmacodynamic changes in the tumor 
microenvironment will be evaluated by immunostaining, hematoxylin and eosin
evaluation (tumor-infiltrating lymphocytes), and gene expression. 
To evaluate mechanisms of resistance to the combination, the residual tumor tissue 
post-surgery will be evaluated for biomarkers related to tumor and immune biology by 
gene expression as well as by immunostaining methodologies.  
Patients will undergo mandatory tumor biopsy sample collection, if deemed clinically 
feasible by the investigator, at the time of first evidence of radiographic disease 
recurrence to evaluate tumor tissue biomarkers related to resistance, disease 
recurrence, and clinical benefit of atezolizumab.
Blood samples will be collected at baseline and during the study to evaluate changes in 
biomarkers.  Changes in biomarkers such as cytokines associated with T-cell activation, 
circulating tumor DNA concentration, and T-cell subpopulations may provide evidence of 
biologic activity of atezolizumab in humans.  Correlations between these biomarkers and 
safety and efficacy endpoints may be explored to identify blood-based biomarkers that 
might predict which patients are more likely to benefit from atezolizumab. 
Tumor and blood samples collected at baseline and, if deemed clinically feasible by the 
investigator, tumor tissue collected at the time of disease recurrence will be analyzed 
through use of whole genome sequencing (WGS) and/or next-generation sequencing
(NGS) to identify somatic mutations that are predictive of response to study treatment, 
are associated with recurrence to a more severe disease state, are associated with 
acquired resistance to study treatment, or can increase the knowledge and 
understanding of disease biology.
Genomics is increasingly informing 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 for developing new therapeutic 
approaches.  Data will be analyzed in the context of this study but will also be explored 
in aggregate with data from other studies.  The availability of a larger dataset will assist 
in identification of important pathways, guiding the development of new targeted agents.


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3.3.6
Rationale for Patient-Reported Outcome Assessments
EBC is largely asymptomatic, with the majority of newly diagnosed patients exhibiting no 
disease-specific, discernable symptoms (Barrett et al. 2009; Ryerson et al. 2015). 
Therefore, toxicities, the corresponding treatment-related symptoms, and their impact 
define the patient experience (i.e., how patients feel and function). These are important 
aspects to consider to help inform on the overall clinical benefit of a novel drug for this 
potentially curable indication. Treatment-related symptoms associated with EBC 
regimens can have significant impact on patient’s lives, including their ability to conduct 
activities of daily living; on physical functioning, and on emotional and social aspects 
(Petersen et al. 2015).  It is therefore critical to document the burden associated with 
EBC treatment and understand the experience of treatment-related symptoms and their 
impact directly from patients to further inform the benefit-risk assessment and treatment 
decision-making (Montazeri 2008; Au et al. 2010; FDA 2013; 
PDUFA Breast Cancer Workshop 2015; EMA 2016). 
A comprehensive assessment of treatment burden from the patient’s perspective in this 
study will be conducted and will include a global assessment of the impact of treatment 
on patients’ functioning (role, physical) and health-related quality of life (HRQoL) as 
secondary endpoints, as well as the experience of treatment-related symptoms and their 
associated level of bother and the impact on emotional and social functioning as 
exploratory endpoints. The GHS/HRQoL, functional, and disease/treatment-related 
symptom items and scales of the European Organisation for the Research and 
Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30; 
see Appendix 5), and the treatment bother item GP5 from the Functional Assessment of 
Cancer Therapy-General (FACT-G; see Appendix 6) Quality of Life Instrument will all be 
used to assess patients’ treatment burden (see Figure 2).




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
Histologically documented TNBC (negative HER2, ER, and PgR status); HER2 
negativity will be defined by central laboratory assessment using ISH or IHC assays 
per ASCO/CAP criteria (Wolff et al. 2013) and ER/PgR negativity will be defined by 
central laboratory assessment using IHC per ASCO/CAP criteria (Hammond et al.
2010).  Central laboratory assessment will occur prior to randomization.
Patients with multifocal tumors (more than one tumor confined to the same 
quadrant as the primary tumor) are eligible provided all discrete lesions are 
sampled and centrally confirmed as TNBC.

Confirmed tumor PD-L1 evaluation as documented through central testing of a 
representative tumor tissue specimen.
In Stage 2, if the iDMC recommendation is to expand to a PD-L1positive 
population, only patients with confirmed tumor PD-L1 positive (IC1/2/3) will be 
considered eligible.

Primary breast tumor size of 2 cm by at least one radiographic or clinical 
measurement

Stage at presentation:  cT2cT4, cN0cN3, cM0

Patient agreement to undergo appropriate surgical management including axillary 
lymph node surgery and partial or total mastectomy after completion of neoadjuvant 
treatment

Baseline LVEF 53% measured by echocardiogram (ECHO) or multiple-gated 
acquisition (MUGA) scans

Adequate hematologic and end-organ function, as defined by the following 
laboratory results obtained within 14 days prior to the first study treatment:
–
ANC 1500 cells/L (without granulocyte colonystimulating factor [G-CSF]
support within 2 weeks prior to Cycle 1, Day 1)
–
Lymphocyte count 500 cells/L
–
Platelet count 100,000 cells/L (without transfusion within 2 weeks prior to 
Cycle 1, Day 1)
–
Hemoglobin 9.0 g/dL
–
AST, ALT, and alkaline phosphatase 2.5the upper limit of normal (ULN)
–
Serum bilirubin 1.0ULN
Patients with known Gilbert syndrome who have serum bilirubin level
3ULN may be enrolled.
–
For patients not receiving therapeutic anticoagulation: INR or aPTT 1.5ULN 
within 14 days prior to initiation of study treatment
–
For patients receiving therapeutic anticoagulation: stable anticoagulant 
regimen and stable INR during the 14 days immediately preceding initiation of 
study treatment
–
Creatinine clearance 30 mL/min (calculated using the Cockcroft-Gault 
formula)


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–
Serum albumin 25 g/L (2.5 g/dL)

Representative formalin-fixed, paraffin-embedded (FFPE) tumor specimen in 
paraffin blocks (preferred) or at least 20 unstained slides, with an associated 
pathology report documenting ER, PgR, and HER2 negativity 
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.
If multiple 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.
In Stage 2, if the recommendation from the iDMC is to expand to a 
PD-L1positive population, no further stratification based on PD-L1 status 
will be conducted.
Acceptable samples include core-needle biopsies for deep tumor tissue 
(minimum three cores) or excisional, incisional, punch, or forceps biopsies 
for cutaneous, subcutaneous, or mucosal lesions.
Fine-needle aspiration, brushing, and cell pellet from cytology specimens 
are not acceptable.

For women of childbearing potential:  agreement to remain abstinent (refrain from 
heterosexual intercourse) or use contraceptive methods, and agreement to refrain 
from donating eggs, as defined below:
Women must remain abstinent or use contraceptive methods that result in a 
failure rate of 1% per year during the treatment period and for at 
least 5 months after the last dose of atezolizumab, or 1 month after the last 
dose of nab-paclitaxel, or 6 months after the last dose of doxorubicin, or 
12 months after the last dose of cyclophosphamide, whichever is later. Women 
must refrain from donating eggs during this same period.
A woman is considered to be of childbearing potential if she is postmenarcheal, 
has not reached a postmenopausal state (12 continuous months of 
amenorrhea with no identified cause other than menopause), and has not 
undergone surgical sterilization (removal of ovaries and/or uterus).
Examples of contraceptive methods with a failure rate of 1% per year, when 
used consistently and correctly, include combined (estrogen and progestogen 
containing) hormonal contraception associated with inhibition of ovulation, 
progestogen-only hormonal contraception associated with inhibition of 
ovulation, bilateral tubal occlusion; male sterilization; intrauterine devices; 
intrauterine hormone-releasing system; and sexual abstinence.


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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. 

For men:  agreement to remain abstinent (refrain from heterosexual intercourse) or 
use contraceptive measures and agreement to refrain from donating sperm, as 
defined below:
With female partners of childbearing potential, men must remain abstinent or 
use a condom plus an additional contraceptive method that together result in a 
failure rate of 1% per year during the treatment period and for 6 months after 
the last dose of nab-paclitaxel, cyclophosphamide, or doxorubicin. Men must 
refrain from donating sperm during this same period.
With pregnant female partners, men must remain abstinent or use a condom 
during the treatment period and for 6 months after the last dose of 
nab-paclitaxel, cyclophosphamide, or doxorubicin to avoid exposing the 
embryo.
The reliability of sexual abstinence should be evaluated in relation to the 
duration of the clinical trial and the preferred and usual lifestyle of the patient.  
Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation 
methods) and withdrawal are not acceptable methods of contraception.

Women who are not postmenopausal (12 months of nontherapy-induced 
amenorrhea) or have undergone a sterilization procedure must have a negative 
serum pregnancy test result within 14 days prior to initiation of study drug

Willingness and ability to comply with scheduled visits, treatment plans, laboratory 
tests, and other study procedures, including the completion of PRO questionnaires
4.1.2
Exclusion Criteria
Patients who meet any of the following criteria will be excluded from study entry:

Prior history of invasive breast cancer

Stage IV (metastatic) breast cancer

Prior systemic therapy for treatment and prevention of breast cancer 

Previous therapy with anthracyclines or taxanes for any malignancy

History of ductal carcinoma in situ (DCIS), except for patients treated exclusively 
with mastectomy 5 years prior to diagnosis of current breast cancer 

History of pleomorphic lobular carcinoma in situ (LCIS), except for patients 
surgically managed 5 years prior to diagnosis of current breast cancer (note that 
patients with non-pleomorphic LCIS [either untreated or treated with surgery] are 
allowed)

Bilateral breast cancer 


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
Undergone incisional and/or excisional biopsy of primary tumor and/or axillary lymph 
nodes. Patients who have undergone SLNB at the baseline may be eligible only if 
the SLNB was free of invasive carcinoma. Any patient with a positive SLN (involved 
with invasive carcinoma) is ineligible to participate in this study.

Axillary lymph node dissection prior to initiation of neoadjuvant therapy 

History of other malignancy within 5 years prior to screening, with the exception of 
those with a negligible risk of metastasis or death (e.g., 5-year OS of 90%), such 
as adequately treated carcinoma in situ of the cervix, non-melanoma skin 
carcinoma, localized prostate cancer, or Stage I uterine cancer

History of cerebrovascular accident within 12 months prior to randomization

Cardiopulmonary dysfunction as defined by any of the following prior to 
randomization:
–
History of NCI CTCAE v4.0 Grade 3 symptomatic congestive heart failure or New 
York Heart Association (NYHA) criteria Class II
–
Angina pectoris requiring anti-anginal medication, serious cardiac arrhythmia not 
controlled by adequate medication, severe conduction abnormality, or clinically 
significant valvular disease
–
High-risk uncontrolled arrhythmias (i.e., atrial tachycardia with a heart rate 100/min 
at rest, significant ventricular arrhythmia [ventricular tachycardia], or higher-grade 
atrioventricular [AV]-block [second-degree AV-block Type 2 [Mobitz 2] or third 
degree AV-block])
–
Significant symptoms (Grade 2) relating to left ventricular dysfunction, cardiac 
arrhythmia, or cardiac ischemia
–
Myocardial infarction within 12 months prior to randomization
–
Uncontrolled hypertension (systolic blood pressure 180 mmHg and/or diastolic 
blood pressure 100 mmHg)
–
Evidence of transmural infarction on ECG
–
Requirement for oxygen therapy

History of severe allergic, anaphylactic, or other hypersensitivity reactions to 
chimeric or humanized antibodies or fusion proteins

Known hypersensitivity to biopharmaceuticals produced in Chinese hamster 
ovary cells

Known allergy or hypersensitivity to the components of the atezolizumab formulation

Known allergy or hypersensitivity to the components of the nab-paclitaxel, 
cyclophosphamide, or doxorubicin formulations

Known allergy or hypersensitivity to filgrastim or pegfilgrastim formulations


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
Active or history of autoimmune disease or immune deficiency, including but not 
limited to myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus 
erythematosus, rheumatoid arthritis, inflammatory bowel disease, antiphospholipid 
syndrome, Wegener granulomatosis, Sjögren syndrome, Guillain-Barré syndrome, 
or multiple sclerosis (see Appendix 8 for a more comprehensive list of autoimmune 
diseases and immune deficiencies) with the following exceptions:
Patients with a history of autoimmune-related hypothyroidism on a stable dose 
of thyroid replacement hormone may be eligible for this study.
Patients with controlled Type I diabetes mellitus on a stable dose of insulin 
regimen may be eligible for this study.
Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with 
dermatologic manifestations only (e.g., patients with psoriatic arthritis are 
excluded) are permitted provided all of following conditions are met:
–
Rash must cover 10% of body surface area
–
Disease is well controlled at baseline and requires only low-potency topical 
corticosteroids
–
No occurrence of acute exacerbations of the underlying condition requiring 
psoralen plus ultraviolet A radiation, methotrexate, retinoids, biologic 
agents, oral calcineurin inhibitors, or high-potency or oral corticosteroids 
within the previous 12 months

History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis 
obliterans), drug-induced pneumonitis, idiopathic pneumonitis, or evidence of active 
pneumonitis on screening chest computed tomography (CT) scan
History of radiation pneumonitis in the radiation field (fibrosis) is permitted.

Positive HIV test at screening

Active hepatitis B virus (HBV) infection, defined as having a positive hepatitis B 
surface antigen (HBsAg) test at screening
Patients with a past or resolved HBV infection, defined as having a negative 
HBsAg test and a positive total hepatitis B core antibody (HBcAb) test at 
screening, are eligible for the study if active HBV infection is ruled out on the 
basis of HBV DNA viral load per local guidelines.

Active hepatitis C virus (HCV) infection, defined as having a positive HCV antibody 
test at screening
Patients who have a positive HCV antibody test are eligible for the study if a 
polymerase chain reaction (PCR) assay is negative for HCV RNA.

Active tuberculosis

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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
Treatment with therapeutic oral or IV antibiotics within 2 weeks prior to initiation of 
study treatment
Patients receiving prophylactic antibiotics (e.g., for prevention of a urinary tract 
infection or to prevent chronic obstructive pulmonary disease exacerbation) are 
eligible for the study.

Major surgical procedure within 4 weeks prior to initiation of study treatment or 
anticipation of need for a major surgical procedure (other than anticipated breast 
surgery) during the course of the study

Prior allogeneic stem cell or solid organ transplantation

Administration of a live attenuated vaccine within 4 weeks prior to initiation of study 
treatment or anticipation of need for such a vaccine during the 
atezolizumab/placebo treatment or within 5 months after the last dose of 
atezolizumab/placebo
Patients must agree not to receive live, attenuated influenza vaccine 
(e.g., FluMist®) within 4 weeks prior to randomization, during treatment or within 
5 months following the last dose of atezolizumab (for patients randomized to 
atezolizumab).

Any other disease, metabolic dysfunction, physical examination finding, or clinical 
laboratory finding giving reasonable suspicion of a disease or condition that 
contraindicates the use of an investigational drug or that may affect the 
interpretation of the results or render the patient at high risk from treatment 
complications

Prior treatment with CD137 agonists or immune checkpointblockade therapies, 
including anti-CD40, antiCTLA-4, antiPD-1, and antiPD-L1 therapeutic 
antibodies

Treatment with systemic immunostimulatory agents (including but not limited to 
interferons, IL-2) within 4 weeks or 5 half-lives of the drug, whichever is longer, prior 
to initiation of study treatment

Treatment with systemic immunosuppressive medications (including but not limited 
to prednisone, cyclophosphamide, azathioprine, methotrexate, thalidomide, and 
antitumor necrosis [anti-TNF] factor agents) within 2 weeks prior to initiation of 
study treatment or anticipation of need for systemic immunosuppressive 
medications during the study
Patients who have received acute, low-dose, systemic immunosuppressant 
medications (e.g., a one-time dose of dexamethasone for nausea) are eligible 
for the study.
The use of inhaled corticosteroids and mineralocorticoids (e.g., fludrocortisone 
for adrenal insufficiency) is allowed.

Pregnant or lactating, or intending to become pregnant during the study
Women of childbearing potential must have a negative serum pregnancy test 
result within 14 days prior to initiation of study treatment.


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4.2
METHOD OF TREATMENT ASSIGNMENT AND BLINDING
This is a double-blind, randomized, placebo-controlled study. 
After written informed consent has been obtained, all screening procedures and 
assessments have been completed, and eligibility has been established, the study
site will enter demographic and baseline characteristics in the interactive voice or 
web-based response system (IxRS). For those patients who are eligible for enrollment, 
the study site will obtain the patient’s identification number and treatment assignment 
from the IxRS.
Randomization will occur in a 1:1 ratio using a permuted-block randomization method. 
Patients will be randomized to one of two treatment arms: atezolizumabnab-pacAC or 
placebonab-pacAC.  The randomization scheme is designed to ensure that an
approximately equal number of patients will be enrolled in each treatment arm within the
categories defined for the following stratification factors at baseline:

AJCC stage at diagnosis (II vs. III) 

Tumor PD-L1 status (IC0 vs. IC1/2/3) for patients enrolled in Stage 1 and Stage 2
(only if the study continues to enroll all-comer patients)
Patients should receive their first dose of study treatment on the day of randomization if 
possible. If treatment is not possible, the first dose should occur no later than 14 days 
after randomization.
The Sponsor and its agents (with the exception of the IxRS service provider [the external 
independent statistical coordinating center responsible for verifying patient 
randomization and study treatment kit assignments], pharmacokinetic/pharmacodynamic 
[PK/PD] laboratory personnel, and the iDMC members); the study site personnel, 
including the investigator; and the patient will be blinded to treatment assignment prior to 
unblinding of treatment assignment as detailed below.
The Sponsor and its agents (with the exception of the PD-L1 assay provider and the
iDMC members); the study site personnel, including the investigators; and the patients
will be blinded to PD-L1 status until all data have been cleaned and verified, and the 
database has been locked for the primary analysis for pCR or the interim analysis for 
pCR at the end of Stage 1. 
If the iDMC recommends to progress to Stage 2 in all-comer population, the Sponsor 
and its agents, the study site personnel, including the investigators, and the patients will 
remain blinded to PD-L1 status until all data have been cleaned and verified, and the 
database has been locked for the primary analysis of pCR at the end of Stage 2.


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If the iDMC recommends to progress to Stage 2 in PD-L1positive population, the 
Sponsor and its agents, the study site personnel, including the investigators, and the 
patients will be aware of the PD-L1 status of patients in screening for Stage 2, so that a 
patient's eligibility for enrollment can be assessed.
If the iDMC recommends to progress to Stage 2 in PD-L1positive population, the 
Sponsor and its agents, the study site personnel, including the investigators, and the 
patients enrolled in Stage 1 may be informed about their PD-L1 status upon request by 
the investigator. 
While PK samples must be collected from patients assigned to the control arm to 
maintain the blinding of treatment assignment, PK assay results for these patients are 
generally not needed for the safe conduct or proper interpretation of this study.
Personnel who are responsible for performing PK assays and sample data reconciliation 
will be unblinded to patients’ treatment assignments to identify appropriate PK samples 
to be analyzed and cleaned. Samples from patients assigned to the control arm will not 
be analyzed except by request (i.e., to evaluate a possible error in dosing). 
Unblinding of Treatment Assignment
A patient's treatment assignment will be unblinded to the site personnel (including the 
investigator) after assessment of the patient's pCR status, in order to inform further 
treatment.
Otherwise, unblinding should occur only in exceptional circumstances when knowledge 
of the actual treatment is absolutely essential for further management of clinically 
significant adverse events experienced by the patient (i.e., emergency unblinding for 
safety reasons).
Per health authority reporting requirements, treatment assignment will be unblinded for 
serious, unexpected study drug-related toxicity (as part of the Investigational New Drug 
[IND] safety reporting process). In these instances, investigators will not be notified of 
individual patient’s treatment assignment as a matter of course. Emergency unblinding 
by the investigator should be a last resort performed only in cases when knowledge of 
treatment assignment will affect the management of a patient who experiences a
treatment-emergent adverse event. Investigators are encouraged to consult with the
Medical Monitor prior to performing emergency unblinding. If unblinding is necessary for 
patient safety management, the investigator is credentialed to break the treatment code 
within the IxRS autonomously by means of a pin code, which is issued to them at the 
start of the study. All such occurrences should be documented in the study file.
Unblinding should not result in the withdrawal of a patient from the study. Every effort 
should be made to retain unblinded patients and continue data collection per protocol.


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4.3
STUDY TREATMENT 
The investigational medicinal products (IMPs) for this study are atezolizumab/placebo 
and nab-paclitaxel.  Additionally, doxorubicin, cyclophosphamide, and 
filgrastim/pegfilgrastim will be administered as background treatment after
nab-paclitaxel.
4.3.1
Formulation, Packaging, and Handling
4.3.1.1
Atezolizumab and Placebo
Atezolizumab will be supplied by the Sponsor as sterile liquid in 20-mL glass vials. 
The vial is designed to deliver 20 mL (1200 mg) of atezolizumab solution but may 
contain more than the stated volume to enable delivery of the entire 20-mL volume.  
Extraction of 14 mL of atezolizumab solution from a 1200-mg vial contains an 
840-mg dose.  For information on the formulation and handling of atezolizumab, refer 
to the pharmacy manual and the Atezolizumab Investigator's Brochure.
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
Background Treatment
For information on the formulation, packaging, and handling of nab-paclitaxel, 
doxorubicin, cyclophosphamide, and filgrastim/pegfilgrastim, see the local prescribing 
information for the respective treatments as available.
Nab-paclitaxel will be supplied by the Sponsor.
4.3.2
Dosage, Administration, and Compliance
4.3.2.1
Atezolizumab or Placebo
Patients will receive atezolizumab 840 mg or placebo administered by IV infusion Q2W
(14 [3] days) for 20 weeks (i.e., 10 doses) in combination with nab-paclitaxel, 
doxorubicin, and cyclophosphamide chemotherapy.  Atezolizumab or placebo should be 
infused over 60 minutes.  If the first infusion is tolerated, subsequent infusions can be 
administered over 30 minutes. Postoperatively (i.e., following unblinding to treatment 
assignment as specified in Section 4.2), those randomized to the atezolizumab arm will 
continue to receive maintenance atezolizumab but at a different dose of 1200 mg 
administered by IV infusion Q3W for 11 doses, for a total of approximately 12 months of 
atezolizumab treatment; those randomized to the placebo arm will stop receiving 
placebo.
For more detailed information on drug preparation, storage, and administration, refer to 
the Atezolizumab Investigator’s Brochure and pharmacy manual. 


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Administration of atezolizumab or placebo will be performed in a setting with emergency
medical facilities and staff who are trained to monitor for and respond to medical 
emergencies.  For anaphylaxis precautions, see Appendix 9.
No premedication will be allowed for the first dose of atezolizumab or placebo.  Patients 
who experience an infusion-related reaction (IRR) with the first infusion may receive 
premedication with antihistamines or antipyretics or analgesics (e.g., acetaminophen) for 
subsequent infusions.
The initial dose of atezolizumab or placebo will be delivered over 60 (15) minutes.  
Subsequent infusions will be delivered over 30 (10) minutes if the previous infusion 
was tolerated without infusion-associated adverse events, or 60 (15) minutes if the 
patient experienced an infusion-associated adverse event with the previous infusion.  
Vital signs are to be measured before, as well as during, and after infusions, if clinically 
indicated, as outlined in Section 4.5.4.
Guidelines for medical management of IRRs are provided in Appendix 13.
No dose modification for atezolizumab is allowed.  Guidelines for treatment interruption 
or discontinuation due to the development of an adverse event are provided in 
Appendix 13.
In case of unacceptable toxicity attributed to chemotherapy, atezolizumab/placebo 
should be held and restarted together with chemotherapy if there is no contraindication.
During the neoadjuvant period, if nab-paclitaxel chemotherapy is discontinued due to 
any reason (e.g., toxicity), patients can proceed to AC chemotherapy plus 
atezolizumab/placebo at the discretion of the investigator.  If AC chemotherapy has to be 
discontinued for any reason (e.g., toxicity), the date of surgery can be brought forward 
and patients can proceed to surgery at the discretion of the investigator.  In any of these 
scenarios all patients who discontinue planned study treatment and proceed to surgery 
will remain on study for pCR assessment and for follow-up of secondary and exploratory 
endpoints unless consent from study participation is withdrawn.
In case of toxicities attributed to atezolizumab/placebo that require a dose delay, 
chemotherapy should be continued independently of atezolizumab/placebo if there is no 
contraindication.  Atezolizumab/placebo may be restarted when the conditions for 
retreatment have been met.  When atezolizumab/placebo is restarted, the infusions 
should remain synchronized and aligned with the chemotherapy schedule.
Study treatment (including atezolizumab or placebo and chemotherapy, if applicable) will 
be discontinued in the event of disease progression or disease recurrence while patient 
is receiving therapy.


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Any dose modification should be noted on the Study Drug Administration electronic 
Case Report Form (eCRF).  Cases of accidental dose or medication error, along with 
any associated adverse events, should be reported as described in Section 5.4.3.4.
4.3.2.2
Background Treatment
Patients will receive nab-paclitaxel (125 mg/m2) administered via IV infusion weekly for 
12 weeks followed by doxorubicin (60 mg/m2)cyclophosphamide (600 mg/m2) 
administered via IV infusion Q2W with filgrastim/pegfilgrastim support for 4 cycles
(i.e., a total of 4 doses of doxorubicin and cyclophosphamide; see Figure 1).  The dose 
of cyclophosphamide should be capped at 1200 mg.
Dose delays and dose reductions for toxicity are permitted.  Guidelines for dosage 
modification and treatment interruption or discontinuation due to the development of an 
adverse event are provided in Section 5.1.5.
During the neoadjuvant period, if nab-paclitaxel chemotherapy is discontinued 
due to any reason (e.g., toxicity), patients can proceed to AC chemotherapy plus 
atezolizumab/placebo at the discretion of the investigator.  If AC chemotherapy has to be 
discontinued for any reason (e.g., toxicity), the date of surgery can be brought forward 
and patients can proceed to surgery at the discretion of the investigator.  In any of these 
scenarios, all patients who discontinue planned study treatment and proceed to surgery 
will remain on study for pCR assessment and for follow-up of secondary and exploratory 
endpoints unless consent from study participation is withdrawn.
Any overdose or incorrect administration of nab-paclitaxel, doxorubicin, or 
cyclophosphamide should be noted on the respective drug administration eCRF.  
Adverse events associated with an overdose or incorrect administration of nab-
paclitaxel, doxorubicin, or cyclophosphamide should be recorded on the 
Adverse Event eCRF.
Nab-Paclitaxel
Nab-paclitaxel will be administered as an IV infusion given over 30 minutes. 
Nab-paclitaxel should be administered after atezolizumab or placebo.  The dose of 
nab-paclitaxel will be 125 mg/m2 administered via IV infusion over 30 minutes QW for 
12 weeks.  Doses of nab-paclitaxel should not be administered more frequently than 
every 7 days.
Sites should follow their institutional standard of care for determining the nab-paclitaxel 
dose adjustments in the event of patient weight changes. The infusion site should be 
closely monitored for possible infiltration during drug administration.
Refer to the local prescribing information for more details regarding the preparation and 
administration of nab-paclitaxel.


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Doxorubicin
Doxorubicin should be given as an IV bolus over 35 minutes or as an IV infusion given 
over 1530 minutes, in accordance with local standards of care. Doxorubicin and 
cyclophosphamide should be administered after atezolizumab or placebo.  The dose of 
doxorubicin will be 60 mg/m2 IV.  Dose delays and reduction for toxicity are permitted. 
Doxorubicin will be administered Q2W for 4 doses (dose-dense AC) with 
filgrastim/pegfilgrastim support.
Refer to the local prescribing information for details regarding the preparation and 
administration of doxorubicin.
Cyclophosphamide
Cyclophosphamide should be given as an IV bolus over 35 minutes or as an IV 
infusion, in accordance with local standards of care. Doxorubicin and cyclophosphamide 
should be administered after atezolizumab or placebo.  The dose of cyclophosphamide 
will be 600 mg/m2 IV.  The dose should be capped at 1200 mg. Dose delays and dose 
reductions for toxicity are permitted. Cyclophosphamide will be administered Q2W for 
4 doses (dose-dense AC) with filgrastim/pegfilgrastim support. Note: Oral 
cyclophosphamide is not permitted.
Chemotherapy-induced nausea and vomiting prophylaxis and treatment should be 
administered as clinically indicated (see Section 4.4.2 for further guidance).  Because
systemic corticosteroids may attenuate the potential beneficial immunologic effects of 
treatment with atezolizumab, alternative agents should be considered when clinically 
feasible.
Refer to the local prescribing information for details regarding the preparation and 
administration of cyclophosphamide.
Premedications
In general, chemotherapy supportive care should be administered per ASCO, EORTC, 
or European Society for Medical Oncology (ESMO) guidelines or local standard of care.  
For further details regarding permitted therapies, see Section 4.4.1.
4.3.3
Investigational Medicinal Product Accountability
All IMPs required for completion of this study (atezolizumab and nab-paclitaxel) will be 
provided by the Sponsor where required by local practices. 
The study site will acknowledge receipt of IMPs using the IxRS to confirm the shipment 
condition and content.  Any damaged shipments will be replaced.
IMPs either will be disposed of at the study site according to the study site’s institutional 
standard operating procedure or will be returned to the Sponsor with the appropriate 
documentation.  The site’s method of IMP destruction must be agreed to by the Sponsor.  


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The site must obtain written authorization from the Sponsor before any IMP is destroyed, 
and IMP destruction must be documented on the appropriate form.
Accurate records of all IMPs received at, dispensed from, returned to, and disposed of 
by the study site should be recorded on the Drug Inventory Log.
4.3.4
Post-Trial 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 providing 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 AND ADDITIONAL RESTRICTIONS
Concomitant therapy during the study 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 
30 days prior to initiation of study treatment to the treatment discontinuation visit.  
All such medications should be reported to the investigator and recorded on the 
Concomitant Medications eCRF.
4.4.1
Permitted Therapy 
Patients are permitted to use the following therapies during the study:

Oral contraceptives

Prophylactic or therapeutic anticoagulation therapy (such as warfarin at a stable 
dose or low-molecular-weight heparin)

Megestrol administered as an appetite stimulant 

Inhaled corticosteroids (e.g., budesonide)

Mineralocorticoids (e.g., fludrocortisone)

Low-dose corticosteroids administered for orthostatic hypotension or adrenocortical 
insufficiency

Vaccinations (such as influenza, COVID-19)
Live, attenuated vaccines are not permitted (see Section 4.4.4)
Premedication with antihistamines may be administered for the second and subsequent 
atezolizumab infusions only, at the discretion of the investigator.


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G-CSF (i.e., filgrastim or pegfilgrastim) treatment is permitted for patients receiving 
chemotherapy and is required during the doxorubicin/cyclophosphamide portion of 
chemotherapy. The primary prophylaxis should be administered per the ASCO, 
EORTC, or ESMO guidelines or per local standard practice; namely, in patients who are 
60 years of age and/or with comorbidities (Smith et al. 2006; Crawford et al. 2009; 
Aapro et al. 2011).
Evidence supporting the use of long-acting (pegylated) forms of G-CSF in patients
receiving weekly nab-paclitaxel is limited and investigators should consider giving
preference to conventional formulations of G-CSF.
In general, investigators should manage a patient’s care with supportive therapies as 
clinically indicated per local standard practice.  Patients who experience 
infusion-associated symptoms may be treated symptomatically with acetaminophen, 
ibuprofen, diphenhydramine, and/or H2-receptor antagonists (e.g., famotidine, 
cimetidine), or equivalent medications per local standard practice.  Serious 
infusion-associated events manifested by dyspnea, hypotension, wheezing, 
bronchospasm, tachycardia, reduced oxygen saturation, or respiratory distress should 
be managed with supportive therapies as clinically indicated (e.g., supplemental oxygen 
and 2-adrenergic agonists; see Appendix 9).
4.4.2
Cautionary Therapy
Systemic corticosteroids, immunosuppressive medications, and TNF-inhibitors may 
attenuate potential beneficial immunologic effects of treatment with atezolizumab.  
Therefore, in situations in which systemic corticosteroids, immunosuppressive 
medications, or TNF-inhibitors would be routinely administered, alternatives, including 
antihistamines, should be considered.  If the alternatives are not feasible, systemic 
corticosteroids, immunosuppressive medications, and TNF-inhibitors may be 
administered at the discretion of the investigator.
Systemic corticosteroids are recommended, at the discretion of the investigator, for the 
treatment of specific immune-mediated adverse events when associated with 
atezolizumab or placebo therapy (refer to Appendix 13 for details).
Concomitant use of herbal therapies is not recommended because their 
pharmacokinetics, safety profiles, and potential drug-drug interactions are generally 
unknown.  However, herbal therapies may be used during the study at the discretion of 
the investigator.
4.4.3
Potential Drug Interactions with Chemotherapy
The chemotherapeutic agents used in this study are associated with potential drug 
interactions.  The metabolism of nab-paclitaxel is catalyzed by cytochrome P450 (CYP) 
isoenzymes CYP2C8 and CYP3A4.  Doxorubicin is a major substrate of CYP3A4 and 
CYP2D6 and P-glycoprotein (P-gp).  Cyclophosphamide is also activated by CYP. 


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Caution should be exercised when nab-paclitaxel is concomitantly administered with 
known inhibitors (e.g., atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, 
nefazodone, nelfinavir, ritonavir, saquinavir, and telithromycin); inducers (e.g., rifampin, 
phenobarbital, phenytoin, St. John’s Wort and carbamazepine); and substrates 
(e.g., midazolam, buspirone, felodipine, lovastatin, eletriptan, sildenafil, simvastatin,
and triazolam) of CYP3A4.  Caution should also be exercised when nab-paclitaxel is 
concomitantly administered with known inhibitors (e.g., gemfibrozil), inducers 
(e.g., rifampin), and substrates (e.g., repaglinide and rosiglitazone) of CYP2C8.
Clinically significant interactions have been reported with inhibitors of CYP3A4, 
CYP2D6, and/or P-gp (e.g., verapamil).  Caution should be exercised and concurrent 
use of doxorubicin with inhibitors and inducers of CYP3A4, CYP2D6, or P-gp should 
be avoided.
Similar cautions should be exercised with cyclophosphamide.
There is a moderate to high potential for drug-drug interactions with any medication 
that is metabolized by or strongly inhibits or induces these enzymes.  Therefore, the 
medications listed above should be avoided when chemotherapy is being administered.  
If use of one of these medications is necessary, the investigator is encouraged to 
discuss the risks and benefits with the Medical Monitor prior to concomitant 
administration with chemotherapy.
The lists of medications shown above are not necessarily comprehensive.  Thus, the 
investigator should consult the prescribing information for any concomitant medication 
as well as the Internet references provided below when determining whether a certain 
medication is metabolized by or strongly inhibits or induces CYP enzymes.  In addition, 
the investigator is encouraged to contact the Medical Monitor if questions arise regarding 
medications not listed above.
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/
Guidances/UCM292362.pdf
http://medicine.iupui.edu/clinpharm/ddis/table.aspx
4.4.4
Prohibited Therapy
Use of the following concomitant therapies is prohibited as described below:

Concomitant therapy intended for the treatment of cancer (including, but not limited 
to, chemotherapy, hormonal therapy, immunotherapy, radiotherapy, and herbal 
therapy), whether health authorityapproved or experimental, is prohibited for 
various time periods prior to starting study treatment, depending on the agent 
(see Section 4.1.2), and during study treatment until disease recurrence is 
documented and the patient has discontinued study treatment, except as outlined 
below or as described elsewhere in the protocol.

Investigational therapy is prohibited during the study.


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
Live, attenuated vaccines (e.g., FluMist) are prohibited within 4 weeks prior to 
initiation of study treatment, during study treatment, and for 5 months after the last 
dose of study treatment.

Systemic immunostimulatory agents (including, but not limited to, interferons and
IL-2) are prohibited within 4 weeks or 5 half-lives of the drug, whichever is longer, 
prior to initiation of study treatment and during study treatment because these 
agents could potentially increase the risk for autoimmune conditions when given in 
combination with atezolizumab.
4.5
STUDY ASSESSMENTS 
Signed informed consent will be obtained from the patient or patient’s legally acceptable 
representative before any study-specific procedures are performed or any prohibited 
medications are withheld for purposes of study participation.
The schedule of activities to be performed during the study is provided in Appendix 1.  
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.
If the timing of a protocol-mandated study visit coincides with a holiday and/or weekend 
that would preclude the visit, the visit should be scheduled on the nearest following 
feasible date. Any delay visits should be reverted to the original schedule within the next 
few subsequent visits. For example, no study drug infusion should be skipped due to a 
visit delay. Assessments scheduled on the day of study drug administration should be 
performed prior to study drug infusion, unless otherwise noted.
Test results or examinations that are performed as standard of care prior to obtaining 
informed consent and appropriately within 30 days prior to randomization may be used 
to satisfy screening requirements rather than repeating required tests; such tests do not 
need to be repeated for screening.
4.5.1
Informed Consent Forms and Screening Log
Written informed consent for participation in the study must be obtained before 
performing any study-related procedures (including screening evaluations).  Informed 
Consent Forms for enrolled patients and for patients who are not subsequently enrolled 
will be maintained at the study site. A separate optional informed consent required for 
collection of optional research samples (see Section 4.5.15.5).


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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.
Please see Appendix 1 for the schedule of screening assessments.
4.5.2
Medical History, Concomitant Medication, and Demographic 
Data
Medical history, including clinically significant diseases, surgeries, cancer history 
(including prior cancer therapies and procedures), reproductive status, smoking 
history, and use of alcohol and drugs of abuse, will be recorded at baseline.  
TNBC history will include surgery and radiation therapy.
In addition, all medications (e.g., prescription drugs, over-the-counter drugs, vaccines, 
herbal or homeopathic remedies, nutritional supplements) used by the patient within 
30 days prior to initiation of study treatment will be recorded.  At the time of each 
follow-up physical examination, an interval medical history should be obtained and any 
changes in medications and allergies should be recorded.
Demographic data will include age, sex, and self-reported race/ethnicity.
4.5.3
Physical Examinations
A complete physical examination, performed at screening, should include an evaluation 
of the head, eyes, ears, nose, and throat, and the cardiovascular, dermatological, 
musculoskeletal, respiratory, gastrointestinal, and neurological systems.  Bilateral breast 
examination, including evaluation of locoregional lymphatics, should be conducted 
(see Section 4.5.5). 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 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, systolic and 
diastolic blood pressure while the patient is in a seated position, and temperature.
At every clinic visit where study treatment is administered, vital signs should be 
measured within 60 minutes prior to the first infusion and, if clinically indicated, during or 
after the infusion.  In addition, vital signs should be measured at other specified 
timepoints as outlined in the schedule of activities (see Appendix 1). Vital signs are not 


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required to be entered into the eCRF unless abnormal and clinically significant, in which 
case they are to be reported as adverse events.
4.5.5
Locoregional Tumor Status 
Physical Examination 
Assessment of primary tumor and regional lymph nodes must be done by physical 
examination during the baseline evaluation, within 3 days prior to each 4-week cycle of 
study treatment during the neoadjuvant phase, and within 14 days prior to surgery. 
The tumor site must be marked with a radiopaque marker via radiographic guidance 
(e.g., ultrasound) prior to initiation of neoadjuvant therapy. Clinical assessment of tumor 
measurement in the breast and/or lymph nodes should be conducted in a consistent 
manner at each evaluation. Clinical measurements of tumor in the breast should be 
performed, preferentially using calipers or a ruler/tape measure. The tumor should be 
accurately measured in at least one dimension (longest diameter to be recorded) with 
conventional techniques (positron emission tomography [PET] scan, CT scan, magnetic 
resonance imaging (MRI), ultrasound, or X-ray). If possible, these measurements 
should be conducted by the same assessor at baseline and throughout the neoadjuvant 
phase. Tumor measurements at baseline and within 14 days prior to surgery are to be 
recorded in the eCRF. The main purpose of performing physical examination prior to 
each cycle is for patient safety and to rule out progressive disease that would lead to 
study treatment discontinuation. 
Ultrasound of Breast and Axilla 
Ultrasound of breast and axilla is mandated at baseline within 28 days prior 
randomization and within 14 days prior to surgery. If on ultrasound examination there is 
evidence of suspicious axillary lymph nodes at the baseline examination, then 
fine-needle aspiration or core-needle biopsy is required. It is strongly recommended that 
the abnormal lymph node be marked by metallic indicator or other standard approach 
prior to neoadjuvant therapy. Sonographic tumor measurements are to be recorded 
in eCRF. 
Additional Lymph Node Assessment 
Patients with clinically negative axilla (by physical examination and radiographic 
imaging) may undergo an SLNB procedure prior to NAST if in keeping with 
local practice.
For patients who undergo SLNB, it is strongly recommended that more than one lymph 
node (two to three minimum) be removed. If the SLNB procedure conducted prior to 
NAST reveals a lymph node involved with cancer, the patient is not a candidate for the 
study and should not be enrolled. 
Mammogram 
Bilateral mammogram must be obtained at baseline. The unaffected breast should have 
been imaged within 60 days prior to randomization. The affected breast should be 


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imaged within 28 days prior to randomization. Subsequent mammograms are optional 
during neoadjuvant treatment and prior to surgery and should be performed per 
investigator’s discretion. Optional procedure mammograms are not required to be 
entered into the eCRF. Bilateral mammogram is mandated at study completion/early 
termination visit and every 12 months (4 weeks) during the follow-up period. 
Patients who have undergone mastectomy do not require mammograms of 
reconstructed breast(s). 
Additional Breast Imaging 
Additional breast imaging such as MRI are per investigator discretion. MRI examination 
is not mandated by the protocol and should be per local practice. If MRI is conducted, 
suggested timelines for MRI are within 28 days prior to protocol therapy, after Cycle 3,
and 14 days prior to surgery.
Surgical Treatment Plan 
A surgeon with experience of breast cancer surgery should evaluate patients. The 
proposed surgical treatment plan at baseline should be documented and reported in the 
eCRF. Patients should be reassessed after completion of neoadjuvant therapy/prior to 
surgery. The patient should be evaluated for the surgical treatment the surgeon feels is 
technically a candidate to undergo after completion of NAST as well as for the planned 
surgical treatment. These treatments should be documented and reported in the eCRF. 
4.5.6
Distant Sites Tumor Assessment 
Baseline distant sites tumor staging procedures should be performed in alignment with 
National Comprehensive Cancer Network (NCCN) or national guidelines, within 28 days 
prior to randomization. 
As a reference, as per NCCN guidelines, staging procedures are based on clinical stage: 

For Stage II and Stage IIIA: Bone scan is to be performed in presence of bone pain 
and/or elevated alkaline phosphatase; abdominal/pelvic CT scan in case of elevated 
alkaline phosphatase, abnormal liver function tests, abdominal symptoms or 
abnormal physical examination; and chest CT scan. 

For Stage IIIB and Stage IIIC: Bone scan and CT scan of chest, abdomen, and 
pelvis should be conducted for all patients.
In addition, liver function tests, bone scans, chest X-ray/diagnostic CT scan, liver 
imaging, and/or other radiographic modalities may be considered when clinically 
indicated to exclude metastatic disease. 
4.5.7
Disease Follow-Up and Confirmation of Disease Progression or
Recurrence
During the neoadjuvant treatment, diagnosis of disease progression or second primary 
breast cancer should be supported by clinical, laboratory, radiological, and/or histological 
findings. Post-operatively, all patients must be followed to assess disease recurrence, 


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second primary cancer, and survival. The designation of disease recurrence, whether 
local, regional or distant, or a diagnosis of a second primary cancer can be made only 
when clinical, laboratory, radiological and/or histological findings support the diagnosis.
During the post-operative portion of this study, disease status should be clinically 
evaluated and documented every 3 months for up to 3 years and at intervals of every 
6 months thereafter.
The diagnosis of a breast cancer progression, recurrence, or second primary tumor 
should be confirmed histologically whenever clinically possible. Given the mechanism 
by which immune-modulating therapies work, patients with radiographic lesions 
suspicious for disease recurrence are strongly recommended to undergo biopsy for 
histologic confirmation of cancer versus immune-mediated inflammatory process.
Some patients may experience a suspicious recurrence that leads to death relatively
quickly, without the possibility of confirming relapse of disease. Efforts should be made 
to obtain an autopsy report in such cases. 
The earliest date of diagnosis of disease progression, recurrent disease, or a diagnosis 
of a second primary cancer should be used and recorded. This date should be based on 
objective clinical, radiological, histological, or cytological evidence. 
Recurrent disease includes local, regional, or distant recurrence and contralateral breast 
cancer. While ipsilateral or contralateral in situ disease and second primary non-breast 
cancers (including in situ carcinomas and non-melanoma skin cancers) will not be 
counted as progressive disease or recurrent disease, these events should be recorded.
Patients who have a diagnosis of in situ breast disease or second (non-breast)
malignancies should be maintained on a regular follow-up schedule whenever possible 
in order to fully capture any subsequent recurrent disease events. 
The definitions of and procedures for confirming disease recurrence, death, and other 
noteworthy events on follow-up are provided in Table 2.


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Table 2
Definitions of and Procedures for Confirming Disease 
Recurrence, Death, and Other Noteworthy Events on Follow-Up
a) Local invasive
recurrence
Ipsilateral 
breast after 
previous 
lumpectomy

Defined as evidence of invasive tumor (except DCIS 
and LCIS) in the ipsilateral breast after lumpectomy. 
Patients who develop clinical evidence of tumor 
recurrence in the remainder of the ipsilateral breast 
should have a biopsy of the suspicious lesion to
confirm the diagnosis. 

Confirmed by positive histology or cytology
Ipsilateral after 
previous 
mastectomy

Defined as evidence of invasive tumor in any soft 
tissue or skin of the ipsilateral chest wall. This 
includes the area bounded by the midline of the 
sternum, extending superiorly to the clavicle and 
inferiorly to the costal margin. Soft tissue recurrences 
in this area extending into the bony chest wall or 
across the midline will be considered as evidence of 
local recurrence. 

Confirmed by positive histology or cytology
b) Regional 
recurrence

Defined as the development of tumor in the ipsilateral internal mammary 
lymph nodes, ipsilateral axillary lymph nodes, or supraclavicular lymph 
nodes as well as extranodal soft tissue of the ipsilateral axilla. Regional 
recurrence does not include tumor in the opposite breast. 

Confirmed by positive histology or cytology, or radiologic evidence 
(especially in case of PET activity or visible internal mammary lymph 
nodes on CT scan or MRI if no biopsy was performed)


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Table 2
Definitions of and Procedures for Confirming Disease Recurrence, 
Death, and Other Noteworthy Events on Follow-Up (cont.)
c) Distant
recurrence

Defined as evidence of tumor in all areas, with the exception of those 
described in a) and b) above 

Confirmed by the following criteria:
Skin, subcutaneous tissue, and lymph nodes (other than local or 
regional) 
Positive cytology, aspirate, or biopsy, OR 
Radiological (CT scan, MRI, PET scan, or ultrasound) evidence of 
metastatic disease 
Bone
X-ray, CT scan, or MRI evidence of lytic or blastic lesions 
consistent with bone metastasis, OR 
Bone scan (requires additional radiological investigation, alone 
not acceptable in case of diagnostic doubt), OR 
Biopsy proof of bone metastases or cytology 
Bone marrow
Positive cytology or histology or MRI
Lung
Radiologic (CT or PET scan) evidence of multiple pulmonary 
nodules consistent with pulmonary metastases 
Positive cytology or histology in case of diagnostic doubt
(particularly for solitary lung lesions) if a biopsy is not performed.  
Serial scans should be obtained if possible to document stability 
or progression. 
Proof of neoplastic pleural effusions should be established by 
cytology or pleural biopsy.
Liver 
Radiologic evidence consistent with liver metastases, OR 
Liver biopsy or fine-needle aspiration 
NOTE: If radiological findings are not definitive (especially 
with solitary liver nodules), a liver biopsy is recommended; 
however, if a biopsy is not performed, serial scans should 
be obtained if possible to document stability or progression. 
Central nervous system 
Positive MRI or CT scan, usually in a patient with neurologic 
symptoms, OR 
Biopsy or cytology in case of inconclusive imaging (e.g., for a 
diagnosis of meningeal involvement) and, depending from the 
general status of the patient, additional investigations (including 
cytology of the cerebrospinal fluid)


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Table 2
Definitions of and Procedures for Confirming Disease Recurrence, 
Death, and Other Noteworthy Events on Follow-Up (cont.)
d) Contralateral 
invasive 
breast cancer

Confirmed by positive cytology or histology 
e) Death from
any cause

Any death occurring without prior breast cancer recurrence or second 
(non-breast) malignancy is considered an event for the following 
endpoints:  EFS, DFS, and OS. 
CTcomputed tomography; DCISductal carcinoma in situ; DFSdisease-free survival; 
EFSevent-free survival; iDFSinvasive disease-free survival; LCISlobular carcinoma in situ; 
MRImagnetic resonance imaging; OSoverall survival; PET positron emission tomography.
4.5.8
Surgical Specimen Pathology
Primary endpoint of the study (pCR) will be as identified by local pathology review. 
Guidelines regarding pathology specimen preparation, labeling, and review as well as 
calculation of the RCB index are outlined in the Pathology Manual. The Sponsor will 
prospectively collect Local Pathology Reports.
4.5.9
Laboratory, Biomarker, and Other Biological Samples
Samples for the following laboratory tests will be sent to the study site's local laboratory 
for analysis as outlined in the schedule of activities (see Appendix 1) and as clinically 
indicated:

Hematology:  WBC count, RBC count, hemoglobin, hematocrit, platelet count, 
differential count (neutrophils, eosinophils, basophils, monocytes, lymphocytes, 
other cells)

Chemistry panel (serum or plasma):  sodium, potassium, magnesium, chloride, 
bicarbonate or total CO2, glucose, BUN or urea, creatinine, total protein, albumin, 
phosphorus, calcium, total bilirubin, alkaline phosphatase, ALT, AST, LDH

Coagulation:  INR, aPTT

Thyroid function testing:  thyroid-stimulating hormone, free triiodothyronine (T3) 
(or total T3 for sites where free T3 is not performed), free thyroxine

HIV serology

HBV serology:  HBsAg, hepatitis B surface antibody, total HBcAb
If a patient has a negative HBsAg test and a positive total HBcAb test at 
screening, an HBV DNA test must be performed to rule out active HBV infection 
on the basis of HBV viral load per local guidelines.

HCV serology:  HCV antibody
If a patient has a positive HCV antibody test at screening, an HCV RNA test 
should be performed to rule out active HCV infection prior to initiation of 
study treatment.


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
Pregnancy test
All women of childbearing potential will have a serum pregnancy test at 
screening.  Urine pregnancy tests will be performed at specified subsequent 
visits.  If a urine pregnancy test is positive, it must be confirmed by a serum 
pregnancy test.
A woman is considered to be of childbearing potential if she is postmenarcheal, 
has not reached a postmenopausal state (12 continuous months of 
amenorrhea with no identified cause other than menopause), and has not 
undergone surgical sterilization (removal of ovaries and/or uterus).

Urinalysis (pH, specific gravity, glucose, protein, ketones, and blood); dipstick 
permitted 
The following samples will be sent to one or several central laboratories or to the 
Sponsor for analysis:

Cardiac troponin T (cTnT; for cardiac safety cohort only) (see Appendix 4)

Serum samples for analysis of autoantibodies: anti-nuclear antibody, 
antidouble-stranded DNA, circulating anti-neutrophil cytoplasmic antibody, and 
perinuclear anti-neutrophil cytoplasmic antibody

Serum samples for atezolizumab PK analysis through use of a validated assay

Serum samples for assessment of ADAs to atezolizumab through use of a 
validated assay

Blood and plasma samples for exploratory research on biomarkers

Tumor tissue sample collected at baseline for determination of PD-L1 expression; 
for confirmation of HER2, ER, and PgR negativity; and for exploratory research on 
biomarkers
A representative FFPE tumor specimen in a paraffin block (preferred) or 
at least 20 slides containing unstained, freshly cut, serial sections must be 
submitted along with an associated pathology report prior to study enrollment.  
After signing of the Informed Consent Form, retrieval and submission of a tumor 
sample can occur outside the 28-day screening period.
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 resections, core-needle biopsies 
(at least three cores, embedded in a single paraffin block), or excisional, 
incisional, punch, or forceps biopsies. For multifocal tumors, three cores should 
be submitted for the main lesion, while one core is sufficient for each of the 
other foci.  Fine-needle aspiration (defined as samples that do not preserve 
tissue architecture and yield cell suspension and/or smears), brushing, and cell 
pellets from cytology samples are not acceptable.  


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If tissue is unavailable and surgery has not occurred, a pretreatment tumor 
biopsy is required or a tumor tissue specimen should be prepared from the 
excised tumor.  Tissue should meet the tumor tissue requirements described in 
the eligibility criteria.  Remaining tumor tissue 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 samples for biomarker evaluation will be collected to promote, facilitate, and 
improve the treatment and mode of action of atezolizumab/abraxane and 
atezolizumab/doxorubicin/cyclophosphamide. An optional core-needle biopsy will be 
requested predose at Week 3 (3 days).  Tissue will also be collected at eventual 
surgical resection.

Tumor tissue sample collected at the time of recurrence, if deemed clinically feasible
by the investigator, for exploratory research on biomarkers
Biopsies should be performed within 40 days after recurrence or prior to the 
next anti-cancer therapy, whichever is sooner.  Acceptable samples include 
those from resections, core-needle biopsies (at least two cores preferred), or 
excisional, incisional, punch, or forceps biopsies.
Exploratory biomarker research may include, but will not be limited to, analysis of genes 
or gene signatures associated with tumor immunobiology, PD-L1, lymphocytes, T-cell 
receptor repertoire, or cytokines associated with T-cell activation and may involve DNA 
or RNA extraction, analysis of somatic mutations, and use of WGS or NGS.
NGS may be performed by Foundation Medicine on the samples obtained at disease 
relapse after surgical resection.  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 for 
the purpose of guiding future treatment decisions.
For sampling procedures, storage conditions, and shipment instructions, see the 
laboratory manual.
Unless the patient gives specific consent for his or her leftover samples to be stored for 
optional exploratory research (see Section 4.5.14), biological samples will be destroyed 
when the final Clinical Study Report has been completed, with the following exceptions:

Serum samples collected for PK analysis and/or immunogenicity analysis may be 
needed for additional immunogenicity characterization and PK and immunogenicity 
assay development and validation; therefore, these samples will be destroyed no 
later than 5 years after the final Clinical Study Report has been completed.


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
Blood samples collected for WGS will be stored until they are no longer needed or 
until they are exhausted.

Leftover plasma, blood, and tumor samples collected during the study will be 
destroyed no later than 15 years after the final Clinical Study Report has been 
completed or in accordance to local regulations.
When a patient withdraws from the study, samples collected prior to the date of 
withdrawal may still be analyzed, unless the patient specifically requests that the 
samples be destroyed or local laws require destruction of the samples.  However, if 
samples have been tested prior to withdrawal, results from those tests will remain as 
part of the overall research data.
Data arising from sample analysis will be subject to the confidentiality standards 
described in Section 8.4.
Given the complexity and exploratory nature of 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 Foundation 
Medicine for the samples obtained at disease relapse.  The aggregate results of any 
conducted research will be available in accordance with the effective Sponsor policy on 
study data publication.
4.5.10
Electrocardiograms
A 12-lead ECG is required at screening and when clinically indicated (see Appendix 1).  
ECGs for each patient should be obtained from the same machine wherever possible.  
Lead placement should be as consistent as possible.  ECG recordings must be 
performed after the patient has been resting in a supine position for at least 10 minutes.
For safety monitoring purposes, the investigator must review, sign, and date all ECG 
tracings.  Paper copies of ECG tracings will be kept as part of the patient's permanent 
study file at the site.  Any morphologic waveform changes or other ECG abnormalities 
must be documented on the eCRF.
4.5.11
Echocardiograms or Multiple-Gated Acquisition Scans
LVEF will be assessed by echocardiography (preferably) or MUGA scan at specified 
timepoints, as outlined in the schedule of activities (see Appendix 1 and Appendix 4) and 
as clinically indicated.  Patients should be reassessed with the same technique used for 
baseline cardiac evaluation throughout the study.


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4.5.12
Pulmonary Function Tests (Spirometry)
Pulmonary function evaluations will be conducted via spirometry at baseline, and if 
clinically indicated, repeat tests may be conducted by the investigator as part of a clinical 
workup to evaluate pulmonary symptoms.  Baseline pulmonary function evaluations will 
include assessments of forced vital capacity (FVC), forced expiratory volume 1 (FEV1), 
and forced expiratory flow 25%75% (FEF25-75).
4.5.13
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; item GP5 of the 
FACT-G, Quality of Life instrument; and the EuroQoL 5-Dimension, 5-Level (EQ-5D-5L).
The PRO instruments, translated as required in the local language, will be distributed by 
the investigator staff and 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 the patient’s responses. If the patient is unable 
to complete the measure on her or his 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 respondent’s initials, study patient number and date and 
time of completion recorded 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 begin completion of the questionnaires with the EORTC QLQ-C30,
followed by the FACT-G single item GP5, and then the EQ-5D-5L at timepoints 
corresponding with in-clinic visits; both while receiving study treatment and after 
treatment discontinuation. Refer to Appendix 1 for the frequency and timing of PRO 
assessments.
4.5.13.1
EORTC QLQ-C30
The EORTC QLQ-C30 is a validated, reliable self-report measure (Aaronson et al. 1993;
see Appendix 5). It consists of 30 questions that assess 5 aspects of patient functioning 
(physical, emotional, role, cognitive, and social), 3 symptom scales (fatigue, nausea and 
vomiting, pain), global health status (GHS), HRQoL, and 6 single items (dyspnea, 
insomnia, appetite loss, constipation, diarrhea, and financial difficulties) with a recall 


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period of the previous week.  Scale scores can be obtained for the multi-item scales.  
The EORTC QLQ-C30 module takes approximately 10 minutes to complete.
4.5.13.2
FACT-G Single Item GP5
The FACT-G instrument Version 4 (see Appendix 6) is a validated and reliable 27-item
questionnaire comprised of 4 subscales that measure physical (7 items), social/family
(7 items), emotional (6 items) and functional well-being (7 items), and is considered
appropriate for use with patients with any form of cancer (Cella et al. 1993; 
Webster et al. 1999). In this study, the single item GP5 (“I am bothered by side effects 
of treatment”) from the physical well-being 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 5-point scale (0, not at all; 
1, a little bit; 2, somewhat; 3, quite a bit; 4, very much). The single item GP5 from the 
FACT-G takes less than a minute to complete.
4.5.13.3
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 7).  There are two components to the EQ-5D-5L:  a five-item health state 
profile that assesses mobility, self-care, usual activities, pain/discomfort, and 
anxiety/depression, as well as a visual analogue scale that measures health state.  
Published weighting systems allow for creation of a single composite score of the 
patient’s health utility.  Utility scores will be used in this study for informing 
pharmacoeconomic evaluations.  As such, the utility results will not be included in the 
CSR.  The EQ-5D-5L takes approximately 3 minutes to complete.
4.5.14
Mandatory Samples for Whole Genome Sequencing
At participating sites, blood samples will be collected for DNA extraction to enable 
WGS to identify germline mutations that are predictive of response to study drug, are 
associated with progression to a more severe disease state, are associated with 
susceptibility to developing adverse events, or can increase the 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 by each site's IRB/EC and, if applicable, an appropriate 
regulatory body. If a site has not been granted approval for WGS sampling, this section 
of the protocol (Section 4.5.14) will not be applicable at that site. 
Genomics is increasingly informing researcher's 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 for 


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developing new therapeutic approaches.  Data will be analyzed in the context of this 
study but will also be explored in aggregate with data from other studies.  The availability 
of a larger dataset will assist in identification of important pathways, guiding the 
development of new targeted agents. 
For sampling procedures, storage conditions, and shipment instructions, see the 
laboratory manual.
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 Informed Consent Form and applicable laws (e.g., health authority 
requirements). 
Patient medical information associated with WGS specimens is confidential and may be 
disclosed to third parties only as permitted by the Informed Consent Form (or separate 
authorization for use and disclosure of personal health information) signed by the 
patient, unless permitted or required by law. 
Given the complexity and exploratory nature of the analyses, data derived from WGS 
specimens will generally not be provided to study investigators or patients unless 
required by law.  The aggregate results of any conducted research will be available in 
accordance with the effective Sponsor policy on study data publication. 
4.5.15
Optional Samples for Research Biosample Repository
4.5.15.1
Overview of the Research Biosample Repository
The Research Biosample Repository (RBR) is a centrally administered group of facilities 
used for the long-term storage of human biologic specimens, including body fluids, solid 
tissues, and derivatives thereof (e.g., DNA, RNA, proteins, peptides).  The collection, 
storage, and analysis of RBR specimens will facilitate the rational design of new 
pharmaceutical agents and the development of diagnostic tests, which may allow for 
individualized drug therapy for patients in the future.
Specimens for the RBR will be collected from patients who give specific consent to 
participate in this optional research.  RBR specimens will be used to achieve the 
following objectives:

To study the association of biomarkers with efficacy, adverse events, or disease 
recurrence

To increase knowledge and understanding of disease biology

To study drug response, including drug effects and the processes of drug absorption 
and disposition

To develop biomarker or diagnostic assays and establish the performance 
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4.5.15.2
Approval by the Institutional Review Board or Ethics 
Committee
Collection and submission of biological samples to the RBR is contingent upon the 
review and approval of the exploratory research and the RBR portion of the Informed 
Consent Form by each site's IRB/EC and, if applicable, an appropriate regulatory body.  
If a site has not been granted approval for RBR sampling, this section of the protocol 
(Section 4.5.15) will not be applicable at that site.
4.5.15.3
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 or diseases:

Whole blood sample for DNA isolation collected from patients who have consented 
to optional RBR sampling at Cycle 1, Day 1 (see Appendix 1)
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 associated with immune biology including but 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 using techniques such as kinetic PCR and DNA sequencing. 

Tumor tissue samples from biopsies performed at the investigator's discretion 
during the study

Leftover blood, plasma, and tumor tissue samples (with the exception of leftover 
tissue from FFPE blocks, which will be returned to sites) and any derivatives thereof
(e.g., DNA, RNA, proteins, peptides), including 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 
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 is increasingly informing 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 for developing new therapeutic 
approaches.  Data will be analyzed in the context of this study but will also be explored 
in aggregate with data from other studies.  The availability of a larger dataset will assist 
in identification of important pathways, guiding the development of new targeted agents.
For sampling procedures, storage conditions, and shipment instructions, see the 
laboratory manual.


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RBR specimens are to be stored until they are no longer needed or until they are 
exhausted.  However, the RBR storage period will be in accordance with the 
IRB/EC-approved Informed Consent Form and applicable laws (e.g., health authority 
requirements).
4.5.15.4
Confidentiality
Specimens and associated data will be labeled with a unique patient identification 
number.
Patient medical information associated with RBR specimens is confidential and may be 
disclosed to third parties only as permitted by the Informed Consent Form (or separate 
authorization for use and disclosure of personal health information) signed by the 
patient, unless permitted or required by law.
Given the complexity and exploratory nature of the analyses of RBR specimens, data 
derived from these analyses will generally not be provided to study investigators or 
patients unless required by law.  The aggregate results of any conducted research will 
be available in accordance with the effective Sponsor policy on study data publication.
Data generated from RBR specimens must be available for inspection upon request by 
representatives of national and local health authorities, and Sponsor monitors, 
representatives, and collaborators, as appropriate.
Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of the RBR data will become and remain the exclusive and unburdened property 
of the Sponsor, except where agreed otherwise.
4.5.15.5
Consent to Participate in the Research Biosample Repository
The Informed Consent Form will contain a separate section that addresses participation 
in the RBR.  The investigator or authorized designee will explain to each patient the 
objectives, methods, and potential hazards of participation in the RBR.  Patients will be 
told that they are free to refuse to participate and may withdraw their specimens at any 
time and for any reason during the storage period.  A separate, specific signature will be 
required to document a patient's agreement to provide optional RBR specimens.  
Patients who decline to participate will not provide a separate signature.
The investigator should document whether or not the patient has given consent to 
participate and (if applicable) the date(s) of consent, by completing the RBR Research 
Sample Informed Consent eCRF.
In the event of an RBR participant's death or loss of competence, the participant's 
specimens and data will continue to be used as part of the RBR research.


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4.5.15.6
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 testing of his or her samples during the study, the investigator must inform the 
Medical Monitor in writing of the patient's wishes through use of the appropriate RBR 
Subject Withdrawal Form and 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 WO39392 does not, by itself, constitute withdrawal of 
specimens from the RBR.  Likewise, a patient's withdrawal from the RBR does not 
constitute withdrawal from Study WO39392.
4.5.15.7
Monitoring and Oversight
RBR specimens will be tracked in a manner consistent with Good Clinical Practice by a 
quality-controlled, auditable, and appropriately validated laboratory information 
management system to ensure compliance with data confidentiality as well as 
adherence to authorized use of specimens as specified in this protocol and in the 
Informed Consent Form.  Sponsor monitors and auditors will have direct access to 
appropriate parts of records relating to patient participation in the RBR for the purposes 
of verifying the data provided to the Sponsor.  The site will permit monitoring, audits, 
IRB/EC review, and health authority inspections by providing direct access to source 
data and documents related to the RBR samples.
4.6
TREATMENT, PATIENT, STUDY, AND SITE DISCONTINUATION
4.6.1
Study Treatment Discontinuation
Patients must permanently discontinue study treatment (atezolizumab) if they 
experience any of the following:

Intolerable toxicity related to study treatment, including development of an 
immune-mediated adverse event determined by the investigator to be unacceptable 
given the individual patient’s potential response to therapy and severity of the event

Any 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 he or she continues 
study treatment

Investigator or Sponsor determines it is in the best interest of the patient


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
Use of another non-protocol anti-cancer therapy

Pregnancy

Confirmation of disease progression or disease recurrence

Withdrawal by patient
The primary reason for study treatment discontinuation should be documented on the 
appropriate eCRF.  Patients who discontinue study treatment prematurely will not be 
replaced.
Patients who discontinue study treatment early because of an unacceptable toxicity
should continue to be followed for both resolution of toxicity and disease recurrence as
specified in Appendix 1. Patients must discontinue study treatment if they experience 
disease progression or recurrence. After disease progression or recurrence, patients 
will be followed until the next treatment and then for survival until study completion.
Patients who are discontinued because of investigator decision will be followed for 
disease recurrence, new anti-cancer therapy, and survival (see Section 4.6.2 for 
further details).
4.6.2
Patient Discontinuation from Study
Patients have the right to voluntarily withdraw from the study at any time for any reason.  
In addition, the investigator has the right to withdraw a patient from the study at any time.  
Reasons for withdrawal from the study may include, but are not limited to, the following:

Patient withdrawal of consent
From study treatment and/or procedures only (i.e., survival follow-up permitted), 
and or
From survival follow-up (patient does not want to be contacted)

Study termination (see Section 4.6.3) or site closure (see Section 4.6.4)

Investigator or Sponsor determines it is in the best interest of the patient

Patient non-compliance, defined as failure to comply with protocol requirements as 
determined by the investigator or Sponsor
Every effort should be made to obtain information on patients who withdraw from the 
study.  The primary reason for withdrawal from the study should be documented on the 
appropriate eCRF.  Patients who withdraw from the study will not be replaced.
4.6.3
Study Discontinuation
The Sponsor has the right to terminate this study at any time.  Reasons for terminating 
the study may include, but are not limited to, the following:

The incidence or severity of adverse events in this or other studies indicates a
potential health hazard to patients.

Patient enrollment is unsatisfactory.


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The Sponsor will notify the investigator if the Sponsor decides to discontinue the study.
Patients who are withdrawn or withdraw from study participation (and not just study 
treatment) will not be followed up for any reason after consent has been withdrawn.  
4.6.4
Site Discontinuation
The Sponsor has the right to close a site at any time.  Reasons for closing a site may 
include, but are not limited to, the following:

Excessively slow recruitment

Poor protocol adherence

Inaccurate or incomplete data recording

Non-compliance with the International Council for Harmonisation (ICH) guideline for 
Good Clinical Practice

No study activity (i.e., all patients have completed the study and all obligations have 
been fulfilled)
5.
ASSESSMENT OF SAFETY
5.1
SAFETY PLAN
The safety plan for patients in this study is based on clinical experience with 
atezolizumab and nab-paclitaxel, doxorubicin, and cyclophosphamide in completed 
and ongoing studies.  The anticipated important safety risks are outlined below 
(see Sections 5.1.15.1.4).  Guidelines for management of patients who experience
specific adverse events are provided in Table 4 (see Section 5.1.5). 
Measures will be taken to ensure the safety of patients participating in this study, 
including the use of stringent inclusion and exclusion criteria (see Section 4.1) and close 
monitoring of patients during the study as indicated below.  Administration of 
atezolizumab will be performed in a monitored setting in which there is immediate 
access to trained personnel and adequate equipment and medicine to manage 
potentially serious reactions.  Adverse events will be reported as described in 
Sections 5.25.6.
An iDMC (see Section 3.1.2) has also been incorporated into the trial design to 
periodically review aggregate safety data.
The potential safety issues anticipated in this trial, as well as measures intended to avoid 
or minimize such toxicities, are outlined in the following sections.
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 


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guidelines or guidelines of applicable professional societies (e.g., American Society of 
Clinical Oncology or European Society for Medical Oncology).
Severe SARS-CoV-2 infection appears to be associated with a CRS involving the 
inflammatory cytokines IL-6, IL-10, IL-2, and IFN-(Merad and Martin 2020).  If a patient 
develops suspected CRS during the study, a differential diagnosis should include 
SARS-CoV-2 infection, which should be confirmed or refuted through assessment of 
exposure history, appropriate laboratory testing, and clinical or radiologic evaluations per 
investigator judgment.  If a diagnosis of SARS-CoV-2 infection is confirmed, the disease 
should be managed as per local or institutional guidelines.
5.1.1
Risks Associated with Atezolizumab
Atezolizumab has been associated with risks such as the following:  IRRs and 
immune-mediated hepatitis, pneumonitis, colitis, pancreatitis, diabetes mellitus, 
hypothyroidism, hyperthyroidism, adrenal insufficiency, hypophysitis, Guillain-Barré 
syndrome, myasthenic syndrome or myasthenia gravis, meningoencephalitis, 
myocarditis, nephritis, myositis, and severe cutaneous adverse reactions.  Immune-
mediated reactions may involve any organ system and may lead to HLH and MAS which 
are considered to be potential risks for atezolizumab.  Adverse events observed with 
atezolizumab in combination with chemotherapy and/or targeted therapies are consistent 
with the known risks of each component of the combination treatment.  Refer to 
Appendix 13 of the protocol and Section 6 of the Atezolizumab Investigator's Brochure 
for a detailed description of anticipated safety risks for atezolizumab.
5.1.2
Risks Associated with Nab-Paclitaxel
In clinical studies and post-marketing experience, nab-paclitaxel has been associated
with alopecia, myelosuppression (primarily neutropenia [including febrile neutropenia],
anemia, thrombocytopenia), neuropathy, cranial nerve palsies, hypersensitivity 
reactions, pneumonitis, gastrointestinal events (i.e., nausea, vomiting, diarrhea), 
myalgia, arthralgia, cardiotoxicity (myocardial disorders, cardiac failure, angina, 
tachycardia, ventricular arrhythmia), cystoid macular edema, Stevens-Johnson 
syndrome/toxic epidermal necrolysis, infections including sepsis, depression, infusion 
site reactions/extravasation, hepatic toxicity (drug-induced liver injury), acute renal 
failure, hemolytic-uremic syndrome, drug-induced lupus erythematous and tumor lysis 
syndrome.
Patients will be monitored for nab-paclitaxelrelated adverse events, including
hematologic, gastrointestinal, hepatic toxicities, and peripheral neuropathy.
For more details regarding the safety profile of nab-paclitaxel, refer to the local 
prescribing information.  Other specific instructions can be found in Sections 4.4.3 and 
5.1.5 for nab-paclitaxel.


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5.1.3
Risks Associated with Doxorubicin
Doxorubicin is known to cause serious cardiomyopathy; arrhythmias, including 
life-threatening arrhythmias; congestive cardiac failure; increased incidence of 
secondary acute myelogenous leukemia and myelodysplastic syndrome; extravasation 
and tissue necrosis; severe myelosuppression resulting in serious infection, septic 
shock, need for transfusions, hospitalization, and death; tumor lysis syndrome; radiation 
sensitization and radiation recall; embryofetal toxicity; alopecia; and vomiting, nausea, 
and other gastrointestinal effects.
Refer to the doxorubicin Summary of Product Characteristics (package insert) for more
details regarding the full safety profile of doxorubicin, including boxed warnings and 
contraindications.
5.1.3.1
Cardiomyopathy
Patients treated with doxorubicin are at risk of developing cumulative dose-related 
myocardial damage. Significant cardiac events, including acute heart failure and LVEF 
of 40%, have been observed in clinical trials of doxorubicin.  Cardiomyopathy may 
develop during treatment or up to several years after completion of treatment.  There is 
an additive or potentially synergistic increase in the risk of cardiomyopathy in patients 
who have received radiotherapy to the mediastinum or concomitant therapy with other 
known cardiotoxic agents such as cyclophosphamide.
Patients must meet specified LVEF requirements to be included in this study 
(see Section 4.1.1). 
Left ventricular function will be monitored by measurement of ejection fraction using 
ECHO or MUGA scans as described in Section 4.5.10 and the schedule of activities 
(see Appendix 1).
5.1.4
Risks Associated with Cyclophosphamide
Cyclophosphamide has been associated with myelosuppression sometimes leading to 
severe immunosuppression and infections that can be serious and sometimes fatal; 
hemorrhagic cystitis, pyelitis, ureteritis, and hematuria; myocarditis, myopericarditis, 
pericardial effusion, arrhythmias, and congestive heart failure; pulmonary toxicity 
including pneumonitis, pulmonary fibrosis, and pulmonary veno-occlusive disease 
leading to respiratory failure; impairment of spermatogenesis; secondary malignancies; 
veno-occlusive liver disease; embryo-fetal toxicity; alopecia; and nausea, vomiting,
and diarrhea.
Refer to the cyclophosphamide Summary of Product Characteristics (package insert) for 
more details regarding the full safety profile of cyclophosphamide, including boxed 
warnings and contraindications.


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5.1.5
Management of Patients Who Experience Specific Adverse 
Events
There will be no dose modifications for atezolizumab or placebo in this study.
For guidelines regarding the management of atezolizumab-specific adverse events, 
please refer to Appendix 13 of the protocol and Section 6 of the Atezolizumab 
Investigator’s Brochure.
Study treatment may be temporarily suspended in patients experiencing toxicity 
considered to be related to study treatment.  If atezolizumab/placebo is withheld for 
12 weeks after the event onset, the patient will be discontinued from 
atezolizumab/placebo.  If the investigator believes the patient is likely to derive clinical 
benefit, atezolizumab/placebo treatment can be resumed after being withheld for 
12 weeks.  The Medical Monitor is available to advise as needed.  If a patient needs to
be tapered off corticosteroids that were used to treat adverse events, the study 
treatment may be withheld for 12 weeks.  The acceptable length of treatment 
interruption must be based on 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.
Dose interruptions for reasons other than toxicity (e.g., surgical procedures) may be 
allowed.  The acceptable length of treatment interruption must be based on 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.
For guidelines regarding the management (i.e., dose modification and treatment 
interruption rules) of doxorubicin- or cyclophosphamide-associated toxicities, please 
refer to the respective local prescribing information for each agent. Doxorubicin rarely 
may induce hyperuricaemia as a consequence of the extensive purine catabolism that 
accompanies rapid lysis of neoplastic cells induced by the medicinal product (TLS) 
(please refer to the local prescriping information for doxorubicin). Blood chemistry (e.g. 
uric acid, potassium, calcium phosphate, and creatinine) should be evaluated after initial 
treatment. Hydration, urine alkalinization, and prophylaxis with allopurinol to prevent 
hyperuricaemia may minimize potential complications of TLS.
For nab-paclitaxelspecific management guidelines, please see below.  For further 
guidance, please refer to local prescribing information for nab-paclitaxel.


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Table 3
Dose Levels for Nab-Paclitaxel (Weekly Dose)
Dose Level 0
(Starting Dose)
Dose Level 1
Dose Level 2
Nab-paclitaxel weekly dose
125 mg/m2
100 mg/m2
Discontinue
nab-paclitaxel
Table 4
Guidelines for Management of Patients Who Experience 
Nab-PaclitaxelSpecific Adverse Events
Event
Action to Be Taken
Hepatotoxicity: Bilirubin or AST or ALT Increased (Grades 24)
Hold nab-paclitaxel until bilirubin returns to baseline grade and 
AST and ALP have returned to Grade 1 (check weekly).
Grade 2
Decrease nab-paclitaxel one dose level.
Grade 3 
Decrease nab-paclitaxel one dose level.
Grade 4
Discontinue nab-paclitaxel.
Neurologic Disorders
Neuropathy, Grade 2 
Withhold nab-paclitaxel if persistent 7 days or caused the next 
cycle to be delayed. 
Resume nab-paclitaxel if event resolves to Grade 1 and 
decrease by 1 dose level.
If persistent after 3 weeks of withholding nab-paclitaxel, 
discontinue nab-paclitaxel.
Neuropathy, Grade 3 or 4 
If first episode, withhold nab-paclitaxel.  If persistent for 7 days 
or caused the next cycle to be delayed, resume nab-paclitaxel if 
event resolves to Grade 1 on Day 1 of the next cycle, and 
decrease by 1 dose level.
If second episode, discontinue nab-paclitaxel permanently.


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Table 4
Guidelines for Management of Patients Who Experience 
Nab-PaclitaxelSpecific Adverse Events (cont.)
Event
Action to Be Taken
Hematologic Toxicity
Neutrophils count decreased
Grade 2
Grade 3 or 4
Maintain nab-paclitaxel dose and add GCSF.
Hold nab-paclitaxel, give GCSF, and observe recovery period:

If recovery to ANC ≥1500 cells/mm3 occurs within 1 week, 
resume nab-paclitaxel at the same dose and continue GCSF
as required.

If recovery to ANC ≥1500 cells/mm3 takes more than 1 week, 
decrease nab-paclitaxel 1 dose level and continue G-CSF as 
required.
Platelet count decreased
Grade 2 or 3
If resolves prior to next treatment cycle, maintain nab-paclitaxel 
dose.
If requires a delay in the administration of next treatment cycle:

Hold nab-paclitaxel until platelets 75,000 cells/mm3.

If recovery takes 1 week, maintain nab-paclitaxel dose.

If recovery takes 23 weeks, decrease 1 dose level.
Grade 4
Hold nab-paclitaxel until platelets 75,000 cells/mm3.
Decrease nab-paclitaxel one dose level.
G-CSFgranulocyte colonystimulating factor.
5.2
SAFETY PARAMETERS AND DEFINITIONS
Safety assessments will consist of monitoring and recording protocol-defined adverse 
events (AEs), including but not restricted to serious adverse events (SAEs) and adverse 
events of special interest, performing protocol-specified safety laboratory assessments,
measuring protocol-specified vital signs, and conducting other protocol-specified tests 
that are deemed critical to the safety evaluation of the study.
Certain types of events require immediate reporting to the Sponsor, as outlined in 
Section 5.4.
5.2.1
Adverse Events
According to the ICH guideline for Good Clinical Practice, an adverse event is any 
untoward medical occurrence in a clinical investigation subject administered a 


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pharmaceutical product, regardless of causal attribution.  An adverse event can 
therefore be any of the following:

Any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal product, 
whether or not considered related to the medicinal product

Any new disease or exacerbation of an existing disease (a worsening in the 
character, frequency, or severity of a known condition), except as described in 
Section 5.3.5.9

Recurrence of an intermittent medical condition (e.g., headache) not present at 
baseline

Any deterioration in a laboratory value or other clinical test (e.g., ECG, X-ray) that is 
associated with symptoms or leads to a change in study treatment or concomitant 
treatment or discontinuation from study treatment

Adverse events that are related to a protocol-mandated intervention, including those 
that occur prior to assignment of study treatment (e.g., screening invasive 
procedures such as biopsies)
5.2.2
Serious Adverse Events (Immediately Reportable to the 
Sponsor)
A serious adverse event is any adverse event that meets any of the following criteria:

Is fatal (i.e., the adverse event actually causes or leads to death)

Is life threatening (i.e., the adverse event, in the view of the investigator, places the 
patient at immediate risk of death)
This does not include any adverse event that had it occurred in a more severe 
form or was allowed to continue might have caused death.

Requires or prolongs inpatient hospitalization (see Section 5.3.5.11)

Results in persistent or significant disability/incapacity (i.e., the adverse event 
results in substantial disruption of the patient’s ability to conduct normal life 
functions)

Is a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to 
study treatment

Is a significant medical event in the investigator's judgment (e.g., may jeopardize the 
patient or may require medical/surgical intervention to prevent one of the outcomes 
listed above)
The terms "severe" and "serious" are not synonymous.  Severity refers to the intensity of 
an adverse event (e.g., rated as mild, moderate, or severe, or according to NCI CTCAE; 
see Section 5.3.3); the event itself may be of relatively minor medical significance 
(such as severe headache without any further findings).
Severity and seriousness need to be independently assessed for each adverse event 
recorded on the eCRF.


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Serious adverse events are required to be reported by the investigator to the Sponsor 
immediately (i.e., no more than 24 hours after learning of the event; see Section 5.4.2 for 
reporting instructions).
5.2.3
Adverse Events of Special Interest (Immediately Reportable to 
the Sponsor)
Adverse events of special interest are required to be reported by the investigator to the 
Sponsor immediately (i.e., no more than 24 hours after learning of the event; see 
Section 5.4.2 for reporting instructions).  Adverse events of special interest for this study 
include the following:

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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

Suspected transmission of an infectious agent by the study treatment, as defined 
below:
Any organism, virus, or infectious particle (e.g., prion proteintransmitting 
transmissible spongiform encephalopathy), pathogenic or non-pathogenic, is 
considered an infectious agent.  A transmission of an infectious agent may be 
suspected from clinical symptoms or laboratory findings that indicate an 
infection in a patient exposed to a medicinal product.  This term applies only
when a contamination of study treatment is suspected.

Pneumonitis

Colitis

Endocrinopathies:  diabetes mellitus, pancreatitis, adrenal insufficiency, 
hyperthyroidism, and hypophysitis

Hepatitis, including AST or ALT 10ULN

Systemic lupus erythematosus

Neurological disorders:  Guillain-Barré syndrome, myasthenic syndrome or 
myasthenia gravis, and meningoencephalitis

Events suggestive of hypersensitivity, infusion-related reactions (IRRs), cytokine 
release syndrome, influenza-like illness, HLH, and MAS 

Nephritis

Ocular toxicities (e.g., uveitis, retinitis)

Myositis

Myopathies, including rhabdomyolysis 


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
Grade 2 cardiac disorders (e.g., atrial fibrillation, myocarditis, pericarditis)

Vasculitis
5.2.4
Selected Adverse Events
Additional data will be collected for the selected adverse events in the following sections.
5.2.4.1
Cardiac, General
Symptomatic left ventricular systolic dysfunction should be reported as a serious 
adverse event. If the diagnosis is heart failure, it should be reported as such and not in 
terms of the individual signs and symptoms thereof.
Heart failure should be graded according to the NCI CTCAE v4.0 for “heart failure” 
(Grade 2, 3, 4, or 5) and in addition according to the NYHA classification.
Heart failure occurring during the study and post-study (see Section 5.6) must be 
reported, irrespective of causal relationship, and followed until one of the following 
occurs: resolution or improvement to baseline status, no further improvement can be 
expected, or death.
5.2.4.2
Asymptomatic Left Ventricular Systolic Dysfunction
Asymptomatic declines in LVEF should generally not be reported as adverse events 
because LVEF data are collected separately in the eCRF. Exceptions to this rule are as 
follows:

An asymptomatic decline in LVEF 10 percentage points from baseline to an LVEF
50% must be reported as an adverse event with the term “asymptomatic ejection 
fraction decreased” as per NCI CTCAE v4.0.

An asymptomatic decline in LVEF requiring treatment delay or leading to
discontinuation of atezolizumab, nab-paclitaxel, doxorubicin, or cyclophosphamide
must also be reported.
5.3
METHODS AND TIMING FOR CAPTURING AND ASSESSING 
SAFETY PARAMETERS
The investigator is responsible for ensuring that all adverse events (see Section 5.2.1 for 
definition) are recorded on the Adverse Event eCRF and reported to the Sponsor in 
accordance with instructions provided in this section and in Sections 5.55.6.
For each adverse event recorded on the Adverse Event eCRF, the investigator will make 
an assessment of seriousness (see Section 5.2.2 for seriousness criteria), severity 
(see Section 5.3.3), and causality (see Section 5.3.4).
5.3.1
Adverse Event Reporting Period
Investigators will seek information on adverse events at each patient contact.  
All adverse events, whether reported by the patient or noted by study personnel, will be 
recorded in the patient’s medical record and on the Adverse Event eCRF.


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After informed consent has been obtained but prior to initiation of study treatment, 
only serious adverse events caused by a protocol-mandated intervention (e.g., invasive 
procedures such as biopsies, discontinuation of medications) should be reported 
(see Section 5.4.2 for instructions for reporting serious adverse events).
After initiation of study treatment, all adverse events will be reported until 30 days
after the last dose of study treatment or until initiation of new anti-cancer therapy, 
whichever occurs first, and serious adverse events and adverse events of special 
interest will continue to be reported until 90 days after the last dose of study treatment or 
until initiation of new anti-cancer therapy, whichever occurs first.
Study drugrelated SAEs will be recorded indefinitely (even if the study has been
closed). Instructions for reporting adverse events that occur after the adverse event 
reporting period are provided in Section 5.6.
5.3.2
Eliciting Adverse Event Information
A consistent methodology of non-directive questioning should be adopted for eliciting 
adverse event information at all patient evaluation timepoints.  Examples of non-directive 
questions include the following:
"How have you felt since your last clinic visit?"
"Have you had any new or changed health problems since you were last here?" 
5.3.3
Assessment of Severity of Adverse Events
The adverse event severity grading scale for the NCI CTCAE (v4.0) will be used for 
assessing adverse event severity.  Table 5 will be used for assessing severity for 
adverse events that are not specifically listed in the NCI CTCAE.


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Table 5
Adverse Event Severity Grading Scale for Events Not Specifically 
Listed in NCI CTCAE
Grade
Severity
1
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
or intervention not indicated
2
Moderate; minimal, local, or non-invasive intervention indicated; or limiting 
age-appropriate instrumental activities of daily living a
3
Severe or medically significant, but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; or 
limiting self-care activities of daily living b,c
4
Life-threatening consequences or urgent intervention indicated d
5
Death related to adverse event d
NCI CTCAENational Cancer Institute Common Terminology Criteria for Adverse Events.
Note:  Based on the most recent version of NCI CTCAE (v4.0), which can be found at:  
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm
a Instrumental activities of daily living refer to preparing meals, shopping for groceries or 
clothes, using the telephone, managing money, and so on.
b Examples of self-care activities of daily living include bathing, dressing and undressing, 
feeding oneself, using the toilet, and taking medications, as performed by patients who are 
not bedridden.
c If an event is assessed as a "significant medical event," it must be reported as a serious 
adverse event (see Section 5.4.2 for reporting instructions), per the definition of serious 
adverse event in Section 5.2.2.
d Grade 4 and 5 events must be reported as serious adverse events (see Section 5.4.2 for 
reporting instructions) per the definition of serious adverse event in Section 5.2.2.
5.3.4
Assessment of Causality of Adverse Events
Investigators should use their knowledge of the patient, the circumstances surrounding 
the event, and an evaluation of any potential alternative causes to determine whether an 
adverse event is considered to be related to study treatment, indicating "yes" or "no"
accordingly.  The following guidance should be taken into consideration (see also 
Table 6):

Temporal relationship of event onset to the initiation of study treatment

Course of the event, with special consideration of the effects of dose reduction, 
discontinuation of study treatment, or reintroduction of study treatment (as
applicable)

Known association of the event with study treatment or with similar treatments

Known association of the event with the disease under study

Presence of risk factors in the patient or use of concomitant medications known to 
increase the occurrence of the event

Presence of non-treatment-related factors that are known to be associated with the 
occurrence of the event


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Table 6
Causal Attribution Guidance
Is the adverse event suspected to be caused by study treatment on the basis of facts, 
evidence, science-based rationales, and clinical judgment?
YES
There is a plausible temporal relationship between the onset of the adverse event and 
administration of study treatment, and the adverse event cannot be readily explained by 
the patient's clinical state, intercurrent illness, or concomitant therapies; and/or the 
adverse event follows a known pattern of response to study treatment; and/or the 
adverse event abates or resolves upon discontinuation of study treatment or dose 
reduction and, if applicable, reappears upon re-challenge.
NO
An adverse event will be considered related, unless it fulfills the criteria specified below:  
Evidence exists that the adverse event has an etiology other than study treatment
(e.g., preexisting medical condition, underlying disease, intercurrent illness, 
or concomitant medication); and/or the adverse event has no plausible temporal 
relationship to administration of study treatment (e.g., cancer diagnosed 2 days after 
first dose of study treatment).
For patients receiving combination therapy, causality will be assessed individually for 
each protocol-mandated therapy.
5.3.5
Procedures for Recording Adverse Events
Investigators should use correct medical terminology/concepts when recording adverse 
events on the Adverse Event eCRF.  Avoid colloquialisms and abbreviations.
Only one adverse event term should be recorded in the event field on the 
Adverse Event eCRF.
5.3.5.1
Infusion-Related Reactions
Adverse events that occur during or within 24 hours after study treatment administration 
and are judged to be related to study treatment infusion should be captured as a 
diagnosis (e.g., "infusion-related reaction") on the Adverse Event eCRF.  If possible,
avoid ambiguous terms such as "systemic reaction."  Associated signs and symptoms 
should be recorded on the dedicated Infusion-Related Reaction eCRF.  If a patient 
experiences both a local and systemic reaction to the same dose of study treatment, 
each reaction should be recorded separately on the Adverse Event eCRF, with signs 
and symptoms also recorded separately on the dedicated Infusion-Related Reaction 
eCRF.
5.3.5.2
Diagnosis versus Signs and Symptoms
For adverse events other than IRRs (see Section 5.3.5.1), a diagnosis (if known) should 
be recorded on the Adverse Event eCRF rather than individual signs and symptoms 
(e.g., record only liver failure or hepatitis rather than jaundice, asterixis, and elevated 
transaminases).  However, if a constellation of signs and/or symptoms cannot be 
medically characterized as a single diagnosis or syndrome at the time of reporting, each 


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individual event should be recorded on the Adverse Event eCRF.  If a diagnosis is 
subsequently established, all previously reported adverse events based on signs and 
symptoms should be nullified and replaced by one adverse event report based on the 
single diagnosis, with a starting date that corresponds to the starting date of the first 
symptom of the eventual diagnosis.
5.3.5.3
Adverse Events That Are Secondary to Other Events
In general, adverse events that are secondary to other events (e.g., cascade events or 
clinical sequelae) should be identified by their primary cause, with the exception of 
severe or serious secondary events.  A medically significant secondary adverse event 
that is separated in time from the initiating event should be recorded as an independent 
event on the Adverse Event eCRF.  For example:

If vomiting results in mild dehydration with no additional treatment in a healthy adult, 
only vomiting should be reported on the eCRF.

If vomiting results in severe dehydration, both events should be reported separately 
on the eCRF.

If a severe gastrointestinal hemorrhage leads to renal failure, both events should be 
reported separately on the eCRF.

If dizziness leads to a fall and consequent fracture, all three events should be 
reported separately on the eCRF.

If neutropenia is accompanied by an infection, both events should be reported 
separately on the eCRF.
All adverse events should be recorded separately on the Adverse Event eCRF if it is 
unclear as to whether the events are associated.
5.3.5.4
Persistent or Recurrent Adverse Events
A persistent adverse event is one that extends continuously, without resolution, between 
patient evaluation timepoints.  Such events should only be recorded once on the 
Adverse Event eCRF.  The initial severity (intensity or grade) of the event will be 
recorded at the time the event is first reported.  If a persistent adverse event becomes 
more severe, the most extreme severity should also be recorded on the Adverse Event 
eCRF.  If the event becomes serious, it should be reported to the Sponsor immediately 
(i.e., no more than 24 hours after learning that the event became serious; see 
Section 5.4.2 for reporting instructions).  The Adverse Event eCRF should be updated 
by changing the event from "non-serious" to "serious," providing the date that the event 
became serious, and completing all data fields related to serious adverse events.
A recurrent adverse event is one that resolves between patient evaluation timepoints 
and subsequently recurs.  Each recurrence of an adverse event should be recorded as a 
separate event on the Adverse Event eCRF.


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5.3.5.5
Abnormal Laboratory Values
Not every laboratory abnormality qualifies as an adverse event.  A laboratory test result 
must be reported as an adverse event if it meets any of the following criteria:

Is accompanied by clinical symptoms

Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation)

Results in a medical intervention (e.g., potassium supplementation for hypokalemia) 
or a change in concomitant therapy

Is clinically significant in the investigator’s judgment 
Note:  For oncology trials, certain abnormal values may not qualify as adverse 
events.
It is the investigator’s responsibility to review all laboratory findings.  Medical and 
scientific judgment should be exercised in deciding whether an isolated laboratory 
abnormality should be classified as an adverse event.
If a clinically significant laboratory abnormality is a sign of a disease or syndrome 
(e.g., alkaline phosphatase and bilirubin 5ULN associated with cholestasis), only the 
diagnosis (i.e., cholestasis) should be recorded on the Adverse Event eCRF.
If a clinically significant laboratory abnormality is not a sign of a disease or syndrome, 
the abnormality itself should be recorded on the Adverse Event eCRF, along with a 
descriptor indicating whether the test result is above or below the normal range 
(e.g., "elevated potassium," as opposed to "abnormal potassium").  If the laboratory 
abnormality can be characterized by a precise clinical term per standard definitions, the 
clinical term should be recorded as the adverse event.  For example, an elevated serum 
potassium level of 7.0 mEq/L should be recorded as "hyperkalemia."
Observations of the same clinically significant laboratory abnormality from visit to visit 
should only be recorded once on the Adverse Event eCRF (see Section 5.3.5.4 for 
details on recording persistent adverse events).
5.3.5.6
Abnormal Vital Sign Values
Not every vital sign abnormality qualifies as an adverse event.  A vital sign result must
be reported as an adverse event if it meets any of the following criteria:

Is accompanied by clinical symptoms

Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation)

Results in a medical intervention or a change in concomitant therapy

Is clinically significant in the investigator’s judgment 


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It is the investigator’s responsibility to review all vital sign findings.  Medical and scientific 
judgment should be exercised in deciding whether an isolated vital sign abnormality 
should be classified as an adverse event.
If a clinically significant vital sign abnormality is a sign of a disease or syndrome 
(e.g., high blood pressure), only the diagnosis (i.e., hypertension) should be recorded on 
the Adverse Event eCRF.
Observations of the same clinically significant vital sign abnormality from visit to visit 
should only be recorded once on the Adverse Event eCRF (see Section 5.3.5.4 for 
details on recording persistent adverse events).
5.3.5.7
Abnormal Liver Function Tests
The finding of an elevated ALT or AST (3ULN) in combination with either an elevated 
total bilirubin (2ULN) or clinical jaundice in the absence of cholestasis or other 
causes of hyperbilirubinemia is considered to be an indicator of severe liver injury
(as defined by Hy's Law).  Therefore, investigators must report as an adverse event the 
occurrence of either of the following:

Treatment-emergent ALT or AST 3 ULN (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
The most appropriate diagnosis or (if a diagnosis cannot be established) the abnormal 
laboratory values should be recorded on the Adverse Event eCRF (see Section 5.3.5.2) 
and reported to the Sponsor immediately (i.e., no more than 24 hours after learning of 
the event), either as a serious adverse event or an adverse event of special interest 
(see Section 5.4.2).
5.3.5.8
Deaths
For this protocol, mortality is an efficacy endpoint.  Deaths that occur during the 
protocol-specified adverse event reporting period (see Section 5.3.1) that are attributed 
by the investigator solely to recurrence and progression of breast cancer should be 
recorded on the Death Attributed to Progressive Disease eCRF.  All other on-study 
deaths, regardless of relationship to study treatment, must be recorded on the Adverse 
Event eCRF and immediately reported to the Sponsor (see Section 5.4.2). An 
independent monitoring committee will monitor the frequency of deaths from all causes.
Death should be considered an outcome and not a distinct event.  The event or condition 
that caused or contributed to the fatal outcome should be recorded as the single medical 
concept on the Adverse Event eCRF.  Generally, only one such event should be 
reported.  If the cause of death is unknown and cannot be ascertained at the time of 
reporting, "unexplained death" should be recorded on the Adverse Event eCRF.  If the 


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cause of death later becomes available (e.g., after autopsy), "unexplained death" should 
be replaced by the established cause of death.  The term "sudden death" should not be 
used unless combined with the presumed cause of death (e.g., "sudden cardiac death").
Deaths that occur after the adverse event reporting period should be reported as 
described in Section 5.6.
5.3.5.9
Preexisting Medical Conditions
A preexisting medical condition is one that is present at the screening visit for this study.  
Such conditions should be recorded on the General Medical History and Baseline 
Conditions eCRF.
A preexisting medical condition should be recorded as an adverse event only if the 
frequency, severity, or character of the condition worsens during the study.  When 
recording such events on the Adverse Event eCRF, it is important to convey the concept 
that the preexisting condition has changed by including applicable descriptors 
(e.g., "more frequent headaches").
5.3.5.10
Lack of Efficacy or Worsening of TNBC
Events that are clearly consistent with the expected pattern of progression of the 
underlying disease should not be recorded as adverse events.  These data will be 
captured as efficacy assessment data only.  Instances of disease recurrence will be 
verified by pathologic confirmation if clinically feasible.  In rare cases, the determination 
of clinical progression will be based on symptomatic deterioration.  However, every effort 
should be made to document progression through use of objective criteria.  If there is 
any uncertainty as to whether an event is due to disease progression, it should be 
reported as an adverse event.
5.3.5.11
Hospitalization or Prolonged Hospitalization
Any adverse event that results in hospitalization (i.e., inpatient admission to a hospital)
or prolonged hospitalization should be documented and reported as a serious 
adverse event (per the definition of serious adverse event in Section 5.2.2), except as 
outlined below.
An event that leads to hospitalization under the following circumstances should not be 
reported as an adverse event or a serious adverse event:

Hospitalization for respite care

Planned hospitalization required by the protocol (e.g., for study treatment
administration or performance of an efficacy measurement for the study)


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
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 recurrence/progression of the underlying cancer
An event that leads to hospitalization under the following circumstances is not 
considered to be a serious adverse event, but should be reported as an adverse 
event instead:

Hospitalization that was necessary because of patient requirement for outpatient 
care outside of normal outpatient clinic operating hours
5.3.5.12
Cases of Accidental Overdose or Medication Error
Accidental overdose and medication error (hereafter collectively referred to as "special 
situations"), are defined as follows:

Accidental overdose:  accidental administration of a drug in a quantity that is higher 
than the assigned dose

Medication error:  accidental deviation in the administration of a drug 
In some cases, a medication error may be intercepted prior to administration of 
the drug.
Special situations are not in themselves adverse events but may result in adverse 
events.  Each adverse event associated with a special situation should be recorded 
separately on the Adverse Event eCRF.  If the associated adverse event fulfills 
seriousness criteria or qualifies as an adverse event of special interest, the event should 
be reported to the Sponsor immediately (i.e., no more than 24 hours after learning of the 
event; see Section 5.4.2).  For atezolizumab and nab-paclitaxel, 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.


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In addition, all special situations associated with atezolizumab and nab-paclitaxel, 
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 
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 using PRO data.  However, if any PRO responses 
suggestive of a possible adverse event are identified during site review of the PRO data, 
the investigator will determine whether the criteria for an adverse event have been met 
and, if so, will report the event on the Adverse Event eCRF.
5.4
IMMEDIATE REPORTING REQUIREMENTS FROM 
INVESTIGATOR TO SPONSOR
Certain events require immediate reporting to allow the Sponsor to take appropriate 
measures to address potential new risks in a clinical trial.  The investigator must report 
such events to the Sponsor immediately; under no circumstances should reporting take 
place more than 24 hours after the investigator learns of the event.  The following is a list 
of events that the investigator must report to the Sponsor within 24 hours after learning 
of the event, regardless of relationship to study treatment:

Serious adverse events (see Section 5.4.2 for further details)

Adverse events of special interest (see Section 5.4.2 for further details)

Pregnancies (see Section 5.4.3 for further details)
For serious adverse events and adverse events of special interest, the investigator must 
report new significant follow-up information for these events to the Sponsor immediately 


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(i.e., no more than 24 hours after becoming aware of the information).  New significant 
information includes the following:

New signs or symptoms or a change in the diagnosis

Significant new diagnostic test results

Change in causality based on new information

Change in the event’s outcome, including recovery

Additional narrative information on the clinical course of the event
Investigators must also comply with local requirements for reporting serious adverse 
events to the local health authority and IRB/EC.
5.4.1
Emergency Medical Contacts
Medical Monitor Contact Information for All Sites
Primary Medical Monitor:
, M.D., Ph.D.
Mobile Telephone No./SMS:
Secondary Medical Monitor/
Roche Medical Responsible:
 M.D.
Telephone No.:
Mobile Telephone No./SMS:
To ensure the safety of 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, as well as 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 Study Treatment Initiation
After informed consent has been obtained but prior to initiation of study treatment, only 
serious adverse events caused by a protocol-mandated intervention should be reported.  
The Serious Adverse Event/Special Situations Reporting Form provided to investigators 
should be completed and submitted to the Sponsor or its designee immediately (i.e., no 
more than 24 hours after learning of the event), either by faxing or by scanning and 
emailing the form using the fax number or email address provided to investigators.


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5.4.2.2
Events That Occur after Study Treatment Initiation
After initiation of study treatment, all adverse events will be reported until 30 days after 
the last dose of study treatment or until initiation of new systemic anti-cancer therapy, 
whichever occurs first, and serious adverse events and adverse events of special 
interest will be reported until 90 days after the last dose of study treatment or until 
initiation of new systemic anti-cancer therapy, whichever occurs first.  Investigators 
should record all case details that can be gathered immediately (i.e., within 24 hours 
after learning of the event) on the Adverse Event eCRF and submit the report via the 
EDC system.  A report will be generated and sent to Roche Safety Risk Management by 
the EDC system.
In the event that the EDC system is unavailable, the Serious Adverse Event/Special 
Situations Reporting Form provided to investigators should be completed and submitted 
to the Sponsor or its designee immediately (i.e., no more than 24 hours after learning of 
the event), either by faxing or by scanning and emailing the form using the fax number or 
email address provided to investigators.  Once the EDC system is available, all 
information will need to be entered and submitted via the EDC system.
Instructions for reporting serious adverse events that occur 90 days after the last dose 
of study treatment are provided in Section 5.6.
5.4.3
Reporting Requirements for Pregnancies
5.4.3.1
Pregnancies in Female Patients
Female patients of childbearing potential will be instructed through the Informed Consent 
Form to immediately inform the investigator if they become pregnant during the study or 
within 5 months after the last dose of atezolizumab, 1 month after the last dose of nab-
paclitaxel, 6 months after the last dose of doxorubicin, or 12 months after the last dose 
of cyclophosphamide, whichever is later.  A Clinical Trial Pregnancy Reporting Form 
should be completed and submitted to the Sponsor or its designee immediately (i.e., no 
more than 24 hours after learning of the pregnancy), either by faxing or by scanning and 
emailing the form using the fax number or email address provided to investigators.  
Pregnancy should not be recorded on the Adverse Event eCRF.  The investigator should 
discontinue study treatment and counsel the patient, discussing the risks of the 
pregnancy and the possible effects on the fetus.  Monitoring of the patient should 
continue until conclusion of the pregnancy.  Any serious adverse events associated with 
the pregnancy (e.g., an event in the fetus, an event in the mother during or after the 
pregnancy, or a congenital anomaly/birth defect in the child) should be reported on the 
Adverse Event eCRF.  In addition, the investigator will submit a Clinical Trial Pregnancy 
Reporting Form when updated information on the course and outcome of the pregnancy 
becomes available.
5.4.3.2
Pregnancies in Female Partners of Male Patients
Male patients will be instructed through the Informed Consent Form to immediately 
inform the investigator if their partner becomes pregnant during the study or within 


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6 months after the last dose of nab-paclitaxel, cyclophosphamide, or doxorubicin.  The 
investigator should report the pregnancy on the paper Clinical Trial Pregnancy Reporting 
Form and submit the form to the Sponsor or its designee immediately (i.e., no more than 
24 hours after learning of the pregnancy), either by faxing or by scanning and emailing 
the form using the fax number or email address provided to investigators.  Attempts 
should be made to collect and report details of the course and outcome of any 
pregnancy in the partner of a male patient exposed to study treatment.  When permitted 
by the site, the pregnant partner would need to sign an Authorization for Use and 
Disclosure of Pregnancy Health Information to allow for follow-up on her pregnancy.  If 
the authorization has been signed, the investigator should submit a Clinical Trial 
Pregnancy Reporting Form with additional information on the pregnant partner and the 
course and outcome of the pregnancy as it becomes available.  An investigator who is 
contacted by the male patient or his pregnant partner may provide information on the 
risks of the pregnancy and the possible effects on the fetus, to support an informed 
decision in cooperation with the investigator and/or obstetrician.
5.4.3.3
Abortions
A spontaneous abortion should be classified as a serious adverse event (as the Sponsor 
considers abortions to be medically significant), recorded on the Adverse Event eCRF, 
and reported to the Sponsor immediately (i.e., no more than 24 hours after learning of 
the event; see Section 5.4.2).
If a therapeutic or elective abortion was performed because of an underlying maternal or 
embryofetal toxicity, the toxicity should be classified as a serious adverse event, 
recorded on the Adverse Event eCRF, and reported to the Sponsor immediately (i.e., no 
more than 24 hours after learning of the event; see Section 5.4.1).  A therapeutic or 
elective abortion performed for reasons other than an underlying maternal or 
embryofetal toxicity is not considered an adverse event.
All abortions should be reported as pregnancy outcomes on the paper Clinical Trial 
Pregnancy Reporting Form.
5.4.3.4
Congenital Anomalies/Birth Defects
Any congenital anomaly/birth defect in a child born to a female patient exposed to study 
treatment or the female partner of a male patient exposed to study treatment should be 
classified as a serious adverse event, recorded on the Adverse Event eCRF, and 
reported to the Sponsor immediately (i.e., no more than 24 hours after learning of the 
event; see Section 5.4.2).
5.5
FOLLOW-UP OF PATIENTS AFTER ADVERSE EVENTS
5.5.1
Investigator Follow-Up
The investigator should follow each adverse event until the event has resolved to baseline 
grade or better, the event is assessed as stable by the investigator, the patient is lost to 
follow-up, or the patient withdraws consent.  Every effort should be made to follow all 


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serious adverse events considered to be related to study treatment or trial-related 
procedures until a final outcome can be reported.
During the study period, resolution of adverse events (with dates) should be documented 
on the Adverse Event eCRF and in the patient’s medical record to facilitate source data 
verification.
All pregnancies reported during the study should be followed until pregnancy outcome.
5.5.2
Sponsor Follow-Up
For serious adverse events, adverse events of special interest, and pregnancies, the 
Sponsor or a designee may follow up with the investigator 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 reporting period for all serious adverse events and adverse events of 
special interest (defined as 90 days after the last dose of 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/Special Situations 
Reporting Form using the fax number or email address provided to investigators.
5.7
EXPEDITED REPORTING TO HEALTH AUTHORITIES, 
INVESTIGATORS, INSTITUTIONAL REVIEW BOARDS, AND 
ETHICS COMMITTEES
The Sponsor will promptly evaluate all serious adverse events and adverse events of 
special interest against cumulative product experience to identify and expeditiously 
communicate possible new safety findings to investigators, IRBs, ECs, and applicable 
health authorities based on applicable legislation.
To determine reporting requirements for single adverse event cases, the Sponsor will 
assess the expectedness of these events using the following reference documents:

Atezolizumab Investigator's Brochure

Local prescribing information (e.g., Section 4.8 of E.U. Summary of Product 
Characteristics for nab-paclitaxel)


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The Sponsor will compare the severity of each event and the cumulative event 
frequency reported for the study with the severity and frequency reported in the 
applicable reference document.
Reporting requirements will also be based on the investigator's assessment of causality 
and seriousness, with allowance for upgrading by the Sponsor as needed.
An iDMC will monitor the incidence of these expected events 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 population for efficacy is the ITT population, defined as all 
randomized patients, and the PD-L1positive subpopulation, defined as patients in the 
ITT population whose PD-L1 status is IC1/2/3 at the time of randomization.  Patients will 
be assigned to the treatment group to which they were randomized.
The PRO-evaluable population is defined as patients in the ITT population with baseline 
PRO assessment.
The primary analysis population for safety is the safety-evaluable population, defined as 
all patients who received at least one dose of study medication.  Patients will be 
assigned to treatment groups as treated, and all patients who received any dose of 
atezolizumab will be included in the atezolizumab treatment arm.
6.1
DETERMINATION OF SAMPLE SIZE
The study will first randomize approximately N1204 patients in Stage 1 
(1:1 randomization ratio). Based on information from these patients and a pre-specified 
adaptive rule, the decision will be made regarding whether or not to randomize 
approximately N2120 patients in Stage 2 (1:1 randomization ratio). 
Details of the adaptive design as well as the statistical procedures to control the overall 
one-sided type I error at 0.025 are described in the sections below.  Additional details 
are provided in Appendix 14 and Appendix 15.
6.1.1
Adaptive Design
The design is a two-stage adaptive enrichment design for the co-primary endpoints of 
pCR in the ITT (F) and PD-L1postive (S) population at the overall one-sided 
significance level  0.025. The design closely follows the general statistical principles 
for adaptive enrichment designs described in Wassmer et al. 2016.


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The study will first randomize approximately  204 patients in Stage 1 
(1:1 randomization ratio). Based on information from these patients and a pre-specified 
adaptive rule, one of the following decisions will be taken:
1.
Not initiate Stage 2 due to efficacy in F, S, or both populations. 
3) Not initiate Stage 2 due to lack of efficacy in both F and S. 
4) Continue the trial to Stage 2.  In Stage 2, another approximately  120 patients will 
be randomized (1:1 randomization ratio).  Based on data from Stage 1, a decision 
will be taken to either randomize patients from the ITT (F) or from the PD-L1positive 
(S) population only in Stage 2. 
This design has two sources of multiplicity: a) Two co-primary populations and b) two 
analyses (Stage 1 data only, Stage 1 and Stage 2 data combined). To protect the 
familywise one-sided type I error of the trial (α) for this study at 0.025 in the strong 
sense, the co-primary endpoints will be tested using Simes’ method at each stage
(Wassmer et al. 2016) and p-values will be combined across stages using the weighted 
inverse normal combination test with pre-defined weights (Wassmer et al. 2016)
 =  ( + )
⁄
and  =  ( + )
⁄
  for Stage 1 and Stage 2, respectively, 
with  = 204 and  = 120 denoting the planned sample sizes for both stages.
Of note, the planned sample size rather than the actual number of recruited patients will 
be used for the determination of the weights to protect type I error. If and   denote 
the p-values based on Stage 1 or Stage 2 data only (for the null hypotheses 
{}, 
{!} or
the intersection null hypothesis 
{,!}, respectively), then the combination p-value is 
defined as #$%& = 1 −({ ∙(*(1 −) +  ∙(*(1 −)} (Wassmer et al. 2016).
Further details regarding the testing procedure are provided in Appendix 14 and
Appendix 15, as well as the Statistical Analysis Plan.
6.1.2
Type I Error Control
The pre-defined one-sided type I error for the interim analysis at Stage 1 is  0.0125 
(i.e., 50% of the total type I error). The co-primary endpoints in F and S at Stage 1 will 
be tested using a closed testing procedure using Simes’ test for the intersection 
hypothesis. As stated in Wassmer et al. 2016, test statistics in F and S are always 
positively correlated, hence type I error rate control of the Simes test can be guaranteed 
in general.
Importantly, the p-value  based on Stage 1 data only and the combination p-value 
#$%& have the same joint distribution under the null hypothesis as the p-values from a 
group-sequential test with two stages at information times + =  and + = 1. 
Thus standard statistical software for group sequential designs can be used for the 
determination of critical values for the adaptive design (Wassmer et al. 2016). As the 
study design uses a critical value of  0.0125 (i.e., 50% of the total type I error) for 
Stage 1, this implies that a critical value of #$%& 0.0184 can be applied to the 
combination p-values.


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6.2
SUMMARIES OF CONDUCT OF STUDY
For all randomized patients (i.e., ITT population), a participant flowchart for depicting the 
progress of subjects through the phases of the trial will be provided by treatment arm,
including a complete description of patient disposition specifying the number of 
randomized patients and completed and discontinued patients from trial treatment and 
study with reasons for premature discontinuation. Documented protocol deviations
including those related to study inclusion/exclusion criteria, conduct of the study, patient 
management, or patient assessment will be also tabulated by treatment arm.
6.3
SUMMARIES OF TREATMENT GROUP COMPARABILITY
Demographic variables such as age, sex, race/ethnicity, and baseline characteristics
(in particular, stratification variables) will be summarized by treatment arm for the ITT as 
well as PD-L1positive population. Only descriptive analyses are planned; no formal 
statistical tests will be applied.  Continuous variables will be reported and summarized 
by use of standard measures of central tendency and dispersion (mean, standard 
deviation, median, and range including minimum and maximum), and categorical 
(i.e., discrete) data will be reported and summarized by frequencies and percentages.
The baseline value of any variable will be defined as the last available value prior to the 
first administration of study treatment.
6.4
EFFICACY ANALYSES
Details of the analyses, including methods for handling missing data, are specified in the 
Statistical Analysis Plan (SAP).
6.4.1
Primary Efficacy Endpoint:  Pathologic Complete Response
The primary efficacy objective for this study is to evaluate the efficacy of neoadjuvant 
atezolizumabnab-pacAC compared with placebonab-pacAC in patients with T2-4d 
TNBC, as measured by pCR defined as eradication of tumor from both breast and lymph 
nodes (ypT0/is ypN0).  The primary efficacy endpoint will be established following 
completion of neoadjuvant therapy and surgery. 
The ITT as well as PD-L1positive populations will be used for the primary analysis of 
pCR.  In the primary analysis, patients whose pCR assessment was missing will be 
counted as not achieving a pCR.  An estimate of the pCR rate and its 95% CI (Clopper 
and Pearson 1934) will be calculated for each treatment arm.  The difference in pCR 
rates will be provided with 95% CI, using the normal approximation to the binomial 
distribution.  For the ITT population, the Cochran-Mantel-Haenszel 2 test stratified 
according to tumor PD-L1 status (IC0 vs. IC1/2/3) and clinical stage at presentation 
(Stage II vs. III) will be used to test pCR rates between treatment groups at a two-sided 
significance level of 5%.  For the PD-L1positive population, similar test will be used with 
stratification only for clinical stage at presentation. An unstratified 2 versions of these 
tests will also be provided as a sensitivity analysis.


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6.4.2
Secondary Efficacy Endpoints
The secondary efficacy endpoints are the following:

EFS in all patients (ITT population) and in the subpopulation with PD-L1positive 
tumor status

DFS in all patients (ITT population) who undergo surgery and in the subpopulation 
of patients with PD-L1-positive tumor status who undergo surgery

OS in all patients (ITT population) and in the PD-L1positive subpopulation

PROs of function (role, physical) and HRQoL 
6.4.2.1
Event-Free Survival
EFS is defined as the time from randomization to the first documented occurrence of 
disease recurrence, disease progression, or death from any cause.
Patients without an event at the time of the analysis will be censored on the date on 
which they are last known to be alive and event free, on or before the clinical data cutoff 
date for the respective analysis.  Patients with no post-baseline information will be 
censored at the date of randomization.
EFS will be compared between treatment arms with an unstratified log-rank test.
The HR for EFS will be estimated using a stratified Cox proportional hazards model.  
The 95% CI for the HR will be provided.  Kaplan-Meier methodology will be used to 
estimate the median EFS (if reached) for each treatment arm, and Kaplan-Meier curves 
will be produced.  Brookmeyer-Crowley methodology will be used to construct the 95% 
CI for the median EFS for each treatment arm (Brookmeyer and Crowley 1982).  The 
Kaplan-Meier approach will be used to estimate 3-year EFS rates and corresponding 
95% CIs for each treatment arm.
The stratification factors for all analyses based on the ITT population will be:  AJCC
disease stage (II vs. III) and PD-L1 status (IC0 vs. IC1/2/3).
The stratification factors for EFS analysis in the PD-L1positive subpopulation will be 
AJCC disease stage (II vs. III).
Results from unstratified analyses will also be provided.
6.4.2.2
Disease-Free Survival
DFS is defined as the time from surgery (i.e., the first date of no disease) to the first 
documented disease recurrence or death from any cause, whichever occurs first.  DFS 
will be analyzed with the use of the same methodology as specified for EFS for both the 
ITT population and the PD-L1positive subpopulation.  The DFS analysis will be 
performed approximately 36 months after the randomization of the last patient.
Patients who do not undergo surgery at the end of neoadjuvant treatment will be 
excluded from the analysis of DFS.  Patients without a DFS event at the time of 


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analysis will be censored at the date when they were last known to be alive and event 
free. Patients who do not have information after surgery will be censored at the date 
of surgery.
6.4.2.3
Overall Survival
OS 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 analyses will be 
censored at the date when they were last known to be alive.  Patients who do not have 
information after baseline will be censored at the date of randomization.  OS will be 
analyzed with the use of the same methodology as specified for EFS for both the ITT 
population and the PD-L1positive subpopulation. 
6.4.2.4
Patient-Reported Outcomes of Role and Physical Function and
GHS/HRQoL―EORTC Data
The primary patient-reported endpoints are mean and mean changes from baseline 
score in function (role, physical) and GHS/HRQoL.  Summary statistics (mean, standard 
deviation, median, and range) of absolute scores and mean changes from baseline will 
be calculated for the functional (role [Question {Q}6, Q7], physical [Q1Q5]) and the 
GHS/HRQoL (Q29, Q30) scales of the EORTC QLQ-C30 at each assessment timepoint 
for each arm. The mean (and 95% CI) and median of the absolute scores and the 
changes from baseline will be reported for interval and continuous variables.  Previously 
published minimally important differences will be used to identify meaningful change 
from baseline within each treatment group on the functional and GHS/HRQoL scales 
(Osoba et al. 1998; Cocks et al. 2011). 
The EORTC QLQ-C30 (Version 3) data will be scored according to the EORTC scoring 
manual (Fayers et al. 2001). PRO completion, compliance rates, and reasons for 
missing data will be summarized at each timepoint by treatment arm. Details of the 
analyses, including methods for handling missing data, will be specified in the SAP.
6.4.3
Exploratory Efficacy Endpoints
The analyses of proportion of patients undergoing breast-conserving surgery, RCB 
index, and correlation of RCB with other clinical endpoints (if deemed appropriate) will 
be detailed in the SAP.
6.4.3.1
Patient-Reported Outcomes of Disease/Treatment-Related 
Symptoms, Emotional and Social Function―EORTC Data
Summary statistics (mean, standard deviation, median, and range) of absolute scores 
and mean changes from baseline will be calculated for all disease/treatment-related 
symptom items and scales, and the emotional, social function scales of the EORTC 
QLQ-C30 (see Appendix 5) at each assessment timepoint for each arm.


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6.4.3.2
Patient-Reported Outcome of Treatment Bother―FACT-G, GP5 
Single Item Data
A descriptive analysis of absolute scores and the proportion of patients selecting each 
response option at each assessment timepoint 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 (see Appendix 6).  Item GP5 from version 4 of the FACT-G questionnaire will 
be scored according to the FACIT scoring manual (Cella 1997). 
6.4.3.3
Health Economic EQ-5D-5L Data
Health utility data from the EQ-5D-5L (see Appendix 7) will be evaluated in 
pharmacoeconomic models.  The results from the health economic data analyses will be 
reported separately from the clinical study report.
6.5
SAFETY ANALYSES
Safety analyses will be performed on the safety population.
Safety will be assessed through summaries of adverse events, changes in laboratory
test results, changes in vital signs, study treatment exposures, and immunogenicity as
measured by anti-drug antibodies (ADAs) and will be presented by treatment arm.
Verbatim descriptions of adverse events will be mapped to Medical Dictionary 
for Regulatory Activities (MedDRA) thesaurus terms and graded according to 
NCI CTCAE v4.0.
Adverse events will be summarized by mapped term and appropriate thesaurus level, 
and adverse event severity will be graded according to NCI CTCAE v4.0.  
The treatment-emergent adverse events leading to withdrawal of study drug, leading to 
dose reduction or interruption, related to study drug, severe (i.e., Grade 3), fatal 
(i.e., Grade 5), serious, and of special interest will be also summarized.
All deaths and causes of death will be summarized.
Laboratory data with values outside of the normal ranges will be identified. Relevant 
laboratory values will be summarized by treatment arm over time, with NCI CTCAE v4.0 
Grade 3 and Grade 4 values identified, where appropriate.  Changes from baseline in 
NCI CTCAE v4.0 grade (i.e., shift tables) will be also provided by treatment arm.
Of note, abnormal laboratory data that are clinically significant will be reported as 
adverse events and summarized in the adverse event tables.
Vital signs and other physical findings will be summarized by treatment arm.


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6.6
PHARMACOKINETIC ANALYSES
Atezolizumab serum concentration data (Cmin and Cmax) will be tabulated and
summarized.  Descriptive statistics will include means, medians, ranges, SDs, coefficient 
of variation (%CV), and others as appropriate.
Additional PK and PD analyses will be conducted as appropriate.
6.7
IMMUNOGENICITY ANALYSES
The immunogenicity analyses will include patients with at least one post-baseline ADA 
assessment, with patients grouped according to treatment received.
The numbers and proportions of ADA-positive patients and ADA-negative patients at 
baseline (baseline prevalence) and after baseline (post-baseline incidence) will be 
summarized by treatment group.  When determining post-baseline incidence, patients 
are considered to be ADA positive if they are ADA negative or are missing data at 
baseline but develop an ADA response following study drug exposure 
(treatment-induced ADA response), or if they are ADA positive at baseline and the titer 
of one or more post-baseline samples is at least 0.60 titer unit greater than the titer of 
the baseline sample (treatment-enhanced ADA response).  Patients are considered to 
be ADA negative if they are ADA negative or are missing data at baseline and all 
post-baseline samples are negative, or if they are ADA positive at baseline but do not 
have any post-baseline samples with a titer that is at least 0.60 titer unit greater than the 
titer of the baseline sample (treatment unaffected).
The relationship between ADA status and safety, efficacy, and pharmacokinetics may be 
investigated.
6.8
BIOMARKER ANALYSES
Exploratory biomarker analyses will be performed in baseline pretreatment, on-
treatment, residual-disease, and post-recurrence samples in an effort to understand the 
association of these markers with study treatment outcome, including efficacy and/or 
adverse events.  The biomarkers may include but will not be limited to PD-L1 and other 
biomarkers in tumor and blood, as defined by IHC, quantitative reverse transcription 
PCR, NGS, or other methods.  Results will be presented in a separate report.
WGS 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.
6.9
INTERIM ANALYSES
6.9.1
Planned Interim Analysis
Up to a total of two analyses of pCR endpoints will be performed.


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An interim efficacy analysis will be initiated for this study after all of the patients enrolled 
in Stage 1 (approximately 204) have received surgery or discontinued early from the 
neo-adjuvant phase.
The interim analysis will be performed by an independent Data Coordinating Center 
(iDCC) and evaluated by an independent Data Monitoring Committee (iDMC).  
Depending on iDMC recommendation at the interim analysis, the study could continue 
enrolling approximately 120 patients in Stage 2 and primary efficacy pCR analysis will 
then be conducted after all of these patients have received surgery or discontinued early 
from the neo-adjuvant phase. The decision rules to be applied at the interim analysis 
will be clearly expressed to the iDMC and documented in the iDMC charter, as well as 
Appendix 14 and the Statistical Analysis Plan, so that the study can be conducted with 
the Sponsor remaining completely blinded to all results at this stage.  Provisions will be 
in place to ensure the study continues to meet the highest standards of integrity when an 
optional interim analysis is executed. Interactions between the iDMC and Sponsor will be 
carried out as specified in the iDMC charter.
The boundaries for statistical significance at the interim and primary analysis for pCR, as 
well as methods to control for the overall type I error are discussed in Section 6.1.2.
6.9.2
Optional Interim Analysis
To adapt to information that may emerge during the course of this study,the Sponsor 
may choose to conduct optional interim analyses before the final analysis for EFS, DFS,
and OS, if needed (e.g., for regulatory or publication purposes). The decision to conduct 
an optional interim analysis, along with the rationale, timing, and statistical details for the 
analysis, will be documented in the Sponsor’s trial master file prior to the conduct of the 
interim analysis.
7.
DATA COLLECTION AND MANAGEMENT
7.1
DATA QUALITY ASSURANCE
The Sponsor will be responsible for data management of this study, including quality 
checking of the data.  Data entered manually will be collected via EDC through use of 
eCRFs.  Sites will be responsible for data entry into the EDC system.  In the event of 
discrepant data, the Sponsor will request data clarification from the sites, which the sites 
will resolve electronically in the EDC system.
The Sponsor will produce an EDC Study Specification document that describes the 
quality checking to be performed on the data.  Central laboratory data and any other 
externally generated electronic study data will be sent directly to the Sponsor, using the 
Sponsor’s standard procedures to handle and process the electronic transfer of 
these data.


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eCRFs and correction documentation will be maintained in the EDC system’s audit trail.  
System backups for data stored by the Sponsor and records retention for the study data 
will be consistent with the Sponsor’s standard procedures.
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 use of a Sponsor-designated EDC system.  
Sites will receive training and have access to a manual for appropriate eCRF 
completion.  eCRFs will be submitted electronically to the Sponsor and should be 
handled in accordance with instructions from the Sponsor.
All eCRFs should be completed by designated, trained site staff.  eCRFs should be 
reviewed and electronically signed and dated by the investigator or a designee.
At the end of the study, the investigator will receive patient data for his or her site in a 
readable format on a compact disc that must be kept with the study records.  
Acknowledgement of receipt of the compact disc is required.
7.3
SOURCE DATA DOCUMENTATION
Study monitors will perform ongoing source data verification and review to confirm that 
critical protocol data (i.e., source data) entered into the eCRFs by authorized site 
personnel are accurate, complete, and verifiable from source documents. 
Source documents (paper or electronic) are those in which patient data are recorded 
and documented for the first time.  They include, but are not limited to, hospital records, 
clinical and office charts, laboratory notes, memoranda, PRO questionnaires, evaluation 
checklists, pharmacy dispensing records, recorded data from automated instruments, 
copies of transcriptions that are certified after verification as being accurate and 
complete, microfiche, photographic negatives, microfilm or magnetic media, X-rays, 
patient files, and records kept at pharmacies, laboratories, and medico-technical 
departments involved in a clinical trial.
Before study initiation, the types of source documents that are to be generated will be 
clearly defined in the Trial Monitoring Plan.  This includes any protocol data to be 
entered directly into the eCRFs (i.e., no prior written or electronic record of the data) and 
considered source data.
Source documents that are required to verify the validity and completeness of data 
entered into the eCRFs must not be obliterated or destroyed and must be retained per 
the policy for retention of records described in Section 7.5.


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To facilitate source data verification and review, the investigators and institutions must 
provide the Sponsor direct access to applicable source documents and reports for 
trial-related monitoring, Sponsor audits, and IRB/EC review.  The study site must also 
allow inspection by applicable health authorities.
7.4
USE OF COMPUTERIZED SYSTEMS
When clinical observations are entered directly into a study site’s computerized medical 
record system (i.e., in lieu of original hardcopy records), the electronic record can serve 
as the source document if the system has been validated in accordance with health 
authority requirements pertaining to computerized systems used in clinical research. 
An acceptable computerized data collection system allows preservation of the original 
entry of data.  If original data are modified, the system should maintain a viewable audit 
trail that shows the original data as well as the reason for the change, name of the 
person making the change, and date of the change.
7.5
RETENTION OF RECORDS
Records and documents pertaining to the conduct of this study and the distribution of 
IMP, including eCRFs, Informed Consent Forms, laboratory test results, and medication 
inventory records, must be retained by the Principal Investigator for 15 years after
completion or discontinuation of the study or for the length of time required by relevant 
national or local health authorities, whichever is longer.  After that period of time, the 
documents may be destroyed, subject to local regulations.  
No records may be disposed of without the written approval of the Sponsor.  Written 
notification should be provided to the Sponsor prior to transferring any records to 
another party or moving them to another location.
Roche will retain study data for 25 years after the final Clinical Study Report has been 
completed or for the length of time required by relevant national or local health 
authorities, whichever is longer.
8.
ETHICAL CONSIDERATIONS
8.1
COMPLIANCE WITH LAWS AND REGULATIONS
This study will be conducted in full conformance with the ICH E6 guideline for Good 
Clinical Practice and the principles of the Declaration of Helsinki, or the applicable laws 
and regulations of the country in which the research is conducted, whichever affords the 
greater protection to the individual.  The study will comply with the requirements of the 
ICH E2A guideline (Clinical Safety Data Management:  Definitions and Standards for 
Expedited Reporting).  Studies conducted in the United States or under a U.S. 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.


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8.2
INFORMED CONSENT
The Sponsor’s sample Informed Consent Form (and ancillary sample Informed Consent 
Forms such as a Child’s Informed Assent Form or Mobile Nursing Informed Consent 
Form, if applicable) will be provided to each site.  If applicable, it will be provided in a 
certified translation of the local language.  The Sponsor or its designee must review and 
approve any proposed deviations from the Sponsor's sample Informed Consent Forms 
or any alternate consent forms proposed by the site (collectively, the "Consent Forms") 
before IRB/EC submission.  The final IRB/ECapproved Consent Forms must be 
provided to the Sponsor for health authority submission purposes according to local 
requirements.
If applicable, the Informed Consent Form will contain separate sections for any optional 
procedures.  The investigator or authorized designee will explain to each patient the 
objectives, methods, and potential risks associated with each optional procedure.  
Patients will be told that they are free to refuse to participate and may withdraw their 
consent at any time for any reason.  A separate, specific signature will be required to 
document a patient's agreement to participate in optional procedures.  Patients who 
decline to participate will not provide a separate signature.
The Consent Forms must be signed and dated by the patient or the patient’s legally 
authorized representative before his or her participation in the study.  The case history or 
clinical records for each patient shall document the informed consent process and that 
written informed consent was obtained prior to participation in the study.
The Consent Forms should be revised whenever there are changes to study procedures 
or when new information becomes available that may affect the willingness of the patient 
to participate.  The final revised IRB/EC-approved Consent Forms must be provided to 
the Sponsor for health authority submission purposes.
Patients must be re-consented to the most current version of the Informed Consent 
Forms (or to a significant new information/findings addendum in accordance with 
applicable laws and IRB/EC policy) during their participation in the study.  For any 
updated or revised Consent Forms, the case history or clinical records for each patient 
shall document the informed consent process and that written informed consent was 
obtained using the updated/revised Consent Forms for continued participation in 
the study.
A copy of each signed Consent Form must be provided to the patient or the patient’s 
legally authorized representative.  All signed and dated Consent Forms must remain in 
each patient’s study file or in the site file and must be available for verification by study 
monitors at any time.
For sites in the United States, each Consent Form may also include patient authorization 
to allow use and disclosure of personal health information in compliance with the U.S. 


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Health Insurance Portability and Accountability Act (HIPAA) of 1996.  If the site utilizes a 
separate Authorization Form for patient authorization for use and disclosure of personal 
health information under the HIPAA regulations, the review, approval, and other 
processes outlined above apply except that IRB review and approval may not be 
required per study site policies.
8.3
INSTITUTIONAL REVIEW BOARD OR ETHICS COMMITTEE
This protocol, the Informed Consent Forms, any information to be given to the patient, 
and relevant supporting information must be submitted to the IRB/EC by the Principal 
Investigator and reviewed and approved by the IRB/EC before the study is initiated.  
In addition, any patient recruitment materials must be approved by the IRB/EC. 
The Principal Investigator is responsible for providing written summaries of the status of 
the study to the IRB/EC annually or more frequently in accordance with the 
requirements, policies, and procedures established by the IRB/EC.  Investigators are 
also responsible for promptly informing the IRB/EC of any protocol amendments 
(see Section 9.5).
In addition to the requirements for reporting all adverse events to the Sponsor, 
investigators must comply with requirements for reporting serious adverse events to the 
local health authority and IRB/EC.  Investigators may receive written IND safety reports 
or other safety-related communications from the Sponsor.  Investigators are responsible 
for ensuring that such reports are reviewed and processed in accordance with health 
authority requirements and the policies and procedures established by their IRB/EC, and 
archived in the site’s study file. 
8.4
CONFIDENTIALITY
The Sponsor maintains confidentiality standards by coding each patient enrolled in the 
study through assignment of a unique patient identification number.  This means that 
patient names are not included in data sets that are transmitted to any Sponsor location.
Patient medical information obtained by this study is confidential and may be disclosed 
to third parties only as permitted by the Informed Consent Form (or separate 
authorization for use and disclosure of personal health information) signed by the 
patient, unless permitted or required by law.
Medical information may be given to a patient’s personal physician or other appropriate 
medical personnel responsible for the patient’s welfare, for treatment purposes.
Given the complexity and exploratory nature of exploratory biomarker analyses, data 
derived from these analyses will generally not be provided to study investigators or 
patients unless required by law.  The aggregate results of any conducted research will 
be available in accordance with the effective Roche policy on study data publication 
(see Section 9.5).


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Data generated by this study must be available for inspection upon request by 
representatives of national and local health authorities, Sponsor monitors, 
representatives, and collaborators, and the IRB/EC for each study site, as appropriate.
8.5
FINANCIAL DISCLOSURE
Investigators will provide the Sponsor with sufficient, accurate financial information in 
accordance with local regulations to allow the Sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate health authorities.  
Investigators are responsible for providing information on financial interests during the 
course of the study and for 1 year after completion of the study (i.e., LPLV).
9.
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION
9.1
STUDY DOCUMENTATION
The investigator must maintain adequate and accurate records to enable the conduct of 
the study to be fully documented, including, but not limited to, the protocol, protocol 
amendments, Informed Consent Forms, and documentation of IRB/EC and 
governmental approval.  In addition, at the end of the study, the investigator will receive 
the patient data, including an audit trail containing a complete record of all changes 
to data.
9.2
PROTOCOL DEVIATIONS
The investigator should document and explain any protocol deviations.  The investigator 
should promptly report any deviations that might have an impact on patient safety and 
data integrity to the Sponsor and to the IRB/EC in accordance with established IRB/EC 
policies and procedures.  The Sponsor will review all protocol deviations and assess 
whether any represent a serious breach of Good Clinical Practice guidelines and require 
reporting to health authorities. As per the Sponsor's standard operating procedures, 
prospective requests to deviate from the protocol, including requests to waive protocol 
eligibility criteria, are not allowed.
9.3
MANAGEMENT OF STUDY QUALITY
The Sponsor will implement a system to manage the quality of the study, focusing on 
processes and data that are essential to ensuring patient safety and data integrity.  The 
Sponsor will identify potential risks associated with critical trial processes and data and 
will implement plans for evaluating and controlling these risks.  Risk evaluation and 
control will include the selection of risk-based parameters (e.g., adverse event rate, 
protocol deviation rate) and the establishment of quality tolerance limits for these 
parameters.  Detection of deviations from quality tolerance limits will trigger an 
evaluation to determine if action is needed.  Details on the establishment and monitoring 
of quality tolerance limits will be provided in a Quality Tolerance Limit Management Plan.


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9.4
SITE INSPECTIONS
Site visits will be conducted by the Sponsor or an authorized representative for 
inspection of study data, patients’ medical records, and eCRFs.  The investigator will 
permit national and local health authorities; Sponsor monitors, representatives, and 
collaborators; and the IRBs/ECs to inspect facilities and records relevant to this study.
9.5
ADMINISTRATIVE STRUCTURE
This study will be sponsored and managed by F. Hoffmann-La Roche Ltd.  The Sponsor 
will provide clinical operations management, data management, and medical monitoring.
Approximately 75 sites globally will participate in the study with approximately
204 patients randomized in Stage 1 and approximately 120 patients in Stage 2.  
Randomization will occur through the IxRS.
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; local laboratory ranges will be collected.  
An iDMC will evaluate safety and efficacy data during the study (see Section 3.1.2).
9.6
PUBLICATION OF DATA AND PROTECTION OF TRADE 
SECRETS
Regardless of the outcome of a trial, the Sponsor is dedicated to openly providing 
information on the trial to healthcare professionals and to the public, at scientific 
congresses, in clinical trial registries, and in peer-reviewed journals. The Sponsor will 
comply with all requirements for publication of study results.  Study data may be shared 
with others who are not participating in this study (see Section 8.4 for details), and 
redacted Clinical Study Reports and other summary reports will be made available upon 
request, provided the requirements of Roche's global policy on data sharing have been 
met.  For more information, refer to the Roche Global Policy on Sharing of Clinical Study 
Information at the following website:
http://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 trials in patients involving an IMP for which a marketing authorization application 
has been filed or approved in any country, the Sponsor aims to submit a journal 
manuscript reporting primary clinical trial results within 6 months after the availability of 
the respective Clinical Study Report.  In addition, for all clinical trials in patients involving 
an IMP for which a marketing authorization application has been filed or approved in any 
country, the Sponsor aims to publish results from analyses of additional endpoints and 
exploratory data that are clinically meaningful and statistically sound.


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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 based on information from other 
studies that may not yet be available to the investigator.
In accordance with standard editorial and ethical practice, the Sponsor will generally 
support publication of multicenter trials only in their entirety and not as individual center 
data.  In this case, a coordinating investigator will be designated by mutual agreement.
Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements.  Any formal publication 
of the study in which contribution of Sponsor personnel exceeded that of conventional 
monitoring will be considered as a joint publication by the investigator and the 
appropriate Sponsor personnel.
Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of data from this study will become and remain the exclusive and unburdened 
property of the Sponsor, except where agreed otherwise.
9.7
PROTOCOL AMENDMENTS
Any protocol amendments will be prepared by the Sponsor.  Protocol amendments will 
be submitted to the IRB/EC and to regulatory authorities in accordance with local 
regulatory requirements.
Approval must be obtained from the IRB/EC and regulatory authorities (as locally 
required) before implementation of any changes, except for changes necessary to 
eliminate an immediate hazard to patients or changes that involve logistical or 
administrative aspects only (e.g., change in Medical Monitor or contact information).


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10.
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Appendix 1: Schedule of Activities (for Both Stage 1 and Stage 2) (cont.)
AtezolizumabF. Hoffmann-La Roche Ltd
128/Protocol WO39392, Version 9
Screening a
Treatment
Completion of Study 
Therapy/Early Term. Visit c
Survival 
Follow-Up d
Neoadjuvant 
Treatment
(28-Day Cycles)
(Cycles 15; 
Weeks 120)
Pre-Surgery Visit/
Surgery b
Arm A: Adjuvant 
Treatment
Arm B: Monitoring
(21-Day Cycles)
(Cycles 616)
Days –28 
to –1
Day 1
(3 days)
Day 1
(3 days)
30 Days after Last Dose 
(Arm A) or Last Monitoring 
Visit (Arm B)
Height
x
Complete physical examination n
x
Limited physical examination o
x g
x
x m
x
ECOG Performance Status p
x
x
x
x
x
ECG (12-lead) q
x
As clinically indicated
ECHO or MUGA scan r
x
As described in footnote “r”
x
x
Spirometry (FVC, FEV1, 
FEV1:FVC, FEF25-75)
x
As clinically indicated
Hematology s
x t
On each infusion 
day
x
x m
x
Chemistry u
x t
On each infusion 
day
x
x m
x
Pregnancy test v
x t
x v
x v
x v
x v
Coagulation (INR, aPTT)
x t
x
x
TSH, free T3 (or total T3 w), 
free T4
x t
x w
x
Viral serology x
x t


Appendix 1: Schedule of Activities (for Both Stage 1 and Stage 2) (cont.)
AtezolizumabF. Hoffmann-La Roche Ltd
129/Protocol WO39392, Version 9
Screening a
Treatment
Completion of Study 
Therapy/Early Term. Visit c
Survival 
Follow-Up d
Neoadjuvant 
Treatment
(28-Day Cycles)
(Cycles 15; 
Weeks 120)
Pre-Surgery Visit/
Surgery b
Arm A: Adjuvant 
Treatment
Arm B: Monitoring
(21-Day Cycles)
(Cycles 616)
Days –28 
to –1
Day 1
(3 days)
Day 1
(3 days)
30 Days after Last Dose 
(Arm A) or Last Monitoring 
Visit (Arm B)
Urinalysis y
x t
As clinically indicated 
Serum PK sample for 
atezolizumab
See Appendix 2 for detailed schedule
Serum ADA sample for 
atezolizumab
See Appendix 2 for detailed schedule
Blood and plasma samples for 
biomarkers
See Appendix 2 for detailed schedule
Blood sample for RBR (optional)  z
x
Tumor tissue (fresh sample 
preferred) at screening, on-study, 
and time of disease recurrence aa
See Appendix 3 for detailed schedule
Radiographic assessments (e.g., 
CT scan, MRI, PET scan)
As clinically indicated
Bilateral mammogram
x bb
x
x cc
Concomitant medications
x dd
x
x ee
x ee
x g, ff
Adverse events gg
x gg
x gg
x
x
x gg
Study treatment administration hh
x
x ii, m


Appendix 1: Schedule of Activities (for Both Stage 1 and Stage 2) (cont.)
AtezolizumabF. Hoffmann-La Roche Ltd
130/Protocol WO39392, Version 9
Screening a
Treatment
Completion of Study 
Therapy/Early Term. Visit c
Survival 
Follow-Up d
Neoadjuvant 
Treatment
(28-Day Cycles)
(Cycles 15; 
Weeks 120)
Pre-Surgery Visit/
Surgery b
Arm A: Adjuvant 
Treatment
Arm B: Monitoring
(21-Day Cycles)
(Cycles 616)
Days –28 
to –1
Day 1
(3 days)
Day 1
(3 days)
30 Days after Last Dose 
(Arm A) or Last Monitoring 
Visit (Arm B)
Survival follow-up and anti-cancer 
treatment
x d, jj
ACdoxorubicincyclophosphamide; ADAanti-drug antibody; CT computed tomography; ECHOechocardiogram; ECOG Eastern Cooperative 
Oncology Group; eCRFelectronic Case Report Form; EORTC QLQ-C30European Organisation for Research and Treatment of Cancer Quality of 
Life Questionnaire Core 30; EQ-5D-5LEuroQoL 5-Dimension, 5-Level; ERestrogen receptor; FACT-GFunctional Assessment of Cancer 
Therapy-General; FCV = Forced Vital Capacity; FEV1 = Forced Expiratory Volume 1; FEF25-75 = Forced Expiratory Flow 25%75%;  
FFPEformalin-fixed, paraffin-embedded; HBcAbhepatitis B core antibody; HBsAbhepatitis B surface antibody; HBsAghepatitis B surface 
antigen; HBVhepatitis B virus; HCVhepatitis C virus; HER2human epidermal growth factor receptor 2; MRImagnetic resonance imaging; 
MUGAmultiple-gated acquisition; PD-L1programmed deathligand-1; PET positron emission tomography; PgRprogesterone receptor; 
PKpharmacokinetic; PRO patient-reported outcome; RBRResearch Biosample Repository; T3triiodothyronine; T4thyroxine; 
Term.termination; TSHthyroid-stimulating hormone.
Notes:  On treatment days, all assessments should be performed prior to dosing, unless otherwise specified.
Assessments shaded in gray should be performed as scheduled, but the associated data do not need to be recorded on the eCRF (except in the case 
of an adverse event).
If treatment is withheld (e.g., by adverse events or delays in initiating post-surgical therapy), the schedule of assessments should be held accordingly 
(e.g., Day 1 of Week 21first administration of atezolizumab post-surgery or Day 1 of Cycle 6).


Appendix 1: Schedule of Activities (for Both Stage 1 and Stage 2) (cont.)
AtezolizumabF. Hoffmann-La Roche Ltd
131/Protocol WO39392, Version 9
a Results of standard-of-care tests or examinations performed prior to obtaining informed consent and within 30 days prior to Day 1 may be used; such 
tests do not need to be repeated for screening.
b Pre-surgical visit and associated assessments should occur within 14 days of surgery. Surgery should be conducted no earlier than 14 days and no 
later than 6 weeks after last dose of neoadjuvant therapy.  Platelet counts should be checked prior to surgery and should be 75,000 cells/L.
c Patients who discontinue study treatment will return to the clinic for a treatment discontinuation visit not more than 30 days after the last dose of 
study treatment.
d The survival follow-up period begins from the date of treatment completion/early termination visit, and has a duration of up to approximately 
51 months from the date of randomization of the first patient in Stage 1). This may increase to approximately 74 months if the study includes Stage 
2 patients.  Visit windows are 28 days for quarterly and semiannual assessments.
e Informed consent must be documented before any study-specific screening procedure is performed and may be obtained more than 28 days before 
initiation of study treatment.
f
After signing of the Informed Consent Form, retrieval and submission of tumor tissue sample can occur outside the 28-day screening period.  Tumor 
tissue should be of good quality based on 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, and lavage samples are not acceptable.  For core-needle biopsy specimens, at least three cores should be submitted for 
evaluation.  Retrieval of tumor sample can occur outside the 28-day screening period.
g Assessment of primary tumor and regional lymph nodes should be done by physical examination at baseline and prior to administration of each cycle 
of study treatment during neoadjuvant therapy. Additionally, standard breast imaging modality should include an ultrasound of breast and axilla 
disease. (Physical examination and ultrasound is mandatory within 28 days prior to randomization and within 14 days pre-surgery.) At baseline, if 
there is evidence of suspicious axillary lymph nodes, then fine-needle aspiration is required. Ultrasound-detected axillary lymph nodes suspicious of 
malignancy include those with cortical thickness 2 mm. Disease status based on all available clinical assessments should be documented every 
3 months during adjuvant study treatment and follow-up up to 3 years after surgery and every 6 months thereafter. In addition, liver function tests, 
bone scans, chest X-ray/diagnostic CT scan, liver imaging, and/or other radiographic modalities may be considered when clinically indicated to 
exclude metastatic disease; these assessments should be performed within a timeline as per current local standard of practice. Whenever possible, 
disease recurrence should be confirmed pathologically. If disease recurrence is diagnosed at any time during the study, patients will discontinue 
scheduled study assessments and will be followed for survival, anti-cancer medications, and new relapse events.
h See Section 4.5.6 in protocol.


Appendix 1: Schedule of Activities (for Both Stage 1 and Stage 2) (cont.)
AtezolizumabF. Hoffmann-La Roche Ltd
132/Protocol WO39392, Version 9
i
All PRO assessments (EORTC QLQ-C30, followed by the FACT-G single item GP5, and then the EQ-5D-5L questionnaires) must be completed by 
the patient at the investigational site at the start of the clinic visit before discussion of the patient’s health state, lab results or health record, before 
administration of study treatment, and/or prior to the performance of any other study assessments that could bias the patient’s responses.  Interview 
assessment by a member of the clinical staff will be allowed if the patient is not able to complete the measure on her or his own.  Study personnel 
should review all questionnaires for completeness before the patient leaves the investigational site.
The EORTC QLQ-C30 and EQ-5D-5L questionnaires will be completed by patients at baseline (Cycle 1, Day 1) and on Day 1 of every cycle 
thereafter. The FACT-G, single item GP5 will not be completed by patients at the baseline visit (Cycle 1, Day 1).
j
Patients who discontinue study treatment for any reason will continue to complete the EORTC QLQ-C30, FACT-G single item GP5, and EQ-5D-5L 
questionnaires in-clinic during the survival follow-up period at the following timepoints: every 3 months (28 days) for Year 1, every 6 months 
(28 days) for years 2-3, and then annually (28 days) thereafter.
k While on study treatment, all patients will complete the FACT-G, single item GP5 beginning on Cycle 2, Day 1 and at Day 1 of every cycle thereafter.
l
Includes respiratory rate, pulse rate, systolic and diastolic blood pressure while the patient is in a seated position, and temperature.  Record 
abnormalities observed at baseline on the General Medical History and Baseline Conditions eCRF.  At subsequent visits, record new or worsened 
clinically significant abnormalities on the Adverse Event eCRF.  For the first infusion, vital signs should be measured within 60 minutes prior to the 
infusion and, if clinically indicated, every 15 (5) minutes during and 30 (10) minutes after the infusion.  For subsequent infusions, vital signs should 
be measured within 60 minutes prior to the infusion and, if clinically indicated or if symptoms occurred during the previous infusion, during and 
30 (10) minutes after the infusion.
m For patients in Arm A only.
n Includes evaluation of the head, eyes, ears, nose, throat, and the cardiovascular, dermatological, musculoskeletal, respiratory, gastrointestinal, and 
neurological systems.  Record abnormalities observed at baseline on the General Medical History and Baseline Conditions eCRF.  At subsequent 
visits, record new or worsened clinically significant abnormalities on the Adverse Event eCRF.
o Perform a limited, symptom-directed examination at specified timepoints and as clinically indicated at other timepoints.  Record new or worsened 
clinically significant abnormalities on the Adverse Event eCRF.
p See Appendix 10.
q ECG recordings will be obtained during screening and as clinically indicated.  Patients should be resting in a supine position for at least 10 minutes 
prior to ECG recording.


Appendix 1: Schedule of Activities (for Both Stage 1 and Stage 2) (cont.)
AtezolizumabF. Hoffmann-La Roche Ltd
133/Protocol WO39392, Version 9
r
Cardiac monitoring (ECHO or MUGA scan) will be performed on all patients enrolled in the study.  ECHO is the preferred method.  The same method 
used for a given patient at screening should be used throughout the study.  ECHO or MUGA scan should be obtained at baseline and after the 
second dose of AC (which would correspond to Week 16 1 week if no study treatment interruptions or discontinuations have occurred) during 
neoadjuvant study treatment. During the adjuvant (Arm A) or monitoring (Arm B) phase of the study, ECHO or MUGA scan should be obtained at 
Cycle 6, Day 1 (which would approximately correspond to Week 21 1 week if no study treatment interruptions or discontinuations have occurred),
and every 3 months afterwards while on the Adjuvant/Monitoring Phase (which would correspond to Cycle 10, Day 1 and Cycle 14, Day 1, or 
approximately Week 33 1 week, and Week 45 1 week respectively, if no treatment interruptions or discontinuations have occurred).  ECHO or 
MUGA scan should be obtained at the completion visit (or the early termination visit) if not performed within the previous 6 weeks.  During the 
survival follow-up period, ECHO or MUGA scan should be obtained annually until the end of study.  For additional cardiac screening tests for 
patients in the cardiac safety cohort, please see Appendix 4.
s Hematology includes WBC count, RBC count, hemoglobin, hematocrit, platelet count, and differential count (neutrophils, eosinophils, basophils, 
monocytes, lymphocytes, other cells).
t
Screening laboratory test results must be obtained within 14 days prior to initiation of study treatment.
u Chemistry panel (serum or plasma) includes sodium, potassium, chloride, bicarbonate or total CO2, glucose, BUN or urea, creatinine, total protein, 
albumin, calcium, total bilirubin, alkaline phosphatase, ALT, AST, and LDH.  Magnesium and phosphorus should be included at screening and as 
clinically indicated during study treatment.
v All women of childbearing potential will have a serum pregnancy test at screening.  Urine pregnancy tests will be performed at the following specified 
subsequent visits for women of child-bearing potential (including premenopausal women who have had tubal ligation) and women not meeting the 
definition of postmenopausal:  Day 1 of Cycles 15; Day 1 of Cycles 6, 8, 10, 12, 14, and 16; at treatment discontinuation (unless administered 
within 30 days); and at 3 months and 6 months after treatment discontinuation.  For all other women, documentation must be present in medical 
history confirming that the patient is not of childbearing potential.  If a urine pregnancy test is positive, it must be confirmed by a serum pregnancy 
test.
w TSH, free T3 (or total T3 for sites where free T3 is not performed), and free T4 will be assessed on Day 1 of Cycle 1 and every fourth cycle 
thereafter.
x At screening, patients will be tested for HIV, HBsAg, HBsAb, total HBcAb, and HCV antibody.  If a patient has a negative HBsAg test and a positive 
total HBcAb test at screening, an HBV DNA test should be performed to rule out active HBV infection prior to initiation of study treatment.  If a patient 
has a positive HCV antibody test at screening, an HCV RNA test should be performed to rule out active HCV infection prior to initiation of study 
treatment.
y Includes pH, specific gravity, glucose, protein, ketones, and blood; dipstick permitted.


Appendix 1: Schedule of Activities (for Both Stage 1 and Stage 2) (cont.)
AtezolizumabF. Hoffmann-La Roche Ltd
134/Protocol WO39392, Version 9
z Not applicable for a site that has not been granted approval for RBR sampling.  Performed only for patients at participating sites who have provided 
written informed consent to participate.  Whole blood for DNA isolation will be collected from patients who have consented to optional RBR sampling 
at Week 1, Day 1. 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.
aa Tumor tissue should be of good quality based on total and viable tumor content (sites will be informed if the quality of the submitted specimen is 
inadequate to determine tumor PD-L1 status).  For tissue sample provided at screening, an FFPE block or at least 20 unstained slides should be 
provided. Retrieval of tumor screening sample can occur outside the 28-day screening period.  Fine-needle aspiration, brushing, cell pellets from 
pleural effusion, and lavage samples are not acceptable.  For core-needle biopsy specimens, at least three cores should be submitted for screening 
and on-study evaluation.  At least two cores should be submitted for disease recurrence specimens.  See Section 4.5.8 and Appendix 3 for specific 
tissue sample requirements for each time point.
bb The unaffected breast should have been imaged within 60 days prior to randomization.  The affected breast should be imaged within 28 days prior to 
randomization.  
cc Mammograms of any remaining breast tissue should be performed at least annually.
dd 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 30 days prior to initiation of study treatment (for the purposes of screening) until 
the treatment discontinuation visit. Record all prior anti-cancer therapies.
ee To be collected for both study arms.  For patients in Arm B (Monitoring), only medications given for reportable adverse events as per protocol (see 
Section 5.3.1) as well as new anti-cancer treatments should be collected.
ff Medications related to the treatment of serious adverse events are to be reported during the follow-up period, as well as new anti-cancer treatments.
gg After informed consent has been obtained but prior to initiation of study treatment, only serious adverse events caused by a protocol-mandated 
intervention should be reported.  After initiation of study treatment, all adverse events will be reported until 30 days after the last dose of study 
treatment or until initiation of new anti-cancer therapy, whichever occurs first, and serious adverse events and adverse events of special interest will 
continue to be reported until 90 days after the last dose of study treatment or until initiation of new anti-cancer therapy, whichever occurs first.  After 
this period, all deaths, regardless of cause, should be reported.  In addition, the Sponsor should be notified if the investigator becomes aware of any 
serious adverse event that is believed to be related to prior exposure to study treatment (see Section 5.6).  The investigator should follow each 
adverse event until the event has resolved to baseline grade or better, the event is assessed as stable by the investigator, the patient is lost to follow-
up, or the patient withdraws consent.  Every effort should be made to follow all serious adverse events considered to be related to study treatment or 
trial-related procedures until a final outcome can be reported.
hh The initial dose of atezolizumab will be delivered over 60 (15) minutes.  Subsequent infusions will be delivered over 30 (10) minutes if the previous 
infusion was tolerated without infusion-associated adverse events, or 60 (15) minutes if the patient experienced an infusion-associated adverse 
event with the previous infusion.


Appendix 1: Schedule of Activities (for Both Stage 1 and Stage 2) (cont.)
AtezolizumabF. Hoffmann-La Roche Ltd
135/Protocol WO39392, Version 9
ii Study drug administration during the maintenance phase for the atezolizumab-containing arm only.
jj After treatment discontinuation, information on survival follow-up and new anti-cancer therapy (including targeted therapy and immunotherapy) will be 
collected via telephone calls, patient medical records, and/or clinic visits (unless the patient withdraws consent or the Sponsor terminates the study).  
If a patient requests to be withdrawn from follow-up, this request must be documented in the source documents and signed by the investigator.  If the 
patient withdraws from study, the study staff may use a public information source (e.g., county records) to obtain information about survival status 
only, where allowable by local regulation.


AtezolizumabF. Hoffmann-La Roche Ltd
136/Protocol WO39392, Version 9
Appendix 2
Schedule of Pharmacokinetic, Immunogenicity, and Fluid 
Biomarker Samples
Visit
Time
Sample
Day 1 of Week 1
(i.e., Cycle 1, Day 1)
Prior to the first dose

Atezolizumab PK (serum)

Atezolizumab ADA (serum)

Biomarker (blood and plasma)

Optional RBR (whole blood)

Autoantibodies b
30 min (10 min) after 
completion of atezolizumab 
infusion

Atezolizumab PK (serum)
Day 1 of Weeks 7 and 15
(i.e., Cycle 2, Day 15; and 
Cycle 4, Day 15)
Predose

Biomarkers (plasma)
Day 1 of Weeks 5 (i.e., Cycle 2, 
Day 1), 9 (Cycle 3, Day 1), 13
(Cycle 4, Day 1), 21 a (Cycle 6, 
Day 1), 27 a (Cycle 8, Day 1), 
39 a (Cycle12, Day1), and 51 a
(Cycle 16, Day1)
Predose

Atezolizumab PK (serum)

Atezolizumab ADA (serum)
Surgical intervention
Pre-surgery

Biomarkers (plasma and blood)
At the time of first clinical visit
post-surgical intervention
NA

Biomarkers (plasma)
Treatment discontinuation visit 
(30 days after last dose) a
NA

Atezolizumab PK (serum)

Atezolizumab ADA (serum)
120 30 days after last dose of 
atezolizumab a
NA

Atezolizumab PK (serum)

Atezolizumab ADA (serum)
At disease recurrence
NA

Biomarkers (plasma and blood)
ADAanti-drug antibody; NAnot applicable; PKpharmacokinetic; RBRResearch Biosample 
Repository; WGS whole genome sequencing.
Notes:  Except for Day 1 of Cycle 1, all other study visits and assessments during the treatment period 
should be performed within 3 days of the scheduled date.  Study assessments may be delayed or 
moved ahead of the window to accommodate holidays, vacations, and unforeseen delays.
If treatment is withheld (e.g., due to adverse events), the pharmacokinetic, immunogenicity, and 
biomarker samples during the neoadjuvant phase should be taken during the same cycle as shown in 
the table above (e.g., if the dose on Day 1 of Week 5 is delayed, the atezolizumab PK [serum] sample 
and atezolizumab ADA [serum] sample scheduled for predose should still be taken on Day 1 of 
Week 5).  The only exception is on Day 1 of Week 1 (Cycle 1, Day 1) when the sample should only be 
taken on the day of the patient’s first dose of the study. 
Biomarker (blood) sample may include whole blood WGS. Please see lab manual for detailed collection 
instructions.
a Following unblinding at Week 20, PK, and ADA sample collections will be limited to the atezolizumab 
arm such that no PK and ADA samples will be collected for the placebo arm at Weeks 21, 27, 39, 51, 
treatment discontinuation after unblinding, and 120 (30) days after last dose of atezolizumab.


Appendix 2: Schedule of Pharmacokinetic, Immunogenicity, and Fluid 
Biomarker Samples (cont.)
AtezolizumabF. Hoffmann-La Roche Ltd
137/Protocol WO39392, Version 9
b Autoantibodies will be collected prior to the first dose and at the time of any immune-mediated 
adverse event.  Autoantibodies to be collected include the following:  anti-nuclear antibody, 
antidouble-stranded DNA, circulating anti-neutrophil cytoplasmic antibody, and perinuclear 
anti-neutrophil cytoplasmic antibody.


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Appendix 3
Tumor Tissue Requirements
Timepoint
Fresh vs. Archival
Number of Slides/Cores
Screening a
Fresh or archival
At least 20 slides fresh from a 
tissue block with at least 
3 cores
Week 3, Day 1
(i.e., Cycle 1, Day 15) 
(optional)
Fresh
Tissue block with at least 
3 cores
Surgical resection
Fresh
Tissue block with at least 
3 cores or equivalent
Post-surgical disease 
relapse
Fresh
Tissue block with at least 
3 cores
TNBCtriple-negative breast cancer.
a Patients with multifocal tumors (more than one tumor confined to the same quadrant as the 
primary tumor) are eligible provided all discrete lesions are sampled and centrally confirmed as 
TNBC.




Appendix 4: Cardiac Safety Cohort Cardiac Assessments (cont.)
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Note:  The first 26 patients enrolled (approximately 13 patients in the control arm and approximately 13 patients in the atezolizumab arm) will be 
part of a cardiac safety cohort and will undergo additional cardiac safety monitoring during the doxorubicin cyclophosphamide portion of 
neoadjuvant treatment. 
Cardiac monitoring (ECHO or MUGA scan) will be performed on all patients enrolled in the study.  ECHO is the preferred method.  The same 
method used for a given patient at screening should be used throughout the study.  
For all patients, ECHO or MUGA scan will be obtained at baseline and after the second dose of AC (which would correspond to Week 16 1 week 
if no study treatment interruptions or discontinuations had occurred) during neoadjuvant study treatment. During the adjuvant (arm A) or monitoring 
(arm B) phase of the study, ECHO or MUGA scan should be obtained at Cycle 6 Day 1 (which would approximately correspond to Week 21 1 
week if no study treatment interruptions or discontinuations had occurred), and every 3 months afterwards while on the adjuvant / monitoring phase 
(which would correspond to Cycle 10 Day 1 and Cycle 14 Day 1, or approximately Week 33 1 week, and Week 45 1 week respectively, if no 
treatment interruptions or discontinuations had occurred). ECHO or MUGA scan should be obtained at the completion visit (or the early 
termination visit) if not performed within the previous 6 weeks.  During the survival follow-up period, ECHO or MUGA scan should be obtained 
annually until the end of study (for further details see the SOA Appendix 1).  Patients in the cardiac safety cohort will receive an additional scan 
after the final dose of AC (Week 20 1 week if no study treatment interruptions or discontinuations had occurred; prior to surgery).
Patients in the cardiac safety cohort will also have cardiac troponin T (cTnT) levels drawn at baseline and within 30 minutes prior to the 
administration of atezolizumab at week 16 and 19.  If levels are found to be elevated, patients should undergo evaluation by a cardiologist.  The 
Medical Monitor is available to advise as needed.


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Appendix 5
European Organisation for Research and Treatment of Cancer
Quality of Life Questionnaire Core 30


Appendix 5: European Organisation for Research and Treatment of Cancer
Quality of Life Questionnaire Core 30 (cont.)
AtezolizumabF. Hoffmann-La Roche Ltd
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AtezolizumabF. Hoffmann-La Roche Ltd
143/Protocol WO39392, Version 9
Appendix 6
FACT-G Single Item GP5


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Appendix 7
EuroQol 5-Dimension, 5-Level Questionnaire:  EQ-5D-5L


Appendix 7: EuroQol 5-Dimension, 5-Level Questionnaire:  EQ-5D-5L (cont.)
AtezolizumabF. Hoffmann-La Roche Ltd
145/Protocol WO39392, Version 9


Appendix 7: EuroQol 5-Dimension, 5-Level Questionnaire:  EQ-5D-5L (cont.)
AtezolizumabF. Hoffmann-La Roche Ltd
146/Protocol WO39392, Version 9


AtezolizumabF. Hoffmann-La Roche Ltd
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Appendix 8
Preexisting Autoimmune Diseases
Subjects 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 below are excluded from 
participating in the study.  Possible exceptions to this exclusion could be subjects with a 
medical history of such entities as atopic disease or childhood arthralgias where the 
clinical suspicion of autoimmune disease is low.  Patients with a history of 
autoimmune-related hypothyroidism on a stable dose of thyroid replacement hormone 
may be eligible for this study.  In addition, transient autoimmune manifestations of an 
acute infectious disease that resolved upon treatment of the infectious agent are not 
excluded (e.g., acute Lyme arthritis).  Caution should be used when considering 
atezolizumab for patients who have previously experienced a severe or lifethreatening 
skin adverse reaction while receiving another immunostimulatory anti-cancer agent.  The 
Medical Monitor is available to advise on any uncertainty over autoimmune exclusions.
Autoimmune Diseases and Immune Deficiencies
Acute disseminated
encephalomyelitis
Addison disease
Ankylosing spondylitis
Antiphospholipid antibody
syndrome
Aplastic anemia
Autoimmune hemolytic 
anemia
Autoimmune hepatitis
Autoimmune
hypoparathyroidism
Autoimmune hypophysitis
Autoimmune myocarditis
Autoimmune 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 syndrome
Stiff-Person syndrome
Takayasu arteritis
Ulcerative colitis
Vitiligo
Vogt-Koyanagi-Harada 
disease
Wegener granulomatosis


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Appendix 9
Anaphylaxis Precautions
EQUIPMENT NEEDED

Oxygen

Epinephrine for subcutaneous, intravenous, and/or endotracheal use in accordance 
with standard practice

Antihistamines

Corticosteroids

Intravenous infusion solutions, tubing, catheters, and tape
PROCEDURES
In the event of a suspected anaphylactic reaction during study treatment infusion, 
the following procedures should be performed:
1.
Stop the study treatment infusion.
5) Maintain an adequate airway.
6) Administer antihistamines, epinephrine, or other medications as required by patient 
status and directed by the physician in charge.
7) Continue to observe the patient and document observations.


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Appendix 10
Eastern Cooperative Oncology Group
Scale of Performance Status
Grade
Performance Status
0
Fully active, able to carry on all pre-disease performance without restriction
1
Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature, eg, light house work, office work
2
Ambulatory and capable of all selfcare but unable to carry out any work 
activities.  Up and about more than 50% of waking hours
3
Capable of only limited selfcare, confined to bed or chair more than 50% of 
waking hours
4
Completely disabled. Cannot carry on any selfcare. Totally confined to bed or 
chair
REFERENCE
Oken MM, Creech RH, Tormey DC, et al. Toxicity and response criteria of the Eastern 
Cooperative Oncology Group. Am J Clin Oncol 1982;5:64955.


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Appendix 11
Guideline on the Management of Axillary Lymph Nodes for 
Study WO39392 (IMpassion031)
ALND axillary lymph node dissection;FNA fine-needle aspiration; LN lymph node; 
Neoadj. neoadjuvant; SLNB sentinel lymph node biopsy; Trmt. treatment; 
US ultrasonography.
Notes: For patients with T2-T3 disease who have clinical or ultrasound detected enlarged 
axillary lymph nodes but the result of the core biopsy or FNA is negative, the investigator 
may follow their local practice guidelines for the management of axilla.
All patients with T4 lesions who have clinically or ultrasound detected enlarged LNs must 
undergo core biopsy/FNA for histological confirmation of LN involvement.
* If SLNB is conducted, it is strongly recommended that more than one lymph node (two to three 
minimum) be removed and that all patients with positive macrometastases in sentinel nodes 
should undergo ALND regardless of the number of positive nodes.




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*** If SLNB is conducted, it is strongly recommended that more than one lymph node (two to three minimum) be removed and that all patients with 
positive macrometastases in sentinel nodes should undergo ALND regardless of the number of positive nodes.


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Appendix 13
Risks Associated with Atezolizumab and Guidelines for 
Management of Adverse Events Associated with Atezolizumab 
Toxicities associated or possibly associated with atezolizumab treatment should be 
managed according to standard medical practice.  Additional tests, such as autoimmune 
serology or biopsies, should be used to evaluate for a possible immunogenic etiology.
Although most immune-mediated adverse events observed with immunomodulatory 
agents have been mild and self-limiting, such events should be recognized early and 
treated promptly to avoid potential major complications.  Discontinuation of atezolizumab 
may not have an immediate therapeutic effect, and in severe cases, immune-mediated
toxicities may require acute management with topical corticosteroids, systemic 
corticosteroids, or other immunosuppressive agents. 
The 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 the benefits and risks and documented 
by the investigator.  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 13:  Risks Associated with Atezolizumab and Guidelines for Management of     
Adverse Events Associated with Atezolizumab (cont.)
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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. c

For recurrent events or events with no improvement after 
4872 hours of corticosteroids, treat as a Grade 3 or 4 event.
Pulmonary 
event, Grade 3 
or 4

Permanently discontinue atezolizumab and contact 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 the benefits and risks 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 the benefits and risks and documented by the investigator. The Medical Monitor is 
available to advise as needed. 


Appendix 13:  Risks Associated with Atezolizumab and Guidelines for Management of     
Adverse Events Associated with Atezolizumab (cont.)
AtezolizumabF. Hoffmann-La Roche Ltd
155/Protocol WO39392, Version 9
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. 
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 the 
benefits and risks 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 the benefits and risks and
documented by the investigator.  The Medical Monitor is available to advise as needed. 


Appendix 13:  Risks Associated with Atezolizumab and Guidelines for Management of     
Adverse Events Associated with Atezolizumab (cont.)
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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 the 
benefits and risks 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 the benefits and risks and
documented by the investigator.  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 13:  Risks Associated with Atezolizumab and Guidelines for Management of     
Adverse Events Associated with Atezolizumab (cont.)
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Table 3
Management Guidelines for Gastrointestinal Events (Diarrhea or 
Colitis)
Event
Management
Diarrhea or 
colitis, Grade 1

Continue atezolizumab.

Initiate symptomatic treatment.

Endoscopy is recommended if symptoms persist for 7 days.

Monitor closely.
Diarrhea or 
colitis, Grade 2

Withhold atezolizumab for up to 12 weeks after event onset. a

Initiate symptomatic treatment.

Patient referral to GI specialist is recommended.

For recurrent events or events that persist5 days, initiate treatment 
with corticosteroids equivalent to 12 mg/kg/day oral prednisone.

If 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 the benefits and risks 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 the benefits 
and risks and documented by the investigator. The Medical Monitor is available to advise 
as needed.


Appendix 13:  Risks Associated with Atezolizumab and Guidelines for Management of     
Adverse Events Associated with Atezolizumab (cont.)
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Table 3
Management Guidelines for Gastrointestinal Events (Diarrhea or 
Colitis) (cont.)
Event
Management
Diarrhea or 
colitis, Grade 4

Permanently discontinue atezolizumab and contact 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 the benefits and risks 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 the benefits
and risks and documented by the investigator.  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 (TSH) 
and free triiodothyronine and thyroxine levels should be measured to determine whether 
thyroid abnormalities are present.  Pituitary hormone levels and function tests 
(e.g., TSH, growth hormone, luteinizing hormone, follicle-stimulating hormone, 
testosterone, prolactin, adrenocorticotropic hormone [ACTH] levels, and ACTH 
stimulation test) and magnetic resonance imaging (MRI) of the brain (with detailed 


Appendix 13:  Risks Associated with Atezolizumab and Guidelines for Management of     
Adverse Events Associated with Atezolizumab (cont.)
AtezolizumabF. Hoffmann-La Roche Ltd
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pituitary sections) may help to differentiate primary pituitary insufficiency from primary 
adrenal insufficiency.


Appendix 13:  Risks Associated with Atezolizumab and Guidelines for Management of     
Adverse Events Associated with Atezolizumab (cont.)
AtezolizumabF. Hoffmann-La Roche Ltd
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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
MRImagnetic resonance imaging; TSHthyroid-stimulating hormone.
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 the benefits and risks 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 the benefits and risks and documented by the investigator. The Medical Monitor is 
available to advise as needed. 


Appendix 13:  Risks Associated with Atezolizumab and Guidelines for Management of     
Adverse Events Associated with Atezolizumab (cont.)
AtezolizumabF. Hoffmann-La Roche Ltd
161/Protocol WO39392, Version 9
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; TSHthyroid-stimulating hormone.
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 the benefits and risks 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 the benefits and risks and documented by the investigator. The Medical Monitor is 
available to advise as needed.


Appendix 13:  Risks Associated with Atezolizumab and Guidelines for Management of     
Adverse Events Associated with Atezolizumab (cont.)
AtezolizumabF. Hoffmann-La Roche Ltd
162/Protocol WO39392, Version 9
Table 4
Management Guidelines for Endocrine Events (cont.)
Event
Management
Hypophysitis 
(pan-hypopituitarism), 
Grade 2 or 3 

Withhold atezolizumab for up to 12 weeks after event 
onset. a

Refer patient to endocrinologist.

Perform brain MRI (pituitary protocol).

Initiate treatment with corticosteroids equivalent to
12 mg/kg/day IV methylprednisolone and convert to 
12 mg/kg/day oral prednisone or equivalent upon 
improvement.

Initiate hormone replacement if clinically indicated.

If event resolves to Grade 1 or better, resume 
atezolizumab. b

If event does not resolve to Grade 1 or better while 
withholding atezolizumab, permanently discontinue 
atezolizumab and contact 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; TSHthyroid-stimulating hormone.
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 the benefits and risks 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 the benefits and risks and documented by the investigator.  The Medical Monitor is 
available to advise as needed. 


Appendix 13:  Risks Associated with Atezolizumab and Guidelines for Management of     
Adverse Events Associated with Atezolizumab (cont.)
AtezolizumabF. Hoffmann-La Roche Ltd
163/Protocol WO39392, Version 9
OCULAR EVENTS
An ophthalmologist should evaluate visual complaints (e.g., uveitis, retinal events).  
Management guidelines for ocular events are provided in Table 5.
Table 5
Management Guidelines for Ocular Events
Event
Management
Ocular event, 
Grade 1 

Continue atezolizumab.

Patient referral to ophthalmologist is strongly recommended.

Initiate treatment with topical corticosteroid eye drops and topical 
immunosuppressive therapy.

If symptoms persist, treat as a Grade 2 event.
Ocular event, 
Grade 2

Withhold atezolizumab for up to 12 weeks after event onset. a

Patient referral to ophthalmologist is strongly recommended.

Initiate treatment with topical corticosteroid eye drops and topical 
immunosuppressive therapy.

If event resolves to Grade 1 or better, resume atezolizumab. b

If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and contact 
Medical Monitor. c
Ocular event, 
Grade 3 or 4

Permanently discontinue atezolizumab and contact Medical 
Monitor. c

Refer patient to ophthalmologist.

Initiate treatment with corticosteroids equivalent to 12 mg/kg/day 
oral prednisone.

If event resolves to Grade 1 or better, taper corticosteroids over 
1 month.
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after event 
onset) to allow for corticosteroids (if initiated) to be reduced to 10 mg/day oral 
prednisone or equivalent.  The acceptable length of the extended period of time must be 
based on an assessment of the benefits and risks 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 the benefits 
and risks and documented by the investigator.  The Medical Monitor is available to 
advise as needed. 


Appendix 13:  Risks Associated with Atezolizumab and Guidelines for Management of     
Adverse Events Associated with Atezolizumab (cont.)
AtezolizumabF. Hoffmann-La Roche Ltd
164/Protocol WO39392, Version 9
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 
gastrointestinal illness), ischemic events, underlying arrhythmias, exacerbation of 
preexisting cardiac conditions, or progression of malignancy.  
All patients with possible myocarditis should be urgently evaluated by performing cardiac 
enzyme assessment, an ECG, a chest X-ray, an echocardiogram, and a cardiac MRI as 
appropriate per institutional guidelines.  A cardiologist should be consulted.  An 
endomyocardial biopsy may be considered to enable a definitive diagnosis and 
appropriate treatment, if clinically indicated.
Patients with signs and symptoms of myocarditis, in the absence of an identified 
alternate etiology, should be treated according to the guidelines in Table 6.


Appendix 13:  Risks Associated with Atezolizumab and Guidelines for Management of     
Adverse Events Associated with Atezolizumab (cont.)
AtezolizumabF. Hoffmann-La Roche Ltd
165/Protocol WO39392, Version 9
Table 6
Management Guidelines for Immune-Mediated Myocarditis
Event
Management
Immune-mediated
myocarditis, Grade 1

Refer patient to cardiologist.

Initiate treatment as per institutional guidelines.
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 the benefits and risks and
documented by the investigator.  The Medical Monitor is available to advise as needed.


Appendix 13:  Risks Associated with Atezolizumab and Guidelines for Management of     
Adverse Events Associated with Atezolizumab (cont.)
AtezolizumabF. Hoffmann-La Roche Ltd
166/Protocol WO39392, Version 9
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 
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 7.
Severe SARS-CoV-2 infection appears to be associated with a CRS involving the 
inflammatory cytokines interleukin (IL)-6, IL-10, IL-2, and IFN-(Merad and Martin 2020).  
If a patient develops suspected CRS during the study, a differential diagnosis should 
include SARS-CoV-2 infection, which should be confirmed or refuted through 
assessment of exposure history, appropriate laboratory testing, and clinical or radiologic 
evaluations per investigator judgment.  If a diagnosis of SARS-CoV-2 infection is 
confirmed, the disease should be managed as per local or institutional guidelines.


Appendix 13:  Risks Associated with Atezolizumab and Guidelines for Management of     
Adverse Events Associated with Atezolizumab (cont.)
AtezolizumabF. Hoffmann-La Roche Ltd
167/Protocol WO39392, Version 9
Table 7
Management Guidelines for Infusion-Related Reactions and 
Cytokine Release Syndrome
Event
Management
Grade 1 a
Fever b with or 
without 
constitutional 
symptoms

Immediately interrupt infusion.

Upon symptom resolution, wait for 30 minutes and then restart infusion 
at half the rate being given at the time of event onset.

If the infusion is tolerated at the reduced rate for 30 minutes, the 
infusion rate may be increased to the original rate.

If symptoms recur, discontinue infusion of this dose.

Administer symptomatic treatment, c including maintenance of IV fluids 
for hydration.

In case of rapid decline or prolonged CRS (2 days) or in patients with 
significant symptoms and/or comorbidities, consider managing as per 
Grade 2.

For subsequent infusions, consider administration of oral premedication 
with antihistamines, 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. e

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.

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 13:  Risks Associated with Atezolizumab and Guidelines for Management of     
Adverse Events Associated with Atezolizumab (cont.)
AtezolizumabF. Hoffmann-La Roche Ltd
168/Protocol WO39392, Version 9
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. f

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. e

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. f

Administer symptomatic treatment. c

Admit patient to ICU and initiate hemodynamic monitoring, mechanical 
ventilation, and/or IV fluids and vasopressors as needed.  Monitor other 
organ function closely.  Manage constitutional symptoms and organ 
toxicities as per institutional practice.

Rule out other inflammatory conditions that can mimic CRS 
(e.g., sepsis).  If no improvement within 24 hours, initiate workup and 
assess for signs and symptoms of HLH or MAS as described in this 
appendix.

Administer IV corticosteroids (e.g., methylprednisolone 2 mg/kg/day or 
dexamethasone 10 mg every 6 hours).

Consider anti-cytokine therapy. e  For patients who are refractory to anti-
cytokine therapy, experimental treatments g may be considered at the 
discretion of the investigator and in consultation with the Medical 
Monitor.

Hospitalize patient until complete resolution of symptoms.


Appendix 13:  Risks Associated with Atezolizumab and Guidelines for Management of     
Adverse Events Associated with Atezolizumab (cont.)
AtezolizumabF. Hoffmann-La Roche Ltd
169/Protocol WO39392, Version 9
Table 7
Management Guidelines for Infusion-Related Reactions and 
Cytokine Release Syndrome (cont.)
ASTCTAmerican Society for Transplantation and Cellular Therapy; BiPAPbi-level positive 
airway pressure; CARchimeric antigen receptor; CPAPcontinuous positive airway pressure; 
CRScytokine release syndrome; CTCAECommon Terminology Criteria for Adverse Events; 
eCRFelectronic Case Report Form; HLHhemophagocytic lymphohistiocytosis; ICUintensive 
care unit; IRRinfusion-related reaction; MASmacrophage activation syndrome; 
NCCNNational Cancer Comprehensive Network; NCINational Cancer Institute.
Note:  The management guidelines have been adapted from NCCN guidelines for management 
of CAR T-cellrelated toxicities (Version 2.2019).
a Grading system for management guidelines is based on ASTCT Consensus Grading Scale 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 There are case reports where anti-cytokine therapy has been used for treatment of CRS with 
immune checkpoint inhibitors (Rotz et al. 2017; Adashek and Feldman 2019), but data are 
limited, and the role of such treatment in the setting of antibody-associated CRS has not been 
established.
f
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 the benefits and risks and documented by 
the investigator.  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.
g Refer to Riegler et al. (2019) for information on experimental treatments for CRS.


Appendix 13:  Risks Associated with Atezolizumab and Guidelines for Management of     
Adverse Events Associated with Atezolizumab (cont.)
AtezolizumabF. Hoffmann-La Roche Ltd
170/Protocol WO39392, Version 9
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.
Table 8
Management Guidelines for Pancreatic Events, Including 
Pancreatitis 
Event
Management
Amylase and/or lipase 
elevation, Grade 2

Continue atezolizumab.

Monitor amylase and lipase weekly.

For prolonged elevation (e.g., 3 weeks), consider treatment 
with 10 mg/day oral prednisone or equivalent.
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 the benefits and risks 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 deicison to re-challenge 
patients with atezolizumab should be based on investigator’s assessment of the benefits and 
risks and documented by the investigator.  The Medical Monitor is available to advise as 
needed.


Appendix 13:  Risks Associated with Atezolizumab and Guidelines for Management of     
Adverse Events Associated with Atezolizumab (cont.)
AtezolizumabF. Hoffmann-La Roche Ltd
171/Protocol WO39392, Version 9
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 the benefits and risks 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 deicision to re-challenge 
patients with atezolizumab should be based on investigator’s assessment of the benefits and 
risks and documented by the investigator.  The Medical Monitor is available to advise as 
needed. 


Appendix 13:  Risks Associated with Atezolizumab and Guidelines for Management of     
Adverse Events Associated with Atezolizumab (cont.)
AtezolizumabF. Hoffmann-La Roche Ltd
172/Protocol WO39392, Version 9
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 for evaluation and, if 
indicated, biopsy.

Initiate treatment with topical corticosteroids.

Consider treatment with higher-potency topical corticosteroids if event 
does not improve.

If unresponsive to topical corticosteroids, consider oral prednisone 
0.5 mg/kg/day.
Dermatologic 
event, Grade 3 

Withhold atezolizumab for up to 12 weeks after event onset. a

Refer patient to dermatologist for evaluation and, if indicated, biopsy.

Initiate treatment with corticosteroids equivalent to 10 mg/day oral 
prednisone, increasing dose to 12 mg/kg/day if event does not 
improve within 4872 hours.

If event resolves to Grade 1 or better, resume atezolizumab. b

If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and contact 
Medical Monitor. c
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after event 
onset) to allow for corticosteroids (if initiated) to be reduced to 10 mg/day oral 
prednisone or equivalent.  The acceptable length of the extended period of time must be 
based on an assessment of the benefits and risks 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 the benefits 
and risks and documented by the investigator.  The Medical Monitor is available to advise 
as needed. 


Appendix 13:  Risks Associated with Atezolizumab and Guidelines for Management of     
Adverse Events Associated with Atezolizumab (cont.)
AtezolizumabF. Hoffmann-La Roche Ltd
173/Protocol WO39392, Version 9
Table 9
Management Guidelines for Dermatologic Events (cont.)
Event
Management
Dermatologic event, 
Grade 4

Permanently discontinue atezolizumab and contact Medical 
Monitor. c
Stevens-Johnson 
syndrome or toxic 
epidermal necrolysis 
(any grade)
Additional guidance for Stevens-Johnson syndrome or toxic 
epidermal necrolysis:

Withhold atezolizumab for suspected Stevens-Johnson syndrome 
or toxic epidermal necrolysis.

Confirm diagnosis by referring patient to a specialist (dermatologist, 
ophthalmologist, or urologist as relevant) for evaluation and, if 
indicated, biopsy.

Follow the applicable treatment and management guidelines above.
If Stevens-Johnson syndrome or toxic epidermal necrolysis is 
confirmed, permanently discontinue atezolizumab.
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after event onset) 
to allow for corticosteroids (if initiated) to be reduced to the equivalent of 10 mg/day oral 
prednisone.  The acceptable length of the extended period of time must be based on an 
assessment of the benefits and risks 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 the benefits and 
risks and documented by the investigator.  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 13:  Risks Associated with Atezolizumab and Guidelines for Management of     
Adverse Events Associated with Atezolizumab (cont.)
AtezolizumabF. Hoffmann-La Roche Ltd
174/Protocol WO39392, Version 9
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 corticosteroids equivalent to
12 mg/kg/day oral or IV prednisone.
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after event 
onset) to allow for corticosteroids (if initiated) to be reduced to 10 mg/day oral 
prednisone or equivalent.  The acceptable length of the extended period of time must
be based on an assessment of the benefits and risks 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 the benefits and risks and documented by the investigator.  The
Medical Monitor is available to advise as needed. 


Appendix 13:  Risks Associated with Atezolizumab and Guidelines for Management of     
Adverse Events Associated with Atezolizumab (cont.)
AtezolizumabF. Hoffmann-La Roche Ltd
175/Protocol WO39392, Version 9
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 corticosteroids equivalent to 12 mg/kg/day IV 
methylprednisolone or equivalent and convert to 12 mg/kg/day oral 
prednisone 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 the benefits and risks and 
documented by the investigator.  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. Renal function, 
including serum creatinine, should be monitored throughout study treatment.  Patients 
with abnormal renal function should be evaluated and treated for other more common 


Appendix 13:  Risks Associated with Atezolizumab and Guidelines for Management of     
Adverse Events Associated with Atezolizumab (cont.)
AtezolizumabF. Hoffmann-La Roche Ltd
176/Protocol WO39392, Version 9
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. c

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 the benefits and risks 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 the benefits and risks and
documented by the investigator.  The Medical Monitor is available to advise as needed. 


Appendix 13:  Risks Associated with Atezolizumab and Guidelines for Management of     
Adverse Events Associated with Atezolizumab (cont.)
AtezolizumabF. Hoffmann-La Roche Ltd
177/Protocol WO39392, Version 9
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
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 the benefits and 
risks 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 the benefits and risks and documented by the 
investigator.  The Medical Monitor is available to advise as needed. 


Appendix 13:  Risks Associated with Atezolizumab and Guidelines for Management of     
Adverse Events Associated with Atezolizumab (cont.)
AtezolizumabF. Hoffmann-La Roche Ltd
178/Protocol WO39392, Version 9
Table 13 Management Guidelines for Immune-Mediated Myositis (cont.)
Event
Management
Immune-mediated
myositis, Grade 3

Withhold atezolizumab for up to 12 weeks after event onset a and contact 
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 the benefits and 
risks 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 the benefits and risks and documented by the 
investigator.  The Medical Monitor is available to advise as needed.


Appendix 13:  Risks Associated with Atezolizumab and Guidelines for Management of     
Adverse Events Associated with Atezolizumab (cont.)
AtezolizumabF. Hoffmann-La Roche Ltd
179/Protocol WO39392, Version 9
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 IL-2 receptor (soluble CD25) elevated 2 standard deviations above age-
adjusted laboratory-specific norms
Patients with suspected MAS should be diagnosed according to published criteria for 
systemic juvenile idiopathic arthritis by Ravelli et al. (2016).  A febrile patient should be 
classified as having MAS if the following criteria are met:

Ferritin 684 mg/L (684 ng/mL)

At least two of the following:
–
Platelet count 181109/L (181,000/L)
–
AST 48 U/L
–
Triglycerides 1.761 mmol/L (156 mg/dL)
–
Fibrinogen 3.6 g/L (360 mg/dL)


Appendix 13:  Risks Associated with Atezolizumab and Guidelines for Management of     
Adverse Events Associated with Atezolizumab (cont.)
AtezolizumabF. Hoffmann-La Roche Ltd
180/Protocol WO39392, Version 9
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.
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 


Appendix 13:  Risks Associated with Atezolizumab and Guidelines for Management of     
Adverse Events Associated with Atezolizumab (cont.)
AtezolizumabF. Hoffmann-La Roche Ltd
181/Protocol WO39392, Version 9
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 14
Statistical Detail of the Adaptive Design for Study WO39392 
(IMpassion031)
The intent-to-treat (ITT) as well as PD-L1positive population will be used for the primary 
analysis of the co-primary endpoints of pathological complete response (pCR) in these 
populations as follows.  The overall one-sided type I error for testing the co-primary 
endpoints of pCR is , = -. -/0.
Two main sources for multiplicity in statistical testing from the current design are:

Multiple target populations, namely ITT and PD-L1positive populations

Study having two stages with target population at Stage 2 depending on results from 
Stage 1
Simes’ closed testing procedure will be used to address multiplicity in target populations 
and weighted inverse p-value combination method is applied to account for the adaptive 
choice of target population at Stage 2 as follows.
At Stage 1
For the interim analysis at end of Stage 1, the co-primary endpoints of pCR in the ITT 
and PD-L1positive population will be tested at the pre-defined one-sided type I error of 
0.0125 (i.e., 50% of the total type I error) following Simes’ procedure.  This involves the 
following p-values:

12
{3} is the p-value from the one-sided Cochran-Mantel-Haenszel (CMH) χ test for 
difference in pCR rates between treatment groups in the ITT population (F) 
stratified according to tumor PD-L1 status (IC0 vs. IC1/2/3) and clinical stage at 
presentation (Stage II vs. III).  The associated elementary null hypothesis is denoted 
as H
{6}:F 0.

12
{7} is the p-value from the CMH χ test for difference in pCR rates between 
treatment groups in the PD-L1positive population (S) stratified according to 
clinical stage at presentation (Stage II vs. III).  The associated elementary null 
hypothesis is denoted as H
{8}:S 0.

12
{3,7} = min <2min=p
{8}, p
{6}> , max =p
{8}, p
{6}>A, p-value based on Simes’ method for 
the intersection hypothesis H
{6,8}, which specifies that there is no proportion 
difference in either F or S.
In addition, the observed difference in pCR rates between arms in S, denoted as ΔC
8 and 
its complementary sub-population of patients with PD-L1 IC0 (C), denoted as ΔC
D will also 
be computed.


Appendix 14: Statistical Detail of the Adaptive Design for Study WO39392 
(IMpassion031) (cont.)
AtezolizumabF. Hoffmann-La Roche Ltd
183/Protocol WO39392, Version 9
Based on p
{6}, p
{8}, p
{6,8}, ΔC
8 and ΔC
D, the following decision could be made at Stage 1:

If p
{6,8} ≤α, the analysis at Stage 1 is considered the primary efficacy analysis for 
pCR with evidence for efficacy declared in either F (if p
{6} ≤α) or S (if p
{8} ≤α) or 
both, the study will therefore not enroll extra patients in Stage 2. 

Otherwise, if both ΔC
8 and ΔC
D  are below the pre-specified thresholds, d8 = 0.12 and 
dD = 0.1, respectively, the study will also not enroll extra patients in Stage 2 for lack 
of efficacy.

Otherwise, if  ΔC
8 ≥d8 and ΔC
D < dD, the study will enroll only patients in S at Stage 2, 
with S being the only target population in the primary efficacy analysis for pCR.

Otherwise, if  ΔC
8 < d8 and ΔC
D ≥dD, the study will enroll all-comer patients (F) in 
Stage 2; however, only F will be the target population in the primary efficacy 
analysis for pCR.

If ΔC
8 ≥d8 and ΔC
D ≥dD, the study will enroll all-comer patients in Stage 2, and the 
co-primary efficacy endpoints of pCR in F and S will be considered in the primary 
efficacy analysis for pCR.
At Stage 2 (if needed)
If the study advances to Stage 2, at the primary efficacy analysis for pCR to protect the 
overall α the corresponding boundary for statistical significance is α=0.0184, accounting 
for the fact that and overall α = 0.0125 having been spent at Stage 1 and the 
information fraction at Stage 1, namely w = N (N + N)
⁄
.  Indeed, the p-value 
p based on Stage 1 data only and the combination p-value p have the same joint 
distribution under the null hypothesis as the p-values from a group-sequential test with 
two stages at information times t = w and t = 1.  Thus, standard statistical software 
for group sequential designs can be used for the determination of critical values for the 
adaptive design (Wassmer and Brannath 2016, Section 6.2.4).
Final test(s) involving the target population(s) selected at Stage 1 will be based on 
weighted inverse normal p-value combination method (Wassmer and Brannath 2016) as 
follows:
Let w = N (N + N)
⁄
and w = N (N + N)
⁄
be the a priori chosen weights 
associated with Stage 1 and Stage 2, respectively.
If both F and S are selected as the co-primary target populations, the following quantities 
are computed:

1/
{7} and 1/
{3} are defined and derived similarly as 12
{7} and 1/
{3}, respectively, with 
derivation based solely on patients enrolled in Stage 2.


Appendix 14: Statistical Detail of the Adaptive Design for Study WO39392 
(IMpassion031) (cont.)
AtezolizumabF. Hoffmann-La Roche Ltd
184/Protocol WO39392, Version 9

1/
{3,7} = min <2min=p
{8}, p
{6}> , max =p
{8}, p
{6}>A, p-value based on Simes’ method for 
the intersection hypothesis H
{6,8} based only on patients enrolled in Stage 2.

12/
{7} = 1 −Φ <w ∙Φ* =1 −p
{8}> + w ∙Φ* =1 −p
{8}>A, the combined p-value for 
H
{8} from stage 1 and 2 following the weighted inverse normal combination method, 
where Φ denotes the cumulative distribution function of a standard normal variate.

12/
{3} = 1 −Φ <w ∙Φ* =1 −p
{6}> + w ∙Φ* =1 −p
{6}>A, the combined p-value for 
H
{6} from Stage 1 and 2 following the weighted inverse normal combination method.

12/
{3,7} = 1 −Φ <w ∙Φ* =1 −p
{6,8}> + w ∙Φ* =1 −p
{6,8}>A, the combined p-value for 
H
{6,8} from Stage 1 and 2 following the weighted inverse normal combination 
method.
If either F or S, but not both of them, is selected as the only target population, there 
remains only one elementary null hypothesis, which is also the intersection hypothesis.  
In general, let Q be the selected target population, that is, Q being either S or F the 
following quantities are computed:

1/
{L} is derived as above and 1/
{3,7} = p
{M}.

12/
{L} and 12/
{3,7} are then computed based on (p
{M}, p
{M})  and (p
{6,8}, p
{6,8}), 
respectively, as mentioned above.  Please note that p
{6,8} is the same as when both 
F and S are selected as the target populations.  In general p
{6,8} is invariant to 
selection of the target population(s) for the primary efficacy analysis for pCR.
In all cases, at the primary efficacy analysis for pCR, the null hypothesis associated with 
a selected target population (Q) is rejected if both p
{M} ≤α and p
{6,8} ≤α following 
Simes’ procedure.
N was fixed at 120 to achieve optimal  statistical operating characteristics across 
several simulation scenarios as provided in Appendix 15.
A summary table that presents the number and proportion of pCR in each treatment 
arm, together with the 2-sided 95% CIs with use of the ClopperPearson method 
(Clopper and Pearson 1934) will be produced by stage and overall for both the ITT and 
PD-L1positive populations.  Confidence intervals for the difference in pCR rate between 
the two arms will be determined using the normal approximation to the binomial 
distribution.  


AtezolizumabF. Hoffmann-La Roche Ltd
185/Protocol WO39392, Version 9
Appendix 15
Statistical Performance of the Adaptive Design
The performance of the proposed design depends on several factors, including the 
underlying proportion of (pCR) responders in each treatment arms for the Subgroup S 
(PD-L1 IC1/2/3) and the complement Group C (PD-L1 IC0).  Simulations were carried 
out to evaluate the operation characteristics of the current design under a variety of 
conditions as follows.
Three simulation scenarios were considered with numerical details provided in Table 1
and results in Tables 2, 3, and 4.

Subgroup S with very strong credentials
Subgroup S has very strong credentials when convincing evidence indicates that the 
benefits of the treatment are limited to the Subgroup S.

Subgroup S with strong credentials
Subgroup S has strong credentials when evidence for the predictive ability of the 
subgroup is convincing enough to assume that the treatment is more likely to be 
effective (and is probably more effective) in the Subgroup S than in the complement 
Subgroup C, but the evidence is not sufficiently compelling to rule out a clinically 
meaningful effect in complement Subgroup C.

Subgroup S with weak credentials
If the Subgroup S has weak credentials when convincing evidence for predictive 
value of the Subgroup S is lacking and the treatment is expected to be broadly 
effective.
Table 1
Definition of Weak, Strong, and Very Strong Credentials on 
Subgroup S
Subgroup S 
Credentials
pCR proportion 
under treatment 
in Full population 
F (F)a
pCR Proportion 
under treatment 
in Subgroup S 
(S)
pCR Proportion 
under treatment 
in complement 
Subgroup C (C)
pCR Proportion 
response under 
Control (control)
Weak
0.68
(F=0.2)
0.68
(S=0.20)
0.68
(C=0.20)
0.48
Strong
0.6376
(F=0.1576)
0.68
(S=0.20)
0.60
(C=0.12)
0.48
Very Strong
0.5952
(F=0.1152)
0.68
(S=0.20)
0.52
(C=0.04)
0.48
a Assuming a prevalence of 0.47 of Subgroup S in the full population.


Appendix 15: Statistical Performance of the Adaptive Design (cont.)
AtezolizumabF. Hoffmann-La Roche Ltd
186/Protocol WO39392, Version 9
Table 2
Relative Frequencies of Decisions at Stage 1 under Weak, 
Strong, and Very Strong Credentials on Subgroup S
Subgroup S 
Credentials
S
C
Relative Frequencya,b,c
Stop for 
efficacy
Stop for 
lack of 
efficacy
Continue
only S
Continue
only F
Continue
S and F
Weak
0.20 0.20
0.64
0.04
0.08
0.14
0.10
Strong
0.20 0.12
0.46
0.10
0.22
0.11
0.11
Very Strong
0.20 0.04
0.33
0.17
0.38
0.05
0.06
a Assuming a prevalence of 0.47 of Subgroup S in the full population.
b Assuming probability of drop-out of 0.05 for each treatment arm.
c Frequency based on 100000 simulations.
Table 3
Rejection Probabilities under Weak, Strong, and Very Strong 
Credentials on Subgroup S
Subgroup S 
Credentials
S
C
Probabilitya,b.c
Reject H
{6}
Reject H
{8}
Reject H
{6}or H
{8}
i.e., Overall Power
Weak
0.20
0.20
0.80
0.49
0.88
Strong
0.20
0.12
0.55
0.57
0.76
Very Strong
0.20
0.04
0.28
0.62
0.67
a Assuming a prevalence of 0.47 of Subgroup S in the full population.
b Assuming probability of drop-out of 0.05 for each treatment arm.
c Probability based on 100000 simulations.


Appendix 15: Statistical Performance of the Adaptive Design (cont.)
AtezolizumabF. Hoffmann-La Roche Ltd
187/Protocol WO39392, Version 9
Table 4
Conditional Rejection Probabilities if Stage 2 Activated under 
Weak, Strong, and Very Strong Credentials on Subgroup S
Subgroup S 
Credentials
S
C
Conditional Probabilitya,b,c,d (if Stage 2 activated)
Reject H
{6}
Reject H
{8}
Reject H
{6}or H
{8}
i.e., Overall “Go” Power
Weak
0.20
0.20
0.54
0.36
0.74
Strong
0.20
0.12
0.29
0.51
0.68
Very Strong
0.20
0.04
0.10
0.63
0.68
a Assuming a prevalence of 0.47 of Subgroup S in the full population.
b Assuming probability of drop-out of 0.05 for each treatment arm.
c Probability based on 100000  simulations.
d Conditional probability of event happening once the trial continues to enroll patients in 
Stage 2 (“go”).

SAP_001.pdf: 
 
Official Title: 
 
A Phase III Randomized Study to Investigate the Efficacy and Safety 
of Atezolizumab (Anti-PD-L1 Antibody) in Combination With 
Neoadjuvant Anthracycline/Nab-Paclitaxel-Based Chemotherapy 
Compared With Placebo and Chemotherapy in Patients With Primary 
Invasive Triple-Negative Breast Cancer 
NCT Number: 
 
NCT03197935 
Document Date: 
 
SAP Version 2: 06-November-2018 
 
 


CONFIDENTIAL
This is a 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 WO39392
STATISTICAL ANALYSIS PLAN
TITLE:
A PHASE III RANDOMIZED STUDY TO INVESTIGATE THE 
EFFICACY AND SAFETY OF ATEZOLIZUMAB 
(ANTIPD-L1 ANTIBODY) IN COMBINATION WITH 
NEOADJUVANT ANTHRACYCLINE /NAB-
PACLITAXEL-BASED CHEMOTHERAPY COMPARED 
WITH PLACEBO AND CHEMOTHERAPY IN PATIENTS 
WITH PRIMARY INVASIVE TRIPLE-NEGATIVE BREAST 
CANCER
PROTOCOL NUMBER:
WO39392
STUDY DRUG:
Atezolizumab (MPDL3280A; RO5541267)
VERSION NUMBER:
2
IND NUMBER:
123277
EUDRACT NUMBER:
2016-004734-22
SPONSOR:
F. Hoffmann-La Roche Ltd
PLAN PREPARED BY:
, Ph.D.
DATE FINAL:
Version 1:  6 December 2017
DATE AMENDED:
Version 2:  See electronic date stamp below
06-Nov-2018 13:15:32
Company Signatory
STATISTICAL ANALYSIS PLAN AMENDMENT APPROVAL
Name                                                             Reason for Signing                              Date and Time
(UTC)


Atezolizumab—F. Hoffmann-La Roche Ltd
2/Statistical Analysis Plan WO39392
STATISTICAL ANALYSIS PLAN AMENDMENT RATIONALE
This Statistical Analysis Plan (SAP) Version 2 for Study WO39392 (IMpassion031) has 
been amended to incorporate an adaptive, two-stage design that uses accumulating 
data to modify aspects of the study as it continues, without undermining the validity and 
integrity of the trial.
Study WO39392 is currently designed (protocol version 4) to randomize 
approximately 204 patients in total (approximately 102 patients per arm) to control 
the type I error for the primary endpoint of pathological complete response (pCR) at 
the 5% level of significance (two-sided) in the intent-to-treat (ITT) population. 
However, we have observed strong evidence of difference in efficacy effect across
the programmed deathligand 1 (PD-L1) subgroups of atezolizumab plus 
nab-paclitaxel arm in metastatic triple negative breast cancer (TNBC) study 
(WO29522) that could impact the WO39392 study. To address the uncertainty 
surrounding design choices based on the effect of PD-L1 and to allow review of 
accumulating information during the ongoing WO39392 study, we plan to change 
the current fixed design to an adaptive design. The proposed adaptive design 
consists of two trial stages. After an interim analysis at the end of stage 1 
(i.e., approximately 204 patients), recommendations will be made to either continue 
the study unchanged or to expand the target population for a subsequent stage 2 of 
the trial (i.e., approximately 120 additional patients).  
To maintain the integrity of the trial, an independent Data Coordinating Center will 
perform the interim analysis and an independent Data Monitoring Committee (iDMC) 
will evaluate the interim analysis results.  The iDMC will provide a recommendation 
as to whether to continue the study unchanged or expand to stage 2. The decision 
rule to be applied at the interim analysis will be clearly expressed to the iDMC and 
documented in the iDMC charter so that the study can be conducted with the 
Sponsor remaining completely blinded to all results unless iDMC recommendation is 
not to expand into stage 2. The iDMC will also monitor safety and study conduct for 
stage 2 of Study WO39392.
To reflect these changes, this SAP has been amended alongside the study protocol.  
Additional minor changes have been made to improve clarity and consistency.


Atezolizumab—F. Hoffmann-La Roche Ltd
3/Statistical Analysis Plan WO39392
TABLE OF CONTENTS
1.
BACKGROUND ............................................................................................ 5
2.
STUDY DESIGN........................................................................................... 5
2.1
Protocol Synopsis.................................................................... 5
2.2
Outcome Measures ................................................................. 5
2.2.1
Primary Efficacy Outcomes ..................................................... 5
2.2.2
Secondary Efficacy Outcomes................................................. 6
2.2.3
Safety Outcomes..................................................................... 6
2.2.4
Pharmacokinetic Outcomes..................................................... 6
2.2.5
Immunogenicity Outcomes ...................................................... 6
2.3
Determination of Sample Size ................................................. 6
3.
STUDY CONDUCT....................................................................................... 7
3.1
Randomization......................................................................... 7
3.2
Data Monitoring ....................................................................... 8
4.
STATISTICAL METHODS ............................................................................ 8
4.1
Definition of Analysis Populations............................................ 8
4.2
Analyses of Study Conduct...................................................... 8
4.3
Analyses of Treatment Group Comparability........................... 9
4.4
Analyses of Efficacy ................................................................ 9
4.4.1
Primary Efficacy Endpoint........................................................ 9
4.4.1.1
Primary Analyses..................................................................... 9
4.4.2
Secondary Efficacy Endpoints............................................... 12
4.4.2.1
Event-Free Survival ............................................................... 12
4.4.2.2
Disease-Free Survival ........................................................... 12
4.4.2.3
Overall Survival ..................................................................... 13
4.4.2.4
Patient-Reported Outcomes of Role and Physical 
Function and Global Health Status/ Health-
Related Quality of Life–EORTC Data .................................... 13
4.4.3
Exploratory Efficacy Analyses ............................................... 14
4.4.3.1
Patient-Reported Outcomes of 
Disease/Treatment Symptoms, Emotional and 
Social Function – EORTC Data............................................. 14


Atezolizumab—F. Hoffmann-La Roche Ltd
4/Statistical Analysis Plan WO39392
4.4.3.2
Patient-Reported Outcome of Treatment Bother –
FACT-G, GP5 Data ............................................................... 14
4.4.3.3
Health Economic EQ-5D-5L Data.......................................... 14
4.4.3.4
Proportion of Patients Undergoing Breast-
Conserving Surgery............................................................... 14
4.4.3.5
Residual Cancer Burden Index.............................................. 14
4.5
Analyses of Safety................................................................. 15
4.5.1
Exposure of Study Medication............................................... 15
4.5.2
Adverse Events ..................................................................... 15
4.5.3
Laboratory Data..................................................................... 16
4.5.4
Vital Signs.............................................................................. 16
4.6
Pharmacokinetic Analyses..................................................... 16
4.7
Immunogenicity Analyses...................................................... 16
4.8
Biomarker Analyses............................................................... 17
4.9
Exploratory Analyses............................................................. 17
4.9.1
Exploratory Biomarker Analyses............................................ 17
4.9.2
Subgroup Analyses ............................................................... 17
4.10
Interim Analyses .................................................................... 18
4.10.1
Planned Interim Analysis ....................................................... 18
4.10.2
Optional Interim Analysis....................................................... 19
5.
REFERENCES ........................................................................................... 20
LIST OF FIGURES
Figure 1
Flowchart of the Decision Rules.................................................. 19
LIST OF APPENDICES
Appendix 1
Protocol Synopsis ....................................................................... 21
Appendix 2
Schedule of Activities (for Both Stage 1 and Stage 2) ................ 32
Appendix 3
Adaptive Multiple Test Design..................................................... 39


Atezolizumab—F. Hoffmann-La Roche Ltd
5/Statistical Analysis Plan WO39392
1.
BACKGROUND
This Statistical Analysis Plan (SAP) describes the analyses that are planned to be 
performed for Study WO39392 (also known as IMpassion031).
2.
STUDY DESIGN
2.1
PROTOCOL SYNOPSIS
Study WO39392 (IMpassion031) is a global Phase III, double-blind, randomized, 
placebo-controlled study designed to evaluate the efficacy and safety of neoadjuvant 
treatment with TECENTRIQ(atezolizumab) and nab-paclitaxel followed by doxorubicin 
and cyclophosphamide with atezolizumab compared with neoadjuvant treatment with 
placebo and nab-paclitaxel followed by doxorubicin and cyclophosphamide with placebo 
in patients with primary invasive early triple-negative breast cancer (TNBC), that are 
eligible for surgery.  The study will enroll patients with initial clinically assessed 
T2-4d TNBC.
The study design consists of two trial stages, 1 and 2, with an a priori fixed sample size 
for both stages.  In stage 1, approximately 204 patients will be randomized in a 1:1 ratio 
to the atezolizumab arm or the placebo arm as described in Section 3.1.
After an interim analysis conducted at the completion of stage 1 (i.e., once all patients 
enrolled in stage 1 have had surgery and pCR assessment), a decision will be made to 
either continue the study unchanged or to expand patient enrolment for a subsequent 
stage 2 of the trial (i.e., approximately 120 additional patients).  If after the first stage, the 
trial is not read out for efficacy or lack of efficacy, the sponsor will proceed into the 
second stage with the selected population.  Approximately 120 additional patients will be 
randomized in a 1:1 ratio to the atezolizumab arm or the placebo arm.  At the conclusion 
of stage 2, the primary analysis of pCR is conducted by combining the p-values of both 
stage 1 and 2 into a single test statistic using a predefined combination function.
Note that the primary analysis of pCR could occur at the end of stage 1 (early stop for 
efficacy) projected to take place approximately 21 months after the first patient has been 
randomized or at the end of stage 2 projected to take place approximately 3544 months 
after the first patient has been randomized depending on the targeted population 
selected at the end of stage 1.
The protocol synopsis for Study WO39392 including a description of the study design is
in Appendix 1.
2.2
OUTCOME MEASURES
2.2.1
Primary Efficacy Outcomes
The co-primary efficacy endpoint for this study is pCR defined as eradication of invasive 
tumor from both breast and lymph nodes (ypT0/is ypN0) in the intent-to-treat (ITT) 


Atezolizumab—F. Hoffmann-La Roche Ltd
6/Statistical Analysis Plan WO39392
population (full population) and in the subpopulation with programmed death-ligand 1
(PD-L1)positive tumor status (tumor-infiltrating immune cell [IC] IC1/2/3)
(see Section 4.1).  Patients whose pCR assessment was missing will be counted as not 
achieving a pCR.
2.2.2
Secondary Efficacy Outcomes

Event-free survival (EFS) defined as the time from randomization until documented
disease recurrence, progression, or death from any cause in all patients and in the
subpopulation with PD-L1positive tumor status.  More details for EFS definition are
given in Section 4.4.2.1.

Disease-free survival (DFS) defined as the time from surgery until documented
disease recurrence or death from any cause in all patients (ITT population) who
undergo surgery and in the subpopulation of patients with PD-L1positive tumor
status who undergo surgery. More details for DFS definition are given in
Section 4.4.2.1.

Overall survival (OS) defined as the time from randomization to the date of death
from any cause in all patients and in the subpopulation with PD-L1positive tumor
status.

Mean and mean changes from baseline score in function (role, physical) and global
health status (GHS)/ health-related quality of life (HRQoL) by cycle and between
treatment arms as assessed by the functional and HRQoL scales of the European
Organisation for Research and Treatment of Cancer (EORTC) Quality of Life
Questionnaire Core 30 (QLQ C30).
2.2.3
Safety Outcomes

Incidence, nature, and severity of adverse events graded according to
National Cancer Institute Common Terminology Criteria in Adverse Events,
Version 4.0 (NCI CTCAE v4.0).

Changes in vital signs and clinical laboratory results.
2.2.4
Pharmacokinetic Outcomes
Serum concentration of atezolizumab at specified timepoints (see Appendix 2).
2.2.5
Immunogenicity Outcomes
Incidence of anti-drug antibodies (ADAs) during the study and the prevalence of ADAs at 
baseline.
2.3
DETERMINATION OF SAMPLE SIZE
The study will randomize approximately 204 patients in stage 1 
(approximately 102 patients per arm) and approximately 120 patients in stage 2 
(approximately 60 patients per arm).
The performance of the study design depends on several factors including the 
underlying proportion of (pCR) responders in each treatment arms for the subgroup S 


Atezolizumab—F. Hoffmann-La Roche Ltd
7/Statistical Analysis Plan WO39392
(PD-L1 IC1/2/3) and the complement group C (PD-L1 IC0). Simulations were carried out 
to evaluate the operation characteristics of the current design under a variety of 
conditions including the overall power defined as the probability to reject any null 
hypothesis at any analysis time point in the study, which is observed to be at least 68% 
across the simulation scenarios under investigation.  More details are provided in 
Appendix 1.
3.
STUDY CONDUCT
3.1
RANDOMIZATION
Randomization will occur in a 1:1 ratio using a permuted-block randomization method.  
Patients will be randomized to one of two treatment arms:

Arm A:  atezolizumab (840 mg fixed dose) administered via intravenous (IV) 
infusion every two weeks (q2w) in combination with nab-pac (125 mg/m2) 
administered via IV infusion every week (qw) for 12 weeks followed by atezolizumab 
(840 mg fixed dose) administered q2w in combination with doxorubicin 
(60 mg/m2)cyclophosphamide (600 mg/m2) administered q2w via IV infusions with 
filgrastim/ pegfilgrastim support for 4 cycles.  Patients randomized to the 
atezolizumab arm will continue to receive unblinded atezolizumab post-surgery at a 
fixed dose of 1200 mg by IV infusion every 3 weeks (q3w) for 11 cycles, for a total of 
approximately 12 months of atezolizumab therapy.

Arm B:  placebo administered q2w via IV infusion in combination with nab-paclitaxel 
(125 mg/m2) administered qw via IV infusion for 12 weeks followed by placebo 
administered q2w in combination with doxorubicin (60 mg/m2)cyclophosphamide 
(600 mg/m2) administered q2w via IV infusions with filgrastim/ pegfilgrastim support 
for 4 cycles.  Patients randomized to the placebo arm will be unblinded post-surgery 
and will continue to be followed up as per the schedule of activities outlined in the 
study protocol.
Postoperative patient management for those in either treatment arm may include 
radiotherapy as clinically indicated, and management of patients who do not achieve a
pCR should follow current standard-of-care guidelines.  For patients in Arm A, 
chemotherapy and/or radiotherapy may be administered concurrently with atezolizumab 
after discussion with Medical Monitor.
The randomization scheme is designed to ensure that an approximately equal number of 
patients will be enrolled in each treatment arm within the categories defined for the 
following stratification factors at baseline:

American Joint Committee on Cancer (AJCC) Stage at diagnosis (II vs. III) for 
patients enrolled in both stages 1 and 2.

Tumor infiltrating immune cells PD-L1 status (IC0 vs. IC1/2/3) for patients enrolled in 
stage 1 as well as stage 2 IF the study continues to enroll all-comer patients in 
stage 2.


Atezolizumab—F. Hoffmann-La Roche Ltd
8/Statistical Analysis Plan WO39392
3.2
DATA MONITORING
An iDMC will evaluate the primary efficacy endpoint of pCR in the ITT and 
PD-L1positive populations at the prespecified interim analysis based on data of 
approximately 204 patients enrolled in stage 1 and will make a recommendation to either 
complete the study unchanged or to expand the target population for the subsequent 
stage 2 of the trial (i.e., approximately 120 additional patients).  The decision rules to be 
applied at the interim analysis will be clearly expressed to the iDMC and documented in 
the iDMC charter so that the study can be conducted with the Sponsor remaining 
completely blinded to all results at this stage.
The iDMC will also evaluate safety data and study conduct on a regular basis during the 
study until the primary analysis of pCR, which is performed at stage 1 (approximately 
204 patients) or stage 2 (approximately 324 patients), if the iDMC recommends 
extending the target population after which, iDMC review of the study data will be 
discontinued. 
Sponsor affiliates will be excluded from iDMC membership.  All summaries and analyses 
for the iDMC review will be prepared by an independent Data Coordinating Center. The 
iDMC will follow a charter that outlines the iDMC’s roles and responsibilities.
4.
STATISTICAL METHODS
The analyses outlined in this SAP supersede those specified in the protocol for 
regulatory filing purposes.
4.1
DEFINITION OF ANALYSIS POPULATIONS
The primary analysis population for efficacy is the ITT population (full population),
defined as all randomized patients, and the PD-L1positive subpopulation, defined as 
patients in the ITT population whose PD-L1 status is IC1/2/3 at the time of randomization.  
Patients will be assigned to the treatment group to which they were randomized.
The primary analysis population for safety is the safety evaluable population defined as 
all patients who received at least one dose of study medication.  Patients will be 
assigned to treatment groups as treated, and all patients who received any dose of 
atezolizumab will be included in the atezolizumab treatment arm.
4.2
ANALYSES OF STUDY CONDUCT
For all randomized patients (i.e., ITT population), a participant flowchart for depicting the 
progress of subjects through the phases of the trial will be provided by treatment arm
and study stage (i.e., 1 and 2) of enrollment, including a complete description of patient 
disposition specifying the number of randomized patients and completed and 
discontinued patients from trial treatment and study with reasons for premature 
discontinuation.  Documented major protocol deviations including those related to study 


Atezolizumab—F. Hoffmann-La Roche Ltd
9/Statistical Analysis Plan WO39392
inclusion/ exclusion criteria, conduct of the study, patient management, or patient 
assessment will be also tabulated by treatment arm and study stage of enrollment.
4.3
ANALYSES OF TREATMENT GROUP COMPARABILITY
Demographic variables such as age, sex, race/ethnicity, and baseline characteristics (in 
particular, stratification variables) will be summarized by treatment arm and study stage 
(i.e., 1 and 2) of enrollment for the ITT as well as PD-L1positive population.  Only 
descriptive analyses are planned; no formal statistical tests will be applied.  Continuous 
variables will be reported and summarized by use of standard measures of central 
tendency and dispersion (mean, SD, median, and range including minimum and 
maximum), and categorical (i.e., discrete) data will be reported and summarized by 
frequencies and percentages.
The baseline value of any variable will be defined as the last available value prior to the 
first administration of study treatment.
4.4
ANALYSES OF EFFICACY
4.4.1
Primary Efficacy Endpoint
4.4.1.1
Primary Analyses
The ITT as well as PD-L1positive population will be used for the primary analysis of the 
co-primary endpoints of pCR in these populations as follows.  The overall one-sided
type I error for testing the co-primary endpoints of pCR is  = . 	.
Two main sources for multiplicity in statistical testing from the current design are:

Multiple target populations, namely ITT and PD-L1positive populations.

Study having 2 stages with target population at stage 2 depending on results from 
stage 1.
Simes’ closed testing procedure will be used to address multiplicity in target populations 
and weighted inverse p-value combination method is applied to account for the adaptive 
choice of target population at stage 2 as follows.
At Stage 1
For the interim analysis at end of stage 1, the co-primary endpoints of pCR in the ITT 
and PD-L1positive population will be tested at the pre-defined one-sided type I error of 
0.0125 (i.e. 50% of the total type I error) following Simes’ procedure.  This involves the 
following p-values:



{} is the p-value from the one-sided Cochran-Mantel-Haenszel (CMH)  test for 
difference in pCR rates between treatment groups in the ITT population (F) 
stratified according to tumor PD-L1 status (IC0 vs. IC1/2/3) and clinical stage at 
presentation (Stage II vs. III).  The associated elementary null hypothesis is denoted 
as H
{}:F 0.


Atezolizumab—F. Hoffmann-La Roche Ltd
10/Statistical Analysis Plan WO39392



{} is the p-value from the CMH  test for difference in pCR rates between 
treatment groups in the PD-L1positive population (S) stratified according to 
clinical stage at presentation (Stage II vs. III). The associated elementary null 
hypothesis is denoted as H
{}:S 0.



{,} =  2 
{}, 
{ }! , "# 
{}, 
{ }!$, p-value based on Simes’ method for 
the intersection hypothesis %
{ ,}, which specifies that there is no proportion 
difference in either F or S.
In addition, the observed difference in pCR rates between arms in S, denoted as Δ'
 and 
its complementary sub-population of patients with PD-L1 IC0 (C), denoted as Δ'
( will also 
be computed.
Based on 
{ }, 
{}, 
{ ,}, Δ'
 and Δ'
(, the following decision could be made at stage 1:
1.
If 
{ ,} ≤*, the analysis at stage 1 is considered the primary efficacy analysis for 
pCR with evidence for efficacy declared in either F (if 
{ } ≤*) or S (if 
{} ≤*) or 
both, the study will therefore not enroll extra patients in stage 2. 
2.
Otherwise, if both Δ'
 and Δ'
( are below the pre-specified thresholds, + = 0.12 and 
+( = 0.1, respectively, the study will also not enroll extra patients in stage 2 for lack 
of efficacy.
3.
Otherwise, if  Δ'
 ≥+ and Δ'
( < +(, the study will enroll only patients in S at stage 2, 
with S being the only target population in the primary efficacy analysis for pCR.
4.
Otherwise, if  Δ'
 < + and Δ'
( ≥+(, the study will enroll all-comer patients (F) in 
stage 2; however, only F will be the target population in the primary efficacy analysis 
for pCR.
5.
If 01
 ≥+ and 01
( ≥+(, the study will enroll all-comer patients in stage 2, and the 
co-primary efficacy endpoints of pCR in F and S will be considered in the primary 
efficacy analysis for pCR.
At Stage 2 (if needed)
If the study advances to stage 2, at the primary efficacy analysis for pCR to protect the 
overall * the corresponding boundary for statistical significance is *=0.0184, 
accounting for the fact that and overall * = 0.0125 having been spent at stage 1 and 
the information fraction at stage 1, namely 3 = 4 (4 + 4)
⁄
.  Indeed, the p-value
 based on stage 1 data only and the combination p-value  have the same joint 
distribution under the null hypothesis as the p-values from a group-sequential test with 
two stages at information times 9 = 3 and 9 = 1. Thus standard statistical software 
for group sequential designs can be used for the determination of critical values for the 
adaptive design (Wassmer and Brannath 2016, Section 6.2.4).


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Final test(s) involving the target population(s) selected at stage 1 will be based on 
weighted inverse normal p-value combination method (Wassmer and Brannath 2016) as 
follows:
Let 3 = :4 (4 + 4)
⁄
and 3 = :4 (4 + 4)
⁄
be the a priori chosen weights 
associated with stage 1 and stage 2, respectively.
If both F and S are selected as the co-primary target populations, the following quantities 
are computed:



{} and 

{} are defined and derived similarly as 

{} and 

{}, respectively, with 
derivation based solely on patients enrolled in stage 2.



{,} =  2 
{}, 
{ }! , "# 
{}, 
{ }!$, p-value based on Simes’ method for 
the intersection hypothesis %
{ ,} based only on patients enrolled in stage 2.



{} = 1 −Φ 3 ∙Φ> 1 −
{}! + 3 ∙Φ> 1 −
{}!$, the combined p-value for 
H
{} from stage 1 and 2 following the weighted inverse normal combination method, 
where Φ denotes the cumulative distribution function of a standard normal variate.



{} = 1 −Φ 3 ∙Φ> 1 −
{ }! + 3 ∙Φ> 1 −
{ }!$, the combined p-value for 
H
{} from stage 1 and 2 following the weighted inverse normal combination method.



{,} = 1 −Φ 3 ∙Φ> 1 −
{ ,}! + 3 ∙Φ> 1 −
{ ,}!$, the combined p-value 
for H
{,} from stage 1 and 2 following the weighted inverse normal combination 
method.
If either F or S, but not both of them, is selected as the only target population, there 
remains only one elementary null hypothesis, which is also the intersection hypothesis.  
In general, let Q be the selected target population, that is, Q being either S or F the 
following quantities are computed:



{?} is derived as above and 

{,} = 
{@}.



{?} and 

{,} are then computed based on (
{@}, 
{@})  and (
{ ,}, 
{ ,}), 
respectively, as mentioned above. Please note that 
{ ,} is the same as when both 
F and S are selected as the target populations.  In general 
{ ,} is invariant to 
selection of the target population(s) for the primary efficacy analysis for pCR.
In all cases, at the primary efficacy analysis for pCR, the null hypothesis associated with 
a selected target population (Q) is rejected if both 
{@} ≤* and 
{ ,} ≤* following 
Simes’ procedure.
Operating characteristics of the current design across several simulation scenarios are 
provided in Appendix 1.


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A summary table that presents the number and proportion of pCR in each treatment arm, 
together with the 2-sided 95% CIs with use of the ClopperPearson method 
(Clopper and Pearson 1934) will be produced by stage and overall for both the ITT and 
PD-L1positive populations.  Confidence intervals for the difference in pCR rate between 
the two arms will be determined using the normal approximation to the binomial 
distribution.  
4.4.2
Secondary Efficacy Endpoints
4.4.2.1
Event-Free Survival
Event-free survival (EFS) is defined as the time from randomization to the first 
documented occurrence of disease recurrence, disease progression, or death from any 
cause.  EFS events covered under “disease recurrence” will include local, regional, or 
distant recurrence and contralateral breast cancer.  Ipsilateral or contralateral in situ 
disease and second primary non-breast cancers will not be counted as EFS events, 
even though they will be recorded in the electronic Case Report Form accordingly.
Patients without an event at the time of the analysis will be censored on the date on 
which they are last known to be alive and event free, on or before the clinical data cutoff 
date for the respective analysis.  Patients with no post-baseline information will be 
censored at the date of randomization.
EFS will be compared between treatment arms with use of the stratified log-rank test.
The hazard ratio (HR) for EFS will be estimated using a stratified Cox proportional 
hazards model. The 95% CI for the HR will be provided. KaplanMeier methodology 
will be used to estimate the median EFS (if reached) for each treatment arm, and
Kaplan-Meier curves will be produced.  The BrookmeyerCrowley methodology will be 
used to construct the 95% CI for the median EFS for each treatment arm 
(Brookmeyer and Crowley 1982).  The KaplanMeier approach will be used to estimate 
3-year EFS rates and corresponding 95% CIs for each treatment arm.
The stratification factors for all analyses based on the ITT population will be:  tumor 
stage (AJCC) at baseline (Stage II vs. III) and PD-L1 status (IC0 vs. IC1/2/3).
The stratification factors for EFS analysis in the PD-L1positive subpopulation will be 
AJCC at baseline (Stage II vs. III).
Results from unstratified analyses will also be provided.
4.4.2.2
Disease-Free Survival
DFS is defined as the time from surgery (i.e., the first date of no disease) to the first 
documented disease recurrence or death from any cause, whichever occurs 
first. DFS will be analyzed with the use of the same methodology as specified for 
EFS for both the ITT population and the PD-L1 positive subpopulation. 


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The DFS analysis will be performed approximately 36 months after the randomization of 
the last patient.
Patients who do not undergo surgery at the end of neoadjuvant treatment will be 
excluded from the analysis of DFS. Patients without a DFS event at the time of analysis 
will be censored at the date when they were last known to be alive and event free.
Patients who do not have information after surgery will be censored at the date of 
surgery.
4.4.2.3
Overall Survival
Overall Survival (OS) 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 
analyses will be censored at the date when they were last known to be alive.  Patients 
who do not have information after baseline will be censored at the date of randomization.  
OS will be analyzed with the use of the same methodology as specified for EFS for both 
the ITT population and the PD-L1positive subpopulation.
4.4.2.4
Patient-Reported Outcomes of Role and Physical Function and 
Global Health Status/ Health-Related Quality of Life–EORTC 
Data
The EORTC QLQ-C30 (version 3) data will be scored according to the EORTC scoring 
manual (Fayers et al. 2001).  Missing data will be assessed and reported by cycle.  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 consistent with the scoring manual and 
validation papers of the measure.  For subscales with less than 50% of the items 
completed, the subscale will be considered missing.  Patient-reported outcomes (PRO) 
completion, compliance rates, and reasons for missing data will be summarized at each
timepoint by treatment arm.
The primary patient-reported endpoints are mean and mean changes from baseline 
score in function (role, physical) and GHS/ HRQoL.  Summary statistics (mean, SD, 
median, and range) of linearly transformed absolute scores and mean changes from 
baseline will be calculated for the functional (role [Question {Q}6, Q7], physical [Q1Q5]) 
and the GHS/ HRQoL (Q29, Q30) scales of the EORTC QLQ-C30 at each assessment 
time point for each arm. The mean change from baseline (and 95% CI) will be assessed 
on patients with at least one post-baseline measurement.  Previously published 
meaningful thresholds of change important differences will be used to identify clinically 
meaningful change from baseline within each treatment group on the functional and 
GHS/ HRQoL scales (Osoba et al. 1998, Cocks et al. 2011).
Longitudinal analysis will be conducted to estimate the effect difference on PRO
repeated responses over a selected period of time and between the treatment arms.
Mixed effect models on a set of covariates (baseline domain score, patient demographic, 
and clinical variables) will be conducted. Change from baseline at subsequent cycles 


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will be presented by treatment arm and will include least squares mean (LS Mean), 
difference in LS Mean between two treatment arms, and 95% CIs for the differences. 
The standard error will also be calculated for each LS Mean.
4.4.3
Exploratory Efficacy Analyses
4.4.3.1
Patient-Reported Outcomes of Disease/Treatment Symptoms, 
Emotional and Social Function – EORTC Data
Summary statistics (mean, SD, median, and range) of linearly transformed absolute 
scores and mean changes from baseline will be calculated for all 
disease/treatment-related symptom items and scales, and the emotional, social function 
scales of the EORTC QLQ-C30 at each assessment timepoint for each arm. The 
analyses of this exploratory endpoint will be analogous to the secondary PRO endpoints 
(see Section 4.4.2.4 for further details).
4.4.3.2
Patient-Reported Outcome of Treatment Bother – FACT-G, GP5 
Data
A descriptive analysis of absolute scores and the proportion of patients selecting each 
response option at each assessment time-point 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).
4.4.3.3
Health Economic EQ-5D-5L Data
Health utility data from the EuroQoL 5 Dimension, 5 Level (EQ-5D-5L), will be evaluated 
in pharmacoeconomic models. The results from the health economic data analyses will 
be reported separately from the clinical study report.
4.4.3.4
Proportion of Patients Undergoing Breast-Conserving Surgery
The proportion of patients undergoing breast-conserving surgery will be compared 
between the treatment arms using the same methodology for pCR analysis in 
Section 4.4.1.1, for the subpopulation of patients having surgery.
4.4.3.5
Residual Cancer Burden Index
Pathological review of the primary tumor site and sampled lymph nodes by the local 
pathologists at surgery will also include the calculation of the Residual Cancer Burden 
(RCB) index.  Such index is computed by taking into account the primary tumor bed area, 
overall cancer cellularity, the percentage of in situ disease, number of positive lymph 
nodes and the diameter of the largest lymph node metastasis (Symmans et al. 2007).  
Pathological complete response would correspond to RCB0, whereas minimal, 
moderate, and extensive residual disease would be indicated by RCB-I, RCB-II, and 
RCB-III, respectively.
The following analyses will be carried out for the population of patient with evaluable 
RCB index.


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A summary table that presents the number and proportion of RCB-0, -I, -II and -III in 
each treatment arm, together with the respective 2-sided 95% CIs with use of the 
Clopper-Pearson method (Clopper and Pearson 1934) will be produced.
Comparison between treatment arms will be done using ordered logit (proportional-odds) 
regression model (Peter McCullagh 1980) stratified for the stratification factors as for the 
primary pCR analysis.
4.4.3.5.1
Association between RCB Index and EFS, OS
The analyses for EFS, DFS and OS, described in Section 4.4.2.1, Section 4.4.2.2, and 
Section 4.4.2.3 respectively, will be repeated for the subgroups of patients with RCB-0, 
RCB-I, RCB-II, and RCB-III.
4.5
ANALYSES OF SAFETY
Safety analyses will be performed on the safety population defined as all patients who 
received any dose of study medication.
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.
4.5.1
Exposure of Study Medication
Study drug exposure, including but not limited to treatment duration, number of cycles, 
and dose intensity, will be summarized with descriptive statistics for each study 
treatment on each treatment arm if deemed appropriate.
4.5.2
Adverse Events
Verbatim descriptions of AEs will be mapped to Medical Dictionary for Regulatory 
Activities (MedDRA) thesaurus terms and graded according to NCI CTCAE v4.0.
Treatment-emergent adverse events (TEAEs), defined as events occurring on or after 
the first dose of study treatment will be summarized by MedDRA term, appropriate 
MedDRA levels, and NCI CTCAE v4.0 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.
The following TEAEs will be summarized separately:

AEs leading to withdrawal of study drug,

AEs leading to dose reduction or interruption,

Grade3 AEs, Grade 5 AEs, serious adverse events (SAEs), and 

Adverse events of special interest (AESIs).
All deaths and causes of death will be summarized.


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4.5.3
Laboratory Data
Laboratory data with values outside of the normal ranges will be identified.  Relevant 
laboratory values will be summarized by treatment arm over time, with NCI CTCAE v4.0 
Grade 3 and Grade 4 values identified, where appropriate.  Changes from baseline in 
NCI CTCAE v4.0 grade (i.e., shift tables) will be also provided by treatment arm.  Of note, 
abnormal laboratory data that are clinically significant will be reported as adverse events 
and summarized in the adverse event tables.
A Hy’s law analysis will be provided.
The finding of an elevated ALT or AST (3baseline value) in combination with either 
an elevated total bilirubin (2ULN) or clinical jaundice in the absence of cholestasis 
or other causes of hyperbilirubinemia is considered to be an indicator of severe liver 
injury (as defined by Hy’s Law).  Therefore, investigators must report as an adverse 
event the occurrence of either of the following:

Treatment-emergent ALT or AST 3 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.
4.5.4
Vital Signs
Changes in selected vital signs will be summarized by treatment arm and by change 
over time including change from baseline.
4.6
PHARMACOKINETIC ANALYSES
Atezolizumab serum concentration data (Cmin and Cmax) will be tabulated and
summarized. Descriptive statistics will include means, medians, ranges, and SDs, as
appropriate.
Additional pharmacokinetic and pharmacodynamic analyses will be conducted as 
appropriate.
4.7
Immunogenicity Analyses
The immunogenicity analyses will include patients with at least one post-baseline ADA 
assessment, with patients grouped according to treatment received.
The numbers and proportions of ADA-positive patients and ADA-negative patients at 
baseline (baseline prevalence) and after baseline (post-baseline incidence) will be 
summarized by treatment group.  When determining post-baseline incidence, patients 
are considered to be ADA-positive if they are ADA-negative or are missing data at 
baseline but develop an ADA response following study drug exposure (treatment 
induced ADA response), or if they are ADA-positive at baseline and the titer of one or 


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more post-baseline samples is at least 0.60 titer unit greater than the titer of the baseline 
sample (treatment-enhanced ADA response).  Patients are considered to be 
ADA-negative if they are ADA-negative or are missing data at baseline and all post 
baseline samples are negative, or if they are ADA-positive at baseline but do not have 
any post-baseline samples with a titer that is at least 0.60 titer unit greater than the titer 
of the baseline sample (treatment unaffected).
The relationship between ADA status and safety, efficacy, and pharmacokinetics may be 
investigated.
4.8
BIOMARKER ANALYSES
EFS, DFS, and OS will be assessed in the PD-L1 IC1/2/3 population as secondary 
endpoints as described in Sections 2.2.2, 4.4.2.1, and 4.4.2.3 respectively.
4.9
EXPLORATORY ANALYSES
4.9.1
Exploratory Biomarker Analyses
Exploratory biomarker analyses will be performed in baseline pretreatment, on-treatment, 
residual-disease, and post recurrence samples in an effort to understand the association 
of these markers with study treatment outcome, including efficacy and/or adverse events.  
The biomarkers may include but will not be limited to PD-L1-expressing tumor cells, 
tumor infiltrating immune cells, RNA-based T-effector signature and other biomarkers in 
tumor and blood, as defined by immunohistochemistry, quantitative reverse transcription 
polymerase chain reaction, next-generation DNA and RNA sequencing, or other 
methods.  Pharmacodynamic changes of these biomarkers at baseline, on-treatment 
samples and at surgical resection.
Circulating tumor DNA (ctDNA) will be evaluated in post-surgery plasma samples and 
compared between control and experimental arms.
Whole genome sequencing 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.
Results from these analyses will be presented in a separate report.
4.9.2
Subgroup Analyses
To assess the consistency of study results in subgroups defined by demographic and
baseline characteristics (including subtypes of triple-negative breast cancer [TNBC]), 
pCR, EFS, DFS, and OS in these subgroups will be examined.  Summaries of EFS, DFS
and OS, including unstratified HRs estimated from Cox proportional hazards models and 
Kaplan-Meier estimates of the median (if reached), will be produced separately for each 
level of the categorical variables.


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4.10
INTERIM ANALYSES
4.10.1
Planned Interim Analysis
An interim analysis will be performed and reviewed by the iDMC at the end of stage 1 
(i.e., once all of the approximately 204 patients enrolled in stage 1 have had surgery and 
pCR assessment).  At this interim analysis, a decision concerning the target population 
for the subsequent stage of the trial has to be made if efficacy or lack thereof cannot be 
declared after stage 1 (as described in Section 4.4.1.1).  This decision is based on the 
observed pCR proportions (in the ITT and PD-L1positive populations) in the first stage 
of the trial and entails either of the following outcomes:
1. The analysis at stage 1 is considered the primary efficacy analysis for pCR with 
statistical evidence for efficacy in either the ITT (F) or PD-L1positive population 
(S) or both.  The study will therefore not enroll extra patients in stage 2.
2. If no statistical evidence for efficacy can be found in both F and S, and both the 
observed difference in pCR proportion between treatment arms in PD-L1-positive 
population (S) (denoted Δ'
) and its complementary (C, IC0 patients) (denoted Δ'
()  
are below the pre-specified threshold, + and +( as specified in Section 4.4.1, 
respectively, the study will not enroll additional patients in stage 2.  Hence, the 
analysis at stage 1 is considered the primary efficacy analysis for pCR.
3. The study will enroll only patients in S at stage 2, with S being the only target 
population in the primary efficacy analysis of pCR.
If  Δ'
 ≥+ and Δ'
( < +(, the study will enroll only PD-L1-positive patients in stage 
2.
4. The study will enroll all-comer patients (F) at stage 2 with F being the only target 
population in the primary efficacy analysis of pCR.
If  Δ'
 < + and Δ'
( ≥+(, the study will enroll all-comer patients in stage 2; 
however, only the pCR endpoint for F will be considered in the primary efficacy 
analysis of pCR.
5. The study will enroll all-comer patients at stage 2, and the co-primary efficacy 
endpoints of pCR in F and S will be considered in the primary efficacy analysis of 
pCR.
If 01
 ≥+ and 01
( ≥+(, the study will enroll all-comer patients in stage 2, and the 
co-primary efficacy endpoint of pCR in F and S will be considered in the primary 
efficacy analysis of pCR.
However, the integrity of the trial is not dependent on strict adherence to these 
thresholds, i.e. the proposed p-value combination test protects type I error regardless of 
how the decision regarding stage 2 is made (Brannath, Gutjahr, and Bauer 2012).
A graphical presentation of the decision rules is given in Figure 1 below with more 
details including selection and determination of the stage-wise boundaries for statistical 
significance provided in Section 4.4.1.1.


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Figure 1
Flowchart of the Decision Rules
Although these guidelines are in place, the iDMC has authority to deviate from these 
guidelines if safety or additional efficacy analyses indicate that a different 
recommendation is more appropriate. 
4.10.2
Optional Interim Analysis
To adapt to information that may emerge during the course of this study, the Sponsor 
may choose to conduct optional interim efficacy analyses after the primary analysis for 
pCR and before the final analysis for EFS, DFS and OS, if needed (e.g., for regulatory or 
publication purposes). The decision to conduct an optional interim analysis, along with 
the rationale, timing, and statistical details for the analysis, will be documented in the 
Sponsor’s trial master file prior to the conduct of the interim analysis.
Enroll 120 patients 
from F
Enroll 120 patients 
from S
Calculate stage-
wise p-values for 
the relevant test 
hypotheses
Perform 
combination test 
based on the 
selected target 
population(s)
Is S 12%?
No
No
Yes
Select F and S as 
target populations
Select F as target 
population
Select S as target 
population
Not go to stage 2 
for lack of efficacy
Calculate effect 
estimators F, S 
and c, in full 
population F, 
subgroup S and 
complementary 
subgroup C, 
respectively
Statistical 
significant effect in 
F and/or S?
Yes
& declare efficacy in 
F and /or S
No
Yes
Is S 12%?
Yes
Is c 10%?
No
Enroll ~204 patients 
from Full 
population F
Not go to stage 2 


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5.
REFERENCES
Brannath W, Gutjahr G, and Bauer P. Probabilistic foundation of confirmatory adaptive 
designs. J Am Stat Assoc, 2012;107:824–832.
Brookmeyer R and Crowley J. A confidence interval for the median survival time. 
Biometrics 1982;38:294.
Cella D. Manual of the Functional Assessment of Chronic Illness Therapy (FACIT) 
Measurement System. Center on Outcomes, Research and Education (CORE), 
Evanston Northwestern Healthcare and Northwestern University, Evanston IL, 
Version 4, 1997.
Clopper CJ, Pearson ES. The use of confidence or fiducial limits illustrated in the case of 
the binomial. Biometrika 1934;26:40413.
Cocks K., King MT, Velikova G, et al. Evidence-based guidelines for determination of 
sample size and interpretation of the European Organization for the Research and 
Treatment of Cancer Quality of Life Questionnaire Core 30. J Clin Oncol 
2011;29:8996. 
Fayers PM, Aaronson NK, Bjordal K, et al. On behalf of the EORTC Quality of Life 
Group. The EORTC QLQ-C30 scoring manual (3rd Edition). Published by: 
European Organisation for Research and Treatment of Cancer, Brussels, 2001.
Jennison C, Turnbull BW. Group sequential methods with applications to clinical trials. 
Chapman and Hall/CRC, 1999.
Osoba D, Rodrigues G, Myles J, et al. Interpreting the significance of changes in 
health-related quality of life score. J Clin Oncol 1998;16:13944.
Peter McCullagh. Regression Models for Ordinal Data. J R Stat Soc Series B Stat 
Methodol. 1980 42 (2):109-42.
Symmans WF, Peintinger F, Hatzis C, et al. Measurement of residual breast cancer 
burden to predict survival after neoadjuvant chemotherapy. J Clin Oncol. 2007 Oct 
1;25(28):4414–22.
Wassmer G, Brannath W. Group sequential and confirmatory adaptive designs in clinical 
trials. Heidelberg: Springer, 2016.


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Appendix 1 Protocol Synopsis
TITLE:
A PHASE III RANDOMIZED STUDY TO INVESTIGATE THE 
EFFICACY AND SAFETY OF ATEZOLIZUMAB (ANTIPD-L1 
ANTIBODY) IN COMBINATION WITH NEOADJUVANT 
ANTHRACYCLINE/NAB-PACLITAXEL-BASED CHEMOTHERAPY 
COMPARED WITH PLACEBO AND CHEMOTHERAPY IN 
PATIENTS WITH PRIMARY INVASIVE TRIPLE-NEGATIVE 
BREAST CANCER
PROTOCOL NUMBER:
WO39392
VERSION NUMBER:
5
EUDRACT NUMBER:
2016-004734-22
IND NUMBER:
123277
TEST PRODUCT:
Atezolizumab (RO5541267)
PHASE:
III
INDICATION:
Triple-negative breast cancer
SPONSOR:
F. Hoffmann-La Roche Ltd
Objectives and Endpoints
Study WO39392 (also known as IMpassion031) will evaluate the efficacy, safety, and 
pharmacokinetics of neoadjuvant nab-paclitaxel and atezolizumab followed by doxorubicin and 
cyclophosphamide with atezolizumab (referred to as atezolizumab nab-pacAC) or 
neoadjuvant nab-paclitaxel and placebo followed by doxorubicin and cyclophosphamide with 
placebo (referred to as placebo nab-pacAC) in patients with T24d triple-negative breast 
cancer (TNBC).  Specific objectives and corresponding endpoints for the study are as follows:
Objectives
Corresponding Endpoints
Primary Efficacy Objective:
To evaluate the efficacy of 
atezolizumabnab-pacAC compared 
with placebonab-pacAC in the 
neoadjuvant setting 
pCR defined as eradication of tumor from both breast 
and lymph nodes (ypT0/is ypN0) in the following:
All patients (ITT population)
Subpopulation of patients with PD-L1positive 
tumor status (IC1/2/3)


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Objectives
Corresponding Endpoints
Secondary Efficacy Objectives:
To evaluate the efficacy of 
atezolizumabnab-pacAC compared 
with placebonab-pacAC in the 
neoadjuvant setting
EFS defined as the time from randomization until 
documented disease recurrence, progression, or 
death from any cause in all patients (ITT population) 
and in the subpopulation with PD-L1positive tumor 
status
DFS defined as the time from surgery until 
documented disease recurrence or death from any 
cause in all patients (ITT population) who undergo 
surgery and in the subpopulation of patients with 
PD-L1positive tumor status who undergo surgery
OS defined as the time from randomization to the 
date of death from any cause in all patients (ITT 
population) and in the subpopulation with PD-
L1positive tumor status
To evaluate PROs of function and 
HRQoL associated with 
atezolizumabnab-pacAC compared 
with placebonab-pacAC, measured 
by the functional and HRQoL scales of 
the EORTC QLQ-C30
Mean and mean changes from baseline score in 
function (role, physical) and GHS/HRQoL by cycle 
and between treatment arms as assessed by the 
functional and HRQoL scales of the EORTC 
QLQ-C30
Exploratory Efficacy Objectives:
To evaluate the efficacy of 
atezolizumabnab-pacAC compared 
with placebonab-pacAC in the 
neoadjuvant setting
Proportion of patients undergoing breast-conserving 
surgery
RCB index
Correlation of RCB with other clinical endpoints 
(if deemed appropriate)
To evaluate PROs of 
disease/treatment-related symptoms 
associated with 
atezolizumabnab-pacAC compared 
with placebonab-pacAC, as 
measured by the EORTC QLQ-C30
Mean and mean changes from baseline score in 
disease/treatment-related symptoms by cycle and 
between treatment arms as assessed by all symptom 
items/scales of the EORTC QLQ-C30
To evaluate any treatment burden 
patients may experience associated 
with the addition of atezolizumab 
tonab-pacAC compared with 
placebonab-pacAC, as measured by 
a single item (GP5: “I am bothered by 
side effects of treatment”) from the 
physical well-being 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 patient’s health utility as 
measured by the EQ-5D-5L 
questionnaire to generate utility scores 
for use in economic models
Utility scores of the EQ-5D-5L questionnaire
Safety Objective:
To evaluate the safety and tolerability 
of atezolizumabnab-pacAC
compared with placebonab-pacAC 
Occurrence and severity of adverse events as 
defined by NCI CTCAE v4.0 


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Objectives
Corresponding Endpoints
Pharmacokinetic Objectives:
To characterize the pharmacokinetics 
of atezolizumab when administered in 
combination with nab-pacAC 
chemotherapy
Serum concentration of atezolizumab at specified 
timepoints
Immunogenicity Objective:
To evaluate the immune response to 
atezolizumab
Incidence of ADAs during the study and the 
prevalence of ADAs at baseline
Exploratory Immunogenicity Objective:
To evaluate potential effects of ADAs
Relationship between ADA status and efficacy, 
safety, and PK endpoints
Exploratory Biomarker Objective:
To assess predictive, prognostic, and 
pharmacodynamic exploratory 
biomarkers in archival and/or fresh 
tumor tissue and blood and their 
association with efficacy endpoints 
including but not limited to pCR
Relationship between PD-L1 IHC and efficacy 
endpoints other than pCR
Relationship between tumor derived RNA-based 
immune gene signatures and efficacy endpoints,
including but not limited to pCR
Relationship between tumor-based tumor infiltrating 
lymphocytes and/or CD8 IHC and efficacy 
endpoints, including but not limited to pCR
Pharmacodynamic changes in cancer-related 
immune, stroma and tumor immune biology 
parameters on-treatment by, but not limited to, gene 
expression and IHC in baseline, on-treatment, and 
residual disease tumor tissues 
Relationship of baseline and on-treatment plasma 
biomarkers and efficacy endpoints, including but not 
limited to pCR
ADA anti-drug antibody; atezolizumab nab-pacAC nab-paclitaxel and atezolizumab 
followed by doxorubicin and cyclophosphamide with atezolizumab; DFS disease-free survival; 
EFSevent-free survival; EORTCEuropean Organisation for Research and Treatment of 
Cancer; EQ-5D-5LEuroQoL 5-Dimension, 5-Level; FACTG Functional Assessment of 
Cancer TherapyGeneral; GHSglobal health status; HRQoLhealth-related quality of life; 
ICtumor-infiltrating immune cell; IHCimmunohistochemistry; ITTintent to treat; NCI
CTCAENational Cancer Institute Common Terminology Criteria for Adverse Events;
OSoverall survival; pCRpathologic complete response; PDL1 programmed deathligand 1; 
PK pharmacokinetics; placebo nab-pacACneoadjuvant nab-paclitaxel and placebo followed 
by doxorubicin and cyclophosphamide with placebo; PRO patient-reported outcome; QLQ-
C30Quality of Life Questionnaire Core 30; RCB residual cancer burden. 
Study Design
Description of Study
This is a global Phase III, double-blind, randomized, placebo-controlled study designed to 
evaluate the efficacy and safety of neoadjuvant treatment with atezolizumab nab-pac-AC, or 
placebo nab-pacAC in patients eligible for surgery with initial clinically assessed T2-4d TNBC.
Female and male patients aged 18 years with an Eastern Cooperative Oncology Group 
(ECOG) performance status of 0 or 1 who have histologically confirmed invasive TNBC with a 
primary tumor size of 2 cm are eligible.


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Human epidermal growth factor receptor 2 (HER2) and estrogen/progesterone receptor (ER/PR) 
status will be used to define TNBC.  HER2 negativity will be defined by central laboratory 
assessment using in situ hybridization (ISH) or immunohistochemistry (IHC) assays per 
American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) criteria, 
and ER/PgR negativity will be defined by using IHC per ASCO/CAP criteria.  Central laboratory 
assessment will occur prior to randomization.  Patients whose tumors are not confirmed to be 
triple negative will not be eligible.  Patients whose tumor tissue is not evaluable for PD-L1 will 
not be eligible.
Patients who do not initially meet all eligibility criteria, other than TNBC status, may be 
rescreened once.
This study has an adaptive design consisting of two stages.  Stage 1 is the randomization and 
treatment of approximately 204 patients.  At the end of Stage 1, an interim analysis for 
efficacy will be done by an iDMC.  Then, a recommendation will be made to either continue 
the study unchanged or to expand the patient population (Stage 2; approximately 120 
additional patients).  If the recommendation is to expand the patient population into Stage 2, 
the Sponsor will remain blinded to the results of the interim analysis performed at the end of 
Stage 1.
Patients who have consented and are eligible will be randomized in a 1:1 ratio to either of the 
following treatment groups:

Arm A:  atezolizumab (840 mg) administered via intravenous (IV) infusion Q2W in 
combination with nab-paclitaxel (125 mg/m2) administered via IV infusion QW for 12 weeks 
followed by atezolizumab (840 mg) administered Q2W in combination with doxorubicin 
(60 mg/m2)cyclophosphamide (600 mg/m2) administered Q2W via IV infusions with 
filgrastim/pegfilgrastim support for 4 cycles.  Patients randomized to the atezolizumab arm 
will continue to receive unblinded atezolizumab post-surgery at a fixed dose of 1200 mg by 
IV infusion every 3 weeks (Q3W) for 11 cycles, for a total of approximately 12 months of 
atezolizumab therapy.  

Arm B: placebo administered Q2W via IV infusion in combination with nab-paclitaxel 
(125 mg/m2) administered QW via IV infusion for 12 weeks followed by placebo 
administered Q2W in combination with doxorubicin (60 mg/m2) cyclophosphamide 
(600 mg/m2) administered Q2W via IV infusions with filgrastim/pegfilgrastim support for 
4 cycles.  Patients randomized to the placebo arm will be unblinded post-surgery and will 
continue to be followed.
For patients in Stage 1 of the the study, randomization will be stratified by the following 
factors:

American Joint Committee on Cancer (AJCC) stage at diagnosis (II vs. III; see below for 
evaluation and classification of lymph nodes)

Tumor PD-L1 status (tumor-infiltrating immune cell [IC] IC0 [<1% PD-L1 expressing 
IC per tumor area] vs. IC1/2/3 [1% PD-L1 expressing IC per tumor area])
Depending on the iDMC recommendation, Stage 2 could follow either an all-comer or PD-L1 
enrichment design.  If an all-comer design is recommended, the patients enrolled in Stage 2 
will be stratified the same as patients enrolled in Stage 1.  If an enrichment design is 
recommended, only PD-L1positive patients will be enrolled, and the AJCC stage at diagnosis 
will be used as the sole randomization stratification factor.
Patients who discontinue neoadjuvant therapy early as a result of disease progression must be 
discontinued from all study treatment, will be managed as per local practice, and will be 
followed for survival only.  Patients who discontinue prematurely from the study will not be 
replaced.
Any patient who receives non-protocol therapy prior to surgery will be discontinued from study 
treatment and will be managed as per local practice; these patients will remain on study for 
survival follow-up.


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The primary efficacy endpoint (pathologic complete response [pCR]; ypT0/is ypN0) will be 
established via local review following completion of neoadjuvant therapy and surgery.  
Pathologists who review study specimens must utilize the evaluations and assessments 
outlined in the Pathology Manual.  Investigator/individual patient unblinding will occur after pCR 
assessment.  Surgery should be performed at least 14 days after the last dose of neoadjuvant 
therapy but no later than 6 weeks after the last infusion.  Platelet counts should be checked 
prior to surgery and should be 75,000 cells/L. 
Patients with clinically positive axillary nodes by physical examination or by any radiographic 
imaging at baseline should undergo fine-needle aspiration or core-needle biopsy prior to 
randomization followed by axillary lymph node dissection (ALND) at time of definitive surgery.  
The results of the baseline fine-needle aspiration or core-needle biopsy will determine the nodal 
staging, so that patients with a positive biopsy result should be staged as lymph-node-positive 
(N1-N3c) whereas patients with a negative or equivocal biopsy result should be staged as 
lymph-node-negative (N0) regardless of any other clinical measurements.
In patients with clinically or fine-needle biopsy (FNA)/core needle biopsy-proven negative 
axillary nodes at baseline, axillary surgical management after completion of neoadjuvant 
therapy should include sentinel lymph node biopsy (SLNB) or ALND.  If SLNB is conducted, it is 
strongly recommended that more than one lymph node (two to three minimum) be removed and 
all patients with positive macrometastases in sentinel nodes should undergo ALND regardless 
of the number of positive nodes.  All patients with T4 tumors should undergo ALND or current 
standard of care as described in international or national guidelines.
Postoperative patient management for those in either treatment arm should include 
radiotherapy as clinically indicated, and management of patients who do not achieve a pCR
should follow current standard-of-care guidelines.  For those randomized to receive 
atezolizumab, patients may receive this therapy simultaneously with atezolizumab.
For those randomized to receive atezolizumab, the first dose of postoperative atezolizumab 
should be administered within 45 days of surgery.
Efficacy, safety, laboratory measurements, patient-reported outcomes (PROs), and 
pharmacokinetics will be assessed throughout the study.  The first 26 patients enrolled 
(approximately 13 patients in the control arm and approximately 13 patients in the atezolizumab
containing arm) will undergo additional cardiac safety monitoring as part of a cardiac safety 
cohort.  Following completion of study treatment and surgery, all patients will continue to be 
followed for efficacy, safety, and PRO objectives until the end of the study.  No interim efficacy 
analyses for early stopping are planned.
Safety assessments will include the occurrence and severity of adverse events and laboratory 
abnormalities graded per National Cancer Institute Common Terminology Criteria for Adverse 
Events (NCI CTCAE) Version 4.0.  Laboratory safety assessments will include the regular 
monitoring of hematology and blood chemistry.  Serum samples will be collected to monitor 
chemotherapy and atezolizumab pharmacokinetics and to detect the presence of antibodies to 
atezolizumab.  Patient samples, including tumor tissues, as well as plasma and blood, will be 
collected for exploratory biomarker assessments.
An iDMC will evaluate the primary efficacy endpoint of pCR in the intent-to-treat (ITT) 
population (defined as all randomized patients) and in the PD-L1positive subpopulation 
based on an interim analysis of efficacy data from the Stage 1 patients (approximately 204 
enrolled patients).  The iDMC will make a recommendation either to continue the study 
unchanged or to enroll an additional 120 patients (Stage 2).  The decision rules to be applied 
at the interim analysis will be clearly expressed to the iDMC and documented in the iDMC 
charter so that the study can be conducted with the Sponsor remaining completely blinded to 
all results at this stage.
The iDMC will evaluate safety data and study conduct on a regular basis during the study 
until the primary analysis of pCR, which is performed at Stage 1 (approximately 204 
patients) or Stage 2 (approximately 324 patients), if the iDMC recommends extending the 
target population.  Afterwhich, iDMC review of the study data will be discontinued.
Sponsor affiliates will be excluded from iDMC membership.  The iDMC will follow a charter that 
outlines the iDMC roles and responsibilities.


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Number of Patients
Approximately 204 patients will be enrolled in this study during Stage 1 and approximately
120 additional patients will be enrolled if the iDMC recommends to expand to Stage 2.  
Enrollment will take place at approximately 75 global sites.
Target Population
Inclusion Criteria
Patients must meet the following criteria for study entry:

Signed Informed Consent Form

Ability to comply with protocol, in the investigator’s judgment

Women or men aged 18 years

ECOG performance status of 0 or 1

Histologically documented TNBC (negative HER2, ER, and PgR status); HER2 negativity 
will be defined by central laboratory assessment using ISH or IHC assays per ASCO/CAP 
criteria and ER/PgR negativity will be defined by central laboratory assessment using IHC 
per ASCO/CAP criteria.  Central laboratory assessment will occur prior to randomization.
Patients with multifocal tumors (more than one tumor confined to the same quadrant as 
the primary tumor) are eligible provided all discrete lesions are sampled and centrally 
confirmed as TNBC.

Confirmed tumor PD-L1 evaluation as documented through central testing of a 
representative tumor tissue specimen
In Stage 2, if the iDMC recommendation is to expand to a PD-L1positive population, 
only patients with confirmed tumor PD-L1 positive (IC1/2/3) will be considered 
eligible.

Primary breast tumor size of 2 cm by at least one radiographic or clinical measurement

Stage at presentation:  cT2cT4, cN0cN3, cM0

Patient agreement to undergo appropriate surgical management including axillary lymph 
node surgery and partial or total mastectomy after completion of neoadjuvant treatment

Baseline LVEF 53% measured by echocardiogram (ECHO) or multiple-gated acquisition 
(MUGA) scans

Adequate hematologic and end-organ function, as defined by the following laboratory 
results obtained within 14 days prior to the first study treatment:
ANC 1500 cells/L (without granulocyte colonystimulating factor [G-CSF] support 
within 2 weeks prior to Cycle 1, Day 1)
Lymphocyte count 500 cells/L
Platelet count 100,000 cells/L (without transfusion within 2 weeks prior to Cycle 1, 
Day 1)
Hemoglobin 9.0 g/dL
AST, ALT, and alkaline phosphatase 2.5 the upper limit of normal (ULN)
Serum bilirubin 1.0 ULN
Patients with known Gilbert syndrome who have serum bilirubin level 3 ULN 
may be enrolled.
For patients not receiving therapeutic anticoagulation: INR or aPTT 1.5 ULN within 
14 days prior to initiation of study treatment
For patients receiving therapeutic anticoagulation:  stable anticoagulant regimen and 
stable INR during the 14 days immediately preceding initiation of study treatment
Creatinine clearance 30 mL/min (calculated using the Cockcroft-Gault formula)
Serum albumin 25 g/L (2.5 g/dL)


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
Representative formalin-fixed, paraffin-embedded (FFPE) tumor specimen in paraffin blocks 
(preferred) or at least 20 unstained slides, with an associated pathology report documenting 
ER, PgR, and HER2 negativity 
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.
If multiple 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.
In Stage 2, if the recommendation from the iDMC is to expand to a 
PD-L1positive population, no further stratification based on PD-L1 status will 
be conducted.
Acceptable samples include core-needle biopsies for deep tumor tissue (minimum 
three cores) or excisional, incisional, punch, or forceps biopsies for cutaneous, 
subcutaneous, or mucosal lesions.
Fine-needle aspiration, brushing, and cell pellet from cytology specimens are not 
acceptable.

For women of childbearing potential:  agreement to remain abstinent (refrain from 
heterosexual intercourse) or use contraceptive methods, and agreement to refrain from 
donating eggs, as defined below:
Women must remain abstinent or use contraceptive methods that result in a failure rate 
of 1% per year during the treatment period and for at least 5 months after the last 
dose of atezolizumab, or 1 month after the last dose of nab-paclitaxel, or 6 months after 
the last dose of doxorubicin, or 12 months after the last dose of cyclophosphamide, 
whichever is later.  Women must refrain from donating eggs during this same period.
A woman is considered to be of childbearing potential if she is postmenarcheal, has not 
reached a postmenopausal state (12 continuous months of amenorrhea with no 
identified cause other than menopause), and has not undergone surgical sterilization 
(removal of ovaries and/or uterus).
Examples of contraceptive methods with a failure rate of 1% per year when used 
consistently and correctly, include combined (estrogen and progestogen containing) 
hormonal contraception associated with inhibition of ovulation, progestogen-only 
hormonal contraception associated with inhibition of ovulation, bilateral tubal occlusion;
male sterilization; intrauterine devices; intrauterine hormone-releasing system; and 
sexual abstinence.
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. 

For men:  agreement to remain abstinent (refrain from heterosexual intercourse) or use
contraceptive measures and agreement to refrain from donating sperm, as defined below:
With female partners of childbearing potential, men must remain abstinent or use a 
condom plus an additional contraceptive method that together result in a failure rate of 
1% per year during the treatment period and for 6 months after the last dose of 
nab-paclitaxel, cyclophosphamide, or doxorubicin.  Men must refrain from donating 
sperm during this same period.
With pregnant female partners, men must remain abstinent or use a condom during the 
treatment period and for 6 months after the last dose of nab-paclitaxel, 
cyclophosphamide, or doxorubicin to avoid exposing the embryo.
The reliability of sexual abstinence should be evaluated in relation to the duration of the 
clinical trial and the preferred and usual lifestyle of the patient.  Periodic abstinence 
(e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal 
are not acceptable methods of contraception.


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
Women who are not postmenopausal (12 months of nontherapy-induced amenorrhea) or 
have undergone a sterilization procedure must have a negative serum pregnancy test result 
within 14 days prior to initiation of study drug

Willingness and ability to comply with scheduled visits, treatment plans, laboratory tests, 
and other study procedures, including the completion of PRO questionnaires
Exclusion Criteria
Patients who meet any of the following criteria will be excluded from study entry:

Prior history of invasive breast cancer

Stage IV (metastatic) breast cancer

Prior systemic therapy for treatment and prevention of breast cancer 

Previous therapy with anthracyclines or taxanes for any malignancy

History of ductal carcinoma in situ (DCIS), except for patients treated exclusively with 
mastectomy 5 years prior to diagnosis of current breast cancer 

History of pleomorphic lobular carcinoma in situ (LCIS), except for patients surgically 
managed 5 years prior to diagnosis of current breast cancer (note that patients with non-
pleomorphic LCIS [either untreated or treated with surgery] are allowed)

Bilateral breast cancer 

Undergone incisional and/or excisional biopsy of primary tumor and/or axillary lymph nodes.  
Patients who have undergone SLNB at the baseline may be eligible only if the SLNB was 
free of invasive carcinoma.  Any patient with a positive SLN (involved with invasive 
carcinoma) is ineligible to participate in this study.

Axillary lymph node dissection prior to initiation of neoadjuvant therapy 

History of other malignancy within 5 years prior to screening, with the exception of those 
with a negligible risk of metastasis or death (e.g., 5-year OS of 90%), such as adequately 
treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, localized prostate 
cancer, or Stage I uterine cancer

History of cerebrovascular accident within 12 months prior to randomization

Cardiopulmonary dysfunction as defined by any of the following prior to randomization:
History of NCI CTCAE v4.0 Grade 3 symptomatic congestive heart failure or New 
York Heart Association (NYHA) criteria Class II
Angina pectoris requiring anti-anginal medication, serious cardiac arrhythmia not 
controlled by adequate medication, severe conduction abnormality, or clinically 
significant valvular disease
High-risk uncontrolled arrhythmias (i.e., atrial tachycardia with a heart rate 100/min at 
rest, significant ventricular arrhythmia [ventricular tachycardia], or higher-grade 
atrioventricular [AV]-block [second-degree AV-block Type 2 [Mobitz 2] or third degree 
AV-block])
Significant symptoms (Grade 2) relating to left ventricular dysfunction, cardiac 
arrhythmia, or cardiac ischemia
Myocardial infarction within 12 months prior to randomization
Uncontrolled hypertension (systolic blood pressure 180 mmHg and/or diastolic blood 
pressure 100 mmHg)
Evidence of transmural infarction on ECG
Requirement for oxygen therapy

History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or 
humanized antibodies or fusion proteins

Known hypersensitivity to biopharmaceuticals produced in Chinese hamster ovary cells

Known allergy or hypersensitivity to the components of the atezolizumab formulation


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
Known allergy or hypersensitivity to the components of the nab-paclitaxel, 
cyclophosphamide, or doxorubicin formulations

Known allergy or hypersensitivity to filgrastim or pegfilgrastim formulations

Active or history of autoimmune disease or immune deficiency, including but not limited to 
myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, 
rheumatoid arthritis, inflammatory bowel disease, antiphospholipid syndrome, Wegener 
granulomatosis, Sjögren syndrome, Guillain-Barré syndrome, or multiple sclerosis with the 
following exceptions:
Patients with a history of autoimmune-related hypothyroidism on a stable dose of 
thyroid replacement hormone may be eligible for this study.
Patients with controlled Type I diabetes mellitus on a stable dose of insulin regimen 
may be eligible for this study.
Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with dermatologic 
manifestations only (e.g., patients with psoriatic arthritis are excluded) are permitted 
provided all of following conditions are met:
Rash must cover 10% of body surface area
Disease is well controlled at baseline and requires only low-potency topical 
corticosteroids
No occurrence of acute exacerbations of the underlying condition requiring 
psoralen plus ultraviolet A radiation, methotrexate, retinoids, biologic agents, oral 
calcineurin inhibitors, or high-potency or oral corticosteroids within the previous 
12 months

History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis obliterans), 
drug-induced pneumonitis, idiopathic pneumonitis, or evidence of active pneumonitis on 
screening chest computed tomography (CT) scan
History of radiation pneumonitis in the radiation field (fibrosis) is permitted.

Positive HIV test at screening

Active hepatitis B virus (HBV) infection, defined as having a positive hepatitis B surface 
antigen (HBsAg) test at screening
Patients with a past or resolved HBV infection, defined as having a negative HBsAg 
test and a positive total hepatitis B core antibody (HBcAb) test at screening, are eligible 
for the study if active HBV infection is ruled out on the basis of HBV DNA viral load per 
local guidelines.

Active hepatitis C virus (HCV) infection, defined as having a positive HCV antibody test at 
screening
Patients who have a positive HCV antibody test are eligible for the study if a 
polymerase chain reaction (PCR) assay is negative for HCV RNA.

Active tuberculosis

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

Treatment with therapeutic oral or IV antibiotics within 2 weeks prior to initiation of study 
treatment
Patients receiving prophylactic antibiotics (e.g., for prevention of a urinary tract infection 
or to prevent chronic obstructive pulmonary disease exacerbation) are eligible for the 
study.

Major surgical procedure within 4 weeks prior to initiation of study treatment or anticipation 
of need for a major surgical procedure (other than anticipated breast surgery) during the 
course of the study

Prior allogeneic stem cell or solid organ transplantation


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
Administration of a live attenuated vaccine within 4 weeks prior to initiation of study 
treatment or anticipation of need for such a vaccine during the atezolizumab/placebo 
treatment or within 5 months after the last dose of atezolizumab/placebo
Patients must agree not to receive live, attenuated influenza vaccine (e.g., FluMist®) 
within 4 weeks prior to randomization, during treatment or within 5 months following the 
last dose of atezolizumab (for patients randomized to atezolizumab).

Any other disease, metabolic dysfunction, physical examination finding, or clinical 
laboratory finding giving reasonable suspicion of a disease or condition that contraindicates 
the use of an investigational drug or that may affect the interpretation of the results or 
render the patient at high risk from treatment complications

Prior treatment with CD137 agonists or immune checkpointblockade therapies, including 
anti-CD40, antiCTLA-4, antiPD-1, and antiPD-L1 therapeutic antibodies

Treatment with systemic immunostimulatory agents (including but not limited to interferons, 
IL-2) within 4 weeks or 5 half-lives of the drug, whichever is longer, prior to initiation of study 
treatment

Treatment with systemic immunosuppressive medications (including but not limited to 
prednisone, cyclophosphamide, azathioprine, methotrexate, thalidomide, and antitumor 
necrosis [anti-TNF] factor agents) within 2 weeks prior to initiation of study treatment or 
anticipation of need for systemic immunosuppressive medications during the study
Patients who have received acute, low-dose, systemic immunosuppressant 
medications (e.g., a one-time dose of dexamethasone for nausea) may be enrolled in 
the study after discussion with and approval by the Medical Monitor.
The use of inhaled corticosteroids and mineralocorticoids (e.g., fludrocortisone for 
adrenal insufficiency) is allowed.

Pregnant or lactating, or intending to become pregnant during the study
Women of childbearing potential must have a negative serum pregnancy test result 
within 14 days prior to initiation of study treatment.
End of Study
The end of the study is defined as the date when the last patient, last visit (LPLV) occurs for 
evaluation of secondary endpoints, or the date of Sponsor decision to end the study, whichever 
is earlier.  
Length of Study
The total duration of the study for Stage 1 is expected to be approximately 51 months.  If the 
iDMC recommends to expand enrollment (Stage 2), the duration of the study may increase to 
approximately 74 months.
Investigational Medicinal Products
The investigational medicinal products (IMPs) for this study are atezolizumab, its placebo, and 
nab-paclitaxel.  
Atezolizumab and Placebo
Patients will receive 840 mg atezolizumab or placebo administered by IV infusion Q2W
(14 [3] days) for 20 weeks (i.e., 10 doses) in combination with nab-paclitaxel, doxorubicin, and 
cyclophosphamide chemotherapy (see below).  Postoperatively, patients randomized to the 
atezolizumab arm will continue to receive unblinded atezolizumab post-surgery at a fixed dose 
of 1200 mg by IV infusion every 3 weeks (Q3W) for 11 cycles, for a total of approximately 
12 months of atezolizumab therapy; patients randomized to the placebo arm will stop receiving 
placebo.
Nab-Paclitaxel
Nab-paclitaxel will be administered as background treatment along with the non-IMPs
doxorubicin, cyclophosphamide, and filgrastim/pegfilgrastim as specified below.


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31/Statistical Analysis Plan WO39392
Non-Investigational Medicinal Products
Patients will receive nab-paclitaxel (125 mg/m2) administered via IV infusion given over 
30 minutes weekly for 12 weeks followed by doxorubicin (60 mg/m2) cyclophosphamide
(600 mg/m2) administered via IV infusion Q2W with filgrastim/pegfilgrastim support for 4 cycles 
(i.e., a total of 4 doses of doxorubicin and cyclophosphamide).  The dose of cyclophosphamide 
should be capped at 1200 mg.
Statistical Methods
Primary Analysis
The primary efficacy objective for this study is to evaluate the efficacy of neoadjuvant 
atezolizumab nab-pacAC compared with placebo nab-pacAC in patients with T2-4d TNBC, 
as measured by pCR defined as eradication of tumor from both breast and lymph nodes 
(ypT0/is ypN0).  The primary efficacy endpoint will be established following completion of 
neoadjuvant therapy and surgery. 
The ITT as well as PD-L1positive populations will be used for the primary analysis of pCR.  In 
the primary analysis, patients whose pCR assessment was missing will be counted as not 
achieving a pCR.  An estimate of the pCR rate and its 95% CI (Clopper and Pearson 1934) will 
be calculated for each treatment arm.  The difference in pCR rates will be provided with 95% CI, 
using the normal approximation to the binomial distribution.  For the ITT population, the 
Cochran-Mantel-Haenszel 2 test stratified according to tumor PD-L1 status (IC0 vs. IC1/2/3) 
and clinical stage at presentation (Stage II vs. III) will be used to test pCR rates between 
treatment groups at a two-sided significance level of 5%.  For the PD-L1positive population, 
similar test will be used with stratification only for clinical stage at presentation. An 
unstratified 2 versions of these tests will also be provided as a sensitivity analysis.
Determination of Sample Size
The study will first randomize approximately N1=204 patients in Stage 1 (1:1 randomization 
ratio).  Based on information from these patients and a pre-specified adaptive rule, the 
decision will be made regarding whether or not to randomize approximately N2=120 patients 
in Stage 2 (1:1 randomization ratio).
The pre-defined one-sided type I error for the interim analysis at Stage 1 is *=0.0125 
(i.e., 50% of the total type I error).  The co-primary endpoints in the ITT and PD-L1-positive 
populations at Stage 1 will be tested using a closed testing procedure using Simes’ test for the 
intersection hypothesis.  Test statistics in ITT and PD-L1-positive populations are always 
positively correlated, hence type I error rate control of the Simes test can be guaranteed in 
general.
Importantly, the p-value  based on Stage 1 data only and the combination p-value ABCD
have the same joint distribution under the null hypothesis as the p-values from a 
group-sequential test with two stages at information times 9 = 3 and 9 = 1.  Thus standard 
statistical software for group sequential designs can be used for the determination of critical 
values for the adaptive design.  As the study design uses a critical value of *=0.0125 (i.e., 50% 
of the total type I error) for Stage 1, this implies that a critical value of *ABCD=0.0184 can be 
applied to the combination p-values.


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32/Statistical Analysis Plan WO39392
Appendix 2 Schedule of Activities (for Both Stage 1 and Stage 2)
Screening a
Treatment
Completion of Study 
Therapy/Early Term. Visit c
Survival 
Follow-Up d
Neoadjuvant 
Treatment
(28-Day Cycles)
(Cycles 15; 
Weeks 120)
Pre-Surgery Visit/
Surgery b
Arm A: Adjuvant 
Treatment
Arm B: Monitoring
(21-Day Cycles)
(Cycles 616)
Days –28 
to –1
Day 1
(3 days)
Day 1
(3 days)
30 Days after Last Dose 
(Arm A) or Last Monitoring 
Visit (Arm B)
Informed consent
x e
Baseline tumor tissue sample 
submission for HER2 and ER/PgR 
determination and exploratory 
biomarkers (mandatory)
x f
Demographic data
x
Medical history and baseline 
conditions
x
Disease status assessments g
x
x
x g
x g
x g
x g
Tumor Staging h
x
Ultrasound g
x
x
EORTC QLQ-C30, EQ-5D-5L i 
x
x
x
x j
FACT-G, Single Item GP5 i
x k
x
x
x j
Vital signs l
x
On each infusion 
day
x
x m
x
Weight
x
x
x m
Height
x


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33/Statistical Analysis Plan WO39392
Appendix 2 Schedule of Activities (for Both Stage 1 and Stage 2) (cont.)
Complete physical examination n
x
Limited physical examination o
x g
x
x m
x
ECOG Performance Status p
x
x
x
x
x
ECG (12-lead) q
x
As clinically indicated
ECHO or MUGA scan r
x
As described in footnote “r”
x
x
Spirometry (FVC, FEV1, 
FEV1:FVC, FEF25-75)
x
As clinically indicated
Hematology s
x t
On each infusion 
day
x
x m
x
Chemistry u
x t
On each infusion 
day
x
x m
x
Pregnancy test v
x t
x v
x v
x v
x v
Coagulation (INR, aPTT)
x t
x
x
TSH, free T3 (or total T3 w), 
free T4
x t
x w
x
Viral serology x
x t
Urinalysis y
x t
As clinically indicated
Serum PK sample for 
atezolizumab
See Appendix 2 for detailed schedule
Serum ADA sample for 
atezolizumab
See Appendix 2 for detailed schedule
Blood and plasma samples for 
biomarkers
See Appendix 2 for detailed schedule
Blood sample for RBR (optional)  z
x


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34/Statistical Analysis Plan WO39392
Appendix 2 Schedule of Activities (for Both Stage 1 and Stage 2) (cont.)
Tumor tissue (fresh sample 
preferred) at screening, on-study, 
and time of disease recurrence aa
See Appendix 3 for detailed schedule
Radiographic assessments (e.g., 
CT scan, MRI, PET scan)
As clinically indicated
Bilateral mammogram
x bb
x
x cc
Concomitant medications
x dd
x
x ee
x ee
x g, ff
Adverse events gg
x gg
x gg
x
x
x gg
Study treatment administration hh
x
x ii, m
Survival follow-up and anti-cancer 
treatment
x d, jj
ACdoxorubicincyclophosphamide; ADAanti-drug antibody; CT computed tomography; ECHO echocardiogram; ECOG Eastern 
Cooperative Oncology Group; eCRF electronic Case Report Form; EORTC QLQ-C30European Organisation for Research and Treatment of 
Cancer Quality of Life Questionnaire Core 30; EQ-5D-5LEuroQoL 5-Dimension, 5-Level; ERestrogen receptor; FACT-G Functional 
Assessment of Cancer Therapy-General; FCV = Forced Vital Capacity; FEV1 = Forced Expiratory Volume 1; FEF25-75 = Forced Expiratory Flow 
25%75%;  FFPEformalin-fixed, paraffin-embedded; HBcAbhepatitis B core antibody; HBsAbhepatitis B surface antibody; HBsAg hepatitis B 
surface antigen; HBVhepatitis B virus; HCVhepatitis C virus; HER2human epidermal growth factor receptor 2; MRImagnetic resonance 
imaging; MUGAmultiple-gated acquisition; PD-L1programmed deathligand-1; PET positron emission tomography; PgRprogesterone 
receptor; PKpharmacokinetic; PRO patient-reported outcome; RBRResearch Biosample Repository; T3triiodothyronine; T4thyroxine; 
Term.termination; TSHthyroid-stimulating hormone.
Notes:  On treatment days, all assessments should be performed prior to dosing, unless otherwise specified.
Assessments shaded in gray should be performed as scheduled, but the associated data do not need to be recorded on the eCRF (except in the 
case of an adverse event).
If treatment is withheld (e.g., by adverse events or delays in initiating post-surgical therapy), the schedule of assessments should be held 
accordingly (e.g., Day 1 of Week 21first administration of atezolizumab post-surgery or Day 1 of Cycle 6).
b Results of standard-of-care tests or examinations performed prior to obtaining informed consent and within 30 days prior to Day 1 may be used; 
such tests do not need to be repeated for screening.
b Pre-surgical visit and associated assessments should occur within 14 days of surgery. Surgery should be conducted no earlier than 14 days and 
no later than 6 weeks after last dose of neoadjuvant therapy.  Platelet counts should be checked prior to surgery and should be 75,000 cells/L.


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35/Statistical Analysis Plan WO39392
Appendix 2 Schedule of Activities (for Both Stage 1 and Stage 2) (cont.)
c Patients who discontinue study treatment will return to the clinic for a treatment discontinuation visit not more than 30 days after the last dose of 
study treatment.
d The survival follow-up period begins from the date of treatment completion/early termination visit, and has a duration of up to approximately 
51 months  from the date of randomization of the first patient in Stage 1).  This may increase to approximately 74 months if the study includes 
Stage 2 patients.  Visit windows are 28 days for quarterly and semiannual assessments.
e Informed consent must be documented before any study-specific screening procedure is performed and may be obtained more than 28 days 
before initiation of study treatment.
f
After signing of the Informed Consent Form, retrieval and submission of tumor tissue sample can occur outside the 28-day screening period.  
Tumor tissue should be of good quality based on 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, and lavage samples are not acceptable.  For core-needle biopsy specimens, at least three cores 
should be submitted for evaluation.  Retrieval of tumor sample can occur outside the 28-day screening period.
g Assessment of primary tumor and regional lymph nodes should be done by physical examination at baseline and prior to administration of each 
cycle of study treatment during neoadjuvant therapy.  Additionally, standard breast imaging modality should include an ultrasound of breast and 
axilla disease.  (Physical examination and ultrasound is mandatory within 28 days prior to randomization and within 14 days pre-surgery.)  At 
baseline, if there is evidence of suspicious axillary lymph nodes, then fine-needle aspiration is required.  Ultrasound-detected axillary lymph 
nodes suspicious of malignancy include those with cortical thickness 2 mm.  Disease status based on all available clinical assessments should 
be documented every 3 months during adjuvant study treatment and follow-up up to 3 years after surgery and every 6 months thereafter.  In 
addition, liver function tests, bone scans, chest X-ray/diagnostic CT scan, liver imaging, and/or other radiographic modalities may be considered 
when clinically indicated to exclude metastatic disease; these assessments should be performed within a timeline as per current local standard 
of practice.  Whenever possible, disease recurrence should be confirmed pathologically. If disease recurrence is diagnosed at any time during 
the study, patients will discontinue scheduled study assessments and will be followed for survival, anti-cancer medications, and new relapse 
events.
h See Section 4.5.6 in protocol. 
i
All PRO assessments (EORTC QLQ-C30, followed by the FACT-G single item GP5, and then the EQ-5D-5L questionnaires) must be completed 
by the patient at the investigational site at the start of the clinic visit before discussion of the patient’s health state, lab results or health record, 
before administration of study treatment, and/or prior to the performance of any other study assessments that could bias the patient’s responses.  
Interview assessment by a member of the clinical staff will be allowed if the patient is not able to complete the measure on her or his own.  Study 
personnel should review all questionnaires for completeness before the patient leaves the investigational site.
The EORTC QLQ-C30 and EQ-5D-5L questionnaires will be completed by patients at baseline (Cycle 1, Day 1) and on Day 1 of every cycle 
thereafter.  The FACT-G, single item GP5 will not be completed by patients at the baseline visit (Cycle 1, Day 1).


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36/Statistical Analysis Plan WO39392
Appendix 2 Schedule of Activities (for Both Stage 1 and Stage 2) (cont.)
j
Patients who discontinue study treatment for any reason will continue to complete the EORTC QLQ-C30, FACT-G single item GP5, and 
EQ-5D-5L questionnaires in-clinic during the survival follow-up period at the following timepoints:  every 3 months (28 days) for Year 1, every 
6 months (28 days) for years 2-3, and then annually (28 days) thereafter.
k While on study treatment, all patients will complete the FACT-G, single item GP5 beginning on Cycle 2, Day 1 and at Day 1 of every cycle 
thereafter.
l
Includes respiratory rate, pulse rate, systolic and diastolic blood pressure while the patient is in a seated position, and temperature.  Record 
abnormalities observed at baseline on the General Medical History and Baseline Conditions eCRF.  At subsequent visits, record new or 
worsened clinically significant abnormalities on the Adverse Event eCRF.  For the first infusion, vital signs should be measured within 60 minutes 
prior to the infusion and, if clinically indicated, every 15 (5) minutes during and 30 (10) minutes after the infusion.  For subsequent infusions, 
vital signs should be measured within 60 minutes prior to the infusion and, if clinically indicated or if symptoms occurred during the previous 
infusion, during and 30 (10) minutes after the infusion.
m For patients in Arm A only.
n Includes evaluation of the head, eyes, ears, nose, throat, and the cardiovascular, dermatological, musculoskeletal, respiratory, gastrointestinal, 
and neurological systems.  Record abnormalities observed at baseline on the General Medical History and Baseline Conditions eCRF.  At 
subsequent visits, record new or worsened clinically significant abnormalities on the Adverse Event eCRF.
o Perform a limited, symptom-directed examination at specified timepoints and as clinically indicated at other timepoints.  Record new or worsened 
clinically significant abnormalities on the Adverse Event eCRF.
p See Appendix 10.
q ECG recordings will be obtained during screening and as clinically indicated.  Patients should be resting in a supine position for at least 10 
minutes prior to ECG recording.
r
Cardiac monitoring (ECHO or MUGA scan) will be performed on all patients enrolled in the study.  ECHO is the preferred method.  The same 
method used for a given patient at screening should be used throughout the study.  ECHO or MUGA scan should be obtained at baseline and 
after the second dose of AC (which would correspond to Week 16 1 week if no study treatment interruptions or discontinuations have 
occurred) during neoadjuvant study treatment.  During the adjuvant (Arm A) or monitoring (Arm B) phase of the study, ECHO or MUGA 
scan should be obtainedat Cycle 6, Day 1 (which would approximately correspond to Week 21 1 week if no study treatment interruptions 
or discontinuations have occurred), and every 3 months afterwards while on the Adjuvant/Monitoring Phase (which would correspond to 
Cycle 10, Day 1 and Cycle 14, Day 1, or approximately Week 33 1 week, and Week 45 1 week respectively, if no treatment interruptions
or discontinuations have occurred).  ECHO or MUGA scan should be obtained at the early termination visit if not performed within the 
previous 6 weeks.  During the survival follow-up period, ECHO or MUGA scan should be obtained annually until the end of study.  For 
additional cardiac screening tests for patients in the cardiac safety cohort, please see Appendix 4.
s Hematology includes WBC count, RBC count, hemoglobin, hematocrit, platelet count, and differential count (neutrophils, eosinophils, basophils, 
monocytes, lymphocytes, other cells).
t
Screening laboratory test results must be obtained within 14 days prior to initiation of study treatment.


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Appendix 2 Schedule of Activities (for Both Stage 1 and Stage 2) (cont.)
u Chemistry panel (serum or plasma) includes sodium, potassium, chloride, bicarbonate or total CO2, glucose, BUN or urea, creatinine, total 
protein, albumin, calcium, total bilirubin, alkaline phosphatase, ALT, AST, and LDH.  Magnesium and phosphorus should be included at 
screening and as clinically indicated during study treatment.
v All women of childbearing potential will have a serum pregnancy test at screening.  Urine pregnancy tests will be performed at the following 
specified subsequent visits for women of child-bearing potential (including premenopausal women who have had tubal ligation) and women not 
meeting the definition of postmenopausal:  Day 1 of Cycles 15; Day 1 of Cycles 6, 8, 10, 12, 14, and 16; at treatment discontinuation (unless 
administered within 30 days); and at 3 months and 6 months after treatment discontinuation.  For all other women, documentation must be 
present in medical history confirming that the patient is not of childbearing potential.  If a urine pregnancy test is positive, it must be confirmed by 
a serum pregnancy test.
w TSH, free T3 (or total T3 for sites where free T3 is not performed), and free T4 will be assessed on Day 1 of Cycle 1 and every fourth cycle 
thereafter.
x At screening, patients will be tested for HIV, HBsAg, HBsAb, total HBcAb, and HCV antibody.  If a patient has a negative HBsAg test and a 
positive total HBcAb test at screening, an HBV DNA test should be performed to rule out active HBV infection prior to initiation of study treatment.  
If a patient has a positive HCV antibody test at screening, an HCV RNA test should be performed to rule out active HCV infection prior to 
initiation of study treatment.
y Includes pH, specific gravity, glucose, protein, ketones, and blood; dipstick permitted.
z Not applicable for a site that has not been granted approval for RBR sampling.  Performed only for patients at participating sites who have 
provided written informed consent to participate.  Whole blood for DNA isolation will be collected from patients who have consented to optional 
RBR sampling at Week 1, Day 1. 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.
aa Tumor tissue should be of good quality based on total and viable tumor content (sites will be informed if the quality of the submitted specimen is 
inadequate to determine tumor PD-L1 status).  For tissue sample provided at screening, an FFPE block or at least 20 unstained slides should be 
provided. Retrieval of tumor screening sample can occur outside the 28-day screening period.  Fine-needle aspiration, brushing, cell pellets from 
pleural effusion, and lavage samples are not acceptable.  For core-needle biopsy specimens, at least three cores should be submitted for 
screening and on-study evaluation.  At least two cores should be submitted for disease recurrence specimens.  See Section 4.5.8 and
Appendix 3 for specific tissue sample requirements for each time point.
bb The unaffected breast should have been imaged within 60 days prior to randomization.  The affected breast should be imaged within 28 days 
prior to randomization.  
cc Mammograms of any remaining breast tissue should be performed at least annually.
dd 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 30 days prior to initiation of study treatment (for the purposes of 
screening) until the treatment discontinuation visit.  Record all prior anti-cancer therapies.


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38/Statistical Analysis Plan WO39392
Appendix 2 Schedule of Activities (for Both Stage 1 and Stage 2) (cont.)
ee To be collected for both study arms.  For patients in Arm B (Monitoring), only medications given for reportable adverse events as per protocol 
(see Section 5.3.1) as well as new anti-cancer treatments should be collected.
ff Medications related to the treatment of serious adverse events are to be reported during the follow-up period, as well as new anti-cancer 
treatments.
gg After informed consent has been obtained but prior to initiation of study treatment, only serious adverse events caused by a protocol-mandated 
intervention should be reported.  After initiation of study treatment, all adverse events will be reported until 30 days after the last dose of study 
treatment or until initiation of new anti-cancer therapy, whichever occurs first, and serious adverse events and adverse events of special interest 
will continue to be reported until 90 days after the last dose of study treatment or until initiation of new anti-cancer therapy, whichever occurs first.  
After this period, all deaths, regardless of cause, should be reported.  In addition, the Sponsor should be notified if the investigator becomes
aware of any serious adverse event that is believed to be related to prior exposure to study treatment (see Section 5.6).  The investigator should 
follow each adverse event until the event has resolved to baseline grade or better, the event is assessed as stable by the investigator, the patient 
is lost to follow-up, or the patient withdraws consent.  Every effort should be made to follow all serious adverse events considered to be related 
to study treatment or trial-related procedures until a final outcome can be reported.
hh The initial dose of atezolizumab will be delivered over 60 (15) minutes.  Subsequent infusions will be delivered over 30 (10) minutes if the 
previous infusion was tolerated without infusion-associated adverse events, or 60 (15) minutes if the patient experienced an infusion-
associated adverse event with the previous infusion.
ii Study drug administration during the maintenance phase for the atezolizumab-containing arm only.
jj After treatment discontinuation, information on survival follow-up and new anti-cancer therapy (including targeted therapy and immunotherapy) 
will be collected via telephone calls, patient medical records, and/or clinic visits (unless the patient withdraws consent or the Sponsor terminates 
the study).  If a patient requests to be withdrawn from follow-up, this request must be documented in the source documents and signed by the 
investigator.  If the patient withdraws from study, the study staff may use a public information source (e.g., county records) to obtain information 
about survival status only, where allowable by local regulation.


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39/Statistical Analysis Plan WO39392
Appendix 3 Adaptive Multiple Test Design
The performance of the proposed design depends on several factors including the 
underlying proportion of (pCR) responders in each treatment arms for the subgroup S 
(PD-L1 IC1/2/3) and the complement group C (PD-L1 IC0). Simulations were carried out 
to evaluate the operation characteristics of the current design under a variety of 
conditions as follows.
Three simulation scenarios were considered with numerical details provided in Table 2.

Subgroup S with very strong credentials
Subgroup S has very strong credentials when convincing evidence indicates that the 
benefits of the treatment are limited to the subgroup S.

Subgroup S with strong credentials
Subgroup S has strong credentials when evidence for the predictive ability of the 
subgroup is convincing enough to assume that the treatment is more likely to be 
effective (and is probably more effective) in the subgroup S than in the complement 
subgroup C, but the evidence is not sufficiently compelling to rule out a clinically 
meaningful effect in complement subgroup C.

Subgroup S with weak credentials
If the subgroup S has weak credentials when convincing evidence for predictive 
value of the subgroup S is lacking and the treatment is expected to be broadly 
effective.
Table 1
Definition of Weak, Strong, and Very Strong Credentials on 
Subgroup S
Subgroup S 
Credentials
pCR proportion 
under treatment in 
Full population F 
(F)a
pCR Proportion 
under treatment in 
Subgroup S (S)
pCR Proportion 
under treatment in 
complement 
Subgroup C (C)
pCR Proportion 
response under 
Control (control)
Weak
0.68
(F=0.2)
0.68
(S=0.20)
0.68
(C=0.20)
0.48
Strong
0.6376
(F=0.1576)
0.68
(S=0.20)
0.60
(C=0.12)
0.48
Very Strong
0.5952
(F=0.1152)
0.68
(S=0.20)
0.52
(C=0.04)
0.48
aAssuming a prevalence of 0.47 of Subgroup S in the full population.


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40/Statistical Analysis Plan WO39392
Appendix 3 Adaptive Multiple Test Design (cont.)
Table 2
Relative Frequencies of Decisions at Stage 1under 
Weak, Strong, and Very Strong Credentials on Subgroup S
Subgroup S 
Credentials
S
C
Relative Frequencya,b,c
Stop for 
efficacy
Stop for 
lack of 
efficacy
Continue
only S
Continue only 
F
Continue
S and F
Weak
0.20 0.20
0.64
0.04
0.08
0.14
0.10
Strong
0.20 0.12
0.46
0.10
0.22
0.11
0.11
Very Strong
0.20 0.04
0.33
0.17
0.38
0.05
0.06
aAssuming a prevalence of 0.47 of Subgroup S in the full population.
bAssuming probability of drop-out of 0.05 for each treatment arm.
cFrequency based on 100000 simulations.
Table 3
Rejection Probabilities under Weak, Strong, and Very Strong 
Credentials on Subgroup S
Subgroup S 
Credentials
S
C
Probabilitya,b.c
Reject %
{ }
Reject %
{}
Reject %
{ }or %
{}
i.e. Overall Power
Weak
0.20
0.20
0.80
0.49
0.88
Strong
0.20
0.12
0.55
0.57
0.76
Very Strong
0.20
0.04
0.28
0.62
0.67
aAssuming a prevalence of 0.47 of Subgroup S in the full population.
bAssuming probability of drop-out of 0.05 for each treatment arm.
cProbability based on 100000 simulations.
Table 4
Conditional Rejection Probabilities if Stage 2 Activated 
under Weak, Strong, and Very Strong Credentials on Subgroup S
Subgroup S 
Credentials
S
C
Conditional Probabilitya,b,c,d (if stage 2 activated)
Reject %
{ }
Reject %
{}
Reject %
{ }or %
{}
i.e. Overall “Go” Power
Weak
0.20
0.20
0.54
0.36
0.74
Strong
0.20
0.12
0.29
0.51
0.68
Very Strong
0.20
0.04
0.10
0.63
0.68
aAssuming a prevalence of 0.47 of Subgroup S in the full population.
bAssuming probability of drop-out of 0.05 for each treatment arm.
cProbability based on 100000 simulations.
dConditional probability of event happening once the trial continues to enroll patients in stage 2 
(“go”).