Conditions: Triple Negative Breast Cancer
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 2199
Healthy volunteers: no

Brief summary:
This study will evaluate the efficacy, safety, and pharmacokinetics of adjuvant atezolizumab in combination with paclitaxel, followed by atezolizumab, dose-dense doxorubicin or epirubicin (investigator's choice), and cyclophosphamide, compared with paclitaxel followed by dose-dense doxorubicin or epirubicin (investigator's choice) and cyclophosphamide alone in patients with Stage II-III TNBC (Triple Negative Breast Cancer)

Detailed description:

Arms:
arm 1: Participants will receive atezolizumab (in combination with chemotherapy as described below) every 2 weeks for 10 doses, followed by atezolizumab maintenance therapy every 3 weeks to complete 1 year of treatment from the first dose

Chemotherapy will consist of paclitaxel every week for 12 weeks, followed by dose-dense doxorubicin +cyclophosphamide or dose-dense epirubicin + cyclophosphamide every 2 weeks, for 4 doses supported with Granulocyte Colony-Stimulating Factor (G-CSF) or Granulocyte-Macrophage Colony Stimulating Factor (GM-CSF) arm 2: Chemotherapy will consist of paclitaxel every week for 12 weeks, followed by dose-dense doxorubicin +cyclophosphamide or dose-dense epirubicin + cyclophosphamide every 2 weeks, for 4 doses supported with Granulocyte Colony-Stimulating Factor (G-CSF) or Granulocyte-Macrophage Colony Stimulating Factor (GM-CSF)

Interventions: intervention 1: Atezolizumab intervention 2: Paclitaxel intervention 3: Dose-dense Doxorubicin or dose-dense Epirubicin intervention 4: Cyclophosphamide
Intervention descriptions: intervention 1: Atezolizumab will be administered by IV, 840 mg every 2 weeks, for 10 doses.

Atezolizumab maintenance will be administered by IV, 1200 mg every 3 weeks to complete 1 year intervention 2: Paclitaxel will be administered by IV, 80 mg/m\^2 every week for 12 weeks. intervention 3: Dose-dense doxorubicin will be administered by IV, 60 mg/m\^2 every 2 weeks for a total of 4 doses.

Or

Dose-dense epirubicin will be administered by IV, (90 mg/m\^2) every 2 weeks for a total of 4 doses intervention 4: Cyclophosphamide will be administered by IV, 600 mg/m\^2 every 2 weeks for 4 doses

Protocol document:
Prot_000.pdf: 
 
Official Title: 
A Phase III, Multicenter, Randomized, Open-Label Study Comparing 
Atezolizumab (Anti-Pd-L1 Antibody) in Combination With Adjuvant 
Anthracycline/Taxane-Based Chemotherapy Versus Chemotherapy 
Alone in Patients With Operable Triple-Negative Breast Cancer 
NCT Number: 
NCT03498716 
Document Date: 
Protocol Version 9: 01-Mar-2023 
 
 


CONFIDENTIAL 
This clinical study is being sponsored globally by F. Hoffmann-La Roche Ltd of Basel, 
Switzerland.  However, it may be implemented in individual countries by Roche’s local affiliates, 
including Genentech, Inc. in the United States.  The information contained in this document, especially 
any unpublished data, is the property of F. Hoffmann-La Roche Ltd (or under its control) and therefore 
is provided to you in confidence as an investigator, potential investigator, or consultant, for review by 
you, your staff, and an applicable Ethics Committee or Institutional Review Board.  It is understood that 
this information will not be disclosed to others without written authorization from Roche except to the 
extent necessary to obtain informed consent from persons to whom the drug may be administered. 
 
AtezolizumabF. Hoffmann-La Roche Ltd 
1/Protocol BIG 16-05/AFT-27/WO39391, Version 9 
PROTOCOL 
TITLE: 
A PHASE III, MULTICENTER, RANDOMIZED, 
OPEN-LABEL STUDY COMPARING 
ATEZOLIZUMAB (ANTI-PD-L1 ANTIBODY) 
IN COMBINATION WITH ADJUVANT 
ANTHRACYCLINE/TAXANE-BASED 
CHEMOTHERAPY VERSUS CHEMOTHERAPY 
ALONE IN PATIENTS WITH OPERABLE 
TRIPLE-NEGATIVE BREAST CANCER 
PROTOCOL NUMBER: 
BIG 16-05/AFT-27/WO39391 
VERSION NUMBER: 
9 
EUDRACT NUMBER: 
2016­003695­47 
IND NUMBER: 
123277 
NCT NUMBER: 
NCT03498716 
TEST PRODUCT: 
Atezolizumab (RO5541267) 
SPONSOR: 
F. Hoffmann-La Roche Ltd 
ACADEMIC PARTNERS: Breast International Group (BIG) 
Alliance Foundation Trials (AFT) 
Institut Jules Bordet/Clinical Trials Support Unit 
(IJB/CTSU) 
Frontier Science Foundation 
APPROVAL DATE: 
See electronic signature and date stamp on the final 
page of this document. 


AtezolizumabF. Hoffmann-La Roche Ltd 
2/Protocol BIG 16-05/AFT-27/WO39391, Version 9 
PROTOCOL HISTORY 
Protocol 
Associated Country Specific Protocols 
Version 
Date Final 
Country 
Version 
Date Final 
9 
See electronic date stamp on 
the final page of this document. 
 
 
 
8 
24 November 2021 
 
 
 
7 
17 February 2021 
 
 
 
6 
14 February 2020 
VHP 
6 
22 April 2020 
 
 
France 
5 
12 Nov 2019 
4 
15 November 2018 
China 
4 
19 June 2019 
3 
30 May 2018 
France 
3 
13 November 2018 
2 
2 November 2017 
VHP 
2 
19 January 2018 
1 
26 July 2017 
 
 
 
 


 
AtezolizumabF. Hoffmann-La Roche Ltd 
3/Protocol BIG 16-05/AFT-27/WO39391, Version 9 
PROTOCOL AMENDMENT, VERSION 9: 
RATIONALE  
Protocol BIG 16-05/AFT-27/WO39391 has been amended in a response to a Health 
Authority’s request to conduct a formal interim analysis to determine the ability of the 
study to provide an acceptable benefit-risk assessment upon trial conclusion.   
• 
Sections 3.1.1, 6.1, and 6.9.1 have been updated to align with the methods and 
analyses described in the statistical analysis plan.  
 
To align with the Atezolizumab Investigator's Brochure, Version 19, and the associated 
Addendums 1 and 2, the following changes have been made: 
• 
The list of identified risks for atezolizumab has been revised to include pericardial 
disorders, myelitis, and facial paresis (Section 5.1.1, Appendix 9). 
• 
Hemophagocytic lymphohistiocytosis has been updated from a potential risk to an 
identified risk associated with atezolizumab, and language has been revised 
accordingly (Section 5.1.1). 
• 
The list of adverse events of special interest has been revised to include myelitis 
and facial paresis (Section 5.2.3).  
• 
Appendix 6 has been revised to indicate that caution should be used when 
considering atezolizumab for patients who have previously experienced a pericardial 
disorder while receiving another immunostimulatory anti-cancer agent andto include 
autoimmune myelitis in the table. 
• 
The guidelines for the management of adverse events have been updated 
(Appendix 9). 
Additional minor changes have been made to improve clarity and consistency including 
the following:   
• 
The email address for withdrawal from the Research Biosample Repository after site 
closure has been corrected (Section 4.6.11.5). 
• 
Text has also been added to indicate that the VENTANA PD-L1 (SP142) Assay may 
be considered  investigational per local regulations (Section 4.6.7). 
• 
A description of the technical and organizational security measures taken to protect 
personal data has been added to align with Roche practices (Section 8.4). 
• 
Management guidelines for Grade 4 hypophysitis have been added to correct an 
inadvertent omission in the previous version (Appendix 9, Table 4). 
 
Substantive new information appears in italics.  This amendment represents cumulative 
changes to the original protocol. 


 
AtezolizumabF. Hoffmann-La Roche Ltd 
4/Protocol BIG 16-05/AFT-27/WO39391, Version 9 
TABLE OF CONTENTS 
PROTOCOL AMENDMENT ACCEPTANCE FORM .......................................... 11 
PROTOCOL SYNOPSIS .................................................................................... 12 
1. 
BACKGROUND ............................................................................ 29 
1.1 
Background on Breast Cancer ................................................. 29 
1.2 
Treatment for Early Triple-Negative Breast Cancer ................. 29 
1.3 
Background on Atezolizumab .................................................. 30 
1.3.1 
Clinical Experience with Atezolizumab in Triple-Negative 
Breast Cancer .......................................................................... 30 
1.4 
Study Rationale and Benefit-Risk Assessment ........................ 31 
2. 
OBJECTIVES AND ENDPOINTS ................................................. 34 
3. 
STUDY DESIGN ........................................................................... 38 
3.1 
Description of the Study ........................................................... 38 
3.1.1 
Independent Data Monitoring Committee ................................ 42 
3.2 
End of Study and Length of Study ........................................... 43 
3.3 
Rationale for Study Design ...................................................... 43 
3.3.1 
Rationale for Atezolizumab Dose and Schedule ...................... 43 
3.3.2 
Rationale for Patient Population and Analysis Groups ............ 44 
3.3.3 
Rationale for Comparator of Paclitaxel Followed by 
Anthracycline and Cyclophosphamide ..................................... 45 
3.3.4 
Rationale for Invasive Disease-Free Survival as 
Primary Endpoint ..................................................................... 46 
3.3.5 
Rationale for Biomarker Assessments ..................................... 46 
3.3.6 
Rationale for Patient-Reported Outcome Assessments ........... 48 
4. 
MATERIALS AND METHODS ...................................................... 49 
4.1 
Patients .................................................................................... 49 
4.1.1 
Inclusion Criteria ...................................................................... 49 
4.1.2 
Exclusion Criteria ..................................................................... 53 
4.2 
Method of Treatment Assignment ............................................ 57 
4.3 
PD-L1 Unblinding ..................................................................... 57 
4.4 
Study Treatment and Other Treatments Relevant To The 
Study Design ........................................................................... 58 


 
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4.4.1 
Study Treatment Formulation, Packaging, and Handling ......... 58 
4.4.1.1 
Atezolizumab ........................................................................... 58 
4.4.1.2 
Background Treatment ............................................................ 58 
4.4.2 
Study Treatment Dosage, Administration, and Compliance .... 58 
4.4.2.1 
Atezolizumab (Arm A Only)...................................................... 59 
4.4.2.2 
Background Treatment ............................................................ 60 
4.4.3 
Investigational Medicinal Product Accountability ..................... 63 
4.4.4 
Post-Trial Access to Atezolizumab .......................................... 63 
4.5 
Concomitant Therapy and Additional Restrictions ................... 63 
4.5.1 
Permitted Therapy ................................................................... 64 
4.5.2 
Cautionary Therapy for Atezolizumab-Treated Patients .......... 65 
4.5.3 
Potential Drug Interactions with Chemotherapy ....................... 65 
4.5.4 
Prohibited Therapy .................................................................. 66 
4.6 
Study Assessments ................................................................. 67 
4.6.1 
Informed Consent Forms and Screening Log .......................... 67 
4.6.2 
Medical History, Concomitant Medication, and 
Demographic Data ................................................................... 68 
4.6.3 
Physical Examinations ............................................................. 68 
4.6.4 
Vital Signs ................................................................................ 69 
4.6.5 
Radiographic Assessments ..................................................... 69 
4.6.5.1 
Baseline Radiologic Exams ..................................................... 69 
4.6.5.2 
Radiologic Exams after Randomization ................................... 69 
4.6.6 
Disease Follow-Up and Confirmation of Disease 
Recurrence .............................................................................. 69 
4.6.7 
Laboratory, Biomarker, and Other Biological Samples ............ 72 
4.6.8 
Electrocardiograms .................................................................. 75 
4.6.9 
Echocardiograms or Multiple-Gated Acquisition Scans ........... 76 
4.6.10 
Patient-Reported Outcomes .................................................... 76 
4.6.10.1 
EORTC QLQ-C30 .................................................................... 77 
4.6.10.2 
FACT-G Single Item GP5 ........................................................ 77 
4.6.10.3 
EQ-5D-5L................................................................................. 77 
4.6.11 
Optional Research Project Biological Samples ........................ 77 
4.6.11.1 
Approval by the Institutional Review Board or 
Ethics Committee ..................................................................... 78 


 
AtezolizumabF. Hoffmann-La Roche Ltd 
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4.6.11.2 
Sample Collection .................................................................... 78 
4.6.11.3 
Confidentiality .......................................................................... 79 
4.6.11.4 
Consent to Participate in Research Project Biological 
Sample Collection .................................................................... 79 
4.6.11.5 
Withdrawal of Consent for Research Project Biological 
Sample Collection .................................................................... 80 
4.6.11.6 
Monitoring and Oversight of RPBS .......................................... 80 
4.7 
Treatment, Patient, Study, and Site Discontinuation ................ 81 
4.7.1 
Study Treatment Discontinuation ............................................. 81 
4.7.2 
Patient Discontinuation from Study .......................................... 81 
4.7.3 
Study Discontinuation .............................................................. 82 
4.7.4 
Site Discontinuation ................................................................. 82 
5. 
ASSESSMENT OF SAFETY ......................................................... 83 
5.1 
Safety Plan .............................................................................. 83 
5.1.1 
Risks Associated with Atezolizumab ........................................ 83 
5.1.2 
Risks Associated with Paclitaxel .............................................. 84 
5.1.3 
Risks Associated with Doxorubicin .......................................... 84 
5.1.3.1 
Cardiomyopathy ....................................................................... 84 
5.1.4 
Risks Associated with Epirubicin ............................................. 85 
5.1.4.1 
Cardiomyopathy ....................................................................... 85 
5.1.5 
Risks Associated with Cyclophosphamide ............................... 85 
5.1.6 
Management of Patients Who Experience Specific 
Adverse Events ........................................................................ 86 
5.2 
Safety Parameters and Definitions .......................................... 89 
5.2.1 
Adverse Events ........................................................................ 89 
5.2.2 
Serious Adverse Events (Immediately Reportable to the 
Sponsor) .................................................................................. 90 
5.2.3 
Adverse Events of Special Interest (Immediately 
Reportable to the Sponsor) ...................................................... 90 
5.2.4 
Selected Adverse Events ......................................................... 92 
5.2.4.1 
Cardiac, General ...................................................................... 92 
5.2.4.2 
Asymptomatic Ejection Fraction Decrease .............................. 92 
5.3 
Methods and Timing for Capturing and Assessing 
Safety Parameters ................................................................... 92 


 
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7/Protocol BIG 16-05/AFT-27/WO39391, Version 9 
5.3.1 
Adverse Event Reporting Period .............................................. 92 
5.3.2 
Eliciting Adverse Event Information ......................................... 93 
5.3.3 
Assessment of Severity of Adverse Events ............................. 93 
5.3.4 
Assessment of Causality of Adverse Events............................ 94 
5.3.5 
Procedures for Recording Adverse Events .............................. 95 
5.3.5.1 
Infusion-Related Reactions and Cytokine-Release 
Syndrome ................................................................................ 95 
5.3.5.2 
Diagnosis versus Signs and Symptoms ................................... 96 
5.3.5.3 
Adverse Events That Are Secondary to Other Events ............. 96 
5.3.5.4 
Persistent or Recurrent Adverse Events .................................. 96 
5.3.5.5 
Abnormal Laboratory Values ................................................... 97 
5.3.5.6 
Abnormal Vital Sign Values ..................................................... 98 
5.3.5.7 
Abnormal Liver Function Tests ................................................ 98 
5.3.5.8 
Deaths ..................................................................................... 99 
5.3.5.9 
Preexisting Medical Conditions ................................................ 99 
5.3.5.10 
Recurrence of TNBC ............................................................... 99 
5.3.5.11 
Hospitalization or Prolonged Hospitalization ............................ 99 
5.3.5.12 
Reporting Requirements for Cases of Accidental Overdose 
or Medication Error ................................................................ 100 
5.3.5.13 
Patient-Reported Outcome Data ............................................ 101 
5.4 
Immediate Reporting Requirements from Investigator to 
Sponsor ................................................................................. 101 
5.4.1 
Emergency Medical Contacts ................................................ 102 
5.4.2 
Reporting Requirements for Serious Adverse Events and 
Adverse Events of Special Interest ........................................ 102 
5.4.2.1 
Events That Occur prior to Study Treatment Initiation ........... 102 
5.4.2.2 
Events That Occur after Study Treatment Initiation ............... 103 
5.4.3 
Reporting Requirements for Pregnancies .............................. 103 
5.4.3.1 
Pregnancies in Female Patients ............................................ 103 
5.4.3.2 
Pregnancies in Female Partners of Male Patients ................. 103 
5.4.3.3 
Abortions................................................................................ 104 
5.4.3.4 
Congenital Anomalies/Birth Defects ...................................... 104 
5.5 
Follow-Up of Patients after Adverse Events........................... 104 
5.5.1 
Investigator Follow-Up ........................................................... 104 


 
AtezolizumabF. Hoffmann-La Roche Ltd 
8/Protocol BIG 16-05/AFT-27/WO39391, Version 9 
5.5.2 
Sponsor Follow-Up ................................................................ 105 
5.6 
Adverse Events That Occur after the Adverse Event 
Reporting Period .................................................................... 105 
5.7 
Expedited Reporting to Health Authorities, Investigators, 
Institutional Review Boards, and Ethics Committees ............. 105 
6. 
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN ....... 106 
6.1 
Determination of Sample Size ............................................... 106 
6.2 
Summaries of Conduct of Study ............................................ 107 
6.3 
Summaries of Treatment Group Comparability ...................... 107 
6.4 
Efficacy Analyses ................................................................... 107 
6.4.1 
Primary Efficacy Endpoint:  Invasive Disease-Free Survival . 108 
6.4.2 
Secondary Efficacy Endpoints ............................................... 108 
6.4.2.1 
iDFS in the Subpopulation with PD-L1-Selected Tumor 
Status (IC1/2/3) ...................................................................... 109 
6.4.2.2 
iDFS in the Subpopulation with Node-Positive Disease ......... 109 
6.4.2.3 
Overall Survival ...................................................................... 109 
6.4.2.4 
iDFS, including Second Primary Non-Breast Cancer ............. 109 
6.4.2.5 
Recurrence-Free Interval ....................................................... 109 
6.4.2.6 
Distant Recurrence-Free Interval ........................................... 109 
6.4.2.7 
Disease-Free Survival ........................................................... 109 
6.4.2.8 
Patient-Reported Outcomes of Role and Physical Function 
and GHS/HRQoL ................................................................... 110 
6.4.3 
Exploratory Efficacy Endpoints .............................................. 111 
6.4.3.1 
Patient-Reported Outcomes of Disease/Treatment-Related 
Symptoms, Emotional and Social Function-EORTC Data ..... 111 
6.4.3.2 
FACT-G, GP5 Single Item Data ............................................. 111 
6.4.3.3 
Health Economic EQ-5D-5L Data .......................................... 111 
6.5 
Safety Analyses ..................................................................... 111 
6.6 
Pharmacokinetic Analyses ..................................................... 112 
6.7 
Immunogenicity Analyses ...................................................... 112 
6.8 
Biomarker Analyses ............................................................... 112 
6.9 
Interim Analyses .................................................................... 113 
6.9.1 
Invasive Disease-Free Survival (Specified) ........................... 113 
6.9.2 
Invasive Disease-Free Survival (Optional) ............................. 113 


 
AtezolizumabF. Hoffmann-La Roche Ltd 
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6.10 
Subgroup Analyses ................................................................ 114 
7. 
DATA COLLECTION AND MANAGEMENT ............................... 114 
7.1 
Data Quality Assurance ......................................................... 114 
7.2 
Electronic Case Report Forms ............................................... 115 
7.3 
Source Data Documentation .................................................. 115 
7.4 
Use of Computerized Systems .............................................. 116 
7.5 
Retention of Records ............................................................. 116 
8. 
ETHICAL CONSIDERATIONS .................................................... 117 
8.1 
Compliance with Laws and Regulations ................................ 117 
8.2 
Informed Consent .................................................................. 117 
8.3 
Institutional Review Board or Ethics Committee .................... 118 
8.4 
Confidentiality ........................................................................ 118 
8.5 
Financial Disclosure ............................................................... 119 
9. 
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION ..................................................................... 119 
9.1 
Study Documentation ............................................................ 119 
9.2 
Protocol Deviations ................................................................ 120 
9.3 
Quality Control and Quality Assurance .................................. 120 
9.4 
Administrative Structure ......................................................... 120 
9.5 
Publication of Data and Protection of Trade Secrets ............. 121 
9.6 
Protocol Amendments ........................................................... 122 
10. 
REFERENCES............................................................................ 123 
 
LIST OF TABLES 
 
Table 1 
Objectives and Corresponding Endpoints ................................... 35 
Table 2 
Administration of First and Subsequent Atezolizumab 
Infusions...................................................................................... 60 
Table 3 
Definitions of and Procedures for Confirming Disease 
Recurrence, Death, and Other Noteworthy Events on Follow-
Up ............................................................................................... 70 
Table 4 
Dose Levels for Paclitaxel (Weekly Dose) .................................. 87 
Table 5 
Guidelines for Management of Patients Who Experience 
Paclitaxel-Specific Adverse Events ............................................. 88 


 
AtezolizumabF. Hoffmann-La Roche Ltd 
10/Protocol BIG 16-05/AFT-27/WO39391, Version 9 
Table 6 
Adverse Event Severity Grading Scale for Events Not 
Specifically Listed in NCI CTCAE ............................................... 94 
Table 7 
Causal Attribution Guidance ....................................................... 95 
 
LIST OF FIGURES 
 
Figure 1 
Study Schema ............................................................................. 40 
Figure 2 
Documenting Treatment Burden in Early Breast Cancer 
Patients ....................................................................................... 49 
 
LIST OF APPENDICES 
 
Appendix 1 
Schedule of Activities ................................................................ 131 
Appendix 2 
Schedule of Pharmacokinetic, Immunogenicity, and 
Biomarker Samples ................................................................... 141 
Appendix 3 
European Organisation for Research and Treatment of 
Cancer Quality-of-Life Questionnaire Core 30 .......................... 142 
Appendix 4 
FACT-G Single-Item GP5 ......................................................... 144 
Appendix 5 
EQ-5D-5L .................................................................................. 145 
Appendix 6 
Preexisting Autoimmune Diseases and Immune Deficiencies .. 148 
Appendix 7 
Anaphylaxis Precautions ........................................................... 149 
Appendix 8 
Radiotherapy Guidelines ........................................................... 150 
Appendix 9 
Risks Associated with Atezolizumab and Guidelines for 
Management of Adverse Events Associated with 
Atezolizumab ............................................................................ 153 


 
AtezolizumabF. Hoffmann-La Roche Ltd 
11/Protocol BIG 16-05/AFT-27/WO39391, Version 9 
PROTOCOL AMENDMENT ACCEPTANCE FORM 
TITLE: 
A PHASE III, MULTICENTER, RANDOMIZED, 
OPEN-LABEL STUDY COMPARING 
ATEZOLIZUMAB (ANTI-PD-L1 ANTIBODY) 
IN COMBINATION WITH ADJUVANT 
ANTHRACYCLINE/TAXANE-BASED 
CHEMOTHERAPY VERSUS CHEMOTHERAPY 
ALONE IN PATIENTS WITH OPERABLE 
TRIPLE-NEGATIVE BREAST CANCER 
PROTOCOL NUMBER: 
BIG 16-05/AFT-27/WO39391 
VERSION NUMBER: 
9 
EUDRACT NUMBER: 
2016­003695­47 
IND NUMBER: 
123277 
NCT NUMBER: 
NCT03498716 
TEST PRODUCT: 
Atezolizumab (RO5541267) 
SPONSOR: 
F. Hoffmann-La Roche Ltd 
ACADEMIC PARTNERS: Breast International Group (BIG) 
Alliance Foundation Trials (AFT) 
Institut Jules Bordet/Clinical Trials Support Unit 
(IJB/CTSU) 
Frontier Science Foundation 
I agree to conduct the study in accordance with the current protocol. 
 
 
 
Principal Investigator’s Name (print) 
 
 
 
 
 
Principal Investigator’s Signature 
 
Date 
 
Please retain the signed original of this form for your study files.  Please return a copy of 
this form to the Sponsor or its designee.  Contact details will be provided to the 
investigator prior to study start. 










 
AtezolizumabF. Hoffmann-La Roche Ltd 
16/Protocol BIG 16-05/AFT-27/WO39391, Version 9 
Patients who provide informed consent and are eligible will be randomized in a 1:1 ratio to 
receive either of the following treatment regimens: 
• 
Arm A:  Atezolizumab and Chemotherapy 
- 
Atezolizumab: atezolizumab (840 mg) administered via IV Q2W in combination with 
chemotherapy (as described below), followed by atezolizumab maintenance therapy 
(1200 mg IV infusion every 3 weeks [Q3W]) to complete a total duration of 1 year of 
atezolizumab treatment from the first administration of atezolizumab. 
- 
Chemotherapy: paclitaxel (80 mg/m2) administered via IV infusion weekly (QW) for 
12 weeks followed by dose-dense doxorubicin (60 mg/m2) or dose-dense epirubicin 
(90 mg/m2) IV (investigator’s choice) + cyclophosphamide (600 mg/m2) IV repeated 
Q2W for 4 doses. 
- 
Granulocyte colony-stimulating factor (G-CSF) (e.g., filgrastim or pegfilgrastim) or 
granulocyte-macrophage colony-stimulating factor (GM-CSF) treatment is permitted for 
patients receiving chemotherapy and is required during the dose-dense 
doxorubicin/epirubicin +  cyclophosphamide portion of chemotherapy.  The primary 
prophylaxis should be administered per the ASCO, European Organisation for Research 
and Treatment of Cancer (EORTC), or European Society for Medical Oncology (ESMO) 
guidelines or per local standard practice. 
• 
Arm B:  Chemotherapy alone 
- 
Paclitaxel (80 mg/m2) administered via IV infusion QW for 12 weeks followed by 
dose-dense doxorubicin (60 mg/m2) or dose-dense epirubicin (90 mg/m2) IV 
(investigator’s choice) + cyclophosphamide (600 mg/m2) IV repeated Q2W for 4 doses. 
- 
Granulocyte colony-stimulating factor (e.g., filgrastim or pegfilgrastim) or GM-
CSF treatment is permitted for patients receiving chemotherapy and is required during 
the dose dense doxorubicin/epirubicin +  cyclophosphamide portion of chemotherapy.  
The primary prophylaxis should be administered per the ASCO, EORTC, or 
ESMO guidelines or per local standard practice. 
 
The study population will be enriched for patients with node-positive disease such that the 
final population will contain no more than 50% of patients with node-negative disease. 
Patients who do not initially meet all eligibility criteria, other than TNBC status, may be 
re-screened once. 
Randomization will be stratified by the following factors: 
• 
Axillary nodal status (0 vs. 1−3 vs. ≥ 4 positive lymph nodes) 
• 
Surgery (breast conserving vs. mastectomy) 
• 
Tumor PD-L1 status (tumor-infiltrating immune cell [IC] 0 vs. IC1/2/3) 
 
Randomization should occur no more than 8 weeks (56 days) after definitive surgery, and 
study drug administration should begin within 1 week (7 days) after randomization but no 
sooner than 2 weeks (14 days) after last surgery.  In case of multiple surgeries performed for 
the breast cancer treatment, this time period should count starting from the last performed 
curative surgery. 
To ensure comparability of study assessments between the treatment arms, including 
assessments for disease recurrence and safety, patients in Arm B will undergo similar 
assessments as patients in Arm A.  These assessments will consist of formal clinic visits for 
evaluation of symptoms and adverse events, including cardiac toxicity.  Following the induction 
period, patients in Arm B will continue PRO assessments, laboratory evaluations, left ventricular 
ejection fraction (LVEF) monitoring, and limited physical examinations on a regular basis for the 
first year after randomization.  For patients in both arms, patient-reported outcome (PRO) 
assessments, LVEF monitoring, physical examinations and other assessments will continue at a 
reduced frequency after the first year after randomization. 
Patients in the control arm will not be allowed to cross over to receive atezolizumab treatment 
within this study. 


 
AtezolizumabF. Hoffmann-La Roche Ltd 
17/Protocol BIG 16-05/AFT-27/WO39391, Version 9 
In case of unacceptable toxicity attributed to chemotherapy in Arm A, atezolizumab should be 
stopped and restarted together with chemotherapy if there is no contraindication.  In cases 
where chemotherapy is permanently discontinued, atezolizumab may be restarted if there is no 
contraindication and should be based on the investigator’s benefit−risk assessment.  The 
Medical Monitor is available to advise as needed.  In case of toxicities attributed to 
atezolizumab, chemotherapy may be continued independently of atezolizumab if there is no 
contraindication.  Atezolizumab may be restarted when the conditions for retreatment have 
been met.  When atezolizumab is restarted, the infusions should remain synchronized and 
aligned with the chemotherapy schedule and it should be administered at a scheduled 
atezolizumab visit (i.e., missed doses of atezolizumab will not be made up). 
Dose delay and modification guidelines for chemotherapy are provided in the protocol.  
Management guidelines for toxicities associated with atezolizumab are provided in the protocol. 
Treatment will be discontinued in the event of disease recurrence, unacceptable 
toxicity/adverse event occurrence, pregnancy, withdrawal of consent, significant protocol 
violations, or study termination.  Patients who prematurely discontinue from the study will not be 
replaced.  Except for patients who withdraw consent from study follow-up, those who have 
prematurely discontinued from treatment will be followed for safety (including cardiac toxicity) 
and efficacy endpoints. 
Efficacy, safety, laboratory, PROs, pharmacokinetic (PK) measures, and biomarkers will be 
assessed throughout the study.  Following completion of study treatment, all patients will 
continue to be followed for efficacy, safety, and PRO objectives until the end of the study. 
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 5.0 (NCI CTCAE v5.0).  The LVEF will be assessed serially by 
echocardiogram (ECHO)/multiple-gated acquisition (MUGA) scans.  Laboratory safety 
assessments will include the regular monitoring of hematology and blood chemistry.  
Serum samples will be collected to monitor 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 Independent Data Monitoring Committee (IDMC) will evaluate safety and efficacy data 
during the study.  No IDMC member may participate in the Study as an investigator, 
co-investigator, sub-investigator, committee member (other than IDMC), or patient, or in any 
other capacity that might compromise his or her independence and privileged activities within 
the IDMC. In order to ensure independence, members should have no involvement in the 
design and conduct of the Study except through their role on the IDMC and have no financial or 
other interests in the sponsor’s business or other Study organizers (BIG, AFT, FS, IJB) that 
could influence (or be perceived to influence) their objectivity in evaluating Study data.  
The IDMC will follow a charter that outlines the IDMC roles and responsibilities. 
NUMBER OF PATIENTS 
Approximately 2300 patients will be enrolled in this study at approximately 370−450 sites 
globally.  It is estimated that the study will enroll patients over approximately 4 years. 
TARGET POPULATION 
Inclusion Criteria 
Patients must meet the following criteria for study entry: 
• 
Signed Informed Consent Form (ICF) 
• 
Ability to comply with protocol, in the investigator’s judgment 
• 
Women or men aged ≥ 18 years at time of signing ICF 
• 
Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1 
• 
Non-metastatic operable Stage II-III breast cancer 
– 
Patients with node-negative disease must have a pathological tumor size > 2 cm.  
Patients with node-negative multifocal, multicentric- or bilateral breast cancer are 
eligible providing that at least one lesion is > 2 cm in size. 


 
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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 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 invasive tumors (more than one tumor confined to the same 
quadrant as the primary tumor) or multicentric invasive tumors (more than one tumor in 
different quadrants of the same breast) are eligible provided all discrete lesions are 
sampled and centrally confirmed as TNBC.  Patients with non-TNBC invasive 
components are not eligible to participate in this study. 
• 
Confirmed tumor PD-L1 evaluation as documented through central testing of a 
representative tumor tissue specimen 
• 
Adequately excised:  Patients must have undergone either breast-conserving surgery or 
mastectomy/nipple- or skin-sparing mastectomy. 
– 
For patients who undergo breast-conserving surgery, the margins of the resected 
specimen must be histologically free of invasive tumor and ductal carcinoma in situ 
(DCIS) as determined by the local pathologist.  If pathologic examination demonstrates 
tumor at the line of resection, additional operative procedures may be performed to 
obtain clear margins.  If tumor is still present at the resected margin after re-excision(s), 
the patient must undergo total mastectomy to be eligible.  In cases in which the patient 
underwent breast-conserving surgery and there was a microscopic positive 
deep margin (with no other positive margins), if the tumor was resected up to the 
chest wall muscle and the surgeon considers that a mastectomy will not provide a 
negative deep margin, the patient does not need to undergo a mastectomy in order to 
be eligible.  Patients with margins positive for lobular carcinoma in situ (LCIS) are 
eligible without additional resection. 
– 
For patients who undergo mastectomy/nipple- or skin-sparing mastectomy, margins 
must be free of gross residual tumor.  It is recommended that patients should have a 
negative microscopic margin in accordance with local pathology protocol.  Patients with 
a microscopic positive deep margin are eligible. 
• 
Pathological tumor-node-metastasis staging (Union for International Cancer 
Control/American Joint Committee on Cancer [UICC/AJCC], 8th edition):  Patient must have 
had sentinel lymph node biopsy (SLNB) and/or axillary lymph node dissection (ALND) for 
evaluation of pathologic nodal status.   
– 
Axillary nodal dissection(s) should yield a total of at least six nodes (including the 
axillary lymph nodes resected at the SLNB plus the lymph nodes collected at the 
axillary nodal dissection).  
– 
Patients with positive SLNB should undergo axillary dissection unless all of the 
following characteristics apply:   
No palpable nodes 
No more than 2 pathologically positive lymph nodes  
Breast-conserving surgery has been completed with tangential whole breast irradiation 
planned OR mastectomy with regional nodal radiotherapy planned. 
Clinical tumor size ≤ T2 (5 cm) 
– 
In the case that all of the above are applicable, it is not mandatory to have the axillary 
dissection but it is left at the discretion of the investigator as per site standard practice. 
– 
In the case of subjects with tumors >2cm and regional lymph node found to have 
micrometastases or isolated tumor cells: Pathological classification of regional lymph 
node micrometastases (tumor deposits > 0.2 mm and ≤ 2 mm) is considered to be pN1, 
and isolated tumor cells are considered to be pN0. 
The study population will be enriched for patients with node-positive disease such that 
the final population will contain at least 50% node-positive patients. 


 
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• 
Patients with synchronous bilateral invasive disease are eligible only if all bilateral 
invasive lesions are histologically confirmed as triple negative by central laboratory and 
have completed adequate pathological tumor-node metastasis staging bilaterally as 
described above. 
• 
No more than 8 weeks (56 days) may elapse between definitive breast surgery (or the 
last surgery with curative intent if additional resection is required for breast cancer) and 
randomization. 
• 
Baseline LVEF ≥ 53% measured by ECHO (preferred) or MUGA scans 
– 
Baseline LVEF to be conducted within 28 days prior to randomization. 
• 
Adequate hematologic and end-organ function, as defined by the following 
laboratory results obtained within 28 days prior to randomization: 
– 
Absolute neutrophil count (ANC) ≥ 1500 cells/µL (without G-CSF support within 
2 weeks prior to Cycle 1, Day 1) 
– 
Lymphocyte count ≥ 500 cells/µL 
– 
Platelet count ≥ 100,000 cells/µL (without transfusion within 2 weeks prior to Cycle 1, 
Day 1) 
– 
Hemoglobin ≥ 9.0 g/dL 
Patients may be transfused or receive erythropoietic treatment to meet this criterion. 
– 
AST, ALT, and alkaline phosphatase ≤ 2.5 × the upper limit of normal (ULN) 
– 
Serum total bilirubin ≤ 1.0 × ULN 
Patients with known Gilbert disease who have serum bilirubin level ≤ 3 × ULN may be 
enrolled. 
– 
For patients not receiving therapeutic anticoagulation: INR or aPTT ≤ 1.5 × ULN within 
28 days prior to randomization 
– 
For patients receiving therapeutic anticoagulation:  stable anticoagulant regimen and 
stable INR during the 28 days immediately preceding randomization 
– 
Creatinine clearance ≥ 30 mL/min (calculated using the Cockcroft-Gault formula) 
– 
Serum albumin ≥ 2.5 g/dL 
• 
Negative HIV test at screening 
• 
Negative hepatitis B surface antigen (HBsAg) test at screening 
• 
Negative total hepatitis B core antibody (HBcAb) test at screening, or positive 
total HBcAb test followed by a negative hepatitis B virus (HBV) DNA test at screening 
– 
The HBV DNA test will be performed only for patients who have a positive 
total HBcAb test. 
• 
Negative hepatitis C virus (HCV) antibody test at screening, or positive HCV antibody test 
followed by a negative HCV RNA test at screening 
– 
The HCV RNA test will be performed only for patients who have a positive 
HCV antibody test. 
• 
Representative formalin-fixed, paraffin embedded (FFPE) tumor specimen from surgical 
resection in paraffin blocks (preferred) or approximately 25 unstained slides (minimum of 
20 slides), with an associated pathology report documenting locally assessed ER, PgR, and 
HER2 negativity.   
– 
Tumor tissue should be of good quality based on total and viable tumor content and 
must be evaluated centrally for PD-L1 expression prior to enrollment.  
Fine-needle aspiration, brushing, cell pellet from cytology specimens are not 
acceptable.  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. 


 
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• 
For women of childbearing potential:  agreement to remain abstinent (refrain from 
heterosexual intercourse) or use contraceptive measures, and agreement to refrain from 
donating eggs, as defined below: 
– 
Women must remain abstinent or use contraceptive methods with a failure rate of 
< 1% per year during the treatment period and for at least 5 months after the last dose 
of atezolizumab, or 6 months after the last dose of paclitaxel or doxorubicin/epirubicin, 
or 12 months after the last dose of cyclophosphamide, whichever is later.  Women must 
refrain from donating eggs during the same period. 
– 
A woman is considered to be of childbearing potential if she is postmenarcheal, has not 
reached a postmenopausal state (≥ 12 continuous months of amenorrhea with no 
identified cause other than menopause), and has not undergone surgical sterilization 
(removal of ovaries and/or uterus). 
– 
Examples of contraceptive methods with a failure rate of < 1% per year include bilateral 
tubal ligation, male sterilization, and copper intrauterine devices. 
– 
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 adequate 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 
paclitaxel, or doxorubicin/epirubicin or 12 months after the last dose of 
cyclophosphamide, whichever is later.  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 paclitaxel, or 
doxorubicin/epirubicin or 12 months after the last dose of cyclophosphamide, whichever 
is later 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 adequate methods of contraception. 
• 
Women who are not postmenopausal (≥ 12 months of non-therapy-induced amenorrhea) 
and have not 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 
• 
Any T4 tumor as defined by tumor-node metastasis classification in UICC/AJCC, 
8th edition, including inflammatory breast cancer 
• 
For the currently diagnosed breast cancer, any previous systemic anti-cancer treatment 
(e.g., neoadjuvant or adjuvant), including, but not limited to, chemotherapy, anti-HER2 
therapy (e.g., trastuzumab, trastuzumab emtansine, pertuzumab, lapatinib, neratinib, or 
other tyrosine kinase inhibitors), hormonal therapy, or anti-cancer RT other than planned in 
the context of this study 
• 
Previous therapy with anthracyclines or taxanes for any malignancy 
• 
History of DCIS and/or LCIS that was treated with any form of systemic, hormonal therapy, 
or RT to the ipsilateral breast where invasive cancer subsequently developed 


 
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– 
Patients who had their DCIS/LCIS treated only with surgery and/or contralateral 
DCIS treated with RT are allowed to enter the study. 
• 
Contraindication to RT when adjuvant RT is clinically indicated 
• 
Cardiopulmonary and/or cerebrovascular dysfunction as defined by any of the following 
prior to randomization 
– 
History of NCI CTCAE (v5.0) Grade ≥ 2 symptomatic congestive heart failure or 
New York Heart Association (NYHA) 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 > 160 mmHg and/or 
diastolic blood pressure > 100 mmHg) 
– 
Evidence of transmural infarction on ECG 
– 
Requirement for oxygen therapy 
– 
Cerebrovascular ischemic event (e.g., ischemic within 12 months prior to 
randomization) 
• 
Prior malignancies within 5 years prior to randomization, with the exception of those with a 
negligible risk of metastasis or death and treated with expected curative outcome 
(i.e., adequately treated carcinoma in situ of the cervix or basal or squamous cell skin 
cancer) 
• 
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 any component of the atezolizumab formulation 
• 
Known allergy or hypersensitivity to any component of the paclitaxel 
(e.g., polyoxyl 35 castor oil), cyclophosphamide, or doxorubicin/epirubicin formulations 
• 
Known allergy or hypersensitivity to G-CSF or GM-CSF 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 are eligible for this study. 
– 
Patients with controlled Type I diabetes mellitus who are on an 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 
eligible for the study provided all the 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. 


 
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There has been 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. 
• 
Current treatment with anti-viral therapy for HBV 
• 
Urinary outflow obstruction 
• 
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. 
• 
Major surgical procedure other than for diagnosis within 4 weeks prior to initiation of 
study treatment or anticipation of need for a major surgical procedure during 
study treatment 
• 
Prior allogeneic stem cell or solid organ transplant 
• 
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 study or within 
5 months after the last dose of atezolizumab 
– 
Patients must agree not to receive live, attenuated influenza vaccine (e.g., FluMist) 
within 28 days prior to initiation of study treatment, 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 that contraindicates the use of an investigational drug, may affect the 
interpretation of the results, or may render the patient at high risk from treatment 
complications 
• 
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, interleukin-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 factor [anti-TNF] alpha agents) within 2 weeks prior to initiation of 
study treatment or anticipation of need for systemic immunosuppressive medication 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 
based on the investigator’s benefit−risk assessment.  The Medical Monitor is available 
to advise as needed. 
– 
The use of inhaled corticosteroids and mineralocorticoids (e.g., fludrocortisone) 
is allowed. 
• 
Pregnant or lactating, or intending to become pregnant during the study 
• 
Known clinically significant liver disease, including alcoholic hepatitis, cirrhosis, and 
inherited liver disease 
• 
Under any legal protection (tutorship/curatorship). 


 
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END OF STUDY 
The study is planned to end after approximately 299 deaths have been observed for the 
analysis of OS. 
LENGTH OF STUDY 
The total duration of the study is expected to be approximately 7 years after the first patient is 
randomized. 
INVESTIGATIONAL MEDICINAL PRODUCTS 
The investigational medicinal products (IMPs) for this study are atezolizumab, paclitaxel, 
doxorubicin, epirubicin, and cyclophosphamide. 
ATEZOLIZUMAB (ARM A ONLY) 
Atezolizumab will be administered by IV infusion at a fixed dose of 840 mg Q2W (14 [± 3] days) 
in combination with T-AC/EC chemotherapy.  Upon completion of chemotherapy, atezolizumab 
will be continued as maintenance therapy at a dose of 1200 mg administered by IV infusion 
Q3W (21 [± 3] days) to complete 1 year of treatment (i.e., approximately 1 year total duration of 
atezolizumab therapy from first administration of atezolizumab). 
BACKGROUND TREATMENT 
Patients will receive paclitaxel (80 mg/m2) administered via IV infusion QW for 12 weeks 
followed by dose-dense doxorubicin (60 mg/m2) or dose-dense epirubicin (90 mg/m2) IV 
(investigator’s choice) + cyclophosphamide (600 mg/m2) administered via IV infusion Q2W with 
G-CSF/GM-CSF support for 4 cycles (i.e., a total of 4 doses of doxorubicin/epirubicin and 
cyclophosphamide). 
STATISTICAL METHODS 
PRIMARY ANALYSIS 
The primary efficacy variable is invasive disease-free survival (iDFS), defined as the time 
between randomization and date of first occurrence of an iDFS event as described in the 
protocol.  Data from patients who have not had an event at the time of data 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 of the respective analysis. 
Patients with no postbaseline information will be censored on the date of randomization. 
The log-rank test, stratified by the protocol-defined stratification factors, will be used to compare 
iDFS between the two treatment arms.  The hazard ratio (HR) for iDFS will be estimated with 
use of a stratified Cox proportional hazards model.  The Kaplan-Meier approach will be used to 
estimate 3-year iDFS rates, and corresponding 95% Cis for each treatment arm will be used to 
describe iDFS in addition to the HR. 
DETERMINATION OF SAMPLE SIZE 
The final analysis of the primary endpoint of iDFS will take place when approximately 
390 iDFS events (approximately 17% of the planned enrollment of 2300 patients experiencing 
an iDFS event) have occurred in the intent-to-treat (ITT) population.  This sample size is 
computed on the basis of the following assumptions: 
• 
Primary statistical test:  two-sided, stratified log-rank test at the 0.05 significance level in the 
ITT population 
• 
Approximately 80% power for iDFS 
• 
A HR of 0.75  
• 
Annual hazard rates of 0.047, 0.108, 0.035, 0.038, 0.029, and 0.014 in Years 1, 2, 3, 4, 
5−6, and 7 and thereafter are assumed for the T-AC/EC arm based on the adjuvant 
TNBC trials ECOG E1199, BEATRICE, and IBCSG 22-00  
• 
Based on the piecewise hazard rates given above for the control arm, and the assumed 
HR of 0.75 (thus reducing the risk of an iDFS event by 25% at each piecewise interval), the 
3 year iDFS rate (probability of not having any iDFS event in the first 3 years) will be 
82.7% in the T-AC/EC arm and 86.7% in the -atezolizumab + T-AC/EC arm 


 
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• 
2.5% annual loss to follow-up for iDFS 
• 
Interim analyses for iDFS in the ITT population (see below) 
 
Accrual is projected to occur over 51 months.  The required number of iDFS events for the final 
analysis in the ITT population is projected to occur 77 months after first patient in.  Also, on the 
basis of these assumptions, an observed HR of 0.81 or better will result in a statistically 
significant difference between the treatment arms (i.e., HR = 0.81 will be the minimally 
detectable difference for the analysis; this corresponds to an improvement in 3-year iDFS from 
82.7% in the T-AC/EC arm to 85.7% in the atezolizumab + T-AC/EC arm). 
The study duration for the secondary endpoint, OS, was determined on the basis of the number 
of events required to demonstrate efficacy with regard to OS.  A total of approximately 
299 deaths are required to achieve 80% power at a two-sided alpha level of 5% to detect an HR 
of 0.72, corresponding to an improvement in 5-year OS rate from 84% in the T-AC/EC arm to 
88.2% in the atezolizumab + T-AC/EC arm assuming a constant hazard.  An annual loss to 
follow-up of 2.5% and three interim analyses of OS are assumed.  The final analysis of OS is 
planned to take place approximately 7 years after the first patient has been randomized. 
INTERIM ANALYSES 
In a response to a Health Authority’s request, a formal interim analysis will be conducted in 
mid-March 2023 to determine the ability of the study to provide an acceptable benefit-risk 
assessment upon trial conclusion.  This interim analysis will include both assessment of 
efficacy and futility for iDFS based on the available efficacy (approximately 62% of the total 
iDFS events) and safety data.  To control the Type I error in multiple efficacy analyses of 
iDFS, the interim and final efficacy analyses boundaries for statistical significance will be 
determined based on the Lan-DeMets α-spending function with an O’Brien-Fleming 
boundary.  For the first interim analysis, statistical significance will be declared if the p-
value from the two-sided stratified log-rank test is ≤ 0.0088 (observed HR ≤ 0.71); a non-
binding futility boundary is set at the iDFS hazard ratio of 1, thus futility can be declared if 
the observed iDFS HR at the first interim analysis is greater than 1. 
The second interim efficacy analysis of iDFS will be performed when approximately 80% of the 
total planned number of iDFS events have occurred.  On the basis of the assumption presented 
above, it is projected that 80% (312) iDFS events will have been observed approximately 
59 months after the first patient randomized. 
For the second interim efficacy analysis of iDFS, statistical significance will be determined 
based on the Lan-DeMets α-spending function with an O’Brien-Fleming boundary.  Statistical 
significance will be declared if the p-value from the two-sided stratified log-rank test is ≤ 0. 0218 
(observed HR ≤ 0.77) depending on the actually observed number of events.  If the null 
hypothesis for iDFS is not rejected at the interim analysis and the study continues, the final 
analysis of iDFS will be performed when approximately 388 iDFS events have occurred; 
statistical significance will be declared if the p-value from the two-sided stratified log-rank test is 
p ≤ 0.0422 (observed HR ≤ 0.81). 
 


 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Definition 
AC 
dose-dense doxorubicin + cyclophosphamide 
AC-T 
doxorubicin + cyclophosphamide followed by paclitaxel 
ADA 
anti-drug antibody, also known as anti-therapeutic antibody 
AFT 
Alliance Foundation Trials 
AJCC 
American Joint Committee on Cancer 
ALND 
axillary lymph node dissection 
ANC 
absolute neutrophil count 
ASCO 
American Society of Clinical Oncology 
Atezo 
atezolizumab 
AV 
atrioventricular 
benda 
bendamustine 
BIG 
Breast International Group 
BRCA1 
breast cancer 1 gene 
BRCA1 
breast cancer 2 gene 
CAP 
College of American Pathologists 
CD 
cluster of differentiation 
CHEK2 
checkpoint kinase 2 
CHOP 
cyclophosphamide, doxorubicin, vincristine, and prednisone 
COVID-19 
Coronavirus Disease 2019 
CRO 
contract research organization 
CRS 
cytokine-release syndrome 
CT 
computed tomography 
CYP 
cytochrome P450 
DCIS 
ductal carcinoma in situ 
DEHP 
bis(2-ethylhexyl) phthalate 
DFS 
disease-free survival 
DRFI 
distant recurrence-free interval 
EBC 
early breast cancer 
EC 
dose-dense epirubicin + cyclophosphamide 
ECHO 
echocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic Case Report Form 
EDC 
electronic data capture 
EORTC 
European Organisation for Research and Treatment of 
Cancer 
EQ-5D-5L 
EuroQoL 5-Dimension, 5-Level 


 
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Abbreviation 
Definition 
ER 
estrogen receptor 
ESMO 
European Society for Medical Oncology 
FACT-G 
Functional Assessment of Cancer Therapy-General 
FFPE 
formalin-fixed paraffin embedded 
FN 
febrile neutropenia 
G 
obinutuzumab 
GCP 
Good Clinical Practice 
G-CSF 
granulocyte colony-stimulating factor 
GHS 
global health status 
GM-CSF 
granulocyte-macrophage colony-stimulating factor 
HbcAb 
hepatitis B core antibody 
HbsAg 
hepatitis B surface antigen 
HBV 
hepatitis B virus 
HCV 
hepatitis C virus 
HER2 
human epidermal growth factor receptor 2 
HGRAC 
Human Genetic Resources Administration of China 
HIPAA 
Health Insurance Portability and Accountability Act 
HLH 
hemophagocytic lymphohistiocytosis  
HR 
hazard ratio 
HRQoL 
health-related quality of life 
IC 
tumor-infiltrating immune cell 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonisation 
IL 
interleukin 
ISC 
Independent Statistical Center 
iDFS 
invasive disease-free survival 
IDMC 
Independent Data Monitoring Committee 
Ig 
immunoglobulin 
IHC 
immunohistochemistry 
IJB/CTSU 
Institut Jules Bordet/Clinical Trials Support Unit 
IMP 
investigational medicinal product 
IND 
Investigational New Drug  
INF 
interferon 
IRB 
Institutional Review Board 
IRR 
infusion-related reaction 
ISH 
in situ hybridization 
ITT 
intention-to-treat 


 
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Abbreviation 
Definition 
IxRS 
interactive voice or Web-based response system 
LCIS 
lobular carcinoma in situ 
LHRHa 
luteinizing hormone releasing hormone agonist 
LVEF 
left ventricular ejection fraction 
MAS 
macrophage activation syndrome 
MRI 
magnetic resonance imaging 
MUGA 
multiple-gated acquisition 
NCI CTCAE 
National Cancer Institute Common Terminology Criteria for 
Adverse Events 
NGS 
next-generation sequencing 
NSCLC 
non-small cell lung cancer 
NYHA 
New York Heart Association 
OS 
overall survival 
PALB2 
partner and localizer of BRCA2 
PCR 
polymerase chain reaction 
PET 
positron emission tomography 
PFS 
progression free survival 
P-gp 
P-glycoprotein 
PgR 
progesterone receptor 
PIK3CA 
phosphatidylinositol 3-kinase, catalytic, α-polypeptide 
PK 
pharmacokinetic 
PRO 
patient-reported outcome 
PTEN 
phosphatase and tensin homolog 
PVC 
polyvinyl chloride 
Q 
question 
Q2W 
every 2 weeks 
Q3W 
every 3 weeks 
QLQ-C30 
Quality of Life Questionnaire Core 30 
QW 
weekly 
RFI 
recurrence-free interval 
RPBS 
Research Project Biological Samples  
RT 
radiotherapy 
SAP 
Statistical Analysis Plan 
SARS-CoV-2 
severe acute respiratory syndrome coronavirus 2 
SC 
Steering Committee 
SFTP 
Secure File Transfer Protocol 
SLNB 
sentinel lymph node biopsy 


 
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Abbreviation 
Definition 
T3 
triiodothyronine 
T-AC/EC 
paclitaxel, dose-dense doxorubicin/epirubicin, and 
cyclophosphamide 
TIL 
tumor-infiltrating lymphocyte 
TNBC 
triple-negative breast cancer 
TNF 
tumor necrosis factor 
UICC 
Union for International Cancer Control 
ULN 
upper limit of normal 
WES 
whole exome sequencing 
WGS 
whole genome sequencing 
 


 
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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. 2012; 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).  Large-scale comprehensive genomic analyses have 
characterized 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 (Ma et al. 2011).  Unfortunately, TNBCs are more 
likely to have aggressive features, such as a high proliferative rate, and exhibit an 
invasive phenotype (Anders and Carey 2008).  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 
Stage I−III (Lehmann et al. 2011; Howlader et al. 2016).  Three-year 
invasive disease-free survival (iDFS) rates of 81% have been reported for patients with 
TNBC who have received adjuvant anthracycline/taxane therapy (Sparano et al. 2015).  
Upon systemic 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 patients with 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 pre-operatively 
(neo-adjuvant setting) or post-operatively (adjuvant setting) to patients with EBC and is 
currently recommended for patients with TNBC in Stage I−III of the 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, platinum agents, cyclophosphamide, and/or taxanes (Early Breast 
Cancer Trialists’ Collaborative Group 2005; Peto et al. 2012).  Studies looking at 


 
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optimizing the dose and schedule of EBC chemotherapy regimens (Citron et al. 2003; 
Sparano et al. 2008; Budd et al. 2014) have established one of the optimal adjuvant 
regimens with respect to maximizing efficacy as doxorubicin 60 mg/m2 and 
cyclophosphamide 600 mg/m2 administered every 2 weeks (Q2W) for 4 cycles with 
granulocyte colony-stimulating factor (G-CSF) support, followed by weekly 
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. 2014).  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 
PD-L1 and inhibits the interaction between PD-L1 and its receptors, PD-1 and B7-1 
(also known as cluster of differentiation 80 [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 has demonstrated anti-tumor activity in both nonclinical models of cancer, 
as well as in patients with different tumor types.  It is currently being investigated as a 
potential treatment across a wide variety of malignancies.  Atezolizumab is approved for 
the treatment of urothelial carcinoma, non-small cell lung cancer, small-cell lung cancer, 
and triple-negative breast cancer, hepatocellular carcinoma, and melanoma.  
Atezolizumab is being studied as a single agent in the advanced cancer and adjuvant 
therapy settings for different tumor types, as well as in combination with chemotherapy, 
targeted therapy, and cancer immunotherapy. 
Refer to the Atezolizumab Investigator’s Brochure for details on nonclinical and 
clinical studies. 
1.3.1 
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 (see the 
Atezolizumab Investigator’s Brochure for study descriptions). 


 
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Much of the available safety and efficacy data in TNBC are from the five studies below: 
• 
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 
• 
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. 
• 
Study WO29522 (IMpassion130), a randomized Phase III trial in patients with 
locally advanced or metastatic TNBC, previously untreated for metastatic disease.  
The addition of atezolizumab to nab-paclitaxel resulted in a statistically significant 
and clinically meaningful progression free survival (PFS) benefit and a 
clinically meaningful OS benefit in the PD-L1 IC positive population (PD-L1 stained 
tumor-infiltrating immune cells ≥ 1% of the tumor area by SP142 assay).  
The safety profile of atezolizumab + nab-paclitaxel was consistent with those of the 
individual treatment components and no new safety concern was identified. 
• 
Study WO39392 (IMpassion031), a randomized Phase III trial demonstrated that 
neoadjuvant treatment with atezolizumab in combination with nab-paclitaxel and 
anthracycline‑based chemotherapy provided a statistically significant and 
clinically meaningful improvement in the rate of pathologic complete response 
at definitive surgery in patients with locally advanced or early TNBC, regardless of 
PD-L1 expression.  No significant new safety concerns were identified and the 
overall safety profile of atezolizumab in combination with nab‑paclitaxel followed by 
atezolizumab in combination with doxorubicin and cyclophosphamide was 
consistent with the known safety profile of the individual therapeutic agents. 
• 
Study MO39196 (IMpassion131), a Phase III study of atezolizumab and paclitaxel 
versus placebo and paclitaxel in patients with previously untreated locally advanced 
or metastatic TNBC did not show a statistically significant improvement for the 
primary endpoint of investigator-assessed PFS and there was also no evidence of a 
survival benefit in patients with PD-L1-positive metastatic TNBC when adding 
atezolizumab to paclitaxel.  The safety profile of the atezolizumab and paclitaxel 
combination was consistent with the known effects of the individual study drugs. 
 
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). 


 
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The PD-L1 pathway serves as an immune checkpoint to temporarily dampen immune 
responses in states of chronic antigen stimulation, such as chronic infection or cancer.  
PD-L1 is an extracellular protein that downregulates immune responses through binding 
to its two receptors, PD-1 and B7-1.  PD-1 is an inhibitory receptor expressed on 
T-cells following T-cell activation, and expression is sustained in states of 
chronic stimulation (Blank et al. 2005; Keir et al. 2008).  B7-1 is a molecule expressed 
on antigen-presenting cells and activated T cells.  Binding of PD-L1 to PD-1 and 
B7-1 inhibits T-cell proliferation and activation, cytokine production, and cytolytic activity, 
leading to the functional inactivation or exhaustion of T-cells (Butte et al. 2007; 
Yang et al. 2011).  Overexpression of PD-L1 on tumor cells has been reported to impede 
antitumor 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 (NSCLC), 
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). 
Atezolizumab has been generally well tolerated.  Adverse events with potentially 
immune-mediated causes consistent with an immunotherapeutic agent, including rash, 
influenza-like illness endocrinopathies, hepatitis or transaminitis, pneumonitis colitis, and 
myasthenia gravis, have been observed (see Atezolizumab Investigator’s Brochure for 
detailed safety results).  To date, these events have been manageable with treatment or 
interruption of atezolizumab treatment. 
Atezolizumab in combination with taxanes (including paclitaxel and nab-paclitaxel) has 
also been explored.  Adverse events observed were similar to those experienced with 
paclitaxel or nab-paclitaxel alone and have generally been manageable.  The risk of 
overlapping toxicities between atezolizumab and paclitaxel, doxorubicin/epirubicin, and 
cyclophosphamide is thought to be minimal based on the mechanism of action of each 
product.  Known serious risks associated with 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, cardiotoxicity, and 
secondary acute myeloid leukemia.  Known serious risks of epirubicin are bone marrow 
suppression (mainly leukopenia and neutropenia), infection, mucositis/stomatitis, nausea 
and vomiting, secondary leukemias, and cardiotoxicity.  Known serious risks associated 


 
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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 3.1.1). 
Neutropenia and lymphopenia associated with chemotherapy may increase the risk for 
developing an infection in patients receiving atezolizumab in combination with 
chemotherapy. 
This study will enroll patients with Stage II−III TNBC (those with node-negative disease 
must have a tumor size > 2 cm).  The study population will be enriched for patients 
with node-positive disease such that the final population will contain no more than 
50% of patients with node-negative disease.  Given the relatively poor prognosis for 
these patients and the lack of targeted agents, this population is considered appropriate 
for trials of novel therapeutic candidates.  The benefit-risk ratio for atezolizumab in 
combination with paclitaxel followed by dose-dense doxorubicin or epirubicin 
(investigator’s choice) and cyclophosphamide 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 COVID-19.  However, it is 
unclear whether or how systemic cancer therapies such as chemotherapy, targeted 
therapy, or immunotherapy, impact the incidence or severity of COVID-19. 
A possible consequence of inhibiting the PD-1/PD-L1 pathway may be the modulation of 
the host immune response to acute infection, which may result in immunopathology or 
dysregulated immune system defenses.  In nonclinical models, PD-1/PD-L1 blockade 
appears to be associated with serious exacerbation of inflammation in the setting of 
acute (as opposed to chronic) viral infection with lymphocytic choriomeningitis virus 
(Clone 13) (Frebel et al. 2012).  However, there are insufficient and inconsistent clinical 
data to assess if outcome from COVID-19 is altered by cancer immunotherapy. 
Severe COVID-19 appears to be associated with a cytokine-release syndrome (CRS) 
involving the inflammatory cytokines interleukin (IL)-6, IL-10, IL-2, and interferon (IFN)-γ 
(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 severe 
acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection while receiving 
atezolizumab.  At this time, there is insufficient evidence for causal association between 
atezolizumab and an increased risk of severe outcomes from COVID-19. 


 
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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 COVID-19-related interstitial pneumonia.  Thus, investigators 
should use their clinical judgment when evaluating and managing patients with 
pulmonary symptoms. 
There are limited data concerning the possible interactions between cancer 
immunotherapy treatment and SARS-CoV-2 vaccination, and it is recognized that human 
immune responses are highly regulated and that immune-modifying therapies may 
positively or negatively impact the efficacy and safety of SARS-CoV-2 vaccination 
(Society for Immunotherapy for Cancer [SITC] 2020). 
Per recommendations of the National Comprehensive Cancer Network® (NCCN®) 
COVID-19 Vaccination Advisory Committee, COVID-19 vaccination is recommended for 
all patients with cancer receiving active therapy (including immune checkpoint inhibitors), 
with the understanding that there are limited safety and efficacy data in such patients 
(NCCN 2021).  Given the lack of clinical data, currently no recommendations can be 
made regarding the optimal sequence of COVID-19 vaccination in patients who are 
receiving cancer immunotherapy (SITC 2020).  For patients enrolling in this study and 
receiving atezolizumab treatment, a decision to administer the vaccine to a patient 
should be made on an individual basis by the investigator in consultation with the 
patient. 
In alignment with clinical practice procedures, factors to consider when making the 
individualized decision for patients receiving atezolizumab treatment to receive 
COVID-19 vaccination include the following:  the risk of SARS-CoV-2 infection and 
potential benefit from the vaccine, the general condition of the patient and potential 
complications associated with SARS-CoV-2 infection, underlying disease, and the 
severity of COVID-19 outbreak in a given area or region.   
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 4.5.1). 
2. 
OBJECTIVES AND ENDPOINTS 
This study (Study BIG 16-05/AFT-27/WO39391, also known as 
ALEXANDRA/IMpassion030) will evaluate the efficacy, safety, and pharmacokinetics of 
adjuvant atezolizumab in combination with paclitaxel followed by atezolizumab, 
dose-dense doxorubicin or epirubicin (investigator’s choice), and cyclophosphamide 
(referred to as atezolizumab + T-AC/EC) compared with paclitaxel followed by 










 
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assessment using IHC assays per the criteria outlined in the ASCO/CAP guidelines for 
ER/PgR testing (Allison et al. 2020).  Central laboratory assessment will occur prior to 
randomization.  Patients whose tumors are not confirmed to be triple negative by central 
laboratory assessment will not be eligible.  The PD-L1 status will be assessed by central 
laboratory.  Patients whose tumor tissue is not evaluable for PD-L1 will not be eligible.  
All site and study team staff will be blinded to PD-L1 status.  For information regarding 
particular situations when unblinding to PD-L1 status to the investigator may be allowed 
see Section 4.3. 
Patients who provide informed consent and are eligible will be randomized in a 1:1 ratio 
to receive either of the following treatment regimens: 
• 
Arm A:  Atezolizumab and Chemotherapy 
– 
Atezolizumab: atezolizumab (840 mg) administered via IV Q2W in combination 
with chemotherapy (as described below), followed by atezolizumab 
maintenance therapy (1200 mg IV infusion every 3 weeks [Q3W]) to complete a 
total duration of 1 year of atezolizumab treatment from the first administration of 
atezolizumab. 
– 
Chemotherapy: paclitaxel (80 mg/m2) administered via IV infusion weekly (QW) 
for 12 weeks followed by dose-dense doxorubicin (60 mg/m2) or 
dose-dense epirubicin (90 mg/m2) IV (investigator’s choice) + cyclophosphamide 
(600 mg/m2) IV repeated Q2W for 4 doses. 
– 
Granulocyte colony stimulating factor (e.g., filgrastim or pegfilgrastim) or 
granulocyte-macrophage colony-stimulating factor (GM-CSF) treatment is 
permitted for patients receiving chemotherapy and is required during the 
dose-dense doxorubicin/epirubicin + cyclophosphamide portion of 
chemotherapy.  The primary prophylaxis should be administered per the ASCO, 
European Organisation for Research and Treatment of Cancer (EORTC), or 
European Society for Medical Oncology (ESMO) guidelines or per local 
standard practice (see Section 4.5.1). 
• 
Arm B:  Chemotherapy alone 
– 
Paclitaxel (80 mg/m2) administered via IV infusion QW for 12 weeks followed by 
dose-dense doxorubicin (60 mg/m2) or dose-dense epirubicin (90 mg/m2) IV 
(investigator’s choice) + cyclophosphamide (600 mg/m2) IV repeated Q2W for 
4 doses. 
– 
Granulocyte colony-stimulating factor (e.g., filgrastim or pegfilgrastim) or 
GM-CSF treatment is permitted for patients receiving chemotherapy and is 
required during the dose-dense doxorubicin/epirubicin + cyclophosphamide 
portion of chemotherapy.  The primary prophylaxis should be administered 
per the ASCO, EORTC, or ESMO guidelines or per local standard practice (see 
Section 4.5.1). 
 




 
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Randomization should occur no more than 8 weeks (56 days) after definitive surgery, 
and study drug administration should begin within 1 week (7 days) after randomization 
but no sooner than 2 weeks (14 days) after last surgery.  In case of multiple surgeries 
performed for the breast cancer treatment, this time period should count starting from 
the last performed curative surgery. 
To ensure comparability of study assessments between the treatment arms, including 
assessments for disease recurrence and safety, patients in Arm B will undergo similar 
assessments as patients in Arm A.  These assessments will consist of formal clinic visits 
for evaluation of symptoms and adverse events, including cardiac toxicity.  Following the 
induction period, patients in Arm B will continue patient-reported outcome (PRO) 
assessments, laboratory evaluations, left ventricular ejection fraction (LVEF) monitoring, 
and limited physical examinations on a regular basis for the first year after 
randomization.  For patients in both arms, PRO assessments, LVEF monitoring, 
physical examinations and other assessments will continue at a reduced frequency after 
the first year after randomization. 
Patients in the control arm will not be allowed to cross over to receive 
atezolizumab treatment within this study. 
In case of unacceptable toxicity attributed to chemotherapy in Arm A, atezolizumab 
should be stopped and restarted together with chemotherapy if there is no 
contraindication.  In cases where chemotherapy is permanently discontinued, 
atezolizumab may be restarted if there is no contraindication and should be based on on 
the investigator’s benefit−risk assessment.  The Medical Monitor is available to advise 
as needed.  In case of toxicities attributed to atezolizumab, chemotherapy may be 
continued independently of atezolizumab if there is no contraindication.  Atezolizumab 
may be restarted when the conditions for retreatment have been met.  When 
atezolizumab is restarted, the infusions should remain synchronized and aligned with the 
chemotherapy schedule and it should be administered at a scheduled atezolizumab visit 
(i.e., missed doses of atezolizumab will not be made up). 
Dose delay and modification guidelines for chemotherapy are provided in Section 5.1.6.  
Management guidelines for toxicities associated with atezolizumab are provided in 
Appendix 9. 
Treatment will be discontinued in the event of disease recurrence, unacceptable 
toxicity/adverse event occurrence, pregnancy, withdrawal of consent, significant 
protocol violations, or study termination.  Patients who prematurely discontinue from the 
study will not be replaced.  Except for patients who withdraw consent from 
study follow-up, those who have prematurely discontinued from treatment will be 
followed for safety (including cardiac toxicity) and efficacy endpoints. 


 
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Efficacy, safety, laboratory, PROs, pharmacokinetic (PK) measures, and biomarkers will 
be assessed throughout the study.  Following completion of study treatment, all patients 
will continue to be followed for efficacy, safety, and PRO objectives until the end of the 
study. 
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 5.0 (NCI CTCAE [v5.0]).  The LVEF will be 
assessed serially by echocardiogram (ECHO)/multiple-gated acquisition (MUGA) scans.  
Laboratory safety assessments will include the regular monitoring of hematology and 
blood chemistry.  Serum samples will be collected to monitor 
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. 
3.1.1 
Independent Data Monitoring Committee 
An IDMC will evaluate safety and efficacy data during the study.  No IDMC member may 
participate in the Study as an investigator, co-investigator, sub-investigator, 
committee member (other than IDMC), or patient, or in any other capacity that might 
compromise his or her independence and privileged activities within the IDMC.  In order 
to ensure independence, members should have no involvement in the design and 
conduct of the Study except through their role on the IDMC and have no financial or 
other interests in the sponsor’s business or other Study organizers (BIG, AFT, FS, and 
IJB) that could influence (or be perceived to influence) their objectivity in evaluating the 
study.  The IDMC will follow a charter that outlines the IDMC roles and responsibilities. 
Unblinded safety data will be reviewed on a periodic basis.  The first safety review will 
occur when 50 patients in each treatment arm have received at least 2 doses of 
doxorubicin/epirubicin and cyclophosphamide (with or without atezolizumab, 
respectively) and the relevant data has been entered in the electronic Case Report Form 
(eCRF).  Subsequent safety reviews will occur at least once every 6 months during the 
study until the last patient has completed or discontinued study treatment. 
A formal futility analysis will be conducted in mid-March 2023 to determine the ability 
of the study to provide an acceptable benefit-risk assessment upon trial completion. 
This will include an efficacy interim analysis of iDFS of available efficacy 
(approximately 62% of the total iDFS events) and safety data. 
Additional, unblinded efficacy data will be reviewed as part of an interim analysis, 
scheduled to occur after approximately 80% (approximately 312 events) of the targeted 
iDFS events are observed in the intent-to-treat (ITT) population (see Section 6.9.1).  All 
summaries and analyses for the IDMC review will be prepared by an Independent 
Statistical Center (ISC). 


 
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After reviewing the data, the IDMC will make a recommendation to the 
Interface Committee as described in the Interface Committee Charter and the 
IDMC Charter.  Final decisions will rest with the Steering Committee (SC).  Rules for the 
decisions if consensus is not achieved are described in the Interface Committee and 
Executive Committee Charters. 
Any outcomes of these data reviews that affect study conduct will be communicated in a 
timely manner to the investigators for notification of their respective Institutional Review 
Boards (IRBs)/Ethics Committees. 
3.2 
END OF STUDY AND LENGTH OF STUDY 
To enable long-term follow-up for survival and safety information, the study is planned to 
end when approximately 299 deaths have been observed for the analysis of OS. 
The total length of this study will be from randomization of the first patient to last patient, 
last visit for the final analysis of OS, which is estimated to occur approximately 7 years 
after the first patient is randomized. 
The study may be terminated, 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 as a flat dose of 840 mg Q2W during the 
chemotherapy portion of treatment to align with the chemotherapy schedule 
(Cycles 1−5).  For the remainder of atezolizumab treatment (Cycles 6−16), atezolizumab 
will be administered at a flat dose of 1200 mg Q3W for patient convenience.  
The total duration of atezolizumab treatment will be one year from first administration of 
atezolizumab. 
The fixed dose of 840 mg Q2W was selected with the intent of selecting a dose that is 
the exposure equivalent of the fixed dose of 1200 mg Q3W (weight-based equivalent of 
15 mg/kg), which has been approved for treating patients with urothelial carcinoma and 
NSCLC (TECENTRIQ Package Insert).  Of note, the exact equivalent dose is 800 mg; 
however, because atezolizumab is formulated at a concentration of 60 mg/mL, 800 mg 
corresponds to a volume of 13.33 mL, and in the interest of simplifying administration, 
the exact dose used in this study will be 840 mg, corresponding to a volume of 14 mL, 
which can be accurately administered with a single syringe.  The 840-mg dose is not 
expected to result in meaningfully different exposure compared with an 800-mg dose. 
Anti-tumor activity has been observed across doses ranging from 1−20 mg/kg Q3W.  
In Study PCD4989g, the maximum tolerated dose of atezolizumab was not reached and 
no DLTs 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 


 
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nonclinical studies (Deng et al. 2016) and available clinical pharmacokinetic, efficacy, 
and safety data (refer to the Atezolizumab Investigator’s Brochure for details). 
3.3.2 
Rationale for Patient Population and Analysis Groups 
This study will enroll patients with Stage II−III operable TNBC, regardless of 
PD-L1 expression (Sections 4.1.1 and 4.1.2).  Those with node-negative disease must 
have a tumor size > 2 cm.  The study population will be enriched for patients with 
node-positive disease such that the final population will contain no more than 50% of 
patients with node-negative disease. 
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 (Allison et al. 2020; Wolff et al. 2018). 
Patients with Stage II−III TNBC were selected for this study because increased 
tumor size and lymphovascular involvement have been identified as poor 
prognostic variables and have 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−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% to 95.0%] for Stage I; 86.2% [95% CI:  85.1% 
to 87.2%] for Stage II; 58.8% [95% CI:  56.3% to 61.2%] for Stage III, and 16.4% 
[95% CI:  13.2% to 19.8%] for Stage IV; 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. 
In Study PCD4989g, atezolizumab monotherapy was generally well tolerated and activity 
was demonstrated in patients with advanced malignancies, including TNBC (refer to the 
Atezolizumab Investigator’s Brochure; Emens et al. 2015).  Efficacy analyses were 
performed on the 93 patients with TNBC who were dosed by 15 May 2015.  
These 93 patients had been preselected for a PD-L1 status of IC0/1 (n = 34) or 
2/3 (n = 56).  Three patients had unknown PD-L1 status.  The majority of patients had 
received at least 4 prior systemic therapies (89%).  Confirmed responses were seen in 
9.7% of patients (95% CI:  4.5% to 17.6%), with a majority of responses included in the 
IC2/3 population (objective response rate 12.5% for IC2/3, and 5.9% for IC0/1). 
In Study GP28328, the combination of atezolizumab and nab-paclitaxel was studied in 
32 patients with TNBC (Adams et al. 2016).  Of the efficacy-evaluable patients, 
13 patients received the treatment combination as first-line therapy, 9 patients received 
the combination as second-line therapy, and 10 patients received it in the third-line or 
later setting.  Confirmed responses were seen in 38% of patients (95% CI:  21% to 
56%), with responses reported in patients regardless of PD-L1 expression.  Results from 


 
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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 result 
in deeper and more durable responses than those observed with 
standard chemotherapy alone (Merritt et al. 2003; Apetoh et al. 2007), and this may 
reasonably occur in tumors regardless of PD-L1 expression.  The inclusion of patients 
with all levels of PD-L1 expression in this study will enable a robust assessment of this 
hypothesis. 
3.3.3 
Rationale for Comparator of Paclitaxel Followed by 
Anthracycline and Cyclophosphamide 
In the adjuvant setting, anthracycline/taxane chemotherapy-based regimens have 
routinely been used for TNBC resulting in reported 5-year DFS rates of 76%−82% 
(Henderson et al. 2003; Mamounas et al. 2005; Sparano et al. 2015) leaving room for 
improvement in outcomes.  One of the most commonly used regimens is 
dose-dense doxorubicin + cyclophosphamide followed by paclitaxel (AC-T), consisting of 
doxorubicin 60 mg/m2 plus cyclophosphamide 600 mg/m2 Q2W for four cycles 
(i.e., 4 doses each), followed by paclitaxel administered at either 175 mg/m2 Q2W for 
four cycles (Citron et al. 2003) or 80 mg/m2 QW for 12 weeks (Budd et al. 2014); this 
regimen is included as a preferred option in international guidelines (Senkus et al. 2015; 
NCCN 2016).  Dose-dense epirubicin 90 mg/m2 plus cyclophosphamide 600 mg/m2 
Q2W for 4 cycles (i.e., 4 doses each) followed by a taxane has also been studied with 
similar outcomes (Del Mastro et al. 2015; Foukakis et al. 2016). 
Adjuvant paclitaxel will be administered prior to 
doxorubicin/epirubicin + cyclophosphamide chemotherapy in this study.  This sequence 
of chemotherapy agents was selected in order to maximize the potential for a robust 
initial immune response because there is less reported neutropenia and potentially 
lower usage of steroids as a prophylactic anti-emetic regimen with paclitaxel compared 
with doxorubicin/epirubicin + cyclophosphamide.  Several small Phase II 
prospective studies and one retrospective study have evaluated the impact of changing 
the sequence of administration for anthracyclines and taxanes in the adjuvant setting for 
TNBC (Cardoso et al. 2001; Piedbois et al. 2007; Puhalla et al. 2008; 
Wildiers et al. 2009; Alvarez et al. 2010; Abe et al. 2013).  In studies where 
efficacy results were reported, reversing the sequence of adjuvant breast cancer 
chemotherapy by starting with the taxane and following with an 
anthracycline-containing regimen did not impact recurrence rates (Bines et al. 2014). 
The safety of atezolizumab in combination with anthracyclines is being explored in 
BO29563, a Phase Ib/II study evaluating atezolizumab (Atezo) in combination with either 
obinutuzumab (G) + bendamustine (benda) or obinutuzumab (G) + cyclophosphamide, 
doxorubicin, vincristine, and prednisone (CHOP) in patients with follicular lymphoma or 
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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 
Atezo-G-CHOP was well tolerated.  None of the stopping criteria defined for the 
safety run-in phase of the study were met.  There were no treatment-related Grade 3 
and 4 adverse events during Cycles 2 and 3 (i.e., safety observation window).  
No treatment delays or treatment discontinuations due to adverse events were 
observed. 
3.3.4 
Rationale for Invasive Disease-Free Survival as 
Primary Endpoint 
The primary objective of Study BIG 16-05/AFT-27/WO39391 is to evaluate the efficacy 
of adjuvant treatment with atezolizumab + T-AC/EC compared with T-AC/EC alone in 
patients with newly diagnosed TNBC as measured by iDFS. 
An expert panel was convened to develop standardized definitions for efficacy endpoints 
in adjuvant breast cancer trials; this panel proposed the adoption of a broad 
composite endpoint that excludes all in situ cancer events (Hudis et al. 2007).  
The presence of in situ disease alone will, therefore, not be considered an event for 
iDFS in this study. 
It is important to note; however, that non-fatal second non-breast primary cancers will 
not be included as events for the primary endpoint because they generally do not relate 
to breast cancer-specific efficacy.  This differs from the panel’s proposed definition 
(Hudis et al. 2007).  Several recent breast cancer registrational studies investigating 
adjuvant aromatase inhibitors and adjuvant anti-HER2 treatments have also excluded 
these as events (see Hudis et al. 2007 and references therein; 
Hoffmann-La Roche 2011, 2013). 
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 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. 
Presence of tumor-infiltrating lymphocytes (TILs) and cytotoxic T-cell biology 
(effector T-cells) are associated with good prognosis in adjuvant and 
neoadjuvant chemotherapy treated patients with TNBC (Denkert et al. 2010).  
Evaluation of TILs and CD8 T-cells may be analyzed in tumor tissue, by hematoxylin and 


 
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eosin stain, IHC, and/or RNA-based gene expression signatures reflecting these 
biologies. 
Triple-negative breast cancer is a genomically heterogeneous disease.  Tumor genomic 
somatic alterations, such as tumor mutation load and PTEN loss (phosphatase and 
tensin homolog), have been associated with response or resistance to 
checkpoint inhibitors, while mutations in genes leading defective antigen presentation or 
enhanced activation of the PIK3CA (phosphatidylinositol 3-kinase, catalytic, 
α-polypeptide) pathway have been described to reduce PD-L1/PD-1 activity 
(Schalper et al. 2014; Lee et al. 2015). 
Patients are required to undergo tumor biopsy sample collection, if deemed 
clinically feasible by the investigator, at the time of first evidence of clinical or 
radiographic disease recurrence to evaluate tumor tissue biomarkers related to 
mechanisms of acquired resistance and disease recurrence.  Examples of when 
tumor biopsy sample collection may be considered not clinically feasible include, but are 
not limited to, cases where the location of the tumor renders tumor biopsy unsafe or not 
clinically feasible per the investigator due to patient concerns or is prohibited by the 
institution or country. 
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 may enable 
DNA and RNA sequencing, as well as protein or metabolite analysis, to identify 
biomarkers that may be predictive and/or prognostic of recurrence to a more severe 
disease state, associated with acquired resistance to study treatment, or increase the 
knowledge and understanding of disease biology. 
Genomics is increasingly informing researchers’ understanding of disease pathobiology.  
Whole genome sequencing (WGS) provides a comprehensive characterization of the 
genome and, along with clinical data collected in this study, may increase the 
opportunity 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, 
after endorsement by the SC.  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 (Barret 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 patients’ lives, including their ability to 
conduct activities of daily living; on physical functioning; and on emotional and social 
aspects (Petersen et al. 2016).  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 benefit-risk assessment and 
treatment decision-making (Montazeri 2008; Au et al. 2010; FDA 2013; FDA 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 global health status (GHS)/HRQoL, functional, and 
disease/treatment-related symptom items and scales of the EORTC Quality of Life 
Questionnaire-Core 30 (EORTC QLQ-C30; see Appendix 3), and the treatment bother 
item GP5 from the Functional Assessment of Cancer Therapy-General (FACT-G; 
see Appendix 4) quality-of-life instrument will all be used to assess 
patients’ treatment burden (see Figure 2). 


 
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Figure 2 Documenting Treatment Burden in Early Breast Cancer Patients 
 
EORTC = European Organisation for Research and Treatment of Cancer; 
FACT-G = Functional Assessment of Cancer Therapy-General; HRQoL = Health-related quality of 
life; QLQ-C30 = Quality of Life Questionnaire Core 30. 
  
Given the duration of treatment and the potential for long-term treatment impact, 
all PRO measures will be assessed at specified timepoints while patients are on 
treatment and after treatment discontinuation as defined in the schedule of activities 
(see Appendix 1).  All PRO data collected will be analyzed per published 
scoring manuals (Cella 1997; Fayers et al. 2001) to support and inform the 
benefit-risk assessment of atezolizumab therapy. 
4. 
MATERIALS AND METHODS 
4.1 
PATIENTS 
Approximately 2300 patients with newly diagnosed Stage II−III primary invasive 
breast cancer that is of triple negative phenotype (as determined by the 
central pathology laboratory), and who will be treated with adjuvant 
systemic chemotherapy following definitive surgery, will be enrolled in this study.  
It is estimated that the study will enroll patients over approximately 4 years. 
4.1.1 
Inclusion Criteria 
Patients must meet the following criteria for study entry: 
• 
Signed Informed Consent Form (ICF) 
• 
Ability to comply with protocol, in the investigator’s judgment 
• 
Women or men aged ≥ 18 years at time of signing ICF 
• 
Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1 


 
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• 
Non-metastatic operable Stage II−III breast cancer 
– 
Patients with node-negative disease must have a pathological tumor 
size > 2 cm.  Patients with node-negative multifocal, multicentric or bilateral 
breast cancer are eligible providing that at least one lesion is > 2 cm in size. 
• 
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. 2018) and ER/PgR negativity 
will be defined by central laboratory assessment using IHC 
per ASCO/CAP criteria (Allison et al. 2020).  Central laboratory assessment will 
occur prior to randomization.  
– 
Patients with multifocal invasive tumors (more than one tumor confined to the 
same quadrant as the primary tumor) or multi-centric invasive tumors (more 
than one tumor in different quadrants of the same breast) are eligible provided 
all discrete lesions are sampled and centrally confirmed as TNBC.  Patients 
with non-TNBC invasive components are not eligible to participate in this study. 
• 
Confirmed tumor PD-L1 evaluation as documented through central testing of a 
representative tumor tissue specimen. 
• 
Adequately excised:  Patients must have undergone either breast-conserving 
surgery or mastectomy/nipple- or skin-sparing mastectomy. 
– 
For patients who undergo breast-conserving surgery, the margins of the 
resected specimen must be histologically free of invasive tumor and 
ductal carcinoma in situ (DCIS) as determined by the local pathologist.  
If pathologic examination demonstrates tumor at the line of resection, additional 
operative procedures may be performed to obtain clear margins.  If tumor is still 
present at the resected margin after re-excision(s), the patient must undergo 
total mastectomy to be eligible.  In cases in which the patient underwent 
breast-conserving surgery and there was a microscopic positive deep margin 
(with no other positive margins), if the tumor was resected up to the chest wall 
muscle and the surgeon considers that a mastectomy will not provide a 
negative deep margin, the patient does not need to undergo a mastectomy in 
order to be eligible.  Patients with margins positive for lobular carcinoma in situ 
(LCIS) are eligible without additional resection. 
– 
For patients who undergo mastectomy/nipple- or skin-sparing mastectomy, 
margins must be free of gross residual tumor.  It is recommended that patients 
should have a negative microscopic margin in accordance with local pathology 
protocol.  Patients with a microscopic positive deep margin are eligible 
(see radiotherapy [RT] guidelines in Appendix 8). 
• 
Pathological tumor-node-metastasis staging (Union for International Cancer 
Control/American Joint Committee on Cancer [UICC/AJCC], 8th edition):  
Patient must have had sentinel lymph node biopsy (SLNB) and/or 
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– 
Axillary nodal dissection(s) should yield a total of at least six nodes (including 
the axillary lymph nodes resected at the SLNB plus the lymph nodes collected 
at the axillary nodal dissection). 
– 
Patients with positive SLNB should undergo axillary dissection unless all of the 
following characteristics apply (Giuliano et al. 2011): 
No palpable nodes 
No more than 2 pathologically positive lymph nodes 
Breast-conserving surgery has been completed with tangential whole breast 
irradiation planned OR mastectomy with regional nodal radiotherapy planned. 
Clinical tumor size ≤ T2 (5 cm) 
– 
In the case that all of the above are applicable, it is not mandatory to have the 
axillary dissection but it is left at the discretion of the investigator as per site 
standard practice. 
– 
In the case of subjects with tumors > 2cm and regional lymph node found to 
have micrometastases or isolated tumor cells.  Pathological classification of 
regional lymph node micrometastases (tumor deposits > 0.2 mm and ≤ 2 mm) is 
considered to be pN1, and isolated tumor cells are considered to be pN0. 
– 
The study population will be enriched for patients with node-positive disease 
such that the final population will contain at least 50% node-positive patients. 
• 
Patients with synchronous bilateral invasive disease are eligible only if all bilateral 
invasive lesions are histologically confirmed as triple negative by central laboratory 
and have completed adequate pathological tumor-node metastasis staging 
bilaterally as described above. 
• 
No more than 8 weeks (56 days) may elapse between definitive breast surgery 
(or the last surgery with curative intent if additional resection is required for 
breast cancer) and randomization. 
• 
Baseline LVEF ≥ 53% measured by ECHO (preferred) or MUGA scans 
– 
Baseline LVEF to be conducted within 28 days prior to randomization. 
• 
Adequate hematologic and end-organ function, as defined by the following 
laboratory results obtained within 28 days prior to randomization: 
– 
Absolute neutrophil count (ANC) ≥ 1500 cells/µL (without G-CSF support within 
2 weeks prior to Cycle 1, Day 1) 
– 
Lymphocyte count ≥ 500 cells/µL 
– 
Platelet count ≥ 100,000 cells/µL (without transfusion within 2 weeks prior to 
Cycle 1, Day 1) 
– 
Hemoglobin ≥ 9.0 g/dL 
Patients may be transfused or receive erythropoietic treatment to meet this 
criterion. 
– 
AST, ALT, and alkaline phosphatase ≤ 2.5 × the upper limit of normal (ULN) 


 
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– 
Serum total bilirubin ≤ 1.0 × ULN 
Patients with known Gilbert disease who have serum bilirubin level ≤ 3 × ULN 
may be enrolled. 
– 
For patients not receiving therapeutic anticoagulation: INR or aPTT ≤ 1.5 × ULN 
within 28 days prior to randomization 
– 
For patients receiving therapeutic anticoagulation:  stable anticoagulant 
regimen and stable INR during the 28 days immediately preceding 
randomization 
– 
Creatinine clearance ≥ 30 mL/min (calculated using the 
Cockcroft-Gault formula) 
– 
Serum albumin ≥ 2.5 g/dL 
• 
Negative HIV test at screening 
• 
Negative hepatitis B surface antigen (HbsAg) test at screening 
• 
Negative total hepatitis B core antibody (HbcAb) test at screening, or positive 
total HbcAb test followed by a negative hepatitis B virus (HBV) DNA test at 
screening 
– 
The HBV DNA test will be performed only for patients who have a positive total 
HbcAb test. 
• 
Negative hepatitis C virus (HCV) antibody test at screening, or positive 
HCV antibody test followed by a negative HCV RNA test at screening 
– 
The HCV RNA test will be performed only for patients who have a positive 
HCV antibody test. 
• 
Representative formalin-fixed, paraffin embedded (FFPE) tumor specimen from 
surgical resection in paraffin blocks (preferred) or approximately 25 unstained slides 
(minimum of 20 slides), with an associated pathology report documenting locally 
assessed ER, PgR, and HER2 negativity.   
– 
Tumor tissue should be of good quality based on total and viable tumor content 
and must be evaluated centrally for PD-L1 expression prior to enrollment.  
Fine-needle aspiration, brushing, cell pellet from cytology specimens are not 
acceptable.  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. 
• 
For women of childbearing potential:  agreement to remain abstinent (refrain from 
heterosexual intercourse) or use contraceptive measures, and agreement to refrain 
from donating eggs, as defined below: 
– 
Women must remain abstinent or use contraceptive methods with a failure rate 
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last dose of atezolizumab, or 6 months after the last dose of paclitaxel or 
doxorubicin/epirubicin, or 12 months after the last dose of cyclophosphamide, 
whichever is later.  Women must refrain from donating eggs during the same 
period. 
– 
A woman is considered to be of childbearing potential if she is postmenarcheal, 
has not reached a postmenopausal state (≥ 12 continuous months of 
amenorrhea with no identified cause other than menopause), and has not 
undergone surgical sterilization (removal of ovaries and/or uterus). 
– 
Examples of contraceptive methods with a failure rate of < 1% per year include 
bilateral tubal ligation, male sterilization, and copper intrauterine devices. 
– 
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 adequate 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 paclitaxel, or doxorubicin/epirubicin or 12 months after the last 
dose of cyclophosphamide, whichever is later.  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 paclitaxel, or 
doxorubicin/epirubicin or 12 months after the last dose of cyclophosphamide, 
whichever is later, 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 adequate methods of contraception. 
• 
Women who are not postmenopausal (≥ 12 months of non-therapy-induced 
amenorrhea) and have not 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 


 
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• 
Any T4 tumor as defined by tumor-node metastasis classification in UICC/AJCC, 
8th edition, including inflammatory breast cancer 
• 
For the currently diagnosed breast cancer, any previous systemic 
anti-cancer treatment (e.g., neoadjuvant or adjuvant), including, but not limited to, 
chemotherapy, anti-HER2 therapy (e.g., trastuzumab, trastuzumab emtansine, 
pertuzumab, lapatinib, neratinib, or other tyrosine kinase inhibitors), 
hormonal therapy, or anti-cancer RT other than planned in the context of this study 
and described in Appendix 8. 
• 
Previous therapy with anthracyclines or taxanes for any malignancy 
• 
History of DCIS and/or LCIS that was treated with any form of systemic, 
hormonal therapy, or RT to the ipsilateral breast where invasive cancer 
subsequently developed 
– 
Patients who had their DCIS/LCIS treated only with surgery and/or contralateral 
DCIS treated with RT are allowed to enter the study. 
• 
Contraindication to RT when adjuvant RT is clinically indicated 
• 
Cardiopulmonary and/or cerebrovascular dysfunction as defined by any of the 
following prior to randomization: 
– 
History of NCI CTCAE (v5.0) Grade ≥ 2 symptomatic congestive heart failure or 
New York Heart Association (NYHA) 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 > 160 and/or 
diastolic blood pressure > 100 mmHg) 
– 
Evidence of transmural infarction on ECG 
– 
Requirement for oxygen therapy 
– 
Cerebrovascular ischemic event (e.g., ischemic within 12 months prior to 
randomization) 
• 
Prior malignancies within 5 years prior to randomization, with the exception of those 
with a negligible risk of metastasis or death and treated with expected curative 
outcome (i.e., adequately treated carcinoma in situ of the cervix or basal or 
squamous cell skin cancer) 
• 
History of severe allergic, anaphylactic, or other hypersensitivity reactions to 
chimeric or humanized antibodies or fusion proteins 


 
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• 
Known hypersensitivity to biopharmaceuticals produced in Chinese hamster 
ovary cells 
• 
Known allergy or hypersensitivity to any component of the atezolizumab formulation 
• 
Known allergy or hypersensitivity to any component of the paclitaxel 
(e.g., polyoxyl 35 castor oil), cyclophosphamide, or doxorubicin/epirubicin 
formulations 
• 
Known allergy or hypersensitivity to G-CSF or GM-CSF 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 (see Appendix 6 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 are eligible for this study. 
– 
Patients with controlled Type I diabetes mellitus who are on an 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 eligible for the study provided all the 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. 
There has been 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. 
• 
Current treatment with anti-viral therapy for HBV 
• 
Urinary outflow obstruction 
• 
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 


 
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– 
Patients receiving prophylactic antibiotics (e.g., for prevention of a urinary tract 
infection or to prevent chronic obstructive pulmonary disease exacerbation) are 
eligible. 
• 
Major surgical procedure other than for diagnosis within 4 weeks prior to initiation of 
study treatment or anticipation of need for a major surgical procedure during 
study treatment 
• 
Prior allogeneic stem cell or solid organ transplant 
• 
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 study or within 
5 months after the last dose of atezolizumab 
– 
Patients must agree not to receive live, attenuated influenza vaccine 
(e.g., FluMist) within 28 days prior to initiation of study treatment, 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 that contraindicates the use of an investigational drug, may 
affect the interpretation of the results, or may render the patient at high risk from 
treatment complications 
• 
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, interleukin-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 factor [anti-TNF] alpha agents) within 2 weeks prior to initiation 
of study treatment or anticipation of need for systemic immunosuppressive 
medication 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 based on the investigator’s benefit−risk assessment.  The 
Medical Monitor is available to advise as needed. 
– 
The use of inhaled corticosteroids and mineralocorticoids (e.g., fludrocortisone) 
is allowed. 
• 
Pregnant or lactating, or intending to become pregnant during the study 
• 
Known clinically significant liver disease, including alcoholic hepatitis, cirrhosis, and 
inherited liver disease 
• 
Under any legal protection (tutorship/curatorship). 
 


 
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4.2 
METHOD OF TREATMENT ASSIGNMENT 
This is a randomized, open-label, 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.  Patients should receive their first dose of study treatment the day of 
randomization, if possible, but no later than 7 days after randomization, unless within 
2 weeks after surgery.  Patients should not receive their first dose of study treatment 
within 2 weeks after surgery.  In this case, patients may receive their first dose of 
study treatment outside the window. 
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 + T-AC/EC or 
T-AC/EC.  The randomization scheme is designed to ensure that an approximately 
equal number of patients will be enrolled in each treatment arm within the following 
stratification factor categories at baseline.  Randomization will be stratified by the 
following factors: 
• 
Axillary nodal status (0 vs. 1−3 vs. ≥ 4 positive lymph nodes) 
• 
Surgery (breast conserving vs. mastectomy) 
• 
Tumor PD-L1 status (IC0 vs. IC1/2/3) 
 
4.3 
PD-L1 UNBLINDING 
All sites and study team staff will be blinded to PD-L1 status.  The PD-L1 results may be 
provided for an individual patient, after discussion with and approval by IJB, only if all the 
following criteria are met: 
• 
Patient has experienced an incurable local-regional invasive breast cancer 
recurrence or distant recurrence 
• 
Investigator provides rationale for the request indicating the result is required for a 
current treatment decision 
• 
It is not possible to obtain a PD-L1 result otherwise due to lack of available testing at 
the site OR in the following scenario: 
– 
Samples adequate for testing PD-L1 are not available to be returned to the site 
by Central Laboratory within a week 
AND 
– 
The investigator confirms the following: 
No other tumor samples for the subject are available at the site 
AND 


 
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No attainable sample for assessment of PD-L1 status from metastatic disease 
(for example, a biopsy is not feasible due to location of metastases, 
patient refusal, etc.) 
 
Only the investigator will be provided the PD-L1 status results.  The study team will 
remain blinded to a subject’s PD-L1 status. 
Patients that have screen failed can request their PD-L1 status without the requirements 
mentioned above.  
4.4 
STUDY TREATMENT AND OTHER TREATMENTS RELEVANT 
TO THE STUDY DESIGN 
The investigational medicinal products (IMPs) for this study are atezolizumab, paclitaxel, 
doxorubicin, epirubicin, and cyclophosphamide. 
4.4.1 
Study Treatment Formulation, Packaging, and Handling 
4.4.1.1 
Atezolizumab 
The atezolizumab 1200 mg drug product will be supplied by the Sponsor in a single-use, 
20-mL USP/Ph. Eur. Type 1 glass vial as a colorless to slightly yellow, sterile, 
preservative-free clear liquid solution intended for IV administration.  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. 
The atezolizumab 840 mg drug product will be supplied by the Sponsor in a single-use, 
15-mL USP/Ph. Eur. Type 1 glass vial as a colorless to slightly yellow, sterile, 
preservative-free clear liquid solution intended for IV administration.  The vial is designed 
to deliver 14 mL (840 mg) of atezolizumab solution, but may contain more than the 
stated volume to enable delivery of the entire 14 mL volume.  The formulation of 
atezolizumab 840-mg drug product is identical to that of atezolizumab 
1200-mg drug product. 
For information on the formulation and handling of atezolizumab, see the 
pharmacy manual and the Atezolizumab Investigator's Brochure. 
4.4.1.2 
Background Treatment 
For information on the formulation, packaging, and handling of paclitaxel, 
doxorubicin/epirubicin, cyclophosphamide, and G-CSF/GM-CSF, see the local 
prescribing information for the respective treatments. 
4.4.2 
Study Treatment Dosage, Administration, and Compliance 
Any dose modification should be noted on the Study Drug Administration eCRF.  
Cases of accidental overdose or medication error, along with any associated 
adverse events, should be reported as described in Section 5.3.5.12. 


 
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Guidelines for treatment interruption or discontinuation for patients who experience 
adverse events are provided in Appendix 9. 
4.4.2.1 
Atezolizumab (Arm A Only) 
Atezolizumab will be administered by IV infusion at a fixed dose of 840 mg Q2W 
(14 [± 3] days) in combination with T-AC/EC chemotherapy.  Upon completion of 
chemotherapy, atezolizumab will be continued as maintenance therapy at a dose of 
1200 mg administered by IV infusion Q3W (21 [± 3] days) to complete 1 year of 
treatment (i.e., approximately 1 year total duration of atezolizumab therapy from 
first administration of atezolizumab). 
In the induction (chemotherapy) period, 1 cycle = 4 weeks; in the maintenance period, 
1 cycle = 3 weeks. 
Administration of atezolizumab will be performed in a monitored setting where there is 
immediate access to trained personnel and adequate equipment and medicine to 
manage potentially serious reactions.  For anaphylaxis precautions, see Appendix 7.  
Atezolizumab infusions will be administered per the instructions outlined in Table 2. 


 
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Table 2 
Administration of First and Subsequent Atezolizumab Infusions 
First Infusion 
Subsequent Infusions 
• 
No premedication is permitted. 
• 
Vital signs (pulse rate, respiratory rate, 
blood pressure, and temperature) should 
be measured within 60 minutes prior to the 
infusion. 
• 
Atezolizumab should be infused over 
60 (± 15) minutes. 
• 
If clinically indicated, vital signs should be 
measured every 15 (± 5) minutes during the 
infusion and at 30 (± 10) minutes after the 
infusion. 
• 
Patients should be informed about the 
possibility of delayed post-infusion 
symptoms and instructed to contact their 
study physician if they develop such 
symptoms. 
• 
If the patient experienced an 
infusion-related reaction with any 
previous infusion, premedication with 
antihistamines, antipyretics, and/or 
analgesics may be administered for 
subsequent doses at the discretion of the 
investigator. 
• 
Vital signs should be measured within 
60 minutes prior to the infusion. 
• 
Atezolizumab should be infused over 
30 (± 10) minutes if the previous infusion 
was tolerated without an infusion-related 
reaction, or 60 (± 15) minutes if the 
patient experienced an 
infusion-related reaction with the previous 
infusion. 
• 
If the patient experienced an 
infusion-related reaction with the previous 
infusion or if clinically indicated, vital 
signs should be measured during the 
infusion and at 30 (± 10) minutes after the 
infusion. 
 
Refer to the pharmacy manual for detailed instructions on drug preparation, storage, and 
administration. 
Guidelines for medical management of infusion-related reactions (IRRs) are provided in 
Appendix 9. 
No dose modification for atezolizumab is allowed.  If atezolizumab is held due to 
adverse events, missed doses will not be made up. 
If chemotherapy is permanently discontinued because of toxicity, atezolizumab may be 
continued as scheduled if there is no contraindication and should be based on the 
investigator’s benefit−risk assessment.  The Medical Monitor is available to advise as 
needed. 
Treatment (including atezolizumab and chemotherapy, if applicable) will be discontinued 
in the event of disease recurrence while patient is receiving therapy. 
4.4.2.2 
Background Treatment 
Patients will receive paclitaxel (80 mg/m2) administered via IV infusion QW for 12 weeks 
followed by dose-dense doxorubicin (60 mg/m2) or dose-dense epirubicin (90 mg/m2) IV 
(investigator’s choice) + cyclophosphamide (600 mg/m2) administered via IV infusion 
Q2W with G-CSF/GM-CSF support for 4 cycles (i.e., a total of 4 doses of 
doxorubicin/epirubicin and cyclophosphamide). 


 
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Note:  For chemotherapy dosing, body surface area should be calculated according to 
patient actual weight and not corrected for ideal weight, nor capped for a maximum 
body surface area of 2 m2.  No capping should be implemented. 
Dose delays and dose reductions for toxicity are permitted.  In case of dose reduction of 
chemotherapy due to an adverse event, it is not possible to re-increase the dose of 
chemotherapy, even after complete resolution of the adverse event. 
Guidelines for dosage modification and treatment interruption or discontinuation due to 
the development of an adverse event are provided in Section 5.1.6 
If chemotherapy is permanently discontinued as a result of toxicity, atezolizumab may be 
continued as scheduled if there is no contraindication and should be based on the 
investigator’s benefit−risk assessment.  The Medical Monitor is available to advise as 
needed. 
Treatment (including atezolizumab and chemotherapy, if applicable) will be discontinued 
in the event of disease recurrence while patient is receiving therapy. 
Paclitaxel 
Paclitaxel should be administered as an IV infusion over a minimum of 1 hour or 
per institutional policy.  Dose delays and reduction for toxicity are permitted.  
Paclitaxel should be administered after the atezolizumab infusion. 
Paclitaxel Injection must be diluted prior to infusion.  Paclitaxel should be diluted in 
0.9% Sodium Chloride Injection, USP; 5% Dextrose Injection, USP; 5% Dextrose and 
0.9% Sodium Chloride Injection, USP; or 5% Dextrose in Ringer’s Injection to a 
final concentration of 0.3 to 1.2 mg/mL. 
Contact of the undiluted concentrate with plasticized polyvinyl chloride (PVC) equipment 
or devices used to prepare solutions for infusion is not recommended.  Paclitaxel should 
be administered through an in-line filter with a microporous membrane that is not greater 
than 0.22 µm.  Use of filter devices such as IVEX-2 filters, which incorporate short inlet 
and outlet PVC-coated tubing, has not resulted in significant leaching of 
bis(2-ethylhexyl) phthalate (DEHP). 
Sites should follow their institutional standard of care for determining the 
paclitaxel dose adjustments in the event of patient weight changes. 
Premedication with corticosteroids should be administered as clinically indicated (see 
Section 4.5.2 for further guidance).  Because systemic corticosteroids may attenuate the 
potential beneficial immunologic effects of treatment with atezolizumab, alternative 
agents, including antihistamines, should be considered when clinically feasible. 


 
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Refer to the local prescribing information for more details regarding the preparation and 
administration of paclitaxel. 
Doxorubicin 
Patients may receive either dose-dense doxorubicin or dose-dense epirubicin 
per investigator’s choice. 
Doxorubicin may be given as an IV bolus over 3−5 minutes or as an infusion over 
15−30 minutes.  Dose delays and reduction for toxicity are permitted.  Doxorubicin will 
be administered Q2W for four doses (dose-dense doxorubicin + cyclophosphamide [AC]) 
with G-CSF/GM-CSF support (see Section 4.5.1 for further guidance).  
Chemotherapy should be administered after the atezolizumab infusion. 
Refer to the local prescribing information for details regarding the preparation and 
administration of doxorubicin. 
Epirubicin 
Patients may receive either dose-dense doxorubicin or dose-dense epirubicin 
per investigator’s choice. 
Epirubicin may be given as an IV bolus over 3−5 minutes or as an infusion over 
15−30 minutes.  Dose delays and reduction for toxicity are permitted.  Epirubicin will be 
administered Q2W for four doses (dose-dense EC) with G-CSF/GM-CSF support (see 
Section 4.5.1 for further guidance).  Chemotherapy should be administered after the 
atezolizumab infusion. 
Refer to the local prescribing information for details regarding the preparation and 
administration of epirubicin. 
Cyclophosphamide 
Cyclophosphamide should be given as an IV bolus over 3−5 minutes or as an infusion in 
accordance with local standard of care.  Dose delays and dose reductions for toxicity are 
permitted.  Cyclophosphamide will be administered Q2W for four doses (as part of AC).  
Chemotherapy should be administered after the atezolizumab infusion.  
Note:  Oral cyclophosphamide is not permitted. 
Chemotherapy-induced nausea and vomiting prophylaxis and treatment should be 
administered as clinically indicated (see Section 4.5.2 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. 


 
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Pre-medications 
In general, chemotherapy supportive care should be administered per ASCO, EORTC, 
or ESMO guidelines or local standard of care.  For further details regarding 
permitted therapies, see Section 4.5.1. 
4.4.3 
Investigational Medicinal Product Accountability 
All IMPs required for completion of this study (atezolizumab, paclitaxel, doxorubicin, 
epirubicin, and cyclophosphamide) will be provided by the Sponsor where required by 
local health authority regulations.  The study site will acknowledge receipt of IMPs 
supplied by the Sponsor using the IxRS to confirm the shipment condition and content.  
Any damaged shipments will be replaced.  The investigator or designee must confirm 
that appropriate temperature conditions have been maintained during transit, either by 
time monitoring (shipment arrival date and time) or temperature monitoring, for all 
IMPs received and that any discrepancies have been reported and resolved before use 
of the IMPs.  All IMPs must be stored in a secure, environmentally controlled, and 
monitored (manual or automated) area in accordance with the labeled storage 
conditions, with access limited to the investigator and authorized staff. 
IMPs will either be disposed of at the study site according to the study site’s institutional 
standard operating procedure or be returned to the Sponsor (if supplied by the Sponsor) 
with the appropriate documentation.  The site’s method of destroying Sponsor-supplied 
IMPs must be agreed to by the Sponsor.  The site must obtain written authorization from 
the Sponsor before any Sponsor-supplied IMP is destroyed, and IMP destruction must 
be documented on the appropriate form. 
Accurate records of all IMPs received at, dispensed from, returned to, and disposed of 
by the study site should be recorded on the Drug Inventory Log. 
4.4.4 
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 
4.5 
CONCOMITANT THERAPY AND ADDITIONAL RESTRICTIONS 
Concomitant therapy consists of any medication (e.g., prescription drugs, 
over-the-counter drugs, vaccines, herbal or homeopathic remedies, 
nutritional supplements) used by a patient in addition to protocol-mandated 
study treatment from 7 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 eCRF. 


 
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4.5.1 
Permitted Therapy 
Intraoperative RT as a boost at the time of primary surgery is acceptable.  
Adjuvant radiotherapy is permitted as clinically indicated and according to guidelines 
included in the protocol (see Appendix 8).  Radiotherapy can only be administered after 
chemotherapy is complete.  Treatment with atezolizumab during adjuvant radiotherapy is 
permitted. 
Patients are permitted to use the following therapies during the study: 
• 
Prophylactic or therapeutic anticoagulation therapy (such as warfarin at a 
stable dose or low-molecular-weight heparin) 
• 
Vaccinations (such as influenza, SARS-COV-2).  Live attenuated vaccines are not 
permitted (see Section 4.5.4) 
• 
Biphosphonates 
• 
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 
• 
Concomitant ovarian suppression with the use of luteinizing hormone releasing 
hormone agonist (LHRHa) during chemotherapy is allowed as a strategy to preserve 
ovarian function and fertility in premenopausal patients 
 
Premedication with antihistamines, antipyretics, and/or analgesics may be administered 
for the second and subsequent atezolizumab infusions only, at the discretion of the 
investigator. 
Granulocyte colony-stimulating factor (e.g., filgrastim or pegfilgrastim) or 
GM-CSF treatment is permitted for patients receiving chemotherapy and is required 
during the doxorubicin/epirubicin + cyclophosphamide portion of chemotherapy.  
The primary prophylaxis should be administered per the ASCO, EORTC, or 
ESMO guidelines or per local standard practice (Smith et al. 2006; Crawford et al. 2009; 
Aapro et al. 2011).  This primary prophylaxis should be started within 3 days after the 
infusion of chemotherapy with doxorubicin/epirubicin + cyclophosphamide and not later 
than that. 
For filgrastim as primary febrile neutropenia (FN) prophylaxis it is recommended to 
prescribe for at least five days of prophylactic filgrastim to be effective for preventing 
chemotherapy-induced FN (Clemons et al. 2020).  Alternatively, a single dose of 
PEGylated G-CSF (pegfilgrastim) on Day 2 of each cycle may provide an effective, 
as well as a more convenient, option to daily filgrastim. 


 
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In case the local standard practice differs from international guidelines recommendation, 
prior contact with medical monitor is recommended. 
In general, investigators should manage a patient’s care (including preexisting 
conditions) with supportive therapies other than those defined as cautionary or 
prohibited therapies (see Section 4.5.2 and Section 4.5.4) 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 β2-adrenergic agonists; see Appendix 7). 
4.5.2 
Cautionary Therapy for Atezolizumab-Treated Patients 
Systemic corticosteroids, immunosuppressive medications, and TNF-α inhibitors may 
attenuate potential beneficial immunologic effects of treatment with atezolizumab.  
Therefore, in situations in which systemic corticosteroids, or TNF-α inhibitors would be 
routinely administered, alternatives, including antihistamines, should be considered.  
If the alternatives are not feasible, systemic corticosteroids, and TNF-α inhibitors may be 
administered at the discretion of the investigator. 
Systemic corticosteroids or immunosuppressive medications are recommended, at the 
discretion of the investigator, for the treatment of specific adverse events when 
associated with atezolizumab therapy (refer to the Atezolizumab Investigator's Brochure 
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. 
4.5.3 
Potential Drug Interactions with Chemotherapy 
The chemotherapeutic agents used in this study are associated with potential 
drug interactions.  The metabolism of 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 a major 
substrate of CYP2B6.  Epirubicin is metabolized extensively by the liver as well. 
Caution should be exercised when 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 


 
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triazolam) of CYP3A4.  Caution should also be exercised when 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. 
Changes in hepatic function induced by concomitant therapies may affect 
epirubicin metabolism, pharmacokinetics, therapeutic efficacy, and/or toxicity; caution 
should be exercised when epirubicin is combined with agents that may affect 
hepatic function. 
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 risks and benefits should be 
assessed by the investigator prior to concomitant administration with chemotherapy.  
The Medical Monitor is available to advise as needed. 
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 Medical Monitor is available to advise if questions arise regarding medications not 
listed above. 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guida
nces/UCM292362.pdf 
http://medicine.iupui.edu/clinpharm/ddis/table.aspx 
4.5.4 
Prohibited Therapy 
Use of the following concomitant therapies is prohibited as described below: 
• 
Concomitant therapy intended for the treatment of cancer other than those 
described in this study  (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. 


 
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• 
Investigational therapy is prohibited during the study. 
• 
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 
interleukin-2) are prohibited within 4 weeks or 5 half-lives of the drug, whichever is 
longer, prior to initiation of study treatment and during study treatment because 
these agents could potentially increase the risk for autoimmune conditions when 
given in combination with atezolizumab. 
• 
Corticosteroids may be administered as clinically indicated or as otherwise 
described within the protocol (see Section 4.5.2 for further guidance). 
• 
Hormonal contraceptives that inhibit ovulation should not be used during treatment 
and during the first 5 years after the diagnosis of breast cancer.  The investigator 
should discuss with the patient other forms of adequate contraception (as listed in 
Section 4.1.1). 
• 
During the study, initiation of contraception using hormone-releasing 
intrauterine devices is prohibited.  Continuation of hormone-releasing 
intrauterine devices is allowed as long as these have been in-situ prior to 
study entry. 
• 
Plinabulin, a new molecule being investigated for the reduction of 
chemotherapy-induced neutropenia is not allowed as a substitute to 
G-CSF/GM-CSF. 
 
4.6 
STUDY ASSESSMENTS 
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 prior or 
following feasible date. 
4.6.1 
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).  The ICFs for 
enrolled patients and for patients who are not subsequently enrolled will be maintained 
at the study site. 
All screening evaluations must be completed and reviewed to confirm that patients meet 
all eligibility criteria before enrollment.  The investigator will maintain a screening log to 


 
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record details of all patients screened and to confirm eligibility or record reasons for 
screening failure, as applicable. 
4.6.2 
Medical History, Concomitant Medication, and 
Demographic Data 
Medical history, including clinically significant diseases, surgeries, breast cancer history 
(including prior cancer therapies and procedures), reproductive status, smoking history, 
breast cancer 1 (BRCA1), breast cancer 2 (BRCA2), partner and localizer of BRCA2 
(PALB2), p53, checkpoint kinase 2 (CHEK2; c.1100delC) gene mutation status 
(if known), and use of alcohol and drugs of abuse, will be recorded at baseline.  
TNBC history will include surgery and RT. 
In addition, all medications (e.g., prescription drugs, over-the-counter drugs, vaccines, 
herbal or homeopathic remedies, nutritional supplements) used by the patient within 
7 days prior to initiation of study treatment will be recorded.  At the time of each 
follow-up physical examination, an interval medical history should be obtained and any 
changes in medications and allergies should be recorded. 
Demographic data will include age, sex, and self-reported race/ethnicity.  The date of 
birth and race should be collected as per country regulation. 
4.6.3 
Physical Examinations 
A complete physical examination, performed at screening and at the treatment 
discontinuation visit, should include an evaluation of the head, eyes, ears, nose, and 
throat, and the cardiovascular, dermatological, musculoskeletal, respiratory, 
gastrointestinal, and neurological systems.  Special attention should be paid to 
cardiovascular symptoms (e.g., abnormally low or irregular pulse, chest pain, 
tachycardia, swollen legs).  Any abnormality identified at baseline should be recorded in 
the eCRF. 
Limited, symptom-directed physical examinations should be performed at 
postbaseline visits (i.e., at Day 1 of every subsequent treatment cycle) and as 
clinically indicated with special attention to be paid to cardiovascular symptoms 
(e.g., abnormally low or irregular pulse, chest pain, tachycardia, swollen legs).  
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. 
Height and weight will also be measured at baseline.  Weight measurements will be 
repeated at other specified timepoints as outlined in the schedule of activities 
(see Appendix 1). 


 
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4.6.4 
Vital Signs 
Vital signs will include measurements of respiratory rate, pulse rate, and systolic and 
diastolic blood pressure while the patient is in a seated position, and temperature. 
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). 
4.6.5 
Radiographic Assessments 
4.6.5.1 
Baseline Radiologic Exams 
Patients with metastatic disease are ineligible to this study.  Therefore, prior to 
randomization, patients must be evaluated according to local standards to exclude 
metastatic disease.  Bilateral mammogram or breast magnetic resonance imaging (MRI) 
(within 6 months prior to randomization) is mandatory, unless there is no residual breast 
tissue.  Radiological examinations, including X-ray, ultrasound, CT scan, bone scan, 
MRI and/or positron emission tomography (PET)/CT are permissible, as long as 
local guidelines are followed, and they were performed within 6 months prior to 
randomization. 
4.6.5.2 
Radiologic Exams after Randomization 
Patients randomized in this study should be submitted to radiological examinations as 
per national or international guidelines in order to assess distant disease recurrence 
status during study treatment and follow-up.  All radiological examinations, including 
X-ray, ultrasound, CT scan, bone scan, MRI and/or PET/CT are permissible, as long as 
they are performed according to guidelines.  Patients with any remaining breast tissue 
should have a mammogram/breast MRI at least annually from the date of the 
mammogram/breast MRI performed at screening/surgery and as clinically indicated, 
based on findings from physical examinations. 
4.6.6 
Disease Follow-Up and Confirmation of Disease Recurrence 
All patients must be followed to assess disease recurrence, second primary cancer, and 
survival.  Disease recurrence or status based on all available clinical assessments 
should be evaluated and documented every 3 months during study treatment and for 
up to 3 years after randomization; at intervals of every 6 months from 3−5 years after 
randomization; and annually thereafter until the end of the study (see Section 3.2). 
The diagnosis of a breast cancer recurrence or second primary tumor should be 
confirmed histologically whenever clinically possible. 
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. 


 
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The earliest date of diagnosis of recurrent disease should be used and recorded.  
This date should be based on objective clinical, radiological, histological, 
or cytological evidence.  The recurrence of disease has to be backdated to the date of 
the first diagnosis of lesion (i.e., an objective finding), not to the date of occurrence of the 
first symptom. 
For example, a patient presenting with abdominal pain is found to have a possible lesion 
on liver CT scan of uncertain significance.  If a subsequent CT scan confirms disease 
progression, the date of the first diagnostic CT scan should be taken as the date of 
recurrence (not the date of presentation with abdominal pain).  Thus, the actual date of 
relapse of disease is the time of first appearance of a suspicious lesion (in a 
radiological procedure in this case), later proven to be a definitive recurrence or 
metastasis. 
Recurrent disease includes local, regional, or distant recurrence and contralateral 
breast cancer.  Patients who have a diagnosis of in situ breast disease or 
second malignancies not requiring systemic therapy should be maintained on a regular 
follow-up schedule wherever possible in order to fully capture any subsequent recurrent 
invasive disease events.  Patients who have a diagnosis of secondary malignancies 
requiring systemic therapy should be followed-up similarly to patients who experience 
disease recurrence. 
The definitions of and procedures for confirming disease recurrence, death, and other 
noteworthy events on follow-up are provided in Table 3. 
Table 3 
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 
extending across the midline will be considered as 
evidence of local recurrence. 
• 
Confirmed by positive histology or cytology 


 
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Table 3 
Definitions of and Procedures for Confirming Disease 
Recurrence, Death, and Other Noteworthy Events on Follow-Up 
(cont.) 
 
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 or MRI if no biopsy was performed) 
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, 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 scan 
– 
Lung 
X-ray, CT scan or PET scan evidence of multiple 
pulmonary nodules consistent with pulmonary metastases 
Positive cytology or histology (practically rarely performed with the 
exception of solitary nodules) 
NOTE: For solitary lung lesions, cytological or histological 
confirmation should be obtained in case of diagnostic doubt.  
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 on the general status of the 
patient additional investigations (including cytology of the 
cerebrospinal fluid). 


 
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Table 3 
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) Second 
primary 
malignancy 
(breast or 
other cancer) 
• 
Any positive diagnosis of a second (non-breast) primary cancer other 
than basal or squamous cell carcinoma of the skin, or CIS of any site will 
not be included in the iDFS primary endpoint. 
• 
LCIS and DCIS of the breast and myelodysplastic syndrome are not 
considered progression events. 
• 
All second primary malignancies are to be reported whenever they occur 
during the study.  The diagnosis of a second primary cancer must be 
confirmed histologically. 
 
NOTE:  Patients diagnosed with a second primary malignancy not requiring 
systemic therapy (i.e., chemotherapy, hormonal therapy, targeted therapy, 
etc.) and with no evidence of breast cancer recurrence will remain in the 
study.  They should continue with study treatment and/or should continue to 
attend visits as per regular follow-up according to the protocol and schedule 
of activities, if considered by the investigator to be in the patient’s best 
interest, whenever possible.  Patients who have a diagnosis of second 
primary malignancies requiring systemic therapy should be followed-up 
similarly to patients who experience disease recurrence. 
f) 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:  iDFS, DFS, and OS. 
g) Other 
noteworthy 
events 
The following events should be recorded on the follow-up eCRF: 
• 
Ipsilateral and contralateral LCIS 
• 
Ipsilateral and contralateral DCIS 
• 
Carcinoma in situ of the cervix 
• 
Basel or squamous cell carcinoma of the skin 
 
NOTE:  These events are not considered recurrent disease for iDFS but must 
be recorded until end of study.  Ipsilateral and contralateral DCIS are 
considered events for the endpoint of DFS. 
CIS = carcinoma in situ; CT = computed tomography; DCIS = ductal carcinoma in situ; 
DFS = disease-free survival; eCRF = electronic Case Report Form; iDFS = invasive disease-free 
survival; LCIS = lobular carcinoma in situ; MRI = magnetic resonance imaging; OS = overall 
survival; PET = positron emission tomography. 
 
4.6.7 
Laboratory, Biomarker, and Other Biological Samples 
Samples for the following laboratory tests will be sent to the study site's local laboratory 
for analysis as outlined in the schedule of activities (see Appendix 1 and Appendix 2) 
and as clinically indicated: 
• 
Hematology:  WBC count, RBC count, hemoglobin, hematocrit, platelet count, 
differential count (neutrophils, eosinophils, basophils, monocytes, lymphocytes) 


 
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• 
Chemistry panel (serum or plasma):  sodium, potassium, magnesium, chloride, 
glucose, BUN or urea, creatinine, total protein, albumin, phosphorus, calcium, 
total bilirubin, alkaline phosphatase, ALT, AST, LDH, and, if clinically indicated or 
considered standard of care, bicarbonate/total CO2, lipase and amylase 
• 
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 
• 
Viral serology 
• 
HIV serology 
• 
HBV serology:  HBsAg, hepatitis B surface antibody, total HBcAb, and 
(if HBsAg test is negative and total HBcAb test is positive) HBV DNA 
– 
If a patient has a negative HBsAg test and a positive total HBcAb test at 
screening, an HBV DNA test must also be performed to determine if the patient 
has an HBV infection. 
• 
HCV serology:  HCV antibody and, if HCV antibody test is positive, HCV RNA 
– 
If a patient has a positive HCV antibody test at screening, an HCV RNA test 
must also be performed to determine if the patient has an HCV infection. 
• 
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 (see Appendix 2): 
• 
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 anti-drug antibodies (ADAs) to atezolizumab 
through use of a validated assay 
• 
Blood and plasma samples for exploratory research on biomarkers 


 
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• 
Tumor tissue sample collected at baseline for determination of PD-L1 expression; 
for determination of HER2, ER, and PgR negativity; and for exploratory research on 
biomarkers 
– 
A representative FFPE tumor specimen from surgical resection in a paraffin 
block (preferred) or approximately 25 slides (minimum of 20 slides) containing 
unstained, freshly cut (PD-L1 epitope stability is 60 days from sectioning), serial 
sections must be submitted along with an associated pathology report prior to 
study enrollment.  After signing of the ICF, retrieval 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 in the surgical tumor tissue material.  
Tumor tissue should be of good quality based on total and viable tumor content.  
The only acceptable samples are surgical resections. 
– 
Tissue should meet the tumor tissue requirements described in the eligibility 
criteria.  Remaining FFPE tumor tissue for enrolled patients will be returned to 
the site upon request.  Left over tissue from FFPE for patients who are not 
enrolled in the study will be returned to the site no later than 6 weeks after 
eligibility determination.  Slides will not be returned. 
– 
Analysis of PD-L1 expression will be performed using the VENTANA PD-L1 
(SP142) Assay which  may be considered investigational per local regulations.    
• 
FFPE 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 and prior to the 
next anti-cancer therapy.  Acceptable samples include those from resections, 
core-needle biopsies (at least two cores preferred, or at least 20 slides), or 
excisional, incisional, punch, or forceps biopsies.  Fine-needle aspiration 
(defined as samples that do not preserve tissue architecture and yield cell 
suspension and/or smears), brushing, cell pellets from pleural effusion, bone 
metastases, and lavage samples are not acceptable. 
 
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 
next generation sequencing (NGS). 
NGS will be performed by Foundation Medicine in the samples collected at 
disease relapse.  The investigator may obtain an NGS report through Foundation 
Medicine's Web portal.  If allowed by local laws, the investigator may share and discuss 
the results with the patient, unless the patient chooses otherwise.  The NGS report is 
generated for research purposes and is not provided for the purpose of guiding future 
treatment decisions.  Results will not be available for samples that do not meet 
testing criteria. 


 
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Depending on local regulations, NGS analyses may not be available to all participating 
countries. 
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 4.6.11), 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. 
• 
Leftover blood, plasma, serum, and tumor samples collected for exploratory analysis 
during the study will be destroyed no later than 15 years after the final 
Clinical Study Report has been completed. 
• 
For patients from China, all samples and data will be handled in accordance with the 
Human Genetic Resource Administration of China (HGRAC) requirement and the 
pertinent HGRAC approval letter for this study. 
 
When a patient withdraws from the study, samples collected prior to the date of 
withdrawal may still be analyzed, unless the patient specifically requests that the 
samples be destroyed or local laws require destruction of the samples. 
Data 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 NGS report for the samples 
obtained at disease relapse.  The aggregate results of any conducted research will be 
available in accordance with the effective ALEXANDRA/IMpassion030 Publication and 
Presentation policy. 
4.6.8 
Electrocardiograms 
A 12-lead ECG is required at screening and when clinically indicated.  The ECGs for 
each patient should be obtained from the same machine wherever possible.  Lead 
placement should be as consistent as possible.  It is recommended that patients be 
resting in a supine position for at least 10 minutes or as per local practice prior to 
ECG recording. 
For safety monitoring purposes, the investigator must review, sign, and date all 
ECG tracings.  Paper copies of ECG tracings will be kept as part of the patient's 


 
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permanent study file at the site.  Any morphologic waveform changes or other 
ECG abnormalities must be documented on the eCRF. 
4.6.9 
Echocardiograms or Multiple-Gated Acquisition Scans 
The LVEF will be assessed by echocardiography (preferably) or MUGA scan at specified 
timepoints, as outlined in the schedule of activities (see Appendix 1) and as 
clinically indicated.  Patients should be reassessed with the same technique used for 
baseline cardiac evaluation throughout the study. 
4.6.10 
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) 
questionnaire. 
Official versions of the PRO instruments in booklet format, 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.  See Appendix 1 for the frequency and timing of 
PRO assessments. 


 
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4.6.10.1 
EORTC QLQ-C30 
The EORTC QLQ-C30 is a validated, reliable self-report measure (Aaronson et al. 1993; 
see Appendix 3).  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/quality of life, and 6 single items (dyspnea, insomnia, 
appetite loss, constipation, diarrhea, and financial difficulties) with a recall period of the 
previous week.  Scale scores can be obtained for the multi-item scales.  
The EORTC QLQ-C30 module takes approximately 10 minutes to complete. 
4.6.10.2 
FACT-G Single Item GP5 
The FACT-G instrument Version 4 (see Appendix 4) 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 five-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. 
4.6.10.3 
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 5).  There are two components to the EQ-5D-5L:  a 5-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 
Clinical Study Report.  The EQ-5D-5L takes approximately 3 minutes to complete. 
4.6.11 
Optional Research Project Biological Samples 
Optional research project biological samples (RPBS) will be stored in a centrally 
administered facility, the study repository, 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 RPBS 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. 


 
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The RPBS will be collected from patients who give specific consent to participate in this 
optional research.  The RPBS 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 characteristics of these assays 
 
4.6.11.1 
Approval by the Institutional Review Board or 
Ethics Committee 
Collection and submission of RPBS is contingent upon the review and approval of the 
exploratory research and the RPBS portion of the ICF by each site's 
IRB/Ethics Committee and, if applicable, an appropriate regulatory body.  If a site has 
not been granted approval for the collection of RPBS, this section of the protocol 
(Section 4.6.11) will not be applicable at that site. 
4.6.11.2 
Sample Collection 
The following RPBS will be stored in the study repository 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 RPBS collection at Cycle 1, Day 1 (see Appendix 2) 
If, however, the genetic blood RPBS 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 interleukin-8, interleukin-6, and related cytokines.  The sample may 
be processed using techniques such as kinetic polymerase chain reaction (PCR) 
and DNA sequencing. 
• 
Leftover blood, plasma, and tumor tissue samples (with the exception of leftover 
screening tissue from FFPE blocks, which will be returned to sites upon request) 
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, whole exome sequencing (WES), 
NGS, or other genomic analysis methods. 


 
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The samples described above will be stored under the guardianship of the 
Breast International Group (BIG) on behalf of the SC in the study repository that is 
independent from any of the Parties.  Any use of and access to the RPBS will be 
governed by the SC. 
Genomics is increasingly informing researchers’ understanding of disease pathobiology.  
WGS and WES provide a comprehensive characterization of the genome and exome, 
respectively, and, along with clinical data collected in this study, may increase the 
opportunity for developing new therapeutic approaches.  Data will be analyzed in the 
context of this study but may also be explored in aggregate with data from other studies 
upon agreement of the SC of the study.  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, refer to the 
laboratory manual. 
The RPBS are to be stored until they are no longer needed or until they are exhausted.  
However, the RPBS storage period will be in accordance with the 
IRB/Ethics Committee-approved ICF and applicable laws (e.g., health authority 
requirements). 
4.6.11.3 
Confidentiality 
Specimens and associated data will be labeled with a unique patient identification 
number. 
Patient medical information associated with RPBS is confidential and may be disclosed 
to third parties only as permitted by the ICF (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 RPBS, 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 ALEXANDRA/IMpassion030 Publication and presentation 
Policy. 
Data generated from RPBS must be available for inspection upon request by 
representatives of national and local health authorities, and Sponsor monitors, 
representatives, and collaborators, as appropriate. 
4.6.11.4 
Consent to Participate in Research Project Biological Sample 
Collection 
The ICF will contain a separate section that addresses RPBS.  The investigator or 
authorized designee will explain to each patient the objectives, methods, and potential 
hazards of participation in RPBS collection.  Patients will be told that they are free to 


 
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refuse to participate and may withdraw their consent 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 RPBS.  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, in the eCRF. 
In the event of an RPBS collection participant's death or loss of competence, the 
participant's specimens and data will continue to be used as part of the RPBS research. 
4.6.11.5 
Withdrawal of Consent for Research Project Biological Sample 
Collection 
Patients who give consent to provide RPBS have the right to withdraw their consent at 
any time for any reason.  After withdrawal of consent, any remaining samples will be 
destroyed.  However, if RPBS have been tested prior to withdrawal of consent, results 
from those tests will remain as part of the overall research data.  If a patient wishes to 
withdraw consent to the testing of his or her specimens, the investigator must inform the 
Medical Monitor in writing of the patient's wishes through use of the appropriate 
RPBS Subject Withdrawal Form and, if the trial is ongoing, must enter the date of 
withdrawal on the eCRF.  If a patient wishes to withdraw consent to the testing of his or 
her RPBS 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 BIG 16-05/AFT-27/WO39391 does not, by itself, 
constitute withdrawal of consent for RPBS collection.  Likewise, a patient's withdrawal of 
consent for RPBS collection does not constitute withdrawal from 
Study BIG 16-05/AFT-27/WO39391. 
4.6.11.6 
Monitoring and Oversight of RPBS 
RPBS will be tracked in a manner consistent with Good Clinical Practice (GCP) by a 
quality-controlled, auditable, and appropriately validated laboratory information 
management system, to ensure compliance with data confidentiality as well as 
adherence to authorized use of specimens as specified in this protocol and in the ICF.  
Sponsor monitors and auditors will have direct access to appropriate parts of records 
relating to patient participation in RPBS collection for the purposes of verifying the data 
provided to the Sponsor.  The site will permit monitoring, audits, IRB/Ethics Committee 
review, and health authority inspections by providing direct access to source data and 
documents related to the RPBS. 


 
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4.7 
TREATMENT, PATIENT, STUDY, AND SITE DISCONTINUATION 
4.7.1 
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 the investigator or Sponsor determines may jeopardize 
the patient’s safety if he or she continues study treatment 
• 
Investigator or Sponsor determines it is in the best interest of the patient 
• 
Use of another non-protocol anti-cancer therapy 
• 
Pregnancy 
• 
Confirmation of disease recurrence 
 
The primary reason for study treatment discontinuation should be documented on the 
appropriate eCRF.  Patients who discontinue study treatment prematurely will not be 
replaced.  For patients (in both Arm A and Arm B) who discontinue study treatment 
prematurely (see Section 4.7.2) due to an adverse event, every effort should be made to 
follow all serious adverse events considered to be related to study treatment or 
trial-related procedures until an outcome can be reported, including during the 
follow-up period.  Additional tests can be performed, if needed, according to 
standard medical practice. 
4.7.2 
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 
if it’s in the patient’s best interest.  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 (i.e., partial withdrawal) 
From survival follow-up (patient does not want to be contacted) 
• 
Study termination or site closure 
• 
Investigator or Sponsor determines it is in the best interest of the patient 
• 
Severe/major non-compliance (e.g., missed doses and/or missed visits) 
The Medical Monitor is available to advise as needed, before removing a patient for 
non-compliance. 
 


 
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Study treatment discontinuation by itself is not a reason for patient discontinuation from 
study.  Patients should continue to have follow-up information collected and submitted 
following treatment discontinuation if at all possible. 
Every effort should be made to obtain information on patients who withdraw from the 
study treatment and/or assessments but have agreed to be contacted for further 
information (i.e., partial withdrawal).  Partial withdrawal from the study, with consent to 
allow collection of information regarding disease recurrence, survival status, and 
reportable toxicity, should be documented in both the medical records and in the eCRF 
(i.e., the patient accepted to be contacted for collection of these data despite 
withdrawing consent from the study treatment and/or procedures). 
The primary reason for withdrawal from the study should be documented on the 
appropriate eCRF.  If a patient requests to be withdrawn from the study, this request 
must be documented in the source documents and signed by the investigator.  
Patients who withdraw from the study will not be replaced. 
4.7.3 
Study Discontinuation 
The Academic partners and Sponsor have 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 as determined by the Academic partners and 
Sponsor. 
 
Such decisions shall be communicated promptly, in order to allow the termination 
procedure to be properly followed.  The Academic partners and Sponsor will also notify 
the investigator if the study is terminated early. 
4.7.4 
Site Discontinuation 
The Academic partners and Sponsor have 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 
GCP 
• 
No study activity (i.e., all patients have completed the study and all obligations have 
been fulfilled) 
 


 
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5. 
ASSESSMENT OF SAFETY 
5.1 
SAFETY PLAN 
The safety plan for patients in this study is based on clinical experience with 
atezolizumab and paclitaxel, doxorubicin/epirubicin, and cyclophosphamide in completed 
and ongoing studies.  The anticipated important safety risks are outlined below 
(see Sections 5.1.1−5.1.5,).  Guidelines for management of patients who experience 
specific adverse events are provided in Table 5 (see Section 5.1.6). 
Measures will be taken to ensure the safety of patients participating in this study, 
including the use of stringent inclusion and exclusion criteria (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. 
Patients with active infection are excluded from study participation.  In the setting of a 
pandemic or epidemic, screening for active infections (including SARS-CoV-2) prior to 
and during study participation should be considered according to local or 
institutional guidelines or guidelines of applicable professional societies (e.g., ASCO or 
ESMO). 
Severe COVID-19 appears to be associated with a CRS involving the inflammatory 
cytokines IL-6, IL-10, IL-2, and IFN-γ (Merad and Martin 2020).  If a patient develops 
suspected CRS during the study, a differential diagnosis should include COVID-19, 
which should be confirmed or refuted through assessment of exposure history, 
appropriate laboratory testing, and clinical or radiologic evaluations per 
investigator judgment.  If a diagnosis of COVID-19 is confirmed, the disease should be 
managed as per local or institutional guidelines. 
An IDMC (see Section 3.1.1) 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. 
5.1.1 
Risks Associated with Atezolizumab 
Atezolizumab has been associated with risks such as the following:  IRRs and 
immune-mediated hepatitis, pneumonitis, colitis, pancreatitis, diabetes mellitus, 
hypothyroidism, hyperthyroidism, adrenal insufficiency, hypophysitis, 
Guillain-Barré syndrome, myasthenic syndrome or myasthenia gravis, facial paresis, 
myelitis, meningoencephalitis, myocarditis, pericardial disorders, nephritis, myositis, 
and severe cutaneous adverse reactions.  In addition, immune-mediated reactions may 


 
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involve any organ system and may lead to hemophagocytic lymphohistiocytosis (HLH).    
See Appendix 9 of the protocol and Section 6 of the Atezolizumab 
Investigator's Brochure for a detailed description of anticipated safety risks for 
atezolizumab. 
Guidelines for managing patients who experience anticipated adverse events are 
provided in Appendix 9. 
5.1.2 
Risks Associated with Paclitaxel 
Paclitaxel is known to cause myelosuppression, alopecia, peripheral neuropathy, 
myalgia, arthralgia, nausea, and vomiting.  Less commonly reported adverse events are 
hypersensitivity reactions, infections, bleeding, diarrhea, mucositis, liver function test 
elevations, injection site reactions, and cardiovascular effects such as hypotension, 
bradycardia, hypertension, arrhythmias, other ECG abnormalities, syncope, and 
venous thrombosis. 
Refer to the paclitaxel Summary of Product Characteristics (package insert) for more 
details regarding the full safety profile of paclitaxel, including boxed warnings and 
contraindications. 
5.1.3 
Risks Associated with Doxorubicin 
Doxorubicin is known to cause serious cardiomyopathy; arrhythmias, including 
life-threatening arrhythmias; increased incidence of secondary acute 
myelogenous leukemia and myelodysplastic syndrome; extravasation and 
tissue necrosis; infection; severe myelosuppression resulting in serious infection, 
septic shock, angioedema of the eyelids and tongue and respiratory impairment need for 
transfusions, phlebosclerosis; hospitalization and death; tumor lysis syndrome; 
radiation sensitization and radiation recall; secondary acute myeloid leukemia, 
embryo fetal toxicity; alopecia, 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 anthracyclines such as 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 
anthracyclines.  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. 


 
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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 4.6.9 and the schedule of activities 
(see Appendix 1). 
5.1.4 
Risks Associated with Epirubicin 
Epirubicin is known to cause serious cardiomyopathy; arrhythmias, including 
life-threatening arrhythmias; increased incidence of secondary acute 
lymphocytic leukemia and secondary acute myelogenous leukemia; 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; embryo fetal toxicity; alopecia; hyperuricemia; 
dizziness; hot flashes; and anorexia, dehydration, vomiting, nausea, and other 
gastrointestinal effects. 
Refer to the epirubicin Summary of Product Characteristics (package insert) for more 
details regarding the full safety profile of epirubicin, including boxed warnings and 
contraindications. 
5.1.4.1 
Cardiomyopathy 
Patients treated with anthracyclines such as epirubicin 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 
anthracyclines.  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 4.6.9 and the schedule of activities 
(see Appendix 1). 
5.1.5 
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 


 
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leading to respiratory failure; secondary malignancies; veno-occlusive liver disease; 
embryo-fetal toxicity; alopecia; cecitis, 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. 
5.1.6 
Management of Patients Who Experience Specific 
Adverse Events 
There will be no dose modifications for atezolizumab in this study.  Missed doses of 
atezolizumab due to interruption of treatment for any reason during the chemotherapy, 
or after, will not be made up (i.e., atezolizumab treatment cannot exceed 1 year 
calculated from date of the first atezolizumab administration). 
For guidelines regarding the management of atezolizumab-specific adverse events, 
please see Appendix 9. 
Study treatment may be temporarily suspended in patients experiencing toxicity 
considered to be related to study treatment.  In case of toxicities attributed to 
atezolizumab, chemotherapy may be continued independently of atezolizumab if there is 
no contraindication.  Atezolizumab may be restarted when the conditions for retreatment 
have been met.  When atezolizumab is restarted, the infusions should remain 
synchronized and aligned with the chemotherapy schedule and it should be 
administered at a scheduled atezolizumab visit. 
In case of unacceptable toxicity attributed to chemotherapy in Arm A, atezolizumab 
should be interrupted and restarted together with chemotherapy if there is no 
contraindication.  If paclitaxel is to be discontinued, patients can proceed to AC or 
dose-dense epirubicin + cyclophosphamide (EC) at the discretion of the investigator.  
In cases where chemotherapy is withdrawn, atezolizumab may be restarted based on 
the investigator’s benefit−risk assessment.  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 the 
investigator’s benefit−risk assessment and in alignment with the protocol requirements 
for the duration of treatment and documented by the investigator.  The Medical Monitor 
is available to advise as needed. 
For guidelines regarding the management (i.e., dose modification and treatment 
interruption rules) of doxorubicin/epirubicin or cyclophosphamide-associated toxicities, 
please refer to the respective local prescribing information for each agent. 


 
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For paclitaxel-specific management guidelines, please see Table 4 below.  For further 
guidance, please refer to local prescribing information for paclitaxel. 
Table 4 
Dose Levels for Paclitaxel (Weekly Dose) 
 
Dose Level 0 
(Starting Dose) 
Dose Level − 1 
Dose Level − 2 
Paclitaxel weekly dose 
80 mg/m2 
64 mg/m2 b 
Discontinue a 
a Switching to an alternative taxane (e.g., docetaxel or nab-paclitaxel) may be considered in 
exceptional circumstances if deemed appropriate by the investigator and discussed with the 
Medical Monitor. 
b If the paclitaxel dose has been lowered due to an adverse event it should remain at the 
lower dose for the remainder of treatment. 
 


 
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Table 5 
Guidelines for Management of Patients Who Experience 
Paclitaxel-Specific Adverse Events 
Event 
Action to Be Taken 
Infusion-Related Reactions and Anaphylaxis 
 
• 
For Grade ≤ 3 paclitaxel hypersensitivity reaction, 
continuation of paclitaxel is at the investigator’s discretion.  
Patient should be managed per local standard of care. 
• 
For Grade 4 paclitaxel hypersensitivity reaction, paclitaxel 
must be permanently discontinued.  Patient should be 
managed per local standard of care. 
• 
For anaphylaxis precautions, see Appendix 7 
Hepatotoxicity: Bilirubin or AST/ALT or ALP Increased (Grades 2−4) 
Grade 2 or 3 
• 
Hold paclitaxel until bilirubin returns to baseline grade and 
AST/ALT and ALP have recovered to Grade 1 or better 
(check weekly).  
• 
Resume subsequent cycle with decrease of paclitaxel by 
one dose level 
Grade 4 
• 
Discontinue paclitaxel. 
Neurologic Disorders 
Neuropathy, Grade 2 
• 
Withhold paclitaxel if persistent > 7 days or caused the next 
dose to be delayed. 
• 
Resume paclitaxel if event resolves to Grade 1 or better 
and decrease by one dose level. 
• 
If persistent after 3 weeks of withholding paclitaxel, 
discontinue paclitaxel. 
Neuropathy, Grade 3 or 4 
• 
If first episode, withhold paclitaxel.  If persistent for > 7 days 
or caused the next dose to be delayed, resume paclitaxel if 
event resolves to Grade 1 or better on Day 1 of the next 
dose and decrease by one dose level. 
• 
If second episode, discontinue paclitaxel permanently. 
Hematologic Toxicity 
Neutrophil count decreased, 
Grade 3, or 4 
• 
If resolves prior to next treatment dose, maintain paclitaxel 
dose. 
• 
If requires a delay in the administration of next treatment 
dose: 
– 
Hold paclitaxel until ANC ≥ 1000 cells/mm3. 
If recovery takes 1−3 weeks, maintain dose and add 
G-CSF. 
If receiving G-CSF and recovery takes 1 week, 
maintain dose; if recovery takes 2−3 weeks, decrease 
one dose level. 
ANC = absolute neutrophil count; G-CSF = granulocyte colony-stimulating factor. 


 
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Table 5 
Guidelines for Management of Patients Who Experience 
Paclitaxel-Specific Adverse Events (cont.)  
Event 
Action to Be Taken 
Hematologic Toxicity (cont.) 
Platelet count decreased, 
Grade 2 or 3 
• 
If resolves prior to next treatment dose, maintain paclitaxel 
dose. 
• 
If requires a delay in the administration of next treatment 
dose: 
– 
Hold paclitaxel until platelets ≥ 75,000 cells/mm3. 
If recovery takes 1 week, maintain paclitaxel dose. 
If recovery takes 2−3 weeks, decrease one dose level. 
Grade 4 
• 
Hold paclitaxel until platelets ≥ 75,000 cells/mm3. 
• 
Decrease paclitaxel one dose level. 
ANC = absolute neutrophil count; G-CSF = granulocyte colony-stimulating factor. 
 
5.2 
SAFETY PARAMETERS AND DEFINITIONS 
Safety assessments will consist of monitoring and recording adverse events, including 
serious adverse events and adverse events of special interest, performing 
protocol-specified safety laboratory assessments, measuring 
protocol-specified vital signs, and conducting other protocol-specified tests that are 
deemed critical to the safety evaluation of the study. 
Certain types of events require immediate reporting to the Sponsor, as outlined in 
Section 5.4. 
5.2.1 
Adverse Events 
According to the ICH guideline for GCP, an adverse event is any untoward medical 
occurrence in a clinical investigation subject administered a pharmaceutical product, 
regardless of causal attribution.  An adverse event can therefore be any of the following: 
• 
Any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal product, 
whether or not considered related to the medicinal product 
• 
Any new disease or exacerbation of an existing disease (a worsening in the 
character, frequency, or severity of a known condition (see Sections 5.3.5.9 and 
5.3.5.10 for more information) 
• 
Recurrence of an intermittent medical condition (e.g., headache) not present at 
baseline 
• 
Any deterioration in a laboratory value or other clinical test (e.g., ECG, X-ray) that is 
associated with symptoms or leads to a change in study treatment or concomitant 
treatment or discontinuation from study treatment 


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


 
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see Section 5.4.2 for reporting instructions).  Adverse events of special interest for this 
study are as follows: 
• 
Cases of potential drug-induced liver injury that include an elevated ALT or AST in 
combination with either an elevated bilirubin or clinical jaundice, as defined by 
Hy's Law (see Section 5.3.5.7) and based on the following observations: 
– 
Treatment-emergent ALT or AST > 3 × baseline value in combination with 
total bilirubin > 2 × ULN (of which ≥ 35% is direct bilirubin) 
– 
Treatment-emergent ALT or AST > 3 × baseline value in combination with 
clinical jaundice 
• 
 
• 
Suspected transmission of an infectious agent by the study treatment, 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, IRRs, cytokine release syndrome, 
influenza-like illness, HLH and MAS 
• 
Nephritis 
• 
Ocular toxicities (e.g., uveitis, retinitis, optic neuritis) 
• 
Grade ≥ 2 cardiac disorders 
• 
Vasculitis 
• 
Autoimmune hemolytic anemia 
• 
Severe cutaneous reactions (e.g., Stevens-Johnson syndrome, dermatitis bullous, 
toxic epidermal necrolysis) 
• 
Myelitis 
• 
Facial paresis 
 


 
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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 (v5.0) 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 must be reported and followed 
until one of the following occurs:  resolution or improvement to baseline status, no further 
improvement can be expected, or death (see Section 5.6). 
5.2.4.2 
Asymptomatic Ejection Fraction Decrease 
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 ″ejection fraction 
decreased as per NCI CTCAE (v5.0), and, in addition, a comment in the 
adverse events comments field should confirm that this was asymptomatic. 
• 
An asymptomatic decline in LVEF requiring treatment delay or leading to 
discontinuation of atezolizumab, paclitaxel, doxorubicin/epirubicin, 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 5.4−5.6. 
For each adverse event recorded on the Adverse Event eCRF, the investigator will make 
an assessment of seriousness (see Section 5.2.2 for seriousness criteria), severity 
(see Section 5.3.3), and causality (see Section 5.3.4). 
5.3.1 
Adverse Event Reporting Period 
Investigators will seek information on adverse events at each patient contact.  
All adverse events, whether reported by the patient or noted by study personnel, will be 
recorded in the patient’s medical record and on the Adverse Event eCRF. 
After informed consent has been obtained but prior to initiation of study treatment, 
only serious adverse events caused by a protocol-mandated intervention 


 
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(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. 
Instructions for reporting adverse events that occur after the adverse event reporting 
period are provided in Section 5.6. 
5.3.2 
Eliciting Adverse Event Information 
A consistent methodology of non-directive questioning should be adopted for eliciting 
adverse event information at all patient evaluation timepoints.  Examples of 
non-directive questions include the following: 
“How have you felt since your last clinic visit?” 
“Have you had any new or changed health problems since you were last here?” 
 
5.3.3 
Assessment of Severity of Adverse Events 
The adverse event severity grading scale for the NCI CTCAE (v5.0) will be used for 
assessing adverse event severity.  Table 6 will be used for assessing severity for 
adverse events that are not specifically listed in the NCI CTCAE. 


 
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Table 6 
Adverse Event Severity Grading Scale for Events Not Specifically 
Listed in NCI CTCAE 
Grade 
Severity 
1 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
or intervention not indicated 
2 
Moderate; minimal, local, or non-invasive intervention indicated; or limiting 
age-appropriate instrumental activities of daily living a 
3 
Severe or medically significant, but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; or 
limiting self-care activities of daily living b, c 
4 
Life-threatening consequences or urgent intervention indicated d 
5 
Death related to adverse event d 
NCI CTCAE = National Cancer Institute Common Terminology Criteria for Adverse Events. 
Note:  Based on the most recent version of NCI CTCAE (v5.0), which can be found at:  
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm 
a Instrumental activities of daily living refer to preparing meals, shopping for groceries or 
clothes, using the telephone, managing money, etc. 
b Examples of self-care activities of daily living include bathing, dressing and undressing, 
feeding oneself, using the toilet, and taking medications, as performed by patients who are 
not bedridden. 
c If an event is assessed as a “significant medical event,” it must be reported as a serious 
adverse event (see Section 5.4.2 for reporting instructions), per the definition of serious 
adverse event in Section 5.2.2. 
d Grade 4 and 5 events, not specifically listed in the NCI CTCAE, 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 (e.g., IMP), indicating “yes” 
or “no” accordingly.  The following guidance should be taken into consideration 
(see also Table 7): 
• 
Temporal relationship of event onset to the initiation of study treatment 
• 
Course of the event, with special consideration of the effects of dose reduction, 
discontinuation of study treatment, or reintroduction of study treatment 
(as applicable) 
• 
Known association of the event with study treatment or with similar treatments 
• 
Known association of the event with the disease under study 
• 
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 7 
Causal Attribution Guidance 
Is the adverse event suspected to be caused by study treatment on the basis of facts, 
evidence, science-based rationales, and clinical judgment? 
YES 
There is a plausible temporal relationship between the onset of the adverse event and 
administration of study treatment, and the adverse event cannot be readily explained by 
the patient's clinical state, intercurrent illness, or concomitant therapies; and/or the 
adverse event follows a known pattern of response to study treatment; and/or the 
adverse event abates or resolves upon discontinuation of study treatment or dose 
reduction and, if applicable, reappears upon re-challenge. 
NO 
An adverse event will be considered related, unless it fulfills the criteria specified below.   
Evidence exists that the adverse event has an etiology other than study treatment 
(e.g., preexisting medical condition, underlying disease, intercurrent illness, 
or concomitant medication); and/or the adverse event has no plausible temporal 
relationship to administration of study treatment (e.g., cancer diagnosed 2 days after 
first dose of study treatment). 
 
For patients receiving combination therapy, causality should be assessed individually by 
the investigator for each protocol-mandated therapy. 
5.3.5 
Procedures for Recording Adverse Events 
Investigators should use correct medical terminology/concepts when recording adverse 
events on the Adverse Event eCRF.  Avoid colloquialisms and abbreviations. 
Only one adverse event term should be recorded in the event field on the Adverse Event 
eCRF. 
5.3.5.1 
Infusion-Related Reactions and Cytokine-Release Syndrome 
There may be significant overlap in signs and symptoms of IRRs and CRS.  Although 
IRRs occur during or within 24 hours after treatment administration, time to onset of CRS 
may vary.  Differential diagnosis should be applied, particularly for late-onset CRS 
(occurring more than 24 hours after treatment administration), to rule  out other 
etiologies such as delayed hypersensitivity reactions, sepsis or infections, HLH, tumor 
lysis syndrome, early disease progression, or other manifestations of systemic 
inflammation. 
Adverse events that occur during or within 24 hours after study treatment administration 
and are judged to be related to study treatment infusion should be captured as a 
diagnosis (e.g., “infusion-related reaction”) or “cytokine-release syndrome”).  Avoid 
ambiguous terms such as “systemic reaction.”  Cases of late-onset CRS should be 
reported as “cytokine-release syndrome” on the Adverse Event eCRF.  Associated signs 
and symptoms should be recorded on the dedicated Infusion-Related Reaction eCRF or 
Cytokine Release Syndrome eCRF, as appropriate. 
If a patient experiences both a local and systemic reaction to a single administration of 
study treatment, each reaction should be recorded separately on the Adverse Event 


 
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eCRF, with signs and symptoms also recorded separately on the dedicated 
Infusion-Related Reaction eCRF or Cytokine Release Syndrome eCRF. 
In recognition of the challenges in clinically distinguishing between IRRs and CRS, 
consolidated guidelines for medical management of IRRs and CRS are provided in 
Appendix 9. 
5.3.5.2 
Diagnosis versus Signs and Symptoms 
For adverse events (see Section 5.3.5.1), a diagnosis (if known) should be recorded on 
the Adverse Event eCRF rather than individual signs and symptoms (e.g., record only 
liver failure or hepatitis rather than jaundice, asterixis, and elevated transaminases).  
However, if a constellation of signs and/or symptoms cannot be medically characterized 
as a single diagnosis or syndrome at the time of reporting, each individual event should 
be recorded on the Adverse Event eCRF.  If a diagnosis is subsequently established, all 
previously reported adverse events based on signs and symptoms should be nullified 
and replaced by one adverse event report based on the single diagnosis, with a starting 
date that corresponds to the starting date of the first symptom of the eventual diagnosis. 
5.3.5.3 
Adverse Events That Are Secondary to Other Events 
In general, adverse events that are secondary to other events (e.g., cascade events or 
clinical sequelae) should be identified by their primary cause, with the exception of 
severe or serious secondary events.  A medically significant secondary adverse event 
that is separated in time from the initiating event should be recorded as an 
independent event on the Adverse Event eCRF.  For example: 
• 
If vomiting results in mild dehydration with no additional treatment in a healthy adult, 
only vomiting should be reported on the eCRF. 
• 
If vomiting results in severe dehydration, both events should be reported separately 
on the eCRF. 
• 
If a severe gastrointestinal hemorrhage leads to renal failure, both events should be 
reported separately on the eCRF. 
• 
If dizziness leads to a fall and consequent fracture, dizziness and the consequent 
fracture 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 
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more severe, the most extreme severity should also be recorded on the Adverse Event 
eCRF.  If the event becomes serious, it should be reported to the Sponsor immediately 
(i.e., no more than 24 hours after learning that the event became serious; 
see Section 5.4.2 for reporting instructions).  The Adverse Event eCRF should be 
updated by changing the event from “non-serious” to “serious,” providing the date that 
the event became serious, and completing all data fields related to serious 
adverse events. 
A recurrent adverse event is one that resolves between patient evaluation timepoints 
and subsequently recurs.  Each recurrence of an adverse event should be recorded as a 
separate event on the Adverse Event eCRF. 
5.3.5.5 
Abnormal Laboratory Values 
Not every laboratory abnormality qualifies as an adverse event.  A laboratory test result 
must be reported as an adverse event if it meets any of the following criteria: 
• 
Is accompanied by clinical symptoms 
• 
Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation) 
• 
Results in a medical intervention (e.g., potassium supplementation for hypokalemia) 
or a change in concomitant therapy 
• 
Is clinically significant in the investigator’s judgment 
• 
Note:  For oncology trials, certain abnormal values may not qualify as 
adverse events. 
 
It is the investigator’s responsibility to review all laboratory findings.  Medical and 
scientific judgment should be exercised in deciding whether an isolated 
laboratory abnormality should be classified as an adverse event. 
If a clinically significant laboratory abnormality is a sign of a disease or syndrome 
(e.g., 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.” 


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


 
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5.3.5.8 
Deaths 
For this protocol, mortality is an efficacy endpoint.  Deaths that occur during the 
protocol-specified adverse event reporting period (see Section 5.3.1) that are attributed 
by the investigator solely to recurrence and progression of breast cancer should be 
recorded on the eCRF.  All other deaths that occur during the adverse event reporting 
period, regardless of relationship to study treatment, must also be recorded on the 
Adverse Event eCRF and immediately reported to the Sponsor (see Section 5.4.2).  
An IDMC will monitor the frequency of deaths from all causes. 
Death should be considered an outcome and not a distinct event.  The event or condition 
that caused or contributed to the fatal outcome should be recorded as the single 
medical concept on the Adverse Event eCRF.  Generally, only one such event should be 
reported.  If the cause of death is unknown and cannot be ascertained at the time of 
reporting, ″unexplained death″ should be recorded on the Adverse Event eCRF.  If the 
cause of death later becomes available (e.g., after autopsy), ″unexplained death″ should 
be replaced by the established cause of death.  The term ″sudden death″ should not be 
used unless combined with the presumed cause of death (e.g., ″sudden cardiac death″). 
Deaths that occur after the 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 
or clinically significant as per the inclusion/exclusion criteria of this study.  Such 
conditions should be recorded on the 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 
Recurrence of TNBC 
Events that are clearly consistent with the expected recurrence or pattern of progression 
of the underlying disease should not be recorded as adverse events.  These data will be 
captured as efficacy assessment data only.  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 
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An event that leads to hospitalization under the following circumstances should not be 
reported as an adverse event or a serious adverse event: 
• 
Hospitalization for respite care 
• 
Planned hospitalization required by the protocol (e.g., for study treatment 
administration or performance of an efficacy measurement for the study) 
• 
Hospitalization for a preexisting condition, provided that all of the following criteria 
are met: 
– 
The hospitalization was planned prior to the study or was scheduled during the 
study for cosmetic or reconstructive surgery or 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 
Reporting Requirements for Cases of Accidental Overdose or 
Medication Error 
Accidental overdose and medication error (hereafter collectively referred to as 
“special situations”), are defined as follows: 
• 
Accidental overdose:  accidental administration of a drug in a quantity that is higher 
than the assigned dose 
• 
Medication error:  accidental deviation in the administration of a drug 
• 
In some cases, a medication error may be intercepted prior to administration of the 
drug. 
 
Special situations are not in themselves adverse events but may result in 
adverse events.  Each adverse event associated with a special situation should be 
recorded separately on the Adverse Event eCRF, see Section 4.5.2.  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; Section 4.5.2).  For atezolizumab, paclitaxel, 
doxorubicin, epirubicin, and cyclophosphamide, 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. 


 
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• 
Medication error that qualifies as an overdose:  Enter the adverse event term.  
Check the “Accidental overdose” and “Medication error” boxes. 
 
In addition, all special situations associated with atezolizumab, paclitaxel, doxorubicin, 
epirubicin, and cyclophosphamide, regardless of whether they result in an 
adverse event, should be recorded on the Adverse Event eCRF as described below: 
• 
Accidental overdose:  Enter the drug name and “accidental overdose” as the 
event term.  Check the ″Accidental overdose″ and ″Medication error″ boxes. 
• 
Medication error that does not qualify as an overdose:  Enter the name of the 
drug administered and a description of the error (e.g., wrong dose administered, 
wrong dosing schedule, incorrect route of administration, wrong drug, expired 
drug administered) as the event term.  Check the ″Medication error″ box. 
• 
Medication error that qualifies as an overdose:  Enter the drug name and 
″accidental overdose″ as the event term.  Check the ″Accidental overdose″ and 
″Medication error″ boxes.  Enter a description of the error in the additional 
case details. 
• 
Intercepted medication error:  Enter the drug name and ″intercepted medication 
error″ as the event term.  Check the ″Medication error″ box.  Enter a description of 
the error in the additional case details. 
 
As an example, an accidental overdose that resulted in a headache would require two 
entries on the Adverse Event eCRF, one entry to report the accidental overdose and one 
entry to report the headache.  The "Accidental overdose" and ″Medication error″ boxes 
would need to be checked for both entries. 
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.  Sites are not expected to review 
the PRO data for adverse events. 
5.4 
IMMEDIATE REPORTING REQUIREMENTS FROM 
INVESTIGATOR TO SPONSOR 
Certain events require immediate reporting to allow the Sponsor to take appropriate 
measures to address potential new risks in a clinical trial.  The investigator must report 
such events to the Sponsor immediately; under no circumstances should reporting take 
place more than 24 hours after the investigator learns of the event.  The following is a list 
of events that the investigator must report to the Sponsor within 24 hours after learning 
of the event, regardless of relationship to study treatment: 
• 
Serious adverse events (defined in Section 5.2.2, see Section 5.4.2 for details on 
reporting requirements) 
• 
Adverse events of special interest (defined in Section 5.2.3, see Section 5.4.2 for 
details on reporting requirements) 
• 
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The investigator must report new significant follow-up information for these events to the 
Sponsor immediately (i.e., no more than 24 hours after becoming aware of the 
information).  New significant information includes the following: 
• 
New signs or symptoms or a change in the diagnosis 
• 
Significant new diagnostic test results 
• 
Change in causality based on new information 
• 
Change in the event’s outcome, including recovery 
• 
Additional narrative information on the clinical course of the event 
 
Investigators must also comply with local requirements for reporting 
serious adverse events to the local health authority and IRB/Ethics Committee. 
5.4.1 
Emergency Medical Contacts 
Roche/Medical Monitor Contact Information 
 
Medical Monitor: 
 M.D., PhD 
Mobile Telephone No.: 
 
Medical Monitor: 
 M.D. 
Telephone No.: 
Mobile Telephone No.: 
 
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/Adverse Event of Special Interest 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 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 
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/Adverse 
Event of Special Interest 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 ICF to 
immediately inform the investigator if they become pregnant during the treatment period 
or within 5 months after the last dose of atezolizumab, or 6 months after the last dose of 
paclitaxel or doxorubicin/epirubicin, 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 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 
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 ICF to immediately inform the investigator 
if their partner becomes pregnant during the treatment period or within 6 months after 
the last dose of paclitaxel or doxorubicin/epirubicin, or 12 months after the last dose of 


 
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cyclophosphamide, whichever is later.  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 treating physician and/or 
obstetrician. 
5.4.3.3 
Abortions 
A spontaneous abortion of a pregnancy for which the onset date falls in the 
reporting requirements mentioned in Section 5.4.3.1 should be classified as a 
serious adverse event (as the Sponsor considers abortions to be medically significant), 
recorded on the Adverse Event eCRF, and reported to the Sponsor immediately 
(i.e., no more than 24 hours after learning of the event; see Section 5.4.2). 
If a therapeutic or elective abortion was performed because of an underlying maternal or 
embryofetal toxicity, the toxicity should be classified as a serious adverse event, 
recorded on the Adverse Event eCRF, and reported to the Sponsor immediately 
(i.e., no more than 24 hours after learning of the event; see Section 5.4.2).  A therapeutic 
or elective abortion performed for reasons other than an underlying maternal or 
embryofetal toxicity is not considered an adverse event. 
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 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, or the patient is dead.  Every effort 


 
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should be made to follow all serious adverse events considered to be related to 
study treatment or trial-related procedures until a final outcome can be reported. 
During the study treatment period and up to treatment discontinuation visit, resolution of 
adverse events (with dates) should be documented on the Adverse Event eCRF and in 
the patient’s medical record to facilitate source data verification. 
All pregnancies reported during the study should be followed until pregnancy outcome. 
5.5.2 
Sponsor Follow-Up 
For serious adverse events, adverse events of special interest, and pregnancies, the 
Sponsor or a designee may follow-up by telephone, fax, email, and/or a monitoring visit 
to obtain additional case details and outcome information (e.g., from hospital discharge 
summaries, consultant reports, autopsy reports) in order to perform an independent 
medical assessment of the reported case. 
5.6 
ADVERSE EVENTS THAT OCCUR AFTER THE ADVERSE 
EVENT REPORTING PERIOD 
After the end of the reporting period for all serious adverse events and adverse events of 
special interest (defined as 90 days after the last dose of study treatment or until 
initiation of new systemic anti-cancer therapy, whichever occurs first), all deaths, 
regardless of cause, should be reported through use of the Long-Term Survival 
Follow-Up eCRF. 
In addition, if the investigator becomes aware of a serious adverse event that is believed 
to be related to prior exposure to study treatment, the event should be reported through 
use of the Adverse Event eCRF.  However, if the EDC system is not available, the 
investigator should report these events directly to the Sponsor or its designee, either by 
faxing or by scanning and emailing the Serious Adverse Event/Adverse Event of Special 
Interest Reporting Form using the fax number or email address provided to investigators.  
Once the EDC system is available, all information will need to be entered and submitted 
via the EDC system. 
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, Ethics Committees, 
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 


 
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• 
EU- Summary of Product Characteristics for paclitaxel, doxorubicin/epirubicin, and 
cyclophosphamide 
 
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.  Patients will be assigned to the treatment group to which they 
were randomized. 
The PD-L1-selected subpopulation is defined as patients in the ITT population whose 
PD-L1 status is IC1/2/3 at the time of randomization. 
The PRO-evaluable population is defined as patients in the ITT population with a 
baseline PRO assessment and a ≥ 1 post-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 group. 
6.1 
DETERMINATION OF SAMPLE SIZE 
The final analysis of the primary endpoint of iDFS will take place when approximately 
390 iDFS events (approximately 17% of the planned enrollment of 2300 patients 
experiencing an iDFS event; see Section 6.4.1) have occurred in the ITT population.  
This sample size is computed on the basis of the following assumptions: 
• 
Primary statistical test:  two-sided, stratified log-rank test at the 0.05 significance 
level in the ITT population 
• 
Approximately 80% power for iDFS 
• 
A hazard ratio (HR) of 0.75 
• 
Annual hazard rates of 0.047, 0.108, 0.035, 0.038, 0.029, and 0.014 in Years 1, 2, 
3, 4, 5−6, and 7 and thereafter are assumed for the T-AC/EC arm based on the 
adjuvant TNBC trials ECOG E1199 (Sparano et al. 2015), 
BEATRICE (Cameron et al. 2013), and IBCSG 22-00 (Colleoni et al. 2016) 


 
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• 
Based on the piecewise hazard rates given above for the control arm, and the 
assumed HR of 0.75 (thus reducing the risk of an iDFS event by 25% at each 
piecewise interval), the 3-year iDFS rate (probability of not having any iDFS event in 
the first 3 years) will be 82.7% in the T-AC/EC arm and 86.7% in the 
atezolizumab + T-AC/EC arm 
• 
2.5% annual loss to follow-up for iDFS 
• 
Interim analyses for iDFS in the ITT population, see Section 6.9.1 
 
Accrual is projected to occur over approximately 51 months.  The required number of 
iDFS events for the final analysis in the ITT population is projected to occur 77 months 
after first patient in.  Also, on the basis of these assumptions, an observed HR of 0.81 or 
better will result in a statistically significant difference between the treatment arms (i.e., 
HR = 0.81 will be the minimally detectable difference for the analysis; this corresponds to 
an improvement in 3-year iDFS from 82.7% in the T-AC/EC arm to 85.7% in the 
atezolizumab + T-AC/EC arm). 
The study duration for the secondary endpoint, OS, was determined on the basis of the 
number of events required to demonstrate efficacy with regard to OS.  A total of 
approximately 299 deaths are required to achieve 80% power at a two-sided alpha level 
of 5% to detect an HR of 0.72, corresponding to an improvement in 5-year OS rate from 
84% in the T-AC/EC arm to 88.2% in the atezolizumab + T-AC/EC arm assuming a 
constant hazard.  An annual loss to follow-up of 2.5% and three interim analyses of OS 
are assumed.  The final analysis of OS is planned to take place approximately 7 years 
after the first patient has been randomized. 
6.2 
SUMMARIES OF CONDUCT OF STUDY 
Enrollment, major protocol violations including major deviations of inclusion/exclusion 
criteria, and discontinuation from the study will be summarized by treatment arm for all 
randomized patients.  The reasons for study discontinuation will be tabulated. 
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 all 
randomized patients.  Continuous variables will be summarized with use of means, 
standard deviations, medians, ranges, and inter-quartile ranges.  Categorical variables 
will be summarized by proportions. 
The baseline value of any variable will be defined as the last available value prior to the 
first administration of study treatment. 
6.4 
EFFICACY ANALYSES 
The primary and secondary efficacy endpoints are described in Table 1 and Table 3.  
The primary and secondary efficacy analyses will include all randomized patients 


 
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(except for iDFS in the subpopulation with PD-L1-selected tumor status [IC1/2/3] and for 
iDFS in the subpopulation with node-positive disease), with patients grouped according 
to their assigned treatment. 
6.4.1 
Primary Efficacy Endpoint:  Invasive Disease-Free Survival 
The primary efficacy variable is iDFS, defined as the time between randomization and 
date of first occurrence of an iDFS event as described in Table 1 and Table 3.  
Data from patients who have not had an event at the time of data 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 of the respective analysis. 
Patients with no postbaseline information will be censored on the date of randomization. 
The log-rank test, stratified by the protocol-defined stratification factors, will be used to 
compare iDFS between the two treatment arms.  The HR for iDFS will be estimated with 
use of a stratified Cox proportional hazards model.  The Kaplan-Meier approach will be 
used to estimate 3-year iDFS rates, and corresponding 95% CIs for each treatment arm 
will be used to describe iDFS in addition to the HR. 
6.4.2 
Secondary Efficacy Endpoints 
To adjust for multiple statistical testing of the key secondary efficacy endpoints, thereby 
controlling the overall type I error rate at a two-sided significance level of 5%, the 
fixed-sequence testing procedure will be used.  These endpoints will be tested at a 
two-sided significance level of 0.05 in the following order: 
• 
iDFS in the subpopulation with PD-L1-selected tumor status (IC1/2/3) 
• 
iDFS in the subpopulation with node-positive disease 
• 
OS 
• 
iDFS, including second primary non-breast invasive cancer (except for 
non-melanoma skin cancers and in situ carcinoma of any site) as an iDFS event 
• 
Recurrence-free interval (RFI) 
• 
Distant recurrence-free interval (DRFI) 
• 
DFS 
 
The testing hierarchy will place the primary endpoint, iDFS in the ITT population, at the 
top of the hierarchy (i.e., no alpha-splitting between iDFS and any other endpoint[s]). 
Secondary endpoints not included in the fixed sequence testing procedure including 
PROs of function (role, physical) and HRQoL are also described in Section 6.4.2.8. 


 
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6.4.2.1 
iDFS in the Subpopulation with PD-L1-Selected Tumor Status 
(IC1/2/3) 
iDFS is defined in an analogous manner to the primary endpoint and will be analyzed 
with the same methodology in the subpopulation of patients with PD-L1-selected 
tumor status (IC1/2/3).  The stratification factors are axillary nodal status 
(0 vs. 1−3 vs. ≥ 4 positive lymph nodes) and surgery (breast conserving vs. 
mastectomy). 
6.4.2.2 
iDFS in the Subpopulation with Node-Positive Disease 
iDFS is defined in an analogous manner to the primary endpoint and will be analyzed 
with the same methodology in the subpopulation of patients with node-positive disease. 
6.4.2.3 
Overall Survival 
OS is defined as the time from randomization to the date of death due to any cause.  
Patients who are not reported as having died at the time of the clinical data cutoff date 
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.  
The OS will be analyzed with the use of the same methodology as specified for iDFS. 
6.4.2.4 
iDFS, including Second Primary Non-Breast Cancer 
iDFS is defined in an analogous manner to the primary endpoint with the addition of 
second primary non-breast invasive cancer as an event (with the exception of 
non-melanoma skin cancers and in situ carcinoma of any site) and will be analyzed with 
the same methodology. 
6.4.2.5 
Recurrence-Free Interval 
RFI is defined as the time from randomization to the first occurrence of any recurrence 
(local, regional [including invasive ipsilateral tumor and invasive locoregional tumor], 
or distant), as determined by investigators. 
Patients without an event at the time of clinical cutoff for the analysis will be censored at 
the last date the patient was known to be alive and event free.  Patients without an event 
who died will be censored at the date of death.  Patients with no postbaseline 
information will be censored on the date of randomization.  The RFI will be analyzed with 
the same methodology as specified for iDFS. 
6.4.2.6 
Distant Recurrence-Free Interval 
DRFI is defined as the time from randomization to distant breast cancer recurrence.  
The censored data will be handled in the same way as RFI.  DRFI will be analyzed with 
the same method as iDFS. 
6.4.2.7 
Disease-Free Survival 
Disease-free survival is defined as the time from randomization to the first occurrence of 
disease recurrence or death from any cause. 


 
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Events defining DFS: 
• 
Ipsilateral invasive breast tumor recurrence (i.e., an invasive breast cancer involving 
the same breast parenchyma as the original primary lesion) 
• 
Ipsilateral local-regional invasive breast cancer recurrence (i.e., an invasive 
breast cancer in the axilla, regional lymph nodes, chest wall, and/or skin of the 
ipsilateral breast) 
• 
Distant recurrence (i.e., evidence of breast cancer in any anatomic siteother than 
the two above mentioned sitesthat has either been histologically confirmed or 
clinically diagnosed as recurrent invasive breast cancer) 
• 
Contralateral invasive breast cancer 
• 
Ipsilateral or contralateral DCIS 
• 
Second primary non-breast invasive cancer (with the exception of 
non-melanoma skin cancers and in situ carcinoma of any site) 
• 
Death attributable to any cause including breast cancer, non-breast cancer, or 
unknown cause (but cause of death should be specified if at all possible) 
 
Disease-free survival will be analyzed with the use of the same methodology as 
specified for iDFS and will follow similar censoring rules. 
6.4.2.8 
Patient-Reported Outcomes of Role and Physical Function and 
GHS/HRQoL 
The primary PRO 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 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 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).  The 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, are specified in the 
Statistical Analysis Plan (SAP). 
Missing data will be assessed and reported by cycle.  In the event of incomplete data, for 
all questionnaire subscales, if more than 50% of the constituent items are completed, a 
pro-rated score will be computed consistent with the scoring manuals and validation 
papers.  For subscales with less than 50% of the items completed, the subscale will be 
considered as missing. 


 
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6.4.3 
Exploratory Efficacy Endpoints 
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 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 (see Appendix 3) at each assessment timepoint for each 
arm. 
6.4.3.2 
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 4).  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 5) 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 
The safety analyses will include all randomized patients who received at least one dose 
of study drug, with patients grouped according to treatment received. 
Safety will be assessed through summaries of adverse events, changes in 
laboratory test results, changes in LVEF, changes in vital signs, and study treatment 
exposures and will be presented by treatment arm. 
Verbatim descriptions of adverse events will be summarized by mapped term, 
appropriate thesaurus level, and toxicity grade.  For each patient, if multiple incidences 
of the same adverse events occur, the maximum severity reported will be used in the 
summaries. 
The following treatment-emergent adverse events will be summarized separately:  
adverse events leading to withdrawal of study drug, adverse events leading to 
dose reduction or interruption, Grade ≥ 3 adverse events, adverse events leading to 
death, serious adverse events, and adverse events of special interest, see Section 5.2.3. 
All deaths and causes of death will be summarized. 
Relevant laboratory values will be summarized by time, with NCI CTCAE (v5.0) Grade 3 
and Grade 4 values identified, where appropriate.  Changes in NCI CTCAE grade will be 
tabulated by treatment arm. 


 
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6.6 
PHARMACOKINETIC ANALYSES 
Samples will be collected for PK analysis of atezolizumab serum concentrations in all 
patients in the atezolizumab-containing arm.  Serum concentrations of atezolizumab will 
be reported as individual values and descriptive statistics will be summarized by 
treatment arm.  Serum concentrations of atezolizumab over time will be plotted as 
individual and as mean concentrations by treatment arm. 
The effect of positive ADA on the serum concentrations of atezolizumab may be 
explored. 
6.7 
IMMUNOGENICITY ANALYSES 
The immunogenicity analyses will include all patients enrolled, 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 (postbaseline incidence) will be 
summarized by treatment group.  When determining postbaseline incidence, patients are 
considered to be ADA positive if they are ADA negative or have 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 
postbaseline 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 have missing data at baseline and all postbaseline 
samples are negative, or if they are ADA positive at baseline but do not have any 
postbaseline 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 
The primary endpoint (iDFS) will be assessed in the PD-L1 IC1/2/3 population as a 
secondary endpoint. 
Exploratory biomarker analyses will be performed in baseline pretreatment, 
on-treatment, follow-up and 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, 
stromal TILs, and other biomarkers in tumor and blood, as defined by IHC, 
quantitative reverse transcription PCR, NGS, or other methods. 


 
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6.9 
INTERIM ANALYSES 
6.9.1 
Invasive Disease-Free Survival (Specified) 
In a response to a Health Authority request, a formal interim analysis will be conducted 
in mid-March 2023 to determine the ability of the study to provide an acceptable 
benefit-risk assessment upon trial conclusion.  This interim analysis will include both 
assessment of efficacy and futility for iDFS based on the available efficacy 
(approximately 62% of the total iDFS events) and safety data.  To control the Type I 
error in multiple efficacy analyses of iDFS, the interim and final efficacy analyses 
boundaries for statistical significance will be determined based on the Lan-DeMets 
α-spending function with an O’Brien-Fleming boundary.  For the first interim 
analysis, statistical significance will be declared if the p-value from the two-sided 
stratified log-rank test is ≤ 0.0088 (observed HR ≤ 0.71); a non-binding futility 
boundary is set at the iDFS hazard ratio of 1, thus futility can be declared if the 
observed iDFS HR at the first interim analysis is greater than 1. 
The second interim efficacy analysis of iDFS will be performed when approximately 80% 
of the total planned number of iDFS events have occurred.  On the basis of the 
assumption presented in Section 6.1, it is projected that 80% (312) iDFS events will 
have been observed approximately 59 months after the first patient is randomized. 
For the second interim efficacy analysis of iDFS, statistical significance will be 
determined based on the Lan-DeMets α-spending function with an O’Brien-Fleming 
boundary.  Statistical significance will be declared if the p-value from the two-sided 
stratified log-rank test is ≤ 0. 0218 (observed HR ≤ 0.77) depending on the actually 
observed number of events.  If the null hypothesis for iDFS is not rejected at the interim 
analyses and the study continues, the final analysis of iDFS will be performed when 
approximately 390 iDFS events have occurred; statistical significance will be declared if 
the p-value from the two-sided stratified log-rank test is p ≤ 0.0422 (observed HR 
≤ 0.81). 
6.9.2 
Invasive Disease-Free Survival (Optional) 
To adapt to information that may emerge during the course of this study, in order to 
ensure patient benefit, the Sponsor may choose to conduct one additional 
interim efficacy analysis after at least 80% of the total planned number of iDFS events 
have occurred for the primary endpoint of iDFS.  This will only be conducted after 
endorsement by the SC.  Below are the specifications in place to ensure the study 
continues to meet the highest standards of integrity when an optional interim analysis is 
executed. 
The interim analysis/analyses will be conducted by an external statistical group and 
reviewed by the IDMC.  The Sponsor will remain blinded to the results.  Interactions 
between the IDMC and Sponsor will be carried out as specified in the IDMC Charter. 


 
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The decision to conduct an additional interim analysis, along with the rationale, timing, 
and statistical details for the analysis, will be documented in the SAP, and the SAP will 
be submitted to relevant health authorities at least 2 months prior to the conduct of the 
interim analysis.  The IDMC Charter will document potential recommendations the 
IDMC can make to the SC of the study as a result of the analysis (e.g., stop the study for 
positive efficacy, stop the study for futility), and the IDMC Charter will also be made 
available to relevant health authorities. 
If there is a potential for the study to be stopped for positive efficacy as a result of the 
interim analysis, the type I error rate will be controlled to ensure statistical validity is 
maintained.  Specifically, the Lan-DeMets alpha-spending function that approximates the 
O’Brien-Fleming boundary will be applied to determine the critical value for stopping for 
positive efficacy at the interim analysis (DeMets and Lan 1994).  If the study continues 
beyond the interim analysis, the critical value at the final analysis would be adjusted 
accordingly to maintain the protocol-specified overall type I error rate, per standard 
Lan-DeMets methodology. 
If there is a potential for the study to be stopped for futility as a result of the 
interim analysis, the threshold for declaring futility will include an assessment of the 
predictive probability that the specified endpoint will achieve statistical significance. 
6.10 
SUBGROUP ANALYSES 
Besides the subgroup analyses of iDFS mentioned in Section 6.4.2 and implicated 
subgroup analyses mentioned in Section 6.8, to assess the consistency of 
treatment benefit study results in subgroups defined by demographic and relevant 
baseline characteristics (including geographical region), iDFS and OS in these 
subgroups will be evaluated. 
7. 
DATA COLLECTION AND MANAGEMENT 
7.1 
DATA QUALITY ASSURANCE 
Institut Jules Bordet/Clinical Trials Support Unit (IJB/CTSU), an academic 
research center affiliated with BIG will be responsible for all data management activities 
of this study.  This will include set-up and build of the EDC system, quality checking of 
the database throughout study conduct, and study closeout.  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, IJB/CTSU will issue queries to the 
sites, which the sites will resolve electronically in the EDC system in a timely manner. 
IJB/CTSU will produce a Data Management Plan that describes the quality checking to 
be performed on the data.  The EDC data and non-CRF data will be transferred from 
Frontier Science in SDTMv format to Roche on an agreed frequency using applicable 
procedures to handle and process the electronic transfer of these data. 


 
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The Sponsor will perform oversight of the data management of this study, including 
approval of IJB/CTSU’s data management plans and specifications.  Data as agreed by 
the Sponsor and IJB/CTSU will be periodically transferred electronically from the 
IJB/CTSU to the Sponsor, and the applicable procedures will be used to handle and 
process the electronic transfer of these data. 
The eCRFs and correction documentation will be maintained in the EDC system’s 
audit trail.  System backups for data stored at the IJB/CTSU and records retention for 
the study data will be consistent with the IJB/CTSU standard procedures. 
The 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 
The eCRFs are to be completed through use of IJB/CTSU’s Rave EDC system.  
Sites will receive training and have access to a manual for appropriate eCRF 
completion.  The 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.  The 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 as 
Subject PDF reports from the study database, which will be shared via a Secure File 
Transfer Protocol (SFTP) with the site and must be kept with the study records.  
Acknowledgement of receipt, download and access to the reports 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.  
The investigator/institution should maintain adequate and accurate source documents, 
which should be attributable, legible, contemporaneous, original, accurate, and 
complete, as referenced in ICH E6 (R2) in Section 8.1. 
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. 


 
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Before study initiation, the types of source documents that are to be generated will be 
clearly defined in the Trial Monitoring Plan.  This includes any protocol data to be 
entered directly into the eCRFs (i.e., no prior written or electronic record of the data) and 
considered source data. 
Source documents that are required to verify the validity and completeness of data 
entered into the eCRFs must not be obliterated or destroyed and must be retained per 
the policy for retention of records described in Section 7.5. 
To facilitate source data verification and review, the investigators and institutions must 
provide the Sponsor/Sponsor Representative/contract research organization (CRO) 
direct access to applicable source documents and reports for trial-related monitoring, 
Sponsor/Sponsor Representative/CRO audits, and IRB/Ethics Committee review.  
The study site must also allow inspection by applicable health authorities. 
7.4 
USE OF COMPUTERIZED SYSTEMS 
When clinical observations are entered directly into a study site’s computerized 
medical record system (i.e., in lieu of original hardcopy records), the electronic record 
can serve as the source document if the system has been validated in accordance with 
health authority requirements pertaining to computerized systems used in clinical 
research.  An acceptable computerized data collection system allows preservation of the 
original entry of data.  If original data are modified, the system should maintain a 
viewable audit trail that shows the original data as well as the reason for the change, 
name of the person making the change, and date of the change. 
7.5 
RETENTION OF RECORDS 
Records and documents pertaining to the conduct of this study and the distribution of 
IMP, including eCRFs, paper PRO data, ICFs, 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.  For patients from China, all 
samples and data will be handled in accordance with the HGRAC requirement and the 
pertinent HGRAC approval letter for this study.  The storage system used during the trial 
and for archiving (irrespective of the type of media used) should provide for document 
identification, version history, search, and retrieval.  After that period of time, the 
documents may be destroyed, subject to local regulations. 
No records may be disposed of without the written approval of the Sponsor.  
Written notification should be provided to the Sponsor prior to transferring any records to 
another party or moving them to another location. 
The Sponsor will retain study data for 25 years after the final Clinical Study Report has 
been completed or for the length of time required by relevant national or 
local health authorities, whichever is longer. 


 
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8. 
ETHICAL CONSIDERATIONS 
8.1 
COMPLIANCE WITH LAWS AND REGULATIONS 
This study will be conducted in full conformance with the ICH E6 (R2) guideline for 
GCP and the principles of the Declaration of Helsinki, or the applicable laws and 
regulations of the country in which the research is conducted, whichever affords the 
greater protection to the individual.  The study will comply with the requirements of the 
ICH E2A guideline (Clinical Safety Data Management:  Definitions and Standards for 
Expedited Reporting).  Studies conducted in the United States or under a 
U.S. Investigational New Drug (IND) Application will comply with U.S. Food and 
Drug Administration regulations and applicable local, state, and federal laws.  
Studies conducted in the European Union or European Economic Area will comply with 
the E.U. Clinical Trial Directive (2001/20/EC) and applicable local, regional, and 
national laws. 
8.2 
INFORMED CONSENT 
A study-dedicated ICF (and ancillary sample ICF 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 ICF, or any alternate consent forms proposed by the site (collectively, 
the ″Consent Forms″) before IRB/Ethics Committee submission.  The final 
IRB/Ethics Committee-approved Consent Forms must be provided to the Sponsor or 
designee for health authority submission purposes according to local requirements. 
If applicable, the ICF 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 ICFs 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 ICFs 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/Ethics Committee-approved ICFs must be provided to 
the Sponsor or designee for health authority submission purposes. 


 
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Patients must be re-consented to the most current version of the ICF (or to a significant 
new information/findings addendum in accordance with applicable laws and 
IRB/Ethics Committee policy) during their participation in the study.  For any updated or 
revised ICFs, 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 ICFs for continued participation in the study. 
A copy of each signed ICF must be provided to the patient or the patient’s legally 
authorized representative.  All signed and dated ICF 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 ICF may also include patient authorization to allow 
use and disclosure of personal health information in compliance with the 
U.S. Health Insurance Portability and Accountability Act (HIPAA) of 1996.  If the site 
utilizes a separate Authorization Form for patient authorization for use and disclosure of 
personal health information under the HIPAA regulations, the review, approval, 
and other processes outlined above apply except that IRB review and approval may not 
be required per study site policies. 
8.3 
INSTITUTIONAL REVIEW BOARD OR ETHICS COMMITTEE 
This protocol, the ICFs, any information to be given to the patient, and relevant 
supporting information must be submitted to the IRB/Ethics Committee by the 
Principal Investigator and reviewed and approved by the IRB/Ethics Committee before 
the study is initiated.  In addition, any patient recruitment materials must be approved by 
the IRB/Ethics Committee. 
The Principal Investigator is responsible for providing written summaries of the status of 
the study to the IRB/Ethics Committee annually or more frequently in accordance with 
the requirements, policies, and procedures established by the IRB/Ethics Committee.  
Investigators are also responsible for promptly informing the IRB/Ethics Committee of 
any protocol amendments (see Section 9.6). 
In addition to the requirements for reporting all adverse events to the Sponsor, 
investigators must comply with requirements for reporting serious adverse events to the 
local health authority and IRB/Ethics Committee.  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/Ethics Committee, and archived in the site’s study file. 
8.4 
CONFIDENTIALITY 
Information technology systems used to collect, process, and store study-related data 
are secured by technical and organizational security measures designed to protect such 


 
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data against accidental or unlawful loss, alteration, or unauthorized disclosure or 
access.  In the event of a data security breach, appropriate mitigation measures will be 
implemented. 
The Sponsor and designees maintain 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 ICF (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 ALEXANDRA/IMpassion030 
Publication and Presentation Policy (see Section 9.5). 
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/Ethics Committee for each study site, 
as appropriate. 
8.5 
FINANCIAL DISCLOSURE 
Investigators will provide the Sponsor or designee with sufficient, accurate financial 
information in accordance with local regulations to allow the Sponsor or designee 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., last patient, last visit). 
9. 
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION 
9.1 
STUDY DOCUMENTATION 
The investigator must maintain adequate and accurate records to enable the conduct of 
the study to be fully documented, including, but not limited to, the protocol, 
protocol amendments, ICF, and documentation of IRB/Ethics Committee and 
governmental approval.  In addition, at the end of the study, the investigator will receive 


 
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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 according to 
defined study procedures.  The investigator should promptly report any deviations that 
might have an impact on patient safety and data integrity to the Sponsor or designee 
and to the IRB/Ethics Committee in accordance with established IRB/Ethics Committee 
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 
QUALITY CONTROL AND QUALITY ASSURANCE 
Site visits and quality assurance audits 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/Ethics Committees to inspect 
facilities and records relevant to this study. 
The purpose of a Sponsor audit or Health Authority inspection is to systematically and 
independently examine all study-related activities and documents to determine whether 
these activities were conducted, and data were recorded, analyzed, and accurately 
reported according to the protocol, ICH GCP, and any applicable regulatory 
requirements.  The investigator should contact the Sponsor or designee immediately if 
contacted by a Health Authority about an upcoming inspection. 
9.4 
ADMINISTRATIVE STRUCTURE 
This study will be sponsored by F. Hoffmann-La Roche Ltd and conducted in 
collaboration with BIG, AFT, IJB/CTSU and Frontier Science Foundation.  Approximately 
370−450 sites globally will participate in the study and up to 2300 patients will be 
randomized.  It is estimated that the study will enroll patients over approximately 4 years.  
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 3.1.1). 


 
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9.5 
PUBLICATION OF DATA AND PROTECTION OF TRADE 
SECRETS 
Regardless of the outcome of a trial, the SC, the Academic partners, and the Sponsor 
are 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 SC, the Academic partners, and the Sponsor will comply with all 
requirements for publication of study results.  A trial-specific publication and presentation 
Policy, namely ALEXANDRA/IMpassion030 Publication and Presentation Policy, 
developed by the Academic partners and the Sponsor, will be adhered to. 
The results of this study will 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 SC, the Academic partners, and the 
Sponsor aim 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 SC, the Academic partners, and the 
Sponsor aim to publish results from analyses of additional endpoints and exploratory 
data that are clinically meaningful and statistically sound. 
All manuscripts and/or abstracts must be provided to BIG headquarters in order to 
submit to the SC and the Sponsor, for review and comment prior to submission for 
publication or presentation.  The SC approval must be granted prior to any publication. 
After the publication of the results of the primary and secondary objectives, 
(or 12 months after the completion of the study as defined in the protocol), 
BIG Groups/individual institutions may be allowed to publish/present the data and results 
from their site(s), provided the following conditions are met: 
• 
The proposed Publication or Presentation is in line with the principles outlined in the 
ALEXANDRA/IMpassion030 Publication and Presentation Policy and first submitted 
to the SC for review and comment. 
• 
Prior to submission of a proposed publication or presentation, Roche, as Sponsor of 
the Study, shall have the right to review and comment on the content of the material 
to be published or presented.  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. 
• 
The publication or presentation cannot be made in the name of the study but should 
acknowledge the study as the source of the data used for the publication or 
presentation, the Academic partners and the Sponsor. 
 
Guidance on the authorship, which must be in line with International Committee of 
Medical Journal Editors authorship requirements, will be provided in the 
ALEXANDRA/IMpassion030 publication and Presentation Policy.  Any formal publication 


 
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or presentation of the study in which contribution of the Academic partners or 
Sponsor personnel exceeded that of conventional monitoring will be considered as a 
joint publication by the investigator and the appropriate Academic partners or 
Sponsor personnel. 
9.6 
PROTOCOL AMENDMENTS 
Any protocol amendments will be prepared by the Sponsor and approved by the SC.  
Protocol amendments will be submitted to the IRB/Ethics Committee and to regulatory 
authorities in accordance with local regulatory requirements. 
Approval must be obtained from the IRB/Ethics Committee 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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Therapy (FACIT) measurement system: validation of version 4 of the core 
questionnaire. Quality of Life Research 1999;8:604. 


 
AtezolizumabF. Hoffmann-La Roche Ltd 
130/Protocol BIG 16-05/AFT-27/WO39391, Version 9 
Wildiers H, Dirix L, Neven P et al. Delivery of adjuvant sequential dose-dense FECDoc 
to patients with breast cancer is feasible, but dose reductions and toxicity are 
dependent on treatment sequence. Breast Cancer Res Treat 2009;114:103−12. 
Wolff AC, Hammond MEH, Allison KH, et al. Human Epidermal Growth Factor Receptor 
2 Testing in Breast Cancer: American Society of Clinical Oncology/College of 
American Pathologists Clinical Practice Guideline Focused Update. J Clin Oncol 
2018;36:2105−22. 
Yang J, Riella LV, Chock S. The novel costimulatory programmed death ligand 1/B7.1 
pathway is functional in inhibiting alloimmune responses in vivo. J Immunol 
2011;187:1113−9. 
 






Appendix 1 
Schedule of Activities (cont.) 
 
AtezolizumabF. Hoffmann-La Roche Ltd 
133/Protocol BIG 16-05/AFT-27/WO39391, Version 9 
 
Screening a 
Treatment b 
Treatment 
Discontinuation c 
≤ 30 days after 
Last Dose 
(Arm A) or Last 
Monitoring Visit 
(Arm B) 
Follow−Up d 
Induction 
(28−day Cycles) 
(Cycles 1−5; 
Weeks 1−20) 
Arm A: Maintenance 
Arm B: Monitoring 
(21−day Cycles) 
(Cycles 6−16; 
Weeks 21−53) 
Days − 28 
to − 1 
Day 1 of each cycle 
(± 3 days) 
Arm A: Day 1 of each 
cycle (± 3 days);  
Arm B: Day 1 of every 
other cycle (± 7 days) 
Hematology p 
x 
On each infusion day 
Arm A: Day 1 of each 
cycle 
Arm B: Day 1 of every 
other cycle (starting 
with Cycle 6) 
x 
 
Chemistry q 
x  
On each infusion day 
Arm A: Day 1 of each 
cycle 
Arm B: Day 1 of every 
other cycle (starting 
with Cycle 6) 
x 
 
Menopausal status 
x 
 
 
x 
1 year after 
treatment 
discontinuation 
at closest visit 
Pregnancy test r 
x s 
x r 
x r 
x r 
x r 
Coagulation (INR, aPTT) 
x 
 
 
x 
 
TSH, free T3 (or total T3 t), free T4 
x 
x t 
x 
 
Viral serology u 
x 
 
 
 
 
 


Appendix 1 
Schedule of Activities (cont.) 
 
AtezolizumabF. Hoffmann-La Roche Ltd 
134/Protocol BIG 16-05/AFT-27/WO39391, Version 9 
 
Screening a 
Treatment b 
Treatment 
Discontinuation c 
≤ 30 days after 
Last Dose 
(Arm A) or Last 
Monitoring Visit 
(Arm B) 
Follow−Up d 
Induction 
(28−day Cycles) 
(Cycles 1−5; 
Weeks 1−20) 
Arm A: Maintenance 
Arm B: Monitoring 
(21−day Cycles) 
(Cycles 6−16; 
Weeks 21−53) 
Days − 28 
to − 1 
Day 1 of each cycle 
(± 3 days) 
Arm A: Day 1 of each 
cycle (± 3 days);  
Arm B: Day 1 of every 
other cycle (± 7 days) 
Urinalysis v 
x  
x w 
 
 
Serum autoantibody sample 
 
See Appendix 2 for detailed schedule. 
Serum PK sample for atezolizumab 
 
See Appendix 2 for detailed schedule (Arm A only). 
Serum ADA sample for atezolizumab 
 
See Appendix 2 for detailed schedule (Arm A only). 
Plasma samples for biomarkers 
 
See Appendix 2 for detailed schedule. 
Blood sample for RPBS (optional) x 
 
x 
 
 
 
Radiographic assessments (e.g., CT, MRI, PET) 
x y,z 
As clinically indicated 
Bilateral mammogram/breast MRI 
x y 
 
x aa 
 
x aa 
Tumor biopsy/tumor tissue at relapse, if clinically 
feasible 
 
At time of recurrence bb 
Concomitant medications ii 
x cc 
x 
Arm A: Day 1 of each 
cycle 
Arm B: Day 1 of every 
other cycle (starting 
with Cycle 6) 
x 
x dd 
  


Appendix 1 
Schedule of Activities (cont.) 
 
AtezolizumabF. Hoffmann-La Roche Ltd 
135/Protocol BIG 16-05/AFT-27/WO39391, Version 9 
 
Screening a 
Treatment b 
Treatment 
Discontinuation c 
≤ 30 days after 
Last Dose 
(Arm A) or Last 
Monitoring Visit 
(Arm B) 
Follow−Up d 
Induction 
(28−day Cycles) 
(Cycles 1−5; 
Weeks 1−20) 
Arm A: Maintenance 
Arm B: Monitoring 
(21−day Cycles) 
(Cycles 6−16; 
Weeks 21−53) 
Days − 28 
to − 1 
Day 1 of each cycle 
(± 3 days) 
Arm A: Day 1 of each 
cycle (± 3 days);  
Arm B: Day 1 of every 
other cycle (± 7 days) 
Adverse events ee 
x ee 
x ee 
Arm A: Day 1 of each 
cycle 
Arm B: Day 1 of every 
other cycle (starting 
with Cycle 6) 
x 
x ee 
Study treatment administration ff 
 
xff 
(± 1 day for weekly 
paclitaxel) 
x gg 
 
 
Survival follow-up and anti-cancer treatment 
 
 
 
 
x d,hh 
AC = dose-dense doxorubicin + cyclophosphamide; AC/EC = dose-dense doxorubicin/epirubicin + cyclophosphamide; ADA = anti-drug antibody; 
CT = computed tomography; EC = dose-dense epirubicin + cyclophosphamide; 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; FACT-G = Functional Assessment of Cancer Therapy−General; 
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; HR = hormone receptor; MRI = magnetic resonance imaging; MUGA = multiple-gated 
acquisition; PET = positron emission tomography; PK = pharmacokinetic; RPBS = Research Project Biological Samples; Q2W = every 2 weeks; 
T3 = triiodothyronine; T4 = thyroxine; TSH = thyroid-stimulating hormone. 
 


Appendix 1 
Schedule of Activities (cont.) 
 
AtezolizumabF. Hoffmann-La Roche Ltd 
136/Protocol BIG 16-05/AFT-27/WO39391, Version 9 
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). 
a Results of standard-of-care tests or examinations performed prior to obtaining informed consent and within 28 days prior to randomization may 
be used; such tests do not need to be repeated for screening. 
b  In the event of treatment delay, study visits should continue as scheduled, if feasible.  Patients (both in Arm A and on Arm B) who discontinue 
study treatment prematurely due to an adverse event should conduct a treatment discontinuation visit and move to the follow-up.  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, including during the follow-up period.  Additional tests can be performed, if needed, according to standard medical practice. 
c Patients will return to the clinic for a treatment discontinuation visit not more than 30 days after the last dose of study treatment (Arm A) or 
within 30 days after the last monitoring visit (Arm B). 
d The follow-up period begins from the date of treatment phase completion/early termination visit with a duration of up to 7 years from the date of 
randomization of the first patient.  Visit windows are ± 28 days for quarterly, semiannual, and annual 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, submission of tumor tissue sample to central laboratory can occur.  Tumor tissue, which can be 
obtained outside the 28-day screening period, 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 approximately 25 unstained slides 
(minimum of 20 slides) should be provided from the surgical resection specimen. Biomarker samples should not be collected for patients 
enrolling from China prior to the approval from Human Genetic Resources Administration of China. 
g Disease status based on all available clinical assessments should be documented from the date of randomization at the following timepoints 
(± 28 days):  every 3 months during study treatment and up to 3 years, every 6 months from 3 to 5 years, and annually thereafter unless a 
recurrence as defined in Section 4.6.6 has occurred.  In addition to physical examinations and mammograms, liver function tests, bone scans, 
chest X-rays/diagnostic CT, liver imaging, or other radiographic modality may be considered when clinically indicated to exclude metastatic 
disease and within a timeline as per current local standard of practice.  Disease recurrence must be confirmed pathologically if clinically 
feasible.  In cases of disease recurrence diagnosed at any time during the study, patients will be out of the study schedule and will be followed 
once a year (starting 1 year after first relapse) until end of study for survival, anti-cancer medications, and new relapse events. 
 


Appendix 1 
Schedule of Activities (cont.) 
 
AtezolizumabF. Hoffmann-La Roche Ltd 
137/Protocol BIG 16-05/AFT-27/WO39391, Version 9 
h 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, laboratory results 
or health record, before administration of study treatment, and/or prior to the performance of any other study assessments that could bias 
patients’ 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) (± 3 days); on Cycle 4, 
Day 1 (± 3 days); on Day 1 of every other cycle thereafter until Cycle 16 (Arm A [± 3 days], Arm B  [± 7days]); and at the end of 
treatment/monitoring visit.  In case the treatment is interrupted/delayed, the patient should repeat the PRO assessment at the next visit, 
corresponding to the treatment administration day. 
i Patients who discontinue the study treatment phase (eg., Arm A Maintenance and Arm B Monitoring) 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 follow-up period at the following timepoints: 
every 3 months (± 28 days) for the first year, every 6 months (± 28 days) for Years 2−3, and then annually (± 28 days) thereafter.  
j While on study treatment, all patients will complete the FACT-G, single item GP5 beginning on Cycle 4, Day 1 (± 3 days); at Day 1 of every 
other cycle thereafter until Cycle 16 (Arm A [± 3 days], Arm B  [± 7days]); and at the end of treatment/monitoring visit.  In case the treatment is 
interrupted/delayed, the patient should repeat the PRO assessment at the next visit, corresponding to the treatment administration day. 
k Includes respiratory rate, pulse rate, and systolic and diastolic blood pressure while the patient is in a seated position, and temperature.  
Record vital signs at baseline in the 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. 
l Includes evaluation of the head, eyes, ears, nose, and throat, and the cardiovascular, dermatological, musculoskeletal, respiratory, 
gastrointestinal, and neurological systems.  Special attention should be paid to cardiovascular symptoms (e.g., abnormally low or irregular 
pulse, chest pain, tachycardia, swollen legs).  Record abnormalities observed at baseline in the eCRF.  At subsequent visits, record new or 
worsened clinically significant abnormalities on the Adverse Event eCRF. 
m Perform a limited, symptom-directed examination at specified timepoints and as clinically indicated at other timepoints.  Special attention 
should be paid to cardiovascular symptoms (e.g., abnormally low or irregular pulse, chest pain, tachycardia, swollen legs).  Record new or 
worsened clinically significant abnormalities on the Adverse Event eCRF. 
n ECG recordings will be obtained during screening and as clinically indicated at other timepoints.  It is recommended that patients be resting in a 
supine position for at least 10 minutes or as per local practice prior to ECG recording. 
o Cardiac monitoring (ECHO/MUGA scans) will be performed in 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. 


Appendix 1 
Schedule of Activities (cont.) 
 
AtezolizumabF. Hoffmann-La Roche Ltd 
138/Protocol BIG 16-05/AFT-27/WO39391, Version 9 
For both Arms A and B, ECHO/MUGA scans should be obtained at baseline (i.e., screening ECHO/MUGA), between the second dose of 
AC/EC and the third dose of AC/EC (which should usually occur approximately between Week 16 and Week 18 if no treatment delays), and 
then every 3 months [i.e., at Week 26 (± 14 days), at Week 39 (± 14 days), and at Week 52 (± 14 days) if no treatment delays].  
ECHO/MUGA scans should be obtained at the early termination visit if not performed within the previous 6 weeks.  During the survival 
follow-up period, ECHO/MUGA scans should be obtained annually until the end of study. 
During the follow-up period, ECHO/MUGA scans should be obtained annually until the end of study (except for patients who experienced a 
recurrence of disease). 
p Hematology includes WBC count, RBC count, hemoglobin, hematocrit, platelet count, differential count (neutrophils, eosinophils, basophils, 
monocytes, lymphocytes, other cells). 
q Chemistry panel (serum or plasma) includes sodium, potassium, chloride, 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.  Lipase and amylase levels should be determined if clinically indicated by the presence of abdominal 
symptoms (e.g., abdominal pain, digestive disorders) suggestive of pancreatitis.  Bicarbonate/total CO2 should be determined if 
clinically indicated or considered standard of care. 
r 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 childbearing potential (including premenopausal women who have had tubal ligation) and women not 
meeting the definition of postmenopausal:  For Arm A at Day 1 of Cycles 1−16, at treatment discontinuation visit, and every 4 weeks until 
6 months after treatment discontinuation (last administered dose of study treatment) including for patients who experienced a disease 
recurrence.  For Arm B at Day 1 of Cycles 1−5, at treatment discontinuation visit, and every 4 weeks until 6 months after last administered dose 
of study treatment including for patients who experienced a disease recurrence.  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. 
s Screening pregnancy test results must be obtained within 14 days prior to initiation of study treatment. 
t 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.  Patients in Arm B can have thyroid function tests at Cycle 1, Cycle 4, and Cycle 8 and then continue being tested every fourth 
cycle. 
u 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 must also be performed to determine if the patient has an HBV infection.  If a patient 
has a positive HCV antibody test at screening, an HCV RNA test must also be performed to determine if the patient has an HCV infection. 
v Includes pH, specific gravity, glucose, protein, ketones, and blood; dipstick permitted. 


Appendix 1 
Schedule of Activities (cont.) 
 
AtezolizumabF. Hoffmann-La Roche Ltd 
139/Protocol BIG 16-05/AFT-27/WO39391, Version 9 
w Urinalysis should be performed as clinically indicated during study treatment. 
x Not applicable for a site that has not been granted approval for RPBS.  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 RPBS at 
Week 1, Day 1 (Cycle 1, Day 1).  If, however, the RPBS 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. 
y Within 6 months prior to randomization (except for patients who do not have any remaining breast tissue due to prior prophylactic 
breast surgery). 
z Per local standard practice 
aa Mammograms of any remaining tissue should be performed at least annually (± 3 months) from the date of the mammogram performed at 
screening/surgery and as clinically indicated based on findings from physical examinations. 
bb Patients are required to undergo tumor biopsy sample collection, if deemed clinically feasible by the investigator, at the time of first evidence of 
radiographic disease relapse.  Examples of when tumor biopsy sample collection may be considered not clinically feasible include, but are not 
limited to, cases where the location of the tumor renders tumor biopsy unsafe or not clinically feasible per the investigator due to patient 
concerns or is prohibited by the institution or country. Biomarker samples should not be collected for patients enrolling from China prior to the 
approval from Human Genetic Resources Administration of China.Biopsies should be performed within 40 days after recurrence.  An FFPE 
block or at least 20 unstained slides should be provided.  Fine-needle aspiration, brushing, cell pellets from pleural effusion, bone metastases, 
and lavage samples are not acceptable.  For core needle biopsy specimens, at least two cores should be submitted for evaluation.  See 
Section 4.6.7 for tissue sample requirements. 
cc Includes any medication (e.g., prescription drugs, over-the-counter drugs, vaccines, herbal or homeopathic remedies, nutritional supplements) 
used by a patient in addition to protocol-mandated study treatment from 7 days prior to initiation of study treatment until the treatment 
discontinuation visit.  Record all prior anti-cancer therapies. 
dd All new anti-cancer treatments are to be reported during the follow-up period. 
ee 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. 


Appendix 1 
Schedule of Activities (cont.) 
 
AtezolizumabF. Hoffmann-La Roche Ltd 
140/Protocol BIG 16-05/AFT-27/WO39391, Version 9 
ff 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.  Paclitaxel should be administered as an IV infusion QW (7 [± 1] days).  During 
the induction treatment phase, the interval between the end of the weekly paclitaxel (Cycle 3 Visit 4) and the initiation of AC or EC Q2W (Cycle 
4 Visit 1) should be 7 days (± 1 day), (i.e., Cycle 4 Visit 1 should be performed at maximum 8 days from Cycle 3 Visit 4, as shown in the study 
schema [see Figure 1 of the Protocol]). Cyclophosphamide and doxorubicin/epirubicin will be administered Q2W (14 [± 3] days).  The 14-
days interval only starts after Cycle 4 Visit 1 and the respective ± 3 days window allowed per protocol is only applicable from Cycle 4 Visit 2. 
gg Study drug administration during the maintenance phase for the atezolizumab-containing arm only  
hh 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 study is terminated).  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 (if allowed 
per country regulation). Every effort should be made to obtain information on patients who withdraw from the study treatment and/or 
assessments but have agreed to be contacted for further information (i.e., partial withdrawal).  Partial withdrawal from the study, with consent to 
allow collection of information regarding disease recurrence, survival status, and reportable toxicity should be documented in both the medical 
records and in the eCRF (i.e., the patient accepted to be contacted for collection of these data despite she/he withdrew consent from the study 
treatment and/or procedures). 
ii 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. 
 


 
AtezolizumabF. Hoffmann-La Roche Ltd 
141/Protocol BIG 16-05/AFT-27/WO39391, Version 9 
Appendix 2 Schedule of Pharmacokinetic, Immunogenicity, and 
Biomarker Samples 
Visit 
Time 
Sample 
Screening/Baseline 
NA 
• 
FFPE tumor tissue from surgical 
resection (block or 25 slides) c 
Day 1 of Week 1 (Cycle 1) 
Prior to the first dose 
• 
Atezolizumab PK (serum) a, b 
• 
Atezolizumab ADA (serum) a, b 
• 
Biomarker (plasma) c 
• 
Serum autoantibody sample 
• 
Optional RPBS (whole blood) 
30 min (± 10 min) following 
atezolizumab infusion 
• 
Atezolizumab PK (serum) a, b 
Day 1 of Week 21 (± 3 days)  
Pre-dose 
• 
Biomarkers (plasma) c 
Day 1 of Weeks 5, 9, 13, 21, 
33, and 45 (Cycles 2, 3, 4, 6, 
10, and 14) 
Pre-dose 
• 
Atezolizumab PK (serum) a, b 
• 
Atezolizumab ADA (serum) a, b 
Treatment discontinuation visit 
(≤ 30 days after last dose) 
NA 
• 
Atezolizumab PK (serum) a, b 
• 
Atezolizumab ADA (serum) a, b 
Day 1 of Week 52 (± 1 week) 
 
• 
Biomarkers (plasma) c 
18 months post initial treatment 
(± 28 days) 
NA 
• 
Biomarkers (plasma) c 
24 months post initial treatment 
(± 28 days) 
NA 
• 
Biomarkers (plasma) c 
36 months post initial treatment 
(± 28 days) 
NA 
• 
Biomarkers (plasma) c 
At disease recurrence 
NA 
• 
FFPE tumor tissue (block or 
20 slides) c 
• 
Biomarkers (plasma) c 
At time of possible 
immune-related toxicity 
NA 
• 
Serum autoantibody sample 
ADA = anti-drug antibody; FFPE = formalin-fixed, paraffin embedded; HGRAC = Human Genetic 
Resources Administration of China; NA = not applicable; PK = pharmacokinetic; RPBS = Research 
Project Biological Samples. 
Note: Unless otherwise described above, all other study visits and assessments in Appendix 2 
should be performed within ± 1 week of the scheduled date.  Study assessments may be delayed 
or moved ahead of the window to accommodate holidays, vacations, and unforeseen delays. 
a Atezolizumab PK and ADA samples are to be taken only in patients receiving atezolizumab 
(Arm A). 
b Patients enrolling from China are exempt from providing atezolizumab PK (serum) and 
atezolizumab ADA (serum) during the study. 
c Biomarker samples (blood, tissue) should not be collected for patients enrolling from China prior 
to the approval from HGRAC. Samples collected should match the number of slides or volume 
of samples allowed per HGRAC approval. 


 
AtezolizumabF. Hoffmann-La Roche Ltd 
142/Protocol BIG 16-05/AFT-27/WO39391, Version 9 
Appendix 3 European Organisation for Research and Treatment 
of Cancer Quality-of-Life Questionnaire Core 30 
Do not reproduce or distribute.  The Sponsor will provide sites with all instruments to 
be completed in this study. 
 
 
 


Appendix 3 
European Organisation for Research and Treatment of Cancer Quality-of-
Life Questionnaire Core 30 (cont.) 
AtezolizumabF. Hoffmann-La Roche Ltd 
143/Protocol BIG 16-05/AFT-27/WO39391, Version 9 
 


 
AtezolizumabF. Hoffmann-La Roche Ltd 
144/Protocol BIG 16-05/AFT-27/WO39391, Version 9 
Appendix 4 FACT-G Single-Item GP5 
Do not reproduce or distribute.  The Sponsor will provide sites with all instruments to 
be completed in this study. 
 


 
AtezolizumabF. Hoffmann-La Roche Ltd 
145/Protocol BIG 16-05/AFT-27/WO39391, Version 9 
Appendix 5 EQ-5D-5L 
 


Appendix 5 
EQ-5D-5L (cont.) 
 
AtezolizumabF. Hoffmann-La Roche Ltd 
146/Protocol BIG 16-05/AFT-27/WO39391, Version 9 
Do not reproduce or distribute.  The Sponsor will provide sites with all instruments to 
be completed in this study. 
Under each heading, please check the ONE box that best describes your health TODAY. 
MOBILITY 
 
I have no problems walking 
 
I have slight problems walking 
 
I have moderate problems walking 
 
I have severe problems walking 
 
I am unable to walk 
 
SELF-CARE 
 
I have no problems washing or dressing myself 
 
I have slight problems washing or dressing myself 
 
I have moderate problems washing or dressing myself 
 
I have severe problems washing or dressing myself 
 
I am unable to wash or dress myself 
 
USUAL ACTIVITIES (e.g. work, study, housework, family or 
leisure activities) 
 
I have no problems doing my usual activities 
 
I have slight problems doing my usual activities 
 
I have moderate problems doing my usual activities 
 
I have severe problems doing my usual activities 
 
I am unable to do my usual activities 
 
PAIN / DISCOMFORT 
 
I have no pain or discomfort 
 
I have slight pain or discomfort 
 
I have moderate pain or discomfort 
 
I have severe pain or discomfort 
 
I have extreme pain or discomfort 
 
ANXIETY / DEPRESSION 
 
I am not anxious or depressed 
 
I am slightly anxious or depressed 
 
I am moderately anxious or depressed 
 
I am severely anxious or depressed 
 
I am extremely anxious or depressed 
 
 


Appendix 5 
EQ-5D-5L (cont.) 
 
AtezolizumabF. Hoffmann-La Roche Ltd 
147/Protocol BIG 16-05/AFT-27/WO39391, Version 9 
 


 
AtezolizumabF. Hoffmann-La Roche Ltd 
148/Protocol BIG 16-05/AFT-27/WO39391, Version 9 
Appendix 6 Preexisting Autoimmune Diseases and 
Immune Deficiencies 
Patients should be carefully questioned regarding their history of acquired or 
congenital immune deficiencies or autoimmune disease.  Patients with any history of 
immune deficiencies or autoimmune disease listed in the table below are excluded from 
participating in the study.  Possible exceptions to this exclusion could be 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 or pericardial disorder while receiving another 
immunostimulatory anti-cancer agent.  The Medical Monitor is available to advise as 
needed in case of 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 myelitis 
• 
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 


 
AtezolizumabF. Hoffmann-La Roche Ltd 
149/Protocol BIG 16-05/AFT-27/WO39391, Version 9 
Appendix 7 Anaphylaxis Precautions 
EQUIPMENT NEEDED 
• 
Tourniquet 
• 
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. 
2. 
Apply a tourniquet proximal to the injection site to slow systemic absorption of 
study treatment.  Do not obstruct arterial flow in the limb. 
3. 
Maintain an adequate airway. 
4. 
Administer antihistamines, epinephrine, or other medications as required by 
patient status and directed by the physician in charge. 
5. 
Continue to observe the patient and document observations 
 


 
AtezolizumabF. Hoffmann-La Roche Ltd 
150/Protocol BIG 16-05/AFT-27/WO39391, Version 9 
Appendix 8 Radiotherapy Guidelines 
Radiotherapy can only be administered after chemotherapy is complete. Treatment with 
atezolizumab during adjuvant radiotherapy is permitted. 
I.   BREAST-CONSERVING THERAPY 
MANDATORY:  BREAST RADIOTHERAPY (RT) AFTER COMPLETE 
LOCAL EXCISION 
Breast RT may be contraindicated in patients with significant comorbidity 
(e.g., scleroderma and systemic lupus erythematous).  Reasons for not delivering 
breast RT after complete local excision of the primary breast cancer should be 
documented in the electronic Case Report Form. 
Target Volume 
• 
Whole breast including the primary tumor bed 
• 
Primary tumor bed boost in conjunction with whole breast RT may be used as per 
local policy declared by the center prior to local activation. 
• 
Partial breast RT may be used as per local policy declared by the center prior to 
local activation. 
• 
Regional nodal RT:  See Item III below. 
 
Dose Fractionation 
• 
Whole breastrecommended schedules:  
a) 50 Gy in 25 fractions, 5 fractions per week; or 
b) 42.5 Gy in 16 fractions, 5 fractions per week; or 
c) 
40 Gy in 15 fractions, 5 fractions per week.  
 
Other schedules may be used as per local policy declared by the center prior to 
local activation. 
• 
Primary tumor bed boost in conjunction with whole breast RT:  As per local policy 
declared by the center prior to local activation. 
• 
Partial breast RT:  As per local policy declared by the center prior to local activation. 
 
Treatment Planning 
• 
Computer tomography (CT)-based treatment planning is strongly recommended for 
whole breast RT and tumor bed boost. 
• 
CT-based treatment planning is mandatory for partial breast irradiation delivered 
using external beam RT. 
 


Appendix 8 
Radiotherapy Guidelines (cont.) 
 
AtezolizumabF. Hoffmann-La Roche Ltd 
151/Protocol BIG 16-05/AFT-27/WO39391, Version 9 
II.   POST-MASTECTOMY RADIOTHERAPY 
MANDATORY: 
a) 4 or more positive axillary nodes or 
b)  “Non-resectable” microscopic positive deep margin (invasive carcinoma or 
ductal carcinoma in situ) 
 
OPTIONAL: 
a) 1−3 positive axillary nodes after axillary dissection 
b) Higher risk node-negative disease (e.g., T3 primary in the presence of high 
histologic grade and/or lymphovascular invasion) 
 
Target Volume 
• 
Whole chest wall 
• 
Primary tumor bed boost in conjunction with chest wall RT may be used as per local 
policy declared by the center prior to local activation.  
• 
Regional nodal RT:  See Item III below. 
 
Dose Fractionation 
• 
Whole chest wall:  Recommended schedule is 50 Gy in 25 fractions, 5 fractions per 
week.  Other schedules may be used as per local policy declared by the center prior 
to local activation. 
• 
Primary tumor bed boost in conjunction with chest wall RT:  As per local policy 
declared by the center prior to local activation. 
 
Treatment Planning 
• 
CT-based treatment planning is strongly recommended for chest wall RT. 
 
III.   REGIONAL NODAL RADIOTHERAPY 
For patients who have completed sentinel lymph node biopsy alone or 
axillary lymph node dissection as per protocol: 
RECOMMENDED: 
Any breast surgery, 4 or more positive axillary nodes 
1−2 positive axillary lymph nodes after mastectomy plus SLNB and no axillary dissection 
performed 
OPTIONAL: 
Any breast surgery, 1−3 positive axillary nodes 


Appendix 8 
Radiotherapy Guidelines (cont.) 
 
AtezolizumabF. Hoffmann-La Roche Ltd 
152/Protocol BIG 16-05/AFT-27/WO39391, Version 9 
Target Volume 
• 
Required: 
a) Supraclavicular fossa if there are 4 or more positive axillary nodes; 
b) Internal mammary nodes if tumor involvement is clinically or pathologically 
confirmed. 
• 
Optional: 
a) Supraclavicular fossa if there are 1−3 positive axillary nodes; 
b) Axilla as per local policy declared by the center prior to local activation 
(e.g., known or high risk of residual axillary disease post-surgery); 
c) 
Internal mammary nodes if there is a high risk of tumor involvement as 
per local policy declared by the center prior to local activation. 
 
Dose Fractionation 
• 
Recommended schedule:  50 Gy in 25 fractions, 5 fractions per week.  Other 
schedules may be used as per local policy declared by the center prior to 
local activation.  Hypofractionated schedules are not recommended. 
 
Treatment Planning 
• 
CT-based treatment planning is strongly recommended for supraclavicular fossa 
and/or axillary RT. 
• 
CT-based treatment planning is mandatory for internal mammary nodal RT. 
 


 
AtezolizumabF. Hoffmann-La Roche Ltd 
153/Protocol BIG 16-05/AFT-27/WO39391, Version 9 
Appendix 9 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 following are general recommendations for management of any other adverse events 
that may occur and are not specifically listed in the following subsections.  
• 
Patients and family caregivers should receive timely and up-to-date information 
about immunotherapies, their mechanism of action, and the clinical profile of possible 
immune-related adverse events prior to initiating therapy and throughout treatment 
and survival follow-up.  There should be a high level of suspicion that new symptoms 
are treatment related. 
• 
In general, atezolizumab therapy should be continued with close monitoring for 
Grade 1 toxicities, with the exception of some neurologic toxicities. 
• 
Consider holding atezolizumab for most Grade 2 toxicities and resume when 
symptoms and/or laboratory values resolve to Grade 1 or better.  Corticosteroids 
(initial dose of 0.5−1 mg/kg/day of prednisone or equivalent) may be administered. 
• 
For Grade 2 recurrent or persistent (lasting for more than 5 days) events, treat as a 
Grade 3 event.   
• 
Hold atezolizumab for Grade 3 toxicities and initiate treatment with high-dose 
corticosteroids (1−2 mg/kg/day prednisone or equivalent).  Corticosteroids should be 
tapered over 1 month to 10 mg/day oral prednisone or equivalent, before 
atezolizumab can be resumed.  If symptoms do not improve within 48 to 72 hours of 
high-dose corticosteroid use, other immunosuppressants may be offered for some 
toxicities. 
• 
In general, Grade 4 toxicities warrant permanent discontinuation of atezolizumab 
treatment, with the exception of endocrinopathies that are controlled by 
hormone-replacement therapy. 
 
The investigator should consider the benefit-risk balance for a given patient prior to further 
administration of atezolizumab.  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 the 
investigator’s assessment of the benefits and risks and documented by the investigator.  
The Medical Monitor is available to advise as needed. 


Appendix 9 
Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab (cont.) 
AtezolizumabF. Hoffmann-La Roche Ltd 
154/Protocol BIG 16-05/AFT-27/WO39391, Version 9 
DOSE MODIFICATIONS 
There will be no dose modifications for atezolizumab in this study. 
TREATMENT INTERRUPTION 
Atezolizumab treatment may be temporarily suspended in patients experiencing toxicity 
considered to be related to study treatment.  If corticosteroids are initiated for treatment of 
the toxicity, they must be tapered over ≥1 month to ≤ 10 mg/day oral prednisone or 
equivalent before atezolizumab can be resumed.  If atezolizumab is withheld for 
> 12 weeks after the event onset, the patient will be discontinued from atezolizumab.  
However, atezolizumab may be withheld for > 12 weeks to allow for patients to taper off 
corticosteroids prior to resuming treatment.  Atezolizumab can be resumed after being 
withheld for > 12 weeks if the patient is likely to derive clinical benefit.  The decision to re-
challenge patients with atezolizumab should be based on the investigator’s benefit−risk 
assessment and documented by the investigator.  The Medical Monitor is available to 
advise as needed.  Atezolizumab treatment may be suspended for reasons other than 
toxicity (e.g., surgical procedures).  The acceptable length of treatment interruption must 
be based on the investigator's benefit−risk assessment and in alignment with the protocol 
requirements for the duration of treatment and documented by the investigator.  The 
Medical Monitor is available to advise as needed. 
MANAGEMENT GUIDELINES 
PULMONARY EVENTS 
Pulmonary events may present as new or worsening cough, chest pain, fever, dyspnea, 
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.  COVID-19 evaluation should be performed per institutional 
guidelines where relevant.  Management guidelines for pulmonary events are provided in 
Table 1. 
 


Appendix 9 
Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab (cont.) 
AtezolizumabF. Hoffmann-La Roche Ltd 
155/Protocol BIG 16-05/AFT-27/WO39391, Version 9 
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 with or without transbronchial biopsy. 
• Initiate treatment with 1−2 mg/kg/day oral prednisone or equivalent. 
• If event resolves to Grade 1 or better, resume atezolizumab. b 
• If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and contact the 
Medical Monitor. c, d 
• 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 the Medical Monitor. 
c, d  
• Oral or IV broad-spectrum antibiotics should be administered in 
parallel to the immunosuppressive treatment. 
• Bronchoscopy or BAL with or without transbronchial biopsy is 
recommended. 
• 
Initiate treatment with 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 the 
investigator’s benefit−risk assessment and in alignment with the protocol requirements for the 
duration of treatment and documented by the investigator.  The Medical Monitor is available to 
advise as needed. 
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 the investigator’s benefit−risk assessment and documented 
by the investigator.  The Medical Monitor is available to advise as needed.  The Medical 
Monitor is available to advise as needed. 
d In case of pneumonitis, atezolizumab should not be resumed after permanent 
discontinuation. 
 


Appendix 9 
Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab (cont.) 
AtezolizumabF. Hoffmann-La Roche Ltd 
156/Protocol BIG 16-05/AFT-27/WO39391, Version 9 
HEPATIC EVENTS 
Eligible patients must have adequate liver function, as manifested by measurements of 
total bilirubin and hepatic transaminases, and liver function will be monitored throughout 
study treatment.  Management guidelines for hepatic events are provided in Table 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 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 the 
Medical Monitor. c 
Hepatic event, 
Grade 3 or 4 
• Permanently discontinue atezolizumab and contact the Medical Monitor. c 
• Consider patient referral to gastrointestinal specialist for evaluation and 
liver biopsy to establish etiology of hepatic injury.  
• Initiate treatment with 1−2 mg/kg/day oral prednisone or equivalent. 
• 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 the 
investigator’s benefit−risk assessment 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 the investigator’s benefit−risk assessment and documented 
by the investigator.  The Medical Monitor is available to advise as needed. 
 


Appendix 9 
Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab (cont.) 
AtezolizumabF. Hoffmann-La Roche Ltd 
157/Protocol BIG 16-05/AFT-27/WO39391, Version 9 
 
GASTROINTESTINAL EVENTS 
Management guidelines for diarrhea or colitis are provided in Table 3. 
All events of diarrhea or colitis should be thoroughly evaluated for other more common 
etiologies.  For events of significant duration or magnitude or associated with signs of 
systemic inflammation or acute-phase reactants (e.g., increased C-reactive protein, 
platelet count, or bandemia):  Perform sigmoidoscopy (or colonoscopy, if appropriate) with 
colonic biopsy, with three to five specimens for standard paraffin block to check for 
inflammation and lymphocytic infiltrates to confirm colitis diagnosis. 
Table 3 
Management Guidelines for Gastrointestinal Events (Diarrhea or 
Colitis) 
Event 
Management 
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.  
• If strong clinical suspicion for immune-mediated colitis, start empiric 
IV steroids while waiting for definitive diagnosis. 
• Patient referral to GI specialist is recommended. 
• For recurrent events or events that persist > 5 days, initiate treatment with 
1−2 mg/kg/day oral prednisone or equivalent.  If the 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 the 
Medical Monitor. c 
  


Appendix 9 
Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab (cont.) 
AtezolizumabF. Hoffmann-La Roche Ltd 
158/Protocol BIG 16-05/AFT-27/WO39391, Version 9 
Table 3 Management Guidelines for Gastrointestinal Events (Diarrhea or Colitis) 
(cont.) 
Event 
Management 
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 1−2 mg/kg/day IV methylprednisolone or 
equivalent and convert to 1−2 mg/kg/day oral prednisone or equivalent 
upon improvement.  If event does not improve within 48 hours after 
initiating corticosteroids, consider adding an immunosuppressive 
agent. 
• 
If event resolves to Grade 1 or better, resume atezolizumab. b 
• 
If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and contact the 
Medical Monitor. c 
Diarrhea or 
colitis, Grade 4 
• 
Permanently discontinue atezolizumab and contact Medical Monitor. c 
• 
Refer patient to GI specialist for evaluation and confirmatory biopsy. 
• 
Initiate treatment with 1−2 mg/kg/day IV methylprednisolone or 
equivalent and convert to 1−2 mg/kg/day oral prednisone or equivalent 
upon improvement. 
• 
If event does not improve within 48 hours after initiating corticosteroids, 
consider adding an immunosuppressive agent. 
• 
If event resolves to Grade 1 or better, taper corticosteroids over 
≥ 1 month. 
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 the 
investigator’s benefit−risk assessment and in alignment with the protocol requirements for the 
duration of treatment and documented by the investigator.  The Medical Monitor is available to 
advise as needed. 
b If corticosteroids have been initiated, they must be tapered over ≥ 1 month to ≤ 10 mg/day oral 
prednisone or equivalent before atezolizumab can be resumed. 
c Resumption of atezolizumab may be considered in patients who are deriving benefit and have 
fully recovered from the immune-mediated event.  The decision to re-challenge patients 
should be based on the investigator’s benefit−risk assessment and documented by the 
investigator.  The Medical Monitor is available to advise as needed.  
  
 


Appendix 9 
Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab (cont.) 
AtezolizumabF. Hoffmann-La Roche Ltd 
159/Protocol BIG 16-05/AFT-27/WO39391, Version 9 
ENDOCRINE EVENTS 
Management guidelines for endocrine events are provided in Table 4. 
Patients with unexplained symptoms such as headache, fatigue, myalgias, impotence, 
constipation, or mental status changes should be investigated for the presence of thyroid, 
pituitary, or adrenal endocrinopathies.  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 pituitary sections) may help to 
differentiate primary pituitary insufficiency from primary adrenal insufficiency. 
Table 4 
Management Guidelines for Endocrine Events 
Event 
• 
Management 
Grade 1 
hypothyroidism 
• 
Continue atezolizumab. 
• 
Initiate treatment with thyroid replacement hormone. 
• 
Monitor TSH closely. 
Grade 2 
hypothyroidism 
• 
Consider withholding 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. 
Grade 3 and 4 
hypothyroidism 
• 
Withhold atezolizumab. 
• 
Initiate treatment with thyroid replacement hormone. 
• 
Monitor TSH closely. 
• 
Refer to an endocrinologist. 
• 
Admit patient to the hospital for developing myxedema 
(bradycardia, hypothermia, and altered mental status). 
• 
Resume atezolizumab when symptoms are controlled, and thyroid 
function is improving. 
• 
Permanently discontinue atezolizumab and contact the Medical 
Monitor for life-threatening immune-mediated hypothyroidism. c 
Grade 1 
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 Grade 2 hyperthyroidism. 
• 
Consider patient referral to endocrinologist. 
 


Appendix 9 
Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab (cont.) 
AtezolizumabF. Hoffmann-La Roche Ltd 
160/Protocol BIG 16-05/AFT-27/WO39391, Version 9 
Table 4 
Management Guidelines for Endocrine Events (cont.) 
Event 
• 
Management 
Grade 2 
hyperthyroidism 
• 
Consider withholding 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. 
Grade 3 and 4 
hyperthyroidism 
• 
Withhold atezolizumab. 
• 
Initiate treatment with anti-thyroid drugs such as methimazole or 
carbimazole as needed. 
• 
Refer to endocrinologist. 
• 
Resume atezolizumab when symptoms are controlled, and thyroid 
function is improving. 
• 
Permanently discontinue atezolizumab and contact the 
Medical Monitor for life-threatening immune-mediated 
hyperthyroidism. c 
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 1−2 mg/kg/day IV methylprednisolone or 
equivalent and convert to 1−2 mg/kg/day oral prednisone or 
equivalent upon improvement. 
• 
If event 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 the 
Medical Monitor. c 
Hyperglycemia, 
Grade 1 or 2  
• 
Continue atezolizumab. 
• 
Initiate treatment with insulin if needed. 
• 
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. 
 


Appendix 9 
Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab (cont.) 
AtezolizumabF. Hoffmann-La Roche Ltd 
161/Protocol BIG 16-05/AFT-27/WO39391, 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 1−2 mg/kg/day IV methylprednisolone or 
equivalent and convert to 1−2 mg/kg/day oral prednisone or 
equivalent upon improvement. 
• 
Initiate hormone replacement if clinically indicated. 
• 
If event resolves to Grade 1 or better, resume atezolizumab. b 
• 
If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and contact 
the Medical Monitor. c 
• 
For recurrent hypophysitis, treat as a Grade 4 event. 
Hypophysitis 
(pan-hypopituitarism), 
Grade 4  
• Permanently discontinue atezolizumab and contact the 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 the investigator’s 
benefit−risk assessment and in alignment with the protocol requirements for the duration of 
treatment and documented by the investigator.  The Medical Monitor is available to advise as 
needed. 
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 the investigator’s benefit−risk assessment and documented by 
the investigator.  The Medical Monitor is available to advise as needed 
 


Appendix 9 
Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab (cont.) 
AtezolizumabF. Hoffmann-La Roche Ltd 
162/Protocol BIG 16-05/AFT-27/WO39391, 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 the 
Medical Monitor. c 
Ocular event, 
Grade 3 or 4 
• 
Permanently discontinue atezolizumab and contact the 
Medical Monitor. c 
• 
Refer patient to ophthalmologist. 
• 
Initiate treatment with 1−2 mg/kg/day oral prednisone or equivalent. 
• 
If event resolves to Grade 1 or better, taper corticosteroids over 
≥ 1 month. 
a Atezolizumab may be withheld for a longer period of time (i.e., > 12 weeks after event onset) 
to allow for corticosteroids (if initiated) to be reduced to ≤ 10 mg/day oral prednisone or 
equivalent.  The acceptable length of the extended period of time must be based on the 
investigator’s benefit−risk assessment and in alignment with the protocol requirements for the 
duration of treatment and documented by the investigator.  The Medical Monitor is available to 
advise as needed. 
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 the investigator's benefit−risk assessment and documented 
by the investigator.  The Medical Monitor is available to advise as needed 
 


Appendix 9 
Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab (cont.) 
AtezolizumabF. Hoffmann-La Roche Ltd 
163/Protocol BIG 16-05/AFT-27/WO39391, Version 9 
IMMUNE-MEDIATED CARDIAC EVENTS 
Management guidelines for cardiac events are provided in Table 6. 
IMMUNE-MEDIATED MYOCARDITIS 
Immune-mediated myocarditis should be suspected in any patient presenting with signs or 
symptoms suggestive of myocarditis, including, but not limited to, laboratory (e.g., B-type 
natriuretic peptide) or cardiac imaging abnormalities, dyspnea, chest pain, palpitations, 
fatigue, decreased exercise tolerance, or syncope.  Myocarditis may also be a clinical 
manifestation of myositis or associated with pericarditis (see section on pericardial 
disorders below) and should be managed accordingly.  Immune-mediated myocarditis 
needs to be distinguished from myocarditis resulting from infection (commonly viral, e.g., 
in a patient who reports a recent history of gastrointestinal illness), ischemic events, 
underlying arrhythmias, exacerbation of preexisting cardiac conditions, or progression of 
malignancy. 
All patients with possible myocarditis should be urgently evaluated by performing cardiac 
enzyme assessment, an ECG, a chest X-ray, 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. 
Immune-Mediated Pericardial Disorders 
Immune-mediated pericarditis should be suspected in any patient presenting with chest 
pain and may be associated with immune-mediated myocarditis (see section on 
myocarditis above). 
Immune-mediated pericardial effusion and cardiac tamponade should be suspected in any 
patient presenting with chest pain associated with dyspnea or hemodynamic instability.  
Patients should be evaluated for other causes of pericardial disorders such as infection 
(commonly viral), cancer related (metastatic disease or chest radiotherapy), cardiac 
injury related (post myocardial infarction or iatrogenic), and autoimmune disorders, and 
should be managed accordingly. 
All patients with suspected pericardial disorders should be urgently evaluated by 
performing an ECG, chest X-ray, transthoracic echocardiogram, and cardiac MRI as 
appropriate per institutional guidelines.  A cardiologist should be consulted.  
Pericardiocentesis should be considered for diagnostic or therapeutic purposes, if 
clinically indicated. 


Appendix 9 
Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab (cont.) 
AtezolizumabF. Hoffmann-La Roche Ltd 
164/Protocol BIG 16-05/AFT-27/WO39391, Version 9 
Patients with signs and symptoms of pericarditis, pericardial effusion, or cardiac 
tamponade, in the absence of an identified alternate etiology, should be treated according 
to the guidelines in Table 6.  Withhold treatment with atezolizumab for Grade 1 
pericarditis and conduct a detailed cardiac evaluation to determine the etiology and 
manage accordingly. 
Table 6 
Management Guidelines for Immune-Mediated Cardiac Events 
Event 
Management 
Immune-mediated 
myocarditis, 
Grades 2−4 
 
Immune-mediated 
pericardial disorders, 
Grades 2−4 
• 
Permanently discontinue atezolizumab and contact the 
Medical Monitor. 
• 
Refer patient to cardiologist. 
• 
Initiate treatment as per institutional guidelines and consider 
antiarrhythmic drugs, temporary pacemaker, ECMO, VAD, or 
pericardiocentesis as appropriate. 
• 
Initiate treatment with 1−2 mg/kg/day IV methylprednisolone or 
equivalent and convert to 1−2 mg/kg/day oral prednisone or 
equivalent upon improvement. 
• 
If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent. 
• 
If event resolves to Grade 1 or better, taper corticosteroids 
over ≥ 1 month. 
ECMO = extracorporeal membrane oxygenation; VAD = ventricular assist device. 
 


Appendix 9 
Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab (cont.) 
AtezolizumabF. Hoffmann-La Roche Ltd 
165/Protocol BIG 16-05/AFT-27/WO39391, 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, antipyretic 
medications, and/or analgesics (e.g., acetaminophen) for subsequent infusions.  
Metamizole (dipyrone) is prohibited in treating atezolizumab-associated IRRs because of 
its potential for causing agranulocytosis. 
IRRs are known to occur with the administration of monoclonal antibodies and have been 
reported with atezolizumab.  These reactions, which are thought to be due to release of 
cytokines and/or other chemical mediators, occur within 24 hours of atezolizumab 
administration and are generally mild to moderate in severity. 
Cytokine-release syndrome 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 the medical management of IRRs and CRS are provided in Table 7. 
Severe SARS-CoV-2 appears to be associated with a CRS involving the 
inflammatory cytokines interleukin (IL)-6, IL10, IL-2, and IFN-γ (Merad and Martin 2020).  If 
a patient develops suspected CRS during the study, a differential diagnosis should include 
COVID-19, which should be confirmed or refuted through assessment of exposure history, 
appropriate laboratory testing, and clinical or radiologic evaluations per investigator’s 
judgment.  If a diagnosis of SARS-CoV-2 is confirmed, the disease should be managed as 
per local or institutional guidelines. 


Appendix 9 
Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab (cont.) 
AtezolizumabF. Hoffmann-La Roche Ltd 
166/Protocol BIG 16-05/AFT-27/WO39391, 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, antipyretic medications, 
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 functions 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 the 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, antipyretic medications, 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 the Medical Monitor. 
 


Appendix 9 
Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab (cont.) 
AtezolizumabF. Hoffmann-La Roche Ltd 
167/Protocol BIG 16-05/AFT-27/WO39391, 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 the 
Medical Monitor. e 
• 
Administer symptomatic treatment. c 
• 
For hypotension, administer IV fluid bolus and vasopressor as 
needed. 
• 
Monitor cardiopulmonary and other organ function closely; monitoring 
in the ICU is recommended.  Administer IV fluids as clinically 
indicated and manage constitutional symptoms and organ toxicities 
as per institutional practice. 
• 
Rule out other inflammatory conditions that can mimic CRS 
(e.g., sepsis).  If no improvement within 24 hours, initiate workup and 
assess for signs and symptoms of HLH or MAS as described in this 
appendix. 
• 
Administer IV corticosteroids (e.g., methylprednisolone 2 mg/kg/day 
or dexamethasone 10 mg every 6 hours). 
• 
Consider anti-cytokine therapy. 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 the 
Medical Monitor. e 
• 
Administer symptomatic treatment. c 
• 
Admit patient to ICU and initiate hemodynamic monitoring, 
mechanical ventilation, and/or IV fluids and vasopressors as needed.  
Monitor other organ function closely.  Manage constitutional 
symptoms and organ toxicities as per institutional practice. 
• 
Rule out other inflammatory conditions that can mimic CRS 
(e.g., sepsis).  If no improvement within 24 hours, initiate workup and 
assess for signs and symptoms of HLH or MAS as described in this 
appendix. 
• 
Administer IV corticosteroids (e.g., methylprednisolone 2 mg/kg/day 
or dexamethasone 10 mg every 6 hours). 
• 
Consider anti-cytokine therapy.  For patients who are refractory to 
anti-cytokine therapy, experimental treatments f may be considered at 
the discretion of the investigator and in consultation with the 
Medical Monitor. 
• 
Hospitalize patient until complete resolution of symptoms. 
 


Appendix 9 
Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab (cont.) 
AtezolizumabF. Hoffmann-La Roche Ltd 
168/Protocol BIG 16-05/AFT-27/WO39391, 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 the NCCN guidelines for the 
management of CAR T-cell-related toxicities (Version 2.2019). 
a Grading system for management guidelines is based on ASTCT consensus grading for CRS.  
NCI CTCAE (v5.0) 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, antipyretic medications, 
analgesics, bronchodilators, and/or oxygen.  For bronchospasm, urticaria, or dyspnea, 
additional treatment may be administered as per institutional practice. 
d Low flow is defined as oxygen delivered at ≤ 6 L/min, and high flow is defined as oxygen 
delivered at > 6 L/min. 
e Resumption of atezolizumab may be considered in patients who are deriving benefit and have 
fully recovered from the event.  The decision to re-challenge patients with atezolizumab 
should be based on the investigator’s benefit−risk assessment and documented by the 
investigator.  The Medical Monitor is available to advise as needed.  For subsequent infusions, 
administer oral premedication with antihistamines, antipyretic medications, and/or analgesics, 
and monitor closely for IRRs and/or CRS.  Premedication with corticosteroids and extending 
the infusion time may also be considered after assessing the benefit-risk ratio. 
f Refer to Riegler et al. (2019). 
 


Appendix 9 
Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab (cont.) 
AtezolizumabF. Hoffmann-La Roche Ltd 
169/Protocol BIG 16-05/AFT-27/WO39391, Version 9 
 
PANCREATIC EVENTS 
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 
Amylase and/or lipase > 1.5−2.0 × ULN: 
• Continue atezolizumab. 
• Monitor amylase and lipase weekly. 
• For prolonged elevation (e.g., > 3 weeks), consider treatment 
with 10 mg/day oral prednisone or equivalent. 
Asymptomatic with amylase and/or lipase > 2.0−5.0 × ULN: 
• Treat as a Grade 3 event. 
Amylase and/or lipase 
elevation, Grade 3 or 4 
• Withhold atezolizumab for up to 12 weeks after event onset. a 
• Refer patient to GI specialist. 
• Monitor amylase and lipase every other day. 
• If no improvement, consider treatment with 1−2 mg/kg/day oral 
prednisone or equivalent. 
• If event resolves to Grade 1 or better, resume atezolizumab. b 
• If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and 
contact the Medical Monitor. c 
• For recurrent events, permanently discontinue atezolizumab and 
contact the Medical Monitor. c 
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 1−2 mg/kg/day IV methylprednisolone or 
equivalent and convert to 1−2 mg/kg/day oral prednisone or 
equivalent upon improvement. 
• If event 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 the Medical Monitor. c 
• For recurrent events, permanently discontinue atezolizumab and 
contact the Medical Monitor. c  
 


Appendix 9 
Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab (cont.) 
AtezolizumabF. Hoffmann-La Roche Ltd 
170/Protocol BIG 16-05/AFT-27/WO39391, Version 9 
Table 8 
Management Guidelines for Pancreatic Events, Including 
Pancreatitis (cont.) 
Event 
Management 
Immune-mediated 
pancreatitis, Grade 4 
• 
Permanently discontinue atezolizumab and contact the 
Medical Monitor. c 
• 
Refer patient to GI specialist. 
• 
Initiate treatment with 1−2 mg/kg/day IV methylprednisolone or 
equivalent and convert to 1−2 mg/kg/day oral prednisone or 
equivalent upon improvement. 
• 
If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent. 
• 
If event resolves to Grade 1 or better, taper corticosteroids over ≥ 1 
month. 
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 the 
investigator’s benefit−risk assessment and in alignment with the protocol requirements for the 
duration of treatment and documented by the investigator.  The Medical Monitor is available to 
advise as needed. 
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 the investigator’s benefit−risk assessment and documented 
by the investigator.  The Medical Monitor is available as needed.  
  


Appendix 9 
Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab (cont.) 
AtezolizumabF. Hoffmann-La Roche Ltd 
171/Protocol BIG 16-05/AFT-27/WO39391, Version 9 
DERMATOLOGIC EVENTS 
The majority of cases of rash reported with the use of atezolizumab were mild in severity 
and self-limiting, with or without pruritus.  Although uncommon, cases of severe cutaneous 
adverse reactions such as Stevens-Johnson syndrome and toxic epidermal necrolysis 
have been reported with atezolizumab.  A dermatologist should evaluate persistent and/or 
severe rash or pruritus.  A biopsy should be considered unless contraindicated.  
Management guidelines for dermatologic events are provided in Table 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 10 mg/day oral prednisone or equivalent, 
increasing dose to 1−2 mg/kg/day if event does not improve within 
48−72 hours. 
• 
If event resolves to Grade 1 or better, resume atezolizumab. b 
• 
If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and contact the 
Medical Monitor. c 
Dermatologic event, 
Grade 4 
• 
Permanently discontinue atezolizumab and contact the 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. 


Appendix 9 
Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab (cont.) 
AtezolizumabF. Hoffmann-La Roche Ltd 
172/Protocol BIG 16-05/AFT-27/WO39391, Version 9 
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 the investigator’s 
benefit−risk assessment and in alignment with the protocol requirements for the duration of 
treatment and documented by the investigator.  The Medical Monitor is available 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 the investigator’s benefit−risk assessment and documented 
by the investigator.  The Medical Monitor is available to advise as needed. 
 


Appendix 9 
Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab (cont.) 
AtezolizumabF. Hoffmann-La Roche Ltd 
173/Protocol BIG 16-05/AFT-27/WO39391, Version 9 
NEUROLOGIC DISORDERS 
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, with specific guidelines for myelitis provided in Table 11. 
Table 10 Management Guidelines for Neurologic Disorders 
Event 
Management 
Immune-mediated 
neuropathy, Grade 1 
• Continue atezolizumab. 
• Investigate etiology. 
• Any cranial nerve disorder (including facial paresis) should be managed 
as per Grade 2 management guidelines below. 
Immune-mediated 
neuropathy, including 
facial paresis, 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. 
• For general immune-mediated neuropathy: 
– 
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 the 
Medical Monitor. c 
• For facial paresis: 
– 
If event resolves fully, resume atezolizumab b 
– 
If event does not resolve fully while withholding atezolizumab, 
permanently discontinue atezolizumab and contact theMedicalMonitor.c 
Immune-mediated 
neuropathy, including 
facial paresis, 
Grade 3 or 4 
• Permanently discontinue atezolizumab and contact the 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 the Medical Monitor. c 
• Refer patient to neurologist. 
• Initiate treatment as per institutional guidelines. 
• Consider initiation of 1−2 mg/kg/day oral or IV prednisone or equivalent. 
a Atezolizumab may be withheld for a longer period of time (i.e., > 12 weeks after event onset) to 
allow for corticosteroids (if initiated) to be reduced to ≤ 10 mg/day oral prednisone or equivalent.  
The acceptable length of the extended period of time must be based on the investigator’s 
benefit−risk assessment and in alignment with the protocol requirements for the duration of 
treatment and documented by the investigator.  The Medical Monitor is available to advise as 
needed. 
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 the investigator’s benefit−risk assessment and documented by 
the investigator.  The Medical Monitor is available to advise as needed.  
 


Appendix 9 
Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab (cont.) 
AtezolizumabF. Hoffmann-La Roche Ltd 
174/Protocol BIG 16-05/AFT-27/WO39391, Version 9 
Table 11 Management Guidelines for Immune-Mediated Myelitis 
Event 
Management 
Immune-mediated myelitis, 
Grade 1 
• 
Continue atezolizumab unless symptoms worsen or do not 
improve. 
• 
Investigate etiology and refer patient to a neurologist.  
Immune-mediated myelitis, 
Grade 2 
• 
Permanently discontinue atezolizumab and contact the 
Medical Monitor.  
• 
Investigate etiology and refer patient to a neurologist. 
• 
Rule out infection. 
• 
Initiate treatment with corticosteroids equivalent to 
1-2 mg/kg/day oral prednisone. 
Immune-mediated myelitis, 
Grade 3 or 4 
• 
Permanently discontinue atezolizumab and contact the 
Medical Monitor. 
• 
Refer patient to a neurologist. 
• 
Initiate treatment as per institutional guidelines. 
 


Appendix 9 
Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab (cont.) 
AtezolizumabF. Hoffmann-La Roche Ltd 
175/Protocol BIG 16-05/AFT-27/WO39391, Version 9 
IMMUNE-MEDIATED MENINGOENCEPHALITIS 
Immune-mediated meningoencephalitis should be suspected in any patient presenting 
with signs or symptoms suggestive of meningitis or encephalitis, including, but not limited 
to, headache, neck pain, confusion, seizure, motor or sensory dysfunction, and altered or 
depressed level of consciousness.  Encephalopathy from metabolic or electrolyte 
imbalances needs to be distinguished from potential meningoencephalitis resulting from 
infection (bacterial, viral, or fungal) or progression of malignancy, or secondary to a 
paraneoplastic process. 
All patients being considered for meningoencephalitis should be urgently evaluated with a 
CT scan and/or MRI scan of the brain to evaluate for metastasis, inflammation, or edema.  
If deemed safe by the treating physician, a lumbar puncture should be performed, and a 
neurologist should be consulted. 
Patients with signs and symptoms of meningoencephalitis, in the absence of an identified 
alternate etiology, should be treated according to the guidelines in Table 12. 
Table 12 Management Guidelines for Immune-Mediated 
Meningoencephalitis 
Event 
Management 
Immune-mediated 
meningoencephalitis, 
all grades 
• Permanently discontinue atezolizumab and contact the 
Medical Monitor. 
• Refer patient to neurologist. 
• Initiate treatment with 1−2 mg/kg/day IV methylprednisolone or 
equivalent and convert to 1−2 mg/kg/day oral prednisone or 
equivalent upon improvement. 
• If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent. 
• If event resolves to Grade 1 or better, taper corticosteroids over 
≥ 1 month. 
 


Appendix 9 
Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab (cont.) 
AtezolizumabF. Hoffmann-La Roche Ltd 
176/Protocol BIG 16-05/AFT-27/WO39391, Version 9 
RENAL EVENTS 
Eligible patients must have adequate renal function.  Renal function, including serum 
creatinine, should be monitored throughout study treatment.  Patients with abnormal renal 
function should be evaluated and treated for other more common etiologies (including 
prerenal and postrenal causes, and concomitant medications such as non-steroidal anti-
inflammatory drugs).  Refer the patient to a renal specialist if clinically indicated.  A renal 
biopsy may be required to enable a definitive diagnosis and appropriate treatment. 
Patients with signs and symptoms of nephritis, in the absence of an identified alternate 
etiology, should be treated according to the guidelines in Table 13. 
Table 13 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 the 
Medical Monitor. c 
Renal event, 
Grade 3 or 4 
• 
Permanently discontinue atezolizumab and contact the 
Medical Monitor. 
• 
Refer patient to renal specialist and consider renal biopsy. 
• 
Initiate treatment with corticosteroids equivalent to 1−2 mg/kg/day oral 
prednisone. 
• 
If event does not improve within 48 hours after initiating corticosteroids, 
consider adding an immunosuppressive agent. 
• 
If event resolves to Grade 1 or better, taper corticosteroids over 
≥ 1 month. 
a Atezolizumab may be withheld for a longer period of time (i.e., > 12 weeks after event onset) to 
allow for corticosteroids (if initiated) to be reduced to the equivalent of ≤ 10 mg/day oral 
prednisone.  The acceptable length of the extended period of time must be based on the 
investigator’s benefit−risk assessment and in alignment with the protocol requirements for the 
duration of treatment and documented by the investigator.  The Medical Monitor is available to 
advise as needed. 
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 the investigator’s benefit−risk assessment and documented by 
the investigator.  The Medical Monitor is available to advise as needed. 


Appendix 9 
Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab (cont.) 
AtezolizumabF. Hoffmann-La Roche Ltd 
177/Protocol BIG 16-05/AFT-27/WO39391, Version 9 
 
IMMUNE-MEDIATED MYOSITIS 
Myositis or inflammatory myopathies are a group of disorders sharing the common feature 
of inflammatory muscle injury; dermatomyositis and polymyositis are among the most 
common disorders.  Initial diagnosis is based on clinical (muscle weakness, muscle pain, 
skin rash in dermatomyositis), biochemical (serum creatine kinase 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 14. 
Table 14 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 the 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 the 
Medical Monitor. c 
 


Appendix 9 
Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab (cont.) 
AtezolizumabF. Hoffmann-La Roche Ltd 
178/Protocol BIG 16-05/AFT-27/WO39391, Version 9 
Table 14 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 the 
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 the 
Medical Monitor. c 
• For recurrent events, treat as a Grade 4 event.  Permanently discontinue 
atezolizumab and contact the Medical Monitor. c 
Immune-mediated 
myositis, Grade 4 
• Permanently discontinue atezolizumab and contact the 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 the investigator’s benefit−risk 
assessment and in alignment with the protocol requirements for the duration of treatment and 
documented by the investigator.  The Medical Monitor is available to advise as needed. 
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 the investigator’s benefit−risk assessment and documented by 
the investigator.  The Medical Monitor is available to advise as needed. 
  


Appendix 9 
Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab (cont.) 
AtezolizumabF. Hoffmann-La Roche Ltd 
179/Protocol BIG 16-05/AFT-27/WO39391, 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). 
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/µL) 
– 
ANC < 1.0 × 109/L (1000/µL) 
• 
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/µL) 
– 
AST ≥ 48 U/L 
– 
Triglycerides > 1.761 mmol/L (156 mg/dL) 
– 
Fibrinogen ≤ 3.6 g/L (360 mg/dL) 
 
Patients with suspected HLH or MAS should be treated according to the guidelines in 
Table 15. 


Appendix 9 
Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab (cont.) 
AtezolizumabF. Hoffmann-La Roche Ltd 
180/Protocol BIG 16-05/AFT-27/WO39391, Version 9 
 
Table 15 Management Guidelines for Suspected Hemophagocytic 
Lymphohistiocytosis or Macrophage Activation Syndrome 
Event 
Management 
Suspected HLH 
or MAS 
• 
Permanently discontinue atezolizumab and contact the 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 the 
Medical Monitor and initiate treatment as appropriate according to 
published guidelines (La Rosée 2015; Schram and Berliner 2015; 
La Rosée et al. 2019) 
• 
If event resolves to Grade 1 or better, taper corticosteroids over 
≥ 1 month. 
HLH = hemophagocytic lymphohistiocytosis; MAS = macrophage activation syndrome. 
 
REFERENCES 
Adashek ML, Feldman M. Cytokine release syndrome resulting from anti−programmed 
death-1 antibody: raising awareness among community oncologist. J Oncol Practice 
2019;15:502−4. 
La Rosée P. Treatment of hemophagocytic lymphohistiocytosis in adults. Hematology Am 
Soc Hematol Educ Protram 2015;1:190−6. 
La Rosée P, Horne A, Hines M, et al. Recommendations for the management of 
hemophagocytic lymphohistiocytosis in adults. Blood 2019;133:2465−77. 
Lee DW, Santomasso BD, Locke FL, et al. ASTCT consensus grading for cytokine release 
syndrome and neurologic toxicity associated with immune effector cells. Biol Blood 
Marrow Transplant 2019;25:625−38. 
McClain KL, Eckstein O. Clinical features and diagnosis of hemophagocytic 
lymphohistiocytosis. Up to Date [resource on the Internet]. 2014 [updated 
29 October 2018; cited: 17 May 2019]. Available from: 
https://www.uptodate.com/contents/clinical-features-and-diagnosis-of-
hemophagocytic-lymphohistiocytosis. 
Merad M, Martin JC. Pathological inflammation in patients with COVID-19: a key role for 
monocytes and macrophages. Nat Rev Immunol 2020;20:355−62. 
Ravelli A, Minoia F, Davi S, et al. 2016 classification criteria for macrophage activation 
syndrome complicating systemic juvenile idiopathic arthritis: a European League 
Against Rheumatism/American College of Rheumatology/Paediatric Rheumatology 


Appendix 9 
Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab (cont.) 
AtezolizumabF. Hoffmann-La Roche Ltd 
181/Protocol BIG 16-05/AFT-27/WO39391, Version 9 
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. 
 
 


Signature Page for Protocol - WO39391 - TECENTRIQ - v9 - Global/Core - Published
System identifier: RIM-CLIN-470731
Approval Task
Company Signatory
01-Mar-2023 21:01:20 GMT+0000

SAP_001.pdf: 
Official Title: 
A Phase III, Multicenter, Randomized, Open-Label Study Comparing 
Atezolizumab (Anti-Pd-L1 Antibody) in Combination With Adjuvant 
Anthracycline/Taxane-Based Chemotherapy Versus Chemotherapy 
Alone in Patients With Operable Triple-Negative Breast Cancer 
NCT Number: 
NCT03498716 
Document Date: 
SAP Version 3: 28-Feb-2023


STATISTICAL ANALYSIS PLAN AMENDMENT APPROVAL 
 
 
SPONSOR: 
LEGAL REGISTERED 
ADDRESS: 
F. Hoffmann-La Roche Ltd 
Grenzacherstrasse 124 
4070 Basel, Switzerland 
DATE FINAL: 
See electronic date stamp on the last page of this 
document  
CONFIDENTIAL 
 
This is an F. Hoffmann-La Roche Ltd document that contains confidential information.  Nothing 
herein is to be disclosed without written consent from F. Hoffmann-La Roche Ltd. 
 
Atezolizumab — F. Hoffmann-La Roche Ltd 
Statistical Analysis Plan BIG 16-05/AFT-27/WO39391 
 
STATISTICAL ANALYSIS PLAN 
STUDY TITLE: A PHASE III, MULTICENTER, RANDOMIZED, OPEN-LABEL STUDY 
COMPARING ATEZOLIZUMAB (ANTI-PD-L1 ANTIBODY) IN 
COMBINATION WITH ADJUVANT ANTHRACYCLINE/TAXANE-BASED 
CHEMOTHEREAPY VERSUS CHEMOTHERAPY ALONE IN PATIENTS 
WITH OPERABLE TRIPLE NEGATIVE BREAST CANCER 
STUDY NUMBER: 
BIG 16-05/AFT-27/WO39391 
STUDY NAME:  
IMpassion030 
VERSION NUMBER: 
3 
ROCHE COMPOUND(S): 
Atezolizumab  
(RO5541267) 
EUDRACT NUMBER: 
2016-003695-47 
IND NUMBER: 
123277 
NCT NUMBER: 
03498716 
PLAN PREPARED BY: 
 (Roche) 
 (FS) 


 
Atezolizumab — F. Hoffmann-La Roche Ltd 
Statistical Analysis Plan BIG 16-05/AFT-27/WO39391 
2 
STATISTICAL ANALYSIS PLAN VERSION HISTORY 
This Statisical Analysis Plan (SAP) was developed based on Roche SAP Legacy model 
document. 
SAP Version 
Approval Date 
Based on Protocol  
(Version, Approval Date) 
3 
see electronic date stamp 
on the last page of this 
document 
V 9, approval pending 
2 
6 September 2022 
V 8, 24 November 2021 
1 
16 March 2020 
V 6, 14 February 2020 
 


 
Atezolizumab — F. Hoffmann-La Roche Ltd 
Statistical Analysis Plan BIG 16-05/AFT-27/WO39391 
3 
STATISTICAL ANALYSIS PLAN AMENDMENT RATIONALE 
This SAP BIG 16-05/AFT-27/WO39391 has been amended to update the interim 
analyses and provide additional clarifications. 
 
Based on the U.S. Food and Drug Administration (FDA)’s request, the planned 
efficacy analyses have been updated and a futility analysis has been added, as 
described in the corresponding Sections 2.3, 2.4, 3.1, 4.10.1, and 4.10.2 of the SAP. 
The updated efficacy and futility analyses are based on the actual number of 
patients randomized at the time of this SAP amendment. 
 
Additional minor changes have been made to improve clarity and consistency. Table 
titles have also been added. 
 


 
Atezolizumab — F. Hoffmann-La Roche Ltd 
Statistical Analysis Plan BIG 16-05/AFT-27/WO39391 
4 
 
TABLE OF CONTENTS 
STATISTICAL ANALYSIS PLAN AMENDMENT RATIONALE ............................. 3 
1. 
BACKGROUND .............................................................................. 9 
2. 
STUDY DESIGN ............................................................................. 9 
2.1 
Protocol Synopsis ...................................................................... 9 
2.2 
Endpoints ................................................................................... 9 
2.3 
Analysis Timing .......................................................................... 9 
2.4 
Determination of Sample Size ................................................. 11 
3. 
STUDY CONDUCT ....................................................................... 12 
3.1 
Randomization ......................................................................... 12 
3.2 
Data Monitoring ....................................................................... 13 
4. 
STATISTICAL METHODS ............................................................ 13 
4.1 
Analysis Poputlations ............................................................... 13 
4.1.1 
Randomized Population – Intent-to-Treat (ITT) ....................... 13 
4.1.2 
PD-L1−Selected Tumor Status (IC1/2/3) Subpopulation ......... 13 
4.1.3 
Node-Positive Disease Subpopulation ..................................... 13 
4.1.4 
Pharmacokinetic-Evaluable Population ................................... 13 
4.1.5 
Safety Population ..................................................................... 14 
4.1.6 
Immunogenicity Populations .................................................... 14 
4.2 
Analysis of Study Conduct ....................................................... 14 
4.3 
Analysis of Treatment Group Comparability ............................ 14 
4.4 
Efficacy Analysis ...................................................................... 14 
4.4.1 
Primary Efficacy Endpoint ........................................................ 14 
4.4.2 
Key Secondary Efficacy Endpoints .......................................... 15 
4.4.2.1 
iDFS in the Subpopulation with PD-L1 – Selected Tumor 
Status (IC1/2/3) ........................................................................ 15 
4.4.2.2 
iDFS in the Subpopulation with Node-Positive Disease ........... 15 
4.4.2.3 
Overall Survival ........................................................................ 16 
4.4.2.4 
iDFS Including Second Primary Non-Breast Cancer ............... 16 
4.4.2.5 
Recurrence-Free Interval ......................................................... 16 
4.4.2.6 
Distant Recurrence-Free Interval ............................................. 16 


 
Atezolizumab — F. Hoffmann-La Roche Ltd 
Statistical Analysis Plan BIG 16-05/AFT-27/WO39391 
5 
4.4.2.7 
Disease-Free Survival ............................................................. 16 
4.4.3 
Supportive Secondary Endpoints ............................................. 16 
4.4.3.1 
Patient-Reported Outcomes of Role and Physical Function 
and HRQoL .............................................................................. 17 
4.4.4 
Exploratory Efficacy Endpoints ................................................ 17 
4.4.4.1 
Patient-Reported Outcomes of Disease/Treatment-Related 
Symptoms, Emotional and Social Function-EORTC Data ....... 17 
4.4.4.2 
FACT-G, GP5 Single Item Data ............................................... 18 
4.4.4.3 
Health Economic EQ-5D-5L Data ............................................ 18 
4.4.5 
Sensitivity Analyses ................................................................. 18 
4.4.6 
Subgroup Analyses .................................................................. 19 
4.5 
Pharmacokinetic and Pharmacodynamic Analyses ................. 19 
4.6 
Safety Analyses ....................................................................... 19 
4.6.1 
Exposure of Study Medication ................................................. 19 
4.6.2 
Adverse Events ........................................................................ 19 
4.6.3 
Laboratory Data ....................................................................... 20 
4.6.4 
Vital Signs and ECOG Performance Status ............................. 20 
4.6.5 
ECG ......................................................................................... 20 
4.7 
Immunogenicity Analyses ........................................................ 20 
4.8 
Biomarker Analyses ................................................................. 21 
4.9 
Missing Data ............................................................................ 21 
4.10 
Interim Analyses ...................................................................... 21 
4.10.1 
Invasive Disease-Free Survival (Specified) ............................. 22 
4.10.2 
Overall Survival (Specified) ..................................................... 23 
4.10.3 
Invasive Disease-Free Survival (and Overall Survival) 
(Optional) ................................................................................. 25 
5. 
REFERENCES.............................................................................. 26 
 


 
Atezolizumab — F. Hoffmann-La Roche Ltd 
Statistical Analysis Plan BIG 16-05/AFT-27/WO39391 
6 
 
LIST OF TABLES 
Table 1 
Interim and Final Analyses of the Primary iDFS .......................... 10 
Table 2 
Overall Survival at iDFS First Interim Analysis ............................ 23 
Table 3 
Overall Survival at iDFS Second Interim Analysis ....................... 24 
Table 4 
Overall Survival at iDFS Final Analysis ....................................... 24 
 
 
LIST OF APPENDICES 
Appendix 1 
Protocol Synopsis ....................................................................... 27 
Appendix 2 
Schedule of Assessments ........................................................... 40 
Appendix 3 
Study Schema ............................................................................. 50 
 


 
Atezolizumab — F. Hoffmann-La Roche Ltd 
Statistical Analysis Plan BIG 16-05/AFT-27/WO39391 
7 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation or Term 
Description 
ADA 
anti-drug antibody, also known as anti-therapeutic antibody 
CCOD 
clinical cut-off date 
CI 
confidence interval 
CSR 
Clinical Study Report 
DFS 
disease-free survival 
DRFI 
distant recurrence-free interval 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic Case Report Form 
EORTC 
European Organization for Research and Treatment of Cancer 
EQ-5D-5L 
EuroQoL 5-Dimension, 5-Level 
FACT-G 
Functional Assessment of Cancer Therapy-General 
FWER 
familywise error rate 
FPI 
first patient in 
G-CSF 
granulocyte colony-stimulating factor 
GHS/QoL 
global health status quality of life 
GM-CSF 
granulocyte-macrophage colony stimulating factor 
HR 
hazard ratio 
HRQoL 
health-related quality of life 
IC 
tumor-infiltrating immune cell 
iDFS 
invasive disease-free survival 
iDMC 
independent Data Monitoring Committee 
IHC 
immunohistochemistry 
ISC 
Independent Statistical Center 
ITT 
intent-to-treat 
IV 
intravenous 
IxRS 
interactive voice or Web-based response system 
LS Mean 
least squares mean 
LVEF 
left ventricular ejection fraction 
MedDRA 
Medical Dictionary for Regulatory Activities 
NCI-CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse 
Events 
NGS 
next-generation sequencing 
NPT 
non-protocol therapy 
OS 
overall survival 


 
Atezolizumab — F. Hoffmann-La Roche Ltd 
Statistical Analysis Plan BIG 16-05/AFT-27/WO39391 
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PCR 
polymerase chain reaction 
PD-L1 
programmed death ligand-1 
PK 
pharmacokinetic 
PRO 
patient-reported outcome 
Q2W 
every 2 weeks 
Q3W 
every 3 weeks 
QLQ-C30 
Quality of Life Questionnaire Core 30 
QW 
weekly 
RFI 
recurrence-free interval 
SAP 
Statistical Analysis Plan 
T-AC/EC 
atezolizumab and paclitaxel followed by atezolizumab, dose dense 
doxorubicin or epirubicin 
TIL 
tumor-infiltrating lymphocytes 
TNBC 
triple-negative breast cancer 


 
Atezolizumab — F. Hoffmann-La Roche Ltd 
Statistical Analysis Plan BIG 16-05/AFT-27/WO39391 
9 
1. 
BACKGROUND 
Study BIG 16-05/AFT-27/WO39391 (also known as ALEXANDRA/IMpassion030) is a 
global Phase III, open-label, randomized, controlled study designed to evaluate the 
efficacy, safety, and pharmacokinetics of adjuvant treatment with atezolizumab and 
paclitaxel followed by atezolizumab, dose dense doxorubicin or epirubicin (investigator’s 
choice), and cyclophosphamide (referred to as atezolizumab      T-AC/EC) compared 
with paclitaxel followed by dose-dense doxorubicin or epirubicin (investigator’s choice) 
and cyclophosphamide alone (referred to as T-AC/EC) in patients with newly diagnosed 
Stage II-III triple-negative breast cancer (TNBC) who have completed surgery with 
curative intent of their primary tumor and are candidates for adjuvant systemic therapy 
following surgery. 
This Statistical Analysis Plan (SAP) describes the analyses that are planned to be 
performed for the Clinical Study Report (CSR) for this study. 
2. 
STUDY DESIGN 
2.1 
PROTOCOL SYNOPSIS 
The Protocol Synopsis is in Appendix 1.  For additional details, see the Schedule of 
Assessments in Appendix 2 or the Study Schema in Appendix 3. 
2.2 
ENDPOINTS 
See the Protocol Synopsis in Appendix 1 for a description of the endpoints. 
2.3 
ANALYSIS TIMING 
Two interim efficacy analyses for the primary endpoint of invasive disease-free survival 
(iDFS) will be performed, the first at a time-based cut-off (clinical cut-off date [CCOD[) in 
February 2023) following a SAP amendment (version 3) and the second at 
approximately 80% of the total planned number of iDFS events.  On the basis of the 
assumptions presented in Section 2.4 and the number of randomized patients and event 
accrual information at the time of the SAP amendment (version 3), it is projected that 
approximately 62% of the iDFS events (242) are observed at the first interim analysis.  
The 80% of the iDFS events (312) required for the second interim analysis is projected 
to be observed approximately 10 months (December 2023) after the CCOD of the first 
interim analysis.  
The interim analysis boundary for statistical significance will be determined based on the 
Lan-DeMets -spending function with an O’Brien-Fleming boundary.  For example, if 
exactly 242 events contribute to the first interim analysis, statistical significance will be 
declared if the p-value from the two-sided stratified log-rank test is   0.0088 (observed 
hazard ratio [HR]   0.71); if the null hypothesis for iDFS is not rejected at the first interim 
analysis and exactly 312 events contribute to the second interim analysis, statistical 
significance will be declared if the p-value from the two-sided stratified log-rank test 


 
Atezolizumab — F. Hoffmann-La Roche Ltd 
Statistical Analysis Plan BIG 16-05/AFT-27/WO39391 
10 
is   0.0218 (observed HR   0.77).  The applied stopping efficacy boundaries will depend 
on the actual observed number of events at the time of each analysis.  If the null 
hypothesis for iDFS is not rejected at the interim analyses and the study continues, the 
final analysis of iDFS will be performed when approximately 390 iDFS events have 
occurred; statistical significance will be declared if the p-value from the two-sided 
stratified log-rank test is   0.0422 (observed HR   0.81), if exactly 390 iDFS events 
contribute to the final analysis. 
At the time of the first interim analysis, a futility analysis will also be conducted.  A 
non-binding futility boundary is set at the iDFS HR of 1, thus futility can be declared if the 
observed iDFS HR is greater than 1 at the futility analysis.  Based on simulations, the 
probability of crossing the futility boundary is about 10.5% when the underlying iDFS HR 
is 0.85, and is about 1.2% when the underlying iDFS HR is 0.75, as shown in Table 1.   
Table 1 
Interim and Final Analyses of the Primary iDFS  
Analysis 
Number of iDFS 
Events 
Percent 
Information 
Adjusted Two-Sided 
Alpha Level 
Cumulative 
Power* 
iDFS First Interim 
242 
62% 
0.0088 
35% 
iDFS Second Interim 
312 
80% 
0.0218 
61% 
iDFS Final 
390 
100% 
0.0422 
80% 
iDFS  invasive disease-free survival 
*For a HR of 0.75 for iDFS 
  
Note:  In addition to the scheduled interim analyses the Sponsor may choose to conduct 
one additional interim efficacy analysis after at least 80% (but less than 100%) of the 
total planned number of iDFS events have occurred for the primary endpoint of iDFS, 
after endorsement by the Steering Committee.  The decision to conduct an additional 
interim analysis will be documented in a SAP amendment which will be submitted to the 
relevant health authorities at least 2 months prior to the conduct of the interim analysis, 
see Section 4.10.3 for details. 
 
Overall survival (OS) will also be analyzed at the interim and primary (final) analyses of 
iDFS. Testing on OS will be conducted hierarchically following the sequence defined in 
Section 4.4.2.  
Based on predicted timing and results of the iDFS interim and primary analyses, 
OS interim and final analyses alpha level and percent information might vary.  
Predictions for OS are based on protocol assumption.  The interim analyses boundaries 
for statistical significance for OS will be determined based on the Lan-DeMets 
-spending function with an O’Brien-Fleming boundary, see Section 4.10.1 for the 
details. 


 
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2.4 
DETERMINATION OF SAMPLE SIZE 
The final analysis of the primary endpoint of iDFS will take place when approximately 
390 iDFS events have occurred in the intent-to-treat (ITT) population 
(approximately 17% of the planned enrollment of 2300 patients experiencing an iDFS 
event).  At the time of the SAP amendment version 3, 2199 patients have been 
randomized.  The sample size is computed on the basis of the following assumptions: 
 
Primary statistical test:  two-sided, stratified log-rank test at the 0.05 significance 
level in the ITT population 
 
Approximately 80% power for iDFS 
 
A HR of 0.75 
 
Annual hazard rates of 0.047, 0.108, 0.035, 0.038, 0.029, and 0.014 in 
Years 1, 2, 3, 4, 5-6, and 7 and thereafter are assumed for the T-AC/EC arm based 
on the adjuvant TNBC trials:  Eastern Cooperative Oncology Group (ECOG) 
(E1199 [Sparano et al. 2015], BEATRICE [Cameron et al. 2013], and 
IBCSG 22-00 [Colleoni et al. 2016]). 
 
Based on the piecewise hazard rates given above for the control arm, and the 
assumed HR of 0.75 (thus reducing the risk of an iDFS event by 25% at each 
piecewise interval), the 3-year iDFS rate (probability of not having any iDFS event in 
the first 3 years) will be 82.7% in the T-AC/EC arm and 86.7% in the 
atezolizumab      T-AC/EC arm. 
 
2.5% annual loss to follow  up for iDFS 
 
Two interim analyses for iDFS in the ITT population at approximately 62% and 
80% of the iDFS, respectively 
 
One futility analysis for iDFS in the ITT population at the same time as the first 
interim analysis 
 
Accrual to-date has occurred over 52 months. Based on the current number of enrolled 
patients, the required number of iDFS events in the ITT population for the final analysis 
is projected to occur approximately 77 months after first patient in (FPI).  Also on the 
basis of these assumptions, an observed HR of 0.81 or better will result in a statistically 
significant difference between the treatment arms (i.e., HR    0.81 will be the minimally 
detectable difference for the analysis; this corresponds to an improvement in 3-year 
iDFS from 82.7% in the T-AC/EC arm to 85.7% in the atezolizumab      T-AC/EC arm).  
The study duration for the secondary endpoint, OS, was determined on the basis of the 
number of events required to demonstrate efficacy with regard to OS.  A total of 
approximately 299 deaths are required to achieve 80% power at a two-sided alpha 
level of 5% to detect an HR of 0.72, corresponding to an improvement in 5-year OS rate 
from 84% in the T-AC/EC arm to 88.2% in the atezolizumab      T-AC/EC arm assuming 
a constant hazard.  An annual loss to follow-up of 2.5% and three interim analyses are 
assumed.  The final analysis of OS is planned to take place approximately 7 years after 
the first patient has been randomized. 


 
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3. 
STUDY CONDUCT 
3.1 
RANDOMIZATION 
Patients who provide informed consent and are eligible will be randomized in a 1:1 ratio 
to receive either of the following treatment regimens: 
 
Arm A:  Atezolizumab and Chemotherapy 
– 
Atezolizumab:  atezolizumab (840 mg) administered via intravenous (IV) every 
2 weeks (Q2W) in combination with chemotherapy (as described below), followed 
by atezolizumab maintenance therapy (1200 mg IV infusion every 3 weeks [Q3W]) 
to complete a total duration of 1 year of atezolizumab treatment from the first 
administration of atezolizumab. 
– 
Chemotherapy:  paclitaxel (80 mg/m2) administered via IV infusion weekly (QW) for 
12 weeks followed by dose-dense doxorubicin (60 mg/m2) or dose-dense epirubicin 
(90 mg/m2) IV (investigator’s choice)    cyclophosphamide (600 mg/m2) IV repeated 
Q2W for 4 doses. 
– 
Granulocyte colony-stimulating factor (G-CSF; e.g., filgrastim or pegfilgrastim) or 
granulocyte-macrophage colony stimulating factor (GM-CSF) treatment is permitted 
for patients receiving chemotherapy and is required during the dose-dense 
doxorubicin/epirubicin    cyclophosphamide portion of chemotherapy. 
 
 
Arm B:  Chemotherapy alone 
– 
Paclitaxel (80 mg/m2) administered via IV infusion QW for 12 weeks followed by 
dose-dense doxorubicin (60 mg/m2) or dose-dense epirubicin (90 mg/m2) IV 
(investigator’s choice)    cyclophosphamide (600 mg/m2) IV repeated Q2W for 
4 doses. 
– 
G-CSF (e.g., filgrastim or pegfilgrastim) or GM-CSF treatment is permitted for 
patients receiving chemotherapy and is required during the dose-dense 
doxorubicin/epirubicin    cyclophosphamide portion of chemotherapy.  
 
The study population will be enriched for patients with node-positive disease such that 
the final population will contain approximately 50% of patients with node-negative 
disease.   
Randomization will be stratified by the following factors: 
 
Axillary nodal status (0 vs. 1-3 vs.   4 positive lymph nodes) 
 
Surgery (breast conserving vs. mastectomy) 
 
Tumor programmed death ligand-1 (PD-L1) status (tumor-infiltrating immune cell 
[IC] 0 vs. IC1/2/3) 
 
Randomization should occur no more than 8 weeks (56 days) after definitive surgery, 
and study drug administration should begin within 1 week (7 days) after randomization, 
but no sooner than 2 weeks (14 days) after last surgery. 


 
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3.2 
DATA MONITORING 
An independent Data Monitoring Committee (iDMC) will evaluate safety and efficacy 
data during the study.  The iDMC will follow the iDMC charter that outlines the iDMC 
roles and responsibilities. 
Unblinded safety data will be reviewed by the iDMC on a periodic basis.  The first safety 
review will occur when 50 patients in each treatment arm have received at least 2 doses 
of doxorubicin/epirubicin and cyclophosphamide (with or without atezolizumab 
respectively) and the relevant data has been entered in the electronic Case Report Form 
(eCRF).  Subsequent safety reviews will occur at least once every 6 months during the 
study until the last patient has completed or discontinued study treatment. 
Unblinded efficacy data will be reviewed by the iDMC as part of the interim analyses, 
described in Section 2.3.  A planned futility analysis will also be conducted by the iDMC 
at the time of the first interim analysis.  All summaries and analyses for the iDMC review 
will be prepared by the Independent Statistical Center (ISC). 
After reviewing the data, the iDMC will make a recommendation to the Interface 
Committee as described in the Interface Committee Charter and the iDMC Charter.  
Final decisions will rest with the Steering Committee. 
4. 
STATISTICAL METHODS 
The analyses outlined in this SAP supersede those specified in the protocol for the 
purpose of a regulatory filing. 
4.1 
ANALYSIS POPUTLATIONS 
4.1.1 
Randomized Population – Intent-to-Treat (ITT) 
The primary analysis population for efficacy is the ITT population, defined as all 
randomized patients, whether or not the assigned study treatment was received.  
Patients will be assigned to the treatment group to which they were randomized. 
4.1.2 
PD-L1−Selected Tumor Status (IC1/2/3) Subpopulation 
The PD-L1  selected tumor status (IC1/2/3) subpopulation is defined as patients in the 
ITT population whose PD-L1 status is IC1/2/3 at the time of randomization. 
4.1.3 
Node-Positive Disease Subpopulation 
The node-positive disease subpopulation is defined as patients in the ITT population 
with node-positive disease as defined in the breast cancer history in the clinical 
database at the time of randomization. 
4.1.4 
Pharmacokinetic-Evaluable Population 
Pharmacokinetic (PK)-evaluable population:  all patients who received atezolizumab 
administration and have at least one evaluable post-baseline PK sample. 


 
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4.1.5 
Safety Population 
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 at least one dose 
of atezolizumab will be included in the atezolizumab treatment group. 
4.1.6 
Immunogenicity Populations 
The pretreatment immunogenicity population includes patients who have a pretreatment 
anti-drug antibody (ADA, also known as anti-therapeutic antibody) assessment.  The 
post-baseline immunogenicity population includes patients with at least one 
post-baseline ADA assessment and who received at least one dose of atezolizumab.  
For both populations, patients are grouped according to treatment received. 
4.2 
ANALYSIS OF STUDY CONDUCT 
Enrollment, major protocol deviations including major deviations of inclusion/exclusion 
criteria, and discontinuation from the study will be summarized by treatment arm for all 
randomized patients.  The reasons for study discontinuation will be tabulated. 
4.3 
ANALYSIS OF TREATMENT GROUP COMPARABILITY 
Demographic variables such as age, sex, race/ethnicity, and baseline characteristics (in 
particular, stratification variables and ECOG status) will be summarized by treatment 
arm for all randomized patients.  Continuous variables will be summarized with use of 
means, standard deviations, medians, ranges, and inter-quartile ranges.  Categorical 
variables will be summarized by proportions.  
The baseline value of any variable will be defined as the last available value prior to the 
first administration of study treatment. 
4.4 
EFFICACY ANALYSIS 
The primary and secondary efficacy analyses will include all randomized patients unless 
otherwise stated with patients grouped according to their assigned treatment 
(ITT population). 
4.4.1 
Primary Efficacy Endpoint 
The primary efficacy endpoint is iDFS, defined as the time between randomization and 
date of first occurrence of an iDFS event, as described in the Protocol Synopsis in 
Appendix 1.  Data from patients who have not had an event at the time of data 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 of the respective analysis.  Patients with no 
post-baseline information will be censored on the date of randomization plus one day. 
The log-rank test, stratified by the protocol-defined stratification factors (as per the 
interactive voice or Web-based response system [IxRS] system), will be used to 


 
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compare iDFS between the two treatment arms.  The HR for iDFS will be estimated with 
use of a stratified Cox proportional hazards model.  Stratification factors are defined 
using IxRS data.  The Kaplan-Meier approach will be used to estimate the 3-year iDFS 
rates, and corresponding 95% confidence intervals (CI), calculated using Greenwood 
method, for each treatment arm which will be used to describe iDFS in addition to the 
HR.  In addition to the 3-year iDFS rate estimates for other time-points (e.g., 4-year, 
5-year) may be evaluated to better characterize the data, if the median follow-up based 
on the inverse censoring method of the iDFS distribution indicates sufficient support for 
estimates at timepoints beyond 3 years.  The difference between the two treatment arms 
and corresponding 95% CI will also be calculated. 
4.4.2 
Key Secondary Efficacy Endpoints 
To adjust for multiple statistical testing of the key secondary efficacy endpoints, thereby 
controlling the overall type I error rate at a two-sided significance level of 5%, the fixed 
sequence testing procedure will be used (where each subsequent hypothesis will be 
tested only if all previously tested hypotheses have been rejected).  These endpoints will 
be tested using hierarchical group-sequential testing with separate error spending 
functions at a two-sided significance level of 0.05 (see Section 4.10) in the following 
order: 
 
iDFS in the subpopulation with PD-L1    selected tumor status (IC1/2/3) 
 
iDFS in the subpopulation with node-positive disease 
 
OS 
 
iDFS, including second primary non-breast invasive cancer (except for 
non-melanoma skin cancers and in situ carcinoma of any site) as an iDFS event 
 
Recurrence-free interval (RFI) 
 
Distant recurrence-free interval (DRFI) 
 
Disease-free survival (DFS) 
 
The testing hierarchy will place the primary endpoint, iDFS in the ITT population, at the 
top of the hierarchy (i.e., no alpha-splitting between iDFS and any other endpoint[s]).  
4.4.2.1 
iDFS in the Subpopulation with PD-L1 – Selected Tumor Status 
(IC1/2/3) 
iDFS is defined in an analogous manner to the primary endpoint, see Section 4.4.1, and 
will be analyzed with the same methodology in the subpopulation of patients with 
PD-L1-selected tumor status (IC1/2/3), see Section 4.1.2.  The stratification factors used 
in the analysis are axillary nodal status and surgery as per IxRS. 
4.4.2.2 
iDFS in the Subpopulation with Node-Positive Disease 
iDFS is defined in an analogous manner to the primary endpoint see Section 4.4.1, and 
will be analyzed with the same methodology in the subpopulation of patients with 
node-positive disease, see Section 4.1.3. 


 
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4.4.2.3 
Overall Survival 
OS is defined as the time from randomization to the date of death due to any cause.  
Patients who are not reported as having died at the time of the clinical data cutoff date 
will be censored at the date when they were last known to be alive.  Patients with no 
post-baseline information will be censored on the date of randomization plus one day.  
OS will be analyzed with the use of the same methodology as specified for the primary 
endpoint, see Section 4.4.1. 
4.4.2.4 
iDFS Including Second Primary Non-Breast Cancer 
iDFS is defined in an analogous manner to the primary endpoint, see Section 4.4.1, with 
the addition of second primary non-breast invasive cancer as an event (with the 
exception of non-melanoma skin cancers and in situ carcinoma of any site) and will be 
analyzed with the same methodology. 
4.4.2.5 
Recurrence-Free Interval 
RFI is defined as the time from randomization to the first occurrence of any recurrence 
(local, regional [including invasive ipsilateral tumor and invasive locoregional tumor], or 
distant), as determined by the investigators. 
Patients without an event at the time of clinical cutoff for the analysis will be censored at 
the last date the patient was known to be alive and event free.  Patients without an event 
who died will be censored at the date of death.  Patients with no post-baseline 
information will be censored on the date of randomization.  RFI will be analyzed with the 
same methodology as specified for the primary endpoint see Section 4.4.1. 
4.4.2.6 
Distant Recurrence-Free Interval 
DRFI is defined as the time from randomization to distant breast cancer recurrence.  The 
censored data will be handled in the same way as RFI, see Section 4.4.2.5.  DRFI will 
be analyzed with the same method as the primary endpoint, see Section 4.4.1. 
4.4.2.7 
Disease-Free Survival 
DFS is defined as the time from randomization until the date of the first occurrence of 
one of the following events: 
 
Any of the events specified as per primary endpoint (iDFS), see the Protocol 
Synopsis in Appendix 1 
 
New diagnosis of an ipsilateral or contralateral non-invasive breast cancer 
 
DFS will be analyzed with the use of the same methodology as specified for iDFS and 
will follow similar censoring rules, see Section 4.4.1. 
4.4.3 
Supportive Secondary Endpoints 
The following endpoints are secondary endpoints, however they are not included in the 
fixed sequence testing procedures.  These include patient-reported outcomes (PROs) of 


 
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function (role, physical) and health-related quality of life (HRQoL) which are also 
described in the Protocol Synopsis in Appendix 1.  
4.4.3.1 
Patient-Reported Outcomes of Role and Physical Function and 
HRQoL 
The European Organisation for Research and Treatment of Cancer (EORTC) Quality of 
Life Questionnaire Core 30 (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, for all questionnaire subscales, if 
more than 50% of the constituent items are completed, a pro-rated score will be 
computed consistent with the scoring manuals and validation papers.  For subscales 
with less than 50% of the items completed, the subscale will be considered as missing.  
PRO completion, compliance rates, and reasons for missing data will be summarized at 
each timepoint by treatment arm using the ITT population. 
The primary PRO endpoints are the mean and mean changes from the baseline score in 
the following scales of the EORTC QLQ-C30:  function (role [Q6, Q7], physical [Q1-Q5]) 
and global health status quality of life (GHS/QoL) (Q29, Q30). These will be analyzed in 
the ITT population, see Section 4.1.4.  Summary statistics (mean [and 95% CI], standard 
deviation, median, and range) of linearly transformed absolute scores and mean 
changes from baseline (and 95% CI) will be calculated and 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/QoL 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 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 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. 
In case of repeated assessments, the latest assessment will be used in the analysis 
described above and in summary tables, although all values will be listed. 
4.4.4 
Exploratory Efficacy Endpoints 
4.4.4.1 
Patient-Reported Outcomes of Disease/Treatment-Related 
Symptoms, Emotional and Social Function-EORTC Data 
Summary statistics (mean [and 95% CI], standard deviation, 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 time-point for each arm. 
These will be analyzed in the ITT population, see Section 4.1.1. 


 
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Repeated assessments will be dealt with as described in Section 4.4.3.1. 
4.4.4.2 
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 Functional Assessment of 
Cancer Therapy-General (FACT-G) physical well-being subscale.  Mean change from 
baseline scores will also be summarized at each assessment time point by treatment 
arm as well as graphical representation of FACT-G GP5 data over time will also be 
provided and summarized over time.  Item GP5 from Version 4 of the FACT-G 
questionnaire will be scored according to the FACIT scoring manual (Cella 1997), and 
data will be analyzed in the ITT population, see Section 4.1.1. 
Repeated assessments will be dealt with as described in Section 4.4.4.1. 
4.4.4.3 
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 CSR. 
4.4.5 
Sensitivity Analyses 
The impact of non-protocol therapy (NPT) on the primary endpoint (iDFS) will be 
evaluated.  NPT is defined as any anti-cancer therapy other than study treatment that 
typically is the subsequent line of therapy.  A sensitivity analysis will be performed in 
which data for patients who received NPT, prior to an iDFS event, will be censored at the 
last disease status assessment date on or before the patient received NPT. 
The impact of misclassification in the patient’s stratification factors of patients on the 
primary endpoint (iDFS) analysis will be evaluated.  A sensitivity analysis will be 
performed by using the stratification factors based on the eCRF values for axillary nodal 
status and surgery.  This sensitivity analysis will only be run if the observed number of 
misclassified stratification factors is greater than 10% between the eCRF data and 
IxRS data.  Note that PD-L1 status is only collected in the IxRS system.  
The impact of the major escalation of the Ukraine-Russia conflict since 
24 February 2022 on the primary analysis of iDFS will be assessed via the following 
sensitivity analysis:  A sensitivity analysis will be performed where data for the patients 
from Ukraine and Russia whose date of iDFS event or censoring was later than the start 
date of the conflict, 24 Feb 2022, will be censored at this date. 
Additional sensitivity analyses may be considered if appropriate. 


 
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4.4.6 
Subgroup Analyses 
Besides the subgroup analyses of iDFS (subpopulations) mentioned in Section 4.4.2 and 
Section 4.4.5 , to assess the consistency of the study results across subgroups, iDFS 
and OS will be evaluated in subgroups defined by: 
 
PD-L1 status 
 
Node status (as defined in Section 4.1.3) 
 
Demographic and relevant baseline characteristics (including geographical region) 
 
Summaries of iDFS and OS, including unstratified HRs estimated from Cox proportional 
hazards models and Kaplan-Meier estimates of the 3-year iDFS rates, will be produced 
separately for each level of the categorical variables.  Forest plots will be used to 
summarize the results.  No formal hypotheses testing will be carried out in subgroups, 
other than those included in Section 4.4.2. 
4.5 
PHARMACOKINETIC AND PHARMACODYNAMIC ANALYSES 
Serum concentrations of atezolizumab will be reported as individual values and 
descriptive group statistics on the PK-evaluable population (Section 4.1.5).  Serum 
concentrations of atezolizumab over time will be plotted as individual and as mean 
concentrations.  Serum atezolizumab concentrations by treatment-emergent ADA status 
will be evaluated.   
4.6 
SAFETY ANALYSES 
The safety analyses will be done for the safety-evaluable population defined in 
Section 4.1.5. 
Safety will be assessed through summaries of adverse events, changes in laboratory 
test results, changes in left ventricular ejection fraction (LVEF), changes in vital signs, 
and study treatment exposures and will be presented by treatment arm. 
4.6.1 
Exposure of Study Medication 
Study treatment exposure, including treatment duration, dose intensity, number of cycles 
received, total cumulative dose and number of missed doses will be summarized with 
descriptive statistics by treatment arm for each study treatment.  A summary table 
reporting treatment with alternative taxanes will also be produced. 
4.6.2 
Adverse Events 
Verbatim descriptions of adverse events will be summarized by mapped term Medical 
Dictionary for Regulatory Activities (MedDRA), appropriate thesaurus level, and toxicity 
grade (according to the National Cancer Institute Common Terminology Criteria for 
Adverse Events [NCI-CTCAE] Version 5.0 [v5]).  For each patient, if multiple incidences 
of the same adverse events occur, the maximum severity reported will be used in the 
summaries. 


 
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The following treatment-emergent adverse events will be summarized separately:  
adverse events leading to withdrawal of study drug, adverse events leading to dose 
reduction or interruption, serious adverse events, adverse events by intensity/severity, 
Grade 3-4 adverse events, adverse events leading to death and adverse events of 
special interest for atezolizumab.  
All deaths and causes of death will be summarized. 
4.6.3 
Laboratory Data 
Relevant laboratory values will be summarized by time, with NCI-CTCAE v5.0 Grade 3 
and Grade 4 values identified, where appropriate.  Clinically relevant shifts from baseline 
(defined as shifts from Grade 0, 1, or 2 at baseline to Grade 3 or 4 post-baseline) will be 
tabulated by treatment arm. 
4.6.4 
Vital Signs and ECOG Performance Status 
For vital signs, baseline values will be summarized by treatment arm.  A table of 
clinically significant abnormal values by time and by treatment arm will also be 
presented.  Change from baseline in selected vital signs will be summarized by 
treatment arm.  
ECOG values (including values collected during the study) will be listed. 
4.6.5 
ECG 
For ECG, baseline values will be summarized by treatment arm and results of on-study 
ECGs (done when clinically indicated) will be listed. 
4.7 
IMMUNOGENICITY ANALYSES 
The immunogenicity analyses will include all patients in the immunogenicity population, 
see Section 4.1.6. 
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.  
When determining post-baseline incidence, patients are considered to be ADA positive if 
they are ADA negative or have 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 
have 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). 


 
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The relationship between ADA status and safety, efficacy, and pharmacokinetics may be 
investigated. 
4.8 
BIOMARKER ANALYSES 
The primary endpoint (iDFS) will be assessed in the subpopulation of patients with 
PD-L1-selected tumor status (IC1/2/3) as a secondary endpoint, see Section 4.4.2.1.  
Exploratory biomarker analyses will be performed in baseline pretreatment, 
on-treatment, follow-up and 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, stromal 
tumor-infiltrating lymphocytes (TILs), and other biomarkers in tumor and blood, as 
defined by immunohistochemistry (IHC), quantitative reverse transcription polymerase 
chain reaction (PCR), next-generation sequencing (NGS,) or other methods. 
4.9 
MISSING DATA 
See Section 4.4.1 and Section 4.4.2 for methods of handling missing data for the 
primary and secondary efficacy endpoints. 
4.10 
INTERIM ANALYSES 
The interim analyses on the primary endpoint (iDFS) will be conducted by an 
independent statistical group (ISC) and reviewed by the iDMC.  The Sponsor will remain 
blinded to the results of interim analyses until the unblinding of the study.  Interactions 
between the iDMC and the Sponsor will be carried out as specified in the iDMC Charter. 
To account for the statistical testing of primary and key secondary endpoints at multiple 
timepoints, hierarchical group-sequential testing with separate error spending functions 
at level 0.05 (two-sided) will be used.  This protects the familywise error rate (FWER) 
strongly at level 0.05, provided that the testing of each endpoint follows the sequence 
testing procedure defined in Section 4.4.2.  We will use the overall hierarchical principle, 
where if the primary endpoint is significant at the interim analysis, then the trial continues 
and the secondary endpoints will be tested at the interim analysis and again at further 
analyses, if not significant before (Glimm et al. 2009).  With this testing strategy, if the 
primary endpoint (iDFS in the ITT population) is found to be significant at the interim 
analysis, according to the O’Brien-Fleming boundaries with a Lan-DeMets alpha 
spending function as defined in Section 4.10.1, then the secondary efficacy endpoints 
will be tested in the order specified in Section 4.4.2 if, and only if, the preceding null 
hypothesis in the specified hierarchical order was rejected.  With this approach, the 
overall alpha level is controlled at 0.05 (two-sided), since FWER will be held at 0.05, if 
this is true for each of the secondary hypotheses tested within the pre-specified 
group-sequential design.   
Note that all the secondary endpoints included in the hierarchical testing with the 
exception of OS, see Section 4.4.2, will be tested using the same boundaries for 


 
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statistical significance calculated for the primary endpoint, see Section 4.10.1.  The 
interim analyses boundaries for statistical significance of key secondary endpoint OS will 
also be determined based on the Lan-DeMets -spending function with an 
O’Brien-Fleming boundary as defined in Section 4.10.2. 
4.10.1 
Invasive Disease-Free Survival (Specified) 
Two interim efficacy analyses for the primary endpoint of invasive disease-free survival 
(iDFS) will be performed, the first at a time-based cut-off (clinical cut-off date [CCOD[) in 
February 2023) following a SAP amendment (version 3) and the second at 
approximately 80% of the total planned number of iDFS events.  On the basis of the 
assumptions presented in Section 2.4 and the number of randomized patients and event 
accrual information at the time of the SAP amendment (version 3), it is projected that 
approximately 62% of the iDFS events (242) are observed at the first interim analysis.  
The 80% of the iDFS events (312) required for the second interim analysis is projected 
to be observed approximately 10 months (December 2023) after the CCOD of the first 
interim analysis.  
The interim analysis boundary for statistical significance will be determined based on the 
Lan-DeMets -spending function with an O’Brien-Fleming boundary.  For example, if 
exactly 242 events contribute to the first interim analysis, statistical significance will be 
declared if the p-value from the two-sided stratified log-rank test is   0.0088 (observed 
HR   0.71); if the null hypothesis for iDFS is not rejected at the first interim analysis and 
exactly 312 events contribute to the second interim analysis, statistical significance will 
be declared if the p-value from the two-sided stratified log-rank test 
is   0.0218 (observed HR   0.77).  The applied stopping boundary will depend on the 
actually observed number of events.  If the null hypothesis for iDFS is not rejected at the 
interim analyses and the study continues, the final analysis of iDFS will be performed 
when approximately 390 iDFS events have occurred; statistical significance will be 
declared if the p-value from the two-sided stratified log-rank test is p   0.0422 (observed 
HR   0.81), if exactly 390 iDFS events contribute to the analysis. 
Note that this analysis boundary will also be used to test the secondary endpoints 
defined in Section 4.4.2, with the exception of OS, for which the analysis boundary is 
discussed in Section 4.10.2.  These are: 
 
iDFS in the subpopulation with PD-L1-selected tumor status (IC1/2/3)  
 
iDFS in the subpopulation with node-positive disease  
 
iDFS, including second primary non-breast invasive cancer (except for 
nonmelanoma skin cancers and in situ carcinoma of any site) as an iDFS event  
 
Recurrence-free interval (RFI) 
 
Distant recurrence-free interval (DRFI) 
 
Disease-free survival (DFS) 
 


 
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Therefore, it is assumed that the information fraction for each of these endpoints is 
similar to the information fraction for the primary iDFS endpoint (in the ITT population) at 
the interim analyses.  In other words, it is assumed that around 62% and 80% of the 
events (for the above endpoints) have occurred at the time of the interim analyses.  
Adjustment for the actual number of events at the final iDFS analysis will be performed 
following the method proposed in Wassmer and Brannath (2016). 
At the time of the first interim analysis of iDFS, a futility analysis will also be conducted.  
A non-binding futility boundary is set at the iDFS HR of 1, thus futility can be declared if 
the observed iDFS HR is greater than 1 at the futility analysis.  Based on simulations, 
the probability of crossing the futility boundary when the underlying iDFS HR is 0.85 is 
about 10.5%, and when the underlying iDFS HR is 0.75 is about 1.2%.   
4.10.2 
Overall Survival (Specified) 
OS will be analyzed at the interim and final analyses of iDFS, as well as after 299 deaths 
are observed (OS Final analysis).  Testing on OS will be conducted using hierarchical 
group-sequential testing with separate error spending functions, after iDFS in the ITT 
population, iDFS in the subpopulation with PD-L1-selected tumor status (IC1/2/3) and 
iDFS in the subpopulation with node-positive disease are found to be significant, see 
Section 4.4.2.  
The interim analysis boundary for statistical significance for OS will be determined based 
on the Lan-DeMets -spending function with an O’Brien-Fleming boundary. 
 
If the null hypothesis for iDFS is rejected at the first iDFS interim analysis, OS may 
be tested, for the first time, hierarchically at the time of the first iDFS interim 
analysis.  At this time, it is projected that approximately 132 deaths have occurred 
and statistical significance will be declared if the p-value from the two-sided stratified 
log-rank test is   0.0015 (observed HR   0.57) depending on the actually observed 
number of events. If the null hypothesis for OS is not rejected at the first OS interim 
analysis, OS may be further tested based on the following timings as shown in 
Table 2. 
 
Table 2 
Overall Survival at iDFS First Interim Analysis  
Analysis 
Number of OS 
Events 
Percent 
Information 
Adjusted Two-Sided 
Alpha Level 
Cumulative 
Power* 
OS First Interim  
(at the iDFS First Interim)   
132 
44% 
0.0015 
10% 
OS Second Interim 
177 
59% 
0.0066 
30% 
OS Third Interim 
251 
84% 
0.0266 
66% 
OS Final 
299 
100% 
0.0410 
80% 
iDFS  invasive disease-free survival; OS  overall survival. 
*For a HR of 0.72 for OS 
  


 
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 
If the null hypothesis for iDFS is not rejected at the first iDFS interim analysis and 
the study continues, OS may be tested, for the first time, hierarchically at the second 
iDFS interim analysis.  At this time, it is projected that approximately 177 deaths will 
have occurred and statistical significance will be declared if the p-value from the 
two-sided stratified log-rank test is p   0.0070 (observed HR   0.67) depending on 
the actually observed number of events.  If the null hypothesis for OS is not rejected 
at the first OS interim analysis, OS may be further tested based on the following 
timings as shown in Table 3.  
 
Table 3 
Overall Survival at iDFS Second Interim Analysis 
Analysis 
Number of OS 
Events 
Percent 
Information 
Adjusted Two-Sided 
Alpha Level 
Cumulative 
Power* 
OS First Interim  
(at the iDFS Second 
Interim)   
177 
59% 
0.0070 
30% 
OS Second Interim 
251 
84% 
0.0267 
66% 
OS Final 
299 
100% 
0.0411 
80% 
iDFS  invasive disease-free survival; OS  overall survival. 
*For a HR of 0.72 for OS 
  
 
If the null hypothesis for iDFS is not rejected at the second iDFS interim analysis 
and the study continues, OS may be tested, for the first time, hierarchically at the 
time of the final analysis of iDFS.  At this time, it is projected that approximately 
251 deaths will have occurred and statistical significance will be declared if the 
p-value from the two-sided stratified log-rank test is p   0.0289 (observed 
HR   0.76) depending on the actually observed number of events.  If the null 
hypothesis for OS is not rejected at the first OS interim analysis, OS may be further 
tested based on the following timings as shown in Table 4.  
Table 4 
Overall Survival at iDFS Final Analysis 
Analysis 
Number of OS 
Events 
Percent 
Information 
Adjusted Two-Sided 
Alpha Level 
Cumulative 
Power* 
OS First Interim  
(at the iDFS Final)   
251 
84% 
0.0289 
66% 
OS Final 
299 
100% 
0.0417 
80% 
iDFS  invasive disease-free survival; OS  overall survival. 
*For a HR of 0.72 for OS 
  
Adjustment for the actual number of events at the final OS analysis may be performed 
following the method proposed in Wassmer and Brannath (2016).  The information 
fraction at the time of each analysis will be re-calculated using the actual number of 
events included in the analysis, and the nominal alpha level re-calculated accordingly. 


 
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4.10.3 
Invasive Disease-Free Survival (and Overall Survival) 
(Optional) 
To adapt to information that may emerge during the course of this study, in order to 
ensure patient benefit, the Sponsor may choose to conduct one additional interim 
efficacy analysis after at least 80% of the total planned number of iDFS events have 
occurred for the primary endpoint of iDFS.  An additional interim efficacy analysis will 
only be conducted after endorsement by the Steering Committee.  The key secondary 
endpoints defined in Section 4.4.2 would also be tested at this time using hierarchical 
group-sequential testing with separate error spending functions at level 0.05.  Below are 
the specifications in place to ensure the study continues to meet the highest standards 
of integrity when an optional interim analysis is executed.  
The decision to conduct an additional interim analysis, along with the rationale, timing, 
and statistical details for the analysis, will be documented in the SAP, and the SAP will 
be submitted to relevant health authorities at least 2 months prior to the conduct of the 
interim analysis.  The iDMC Charter will document potential recommendations the iDMC 
can make to the Steering Committee of the study as a result of the analysis (continuation 
of the study without modifications, continuation of the study with modification(s) for 
reasons including, but not restricted to, safety concerns and discontinuation or 
temporary suspension for reasons including, but not restricted to, safety concerns), and 
the iDMC Charter will also be made available to relevant health authorities. 
If there is a potential for the study to be stopped for positive efficacy as a result of the 
interim analysis, the type I error rate will be controlled to ensure statistical validity is 
maintained.  Specifically, the Lan-DeMets alpha-spending function that approximates the 
O’Brien-Fleming boundary will be applied to determine the critical value for stopping for 
positive efficacy at the interim analysis (DeMets and Lan 1994).  If the study continues 
beyond the interim analyses, the critical value at the final analysis would be adjusted 
accordingly to maintain the protocol-specified overall type I error rate, per standard 
Lan-DeMets methodology.  
If there is a potential for the study to be stopped for futility as a result of the interim 
analysis, the threshold for declaring futility will include an assessment of the predictive 
probability that the specified endpoint will achieve statistical significance.


 
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5. 
REFERENCES 
Cameron D, Brown J, Dent R, et al. Adjuvant bevacizumab-containing therapy in triple-
negative breast cancer (BEATRICE): primary results of a randomised, phase 3 
trial. Lancet Oncol 2013;14:933–42. 
Cella D. Manual of the functional assessment of chronic illness therapy (FACIT) 
measurement system version 4. Evanston, IL: Center on Outcomes, Research and 
Education (CORE) at Evanston Northwestern Healthcare and Northwestern 
University, 1997. 
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. 
Colleoni M, Gray KP, Gelber S, et al. Low-dose oral cyclophosphamide and 
methotrexate maintenance for hormone receptor-negative early breast cancer: 
International Breast Cancer Study Group Trial 22-00. J Clin Oncol 2016;34:3400-8. 
DeMets D, Lan KKG. Interim analysis: the alpha spending function approach. Stat Med 
1994;13:1341-52. 
Fayers PM, Aaronson NK, Bjordal K, et al. The EORTC QLQ-C30 scoring manual, 3rd 
ed. Brussels: European Organisation for Research and Treatment of Cancer, 
2001. 
Glimm E, Maurer W, Bretz F. Hierarchical testing of multiple endpoints in group-
sequential trials. Stat Med 2010; 29:219-28. 
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. 
Sparano JA, Zhao F, Martino S, et al. Long-term follow-up of the E1199 phase III trial 
evaluating the role of taxane and schedule in operable breast cancer. J Clin Oncol 
2015;33:2353-60. 
Wassmer G, Brannath W. Group Sequential and confirmatory adaptve designs in clinical 
trials. Heidelberg: Springer, 2016.










 
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Patients who provide informed consent and are eligible will be randomized in a 1:1 ratio to 
receive either of the following treatment regimens: 
 
Arm A:  Atezolizumab and Chemotherapy 
- 
Atezolizumab:  atezolizumab (840 mg) administered via IV Q2W in combination with 
chemotherapy (as described below), followed by atezolizumab maintenance therapy 
(1200 mg IV infusion every 3 weeks [Q3W]) to complete a total duration of 1 year of 
atezolizumab treatment from the first administration of atezolizumab. 
- 
Chemotherapy:  paclitaxel (80 mg/m2) administered via IV infusion weekly (QW) for 
12 weeks followed by dose-dense doxorubicin (60 mg/m2) or dose-dense epirubicin 
(90 mg/m2) IV (investigator’s choice)    cyclophosphamide (600 mg/m2) IV repeated 
Q2W for 4 doses. 
- 
Granulocyte colony-stimulating factor (G-CSF) (e.g., filgrastim or pegfilgrastim) or 
granulocyte-macrophage colony-stimulating factor (GM-CSF) treatment is permitted for 
patients receiving chemotherapy and is required during the dose-dense 
doxorubicin/epirubicin     cyclophosphamide portion of chemotherapy.  The primary 
prophylaxis should be administered per the ASCO, European Organisation for Research 
and Treatment of Cancer (EORTC), or European Society for Medical Oncology (ESMO) 
guidelines or per local standard practice. 
 
Arm B:  Chemotherapy alone 
- 
Paclitaxel (80 mg/m2) administered via IV infusion QW for 12 weeks followed by 
dose-dense doxorubicin (60 mg/m2) or dose-dense epirubicin (90 mg/m2) IV 
(investigator’s choice)    cyclophosphamide (600 mg/m2) IV repeated Q2W for 4 doses. 
- 
Granulocyte colony-stimulating factor (e.g., filgrastim or pegfilgrastim) or 
GM-CSF treatment is permitted for patients receiving chemotherapy and is required 
during the dose-dense doxorubicin/epirubicin     cyclophosphamide portion of 
chemotherapy.  The primary prophylaxis should be administered per the ASCO, 
EORTC, or ESMO guidelines or per local standard practice. 
 
The study population will be enriched for patients with node-positive disease such that the 
final population will contain no more than 50% of patients with node-negative disease. 
Patients who do not initially meet all eligibility criteria, other than TNBC status, may be 
re-screened once. 
Randomization will be stratified by the following factors: 
 
Axillary nodal status (0 vs. 1-3 vs.   4 positive lymph nodes) 
 
Surgery (breast conserving vs. mastectomy) 
 
Tumor PD-L1 status (tumor-infiltrating immune cell [IC]0 vs. IC1/2/3) 
 
Randomization should occur no more than 8 weeks (56 days) after definitive surgery, and 
study drug administration should begin within 1 week (7 days) after randomization but no 
sooner than 2 weeks (14 days) after last surgery.  In case of multiple surgeries performed for 
the breast cancer treatment, this time period should count starting from the last performed 
curative surgery. 
To ensure comparability of study assessments between the treatment arms, including 
assessments for disease recurrence and safety, patients in Arm B will undergo similar 
assessments as patients in Arm A.  These assessments will consist of formal clinic visits for 
evaluation of symptoms and adverse events, including cardiac toxicity.  Following the induction 
period, patients in Arm B will continue PRO assessments, laboratory evaluations, left ventricular 
ejection fraction (LVEF) monitoring, and limited physical examinations on a regular basis for the 
first year after randomization.  For patients in both arms, patient-reported outcome (PRO) 
assessments, LVEF monitoring, physical examinations and other assessments will continue at a 
reduced frequency after the first year after randomization. 
Patients in the control arm will not be allowed to cross over to receive atezolizumab treatment 
within this study. 


 
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In case of unacceptable toxicity attributed to chemotherapy in Arm A, atezolizumab should be 
stopped and restarted together with chemotherapy if there is no contraindication.  In cases 
where chemotherapy is permanently discontinued, atezolizumab may be restarted if there is no 
contraindication and should be based on investigator’s assessment of benefitrisk.  The 
Medical Monitor is available to advise as needed.  In case of toxicities attributed to 
atezolizumab, chemotherapy may be continued independently of atezolizumab if there is no 
contraindication.  Atezolizumab may be restarted when the conditions for retreatment have 
been met.  When atezolizumab is restarted, the infusions should remain synchronized and 
aligned with the chemotherapy schedule and it should be administered at a scheduled 
atezolizumab visit (i.e., missed doses of atezolizumab will not be made up). 
Dose delay and modification guidelines for chemotherapy are provided in the protocol.  
Management guidelines for toxicities associated with atezolizumab are provided in the protocol. 
Treatment will be discontinued in the event of disease recurrence, unacceptable 
toxicity/adverse event occurrence, pregnancy, withdrawal of consent, significant protocol 
violations, or study termination.  Patients who prematurely discontinue from the study will not be 
replaced.  Except for patients who withdraw consent from study follow-up, those who have 
prematurely discontinued from treatment will be followed for safety (including cardiac toxicity) 
and efficacy endpoints. 
Efficacy, safety, laboratory, PROs, pharmacokinetic (PK) measures, and biomarkers will be 
assessed throughout the study.  Following completion of study treatment, all patients will 
continue to be followed for efficacy, safety, and PRO objectives until the end of the study. 
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 5.0 (NCI CTCAE v5.0).  The LVEF will be assessed serially by 
echocardiogram (ECHO)/multiple-gated acquisition (MUGA) scans.  Laboratory safety 
assessments will include the regular monitoring of hematology and blood chemistry.  
Serum samples will be collected to monitor 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 Independent Data Monitoring Committee (IDMC) will evaluate safety and efficacy data 
during the study. No IDMC member may participate in the Study as an investigator, 
co-investigator, sub-investigator, committee member (other than IDMC), or patient, or in any 
other capacity that might compromise his or her independence and privileged activities within 
the IDMC. In order to ensure independence, members should have no involvement in the 
design and conduct of the Study except through their role on the IDMC and have no financial or 
other interests in the sponsor’s business or other Study organizers (BIG, AFT, FS, IJB) that 
could influence (or be perceived to influence) their objectivity in evaluating Study data.  
The IDMC will follow a charter that outlines the IDMC roles and responsibilities. 
NUMBER OF PATIENTS 
Approximately 2300 patients will be enrolled in this study at approximately 370450 sites 
globally.  It is estimated that the study will enroll patients over approximately 4 years. 
TARGET POPULATION 
Inclusion Criteria 
Patients must meet the following criteria for study entry: 
 
Signed Informed Consent Form (ICF) 
 
Ability to comply with protocol, in the investigator’s judgment 
 
Women or men aged  18 years at time of signing ICF 
 
Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1 
 
Non-metastatic operable Stage II-III breast cancer 
– 
Patients with node-negative disease must have a pathological tumor size  2 cm.  
Patients with node-negative multifocal, multicentric- or bilateral breast cancer are 
eligible providing that at least one lesion is  2 cm in size. 
 
Histologically documented TNBC (negative HER2, ER, and PgR status) 


 
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– 
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 invasive tumors (more than one tumor confined to the same 
quadrant as the primary tumor) or multicentric invasive tumors (more than one tumor in 
different quadrants of the same breast) are eligible provided all discrete lesions are 
sampled and centrally confirmed as TNBC.  Patients with non-TNBC invasive 
components are not eligible to participate in this study. 
 
Confirmed tumor PD-L1 evaluation as documented through central testing of a 
representative tumor tissue specimen 
 
Adequately excised:  Patients must have undergone either breast-conserving surgery or 
mastectomy/nipple- or skin-sparing mastectomy. 
– 
For patients who undergo breast-conserving surgery, the margins of the resected 
specimen must be histologically free of invasive tumor and ductal carcinoma in situ 
(DCIS) as determined by the local pathologist.  If pathologic examination demonstrates 
tumor at the line of resection, additional operative procedures may be performed to 
obtain clear margins.  If tumor is still present at the resected margin after re-excision(s), 
the patient must undergo total mastectomy to be eligible.  In cases in which the patient 
underwent breast-conserving surgery and there was a microscopic positive 
deep margin (with no other positive margins), if the tumor was resected up to the 
chest wall muscle and the surgeon considers that a mastectomy will not provide a 
negative deep margin, the patient does not need to undergo a mastectomy in order to 
be eligible.  Patients with margins positive for lobular carcinoma in situ (LCIS) are 
eligible without additional resection. 
– 
For patients who undergo mastectomy/nipple- or skin-sparing mastectomy, margins 
must be free of gross residual tumor.  It is recommended that patients should have a 
negative microscopic margin in accordance with local pathology protocol.  Patients with 
a microscopic positive deep margin are eligible. 
 
Pathological tumor-node-metastasis staging (Union for International Cancer 
Control/American Joint Committee on Cancer [UICC/AJCC], 8th edition):  Patient must have 
had sentinel lymph node biopsy (SLNB) and/or axillary lymph node dissection (ALND) for 
evaluation of pathologic nodal status.   
– 
Axillary nodal dissection(s) should yield a total of at least six nodes (including the 
axillary lymph nodes resected at the SLNB plus the lymph nodes collected at the 
axillary nodal dissection).  
– 
Patients with positive SLNB should undergo axillary dissection unless all of the 
following characteristics apply:   
No palpable nodes 
No more than 2 pathologically positive lymph nodes  
Breast-conserving surgery has been completed with tangential whole breast irradiation 
planned OR mastectomy with regional nodal radiotherapy planned. 
Clinical tumor size  T2 (5 cm) 
– 
In the case that all of the above are applicable, it is not mandatory to have the axillary 
dissection but it is left at the discretion of the investigator as per site standard practice. 
– 
In the case of subjects with tumors >2cm and regional lymph node found to have 
micrometastases or isolated tumor cells: Pathological classification of regional lymph 
node micrometastases (tumor deposits  0.2 mm and  2 mm) is considered to be pN1, 
and isolated tumor cells are considered to be pN0. 
The study population will be enriched for patients with node-positive disease such that 
the final population will contain at least 50% node-positive patients. 


 
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 
Patients with synchronous bilateral invasive disease are eligible only if all bilateral 
invasive lesions are histologically confirmed as triple negative by central laboratory and 
have completed adequate pathological tumor-node metastasis staging bilaterally as 
described above. 
 
No more than 8 weeks (56 days) may elapse between definitive breast surgery (or the 
last surgery with curative intent if additional resection is required for breast cancer) and 
randomization. 
 
Baseline LVEF  53% measured by ECHO (preferred) or MUGA scans 
– 
Baseline LVEF to be conducted within 28 days prior to randomization. 
 
Adequate hematologic and end-organ function, as defined by the following 
laboratory results obtained within 28 days prior to randomization: 
– 
Absolute neutrophil count (ANC)  1500 cells/L (without 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 
Patients may be transfused or receive erythropoietic treatment to meet this criterion. 
– 
AST, ALT, and alkaline phosphatase  2.5  the upper limit of normal (ULN) 
– 
Serum total bilirubin  1.0  ULN 
Patients with known Gilbert disease who have serum bilirubin level  3  ULN may be 
enrolled. 
– 
For patients not receiving therapeutic anticoagulation: INR or aPTT  1.5  ULN within 
28 days prior to randomization 
– 
For patients receiving therapeutic anticoagulation:  stable anticoagulant regimen and 
stable INR during the 28 days immediately preceding randomization 
– 
Creatinine clearance  30 mL/min (calculated using the Cockcroft-Gault formula) 
– 
Serum albumin  2.5 g/dL 
 
Negative HIV test at screening 
 
Negative hepatitis B surface antigen (HBsAg) test at screening 
 
Negative total hepatitis B core antibody (HBcAb) test at screening, or positive 
total HBcAb test followed by a negative hepatitis B virus (HBV) DNA test at screening 
– 
The HBV DNA test will be performed only for patients who have a positive 
total HBcAb test. 
 
Negative hepatitis C virus (HCV) antibody test at screening, or positive HCV antibody test 
followed by a negative HCV RNA test at screening 
– 
The HCV RNA test will be performed only for patients who have a positive 
HCV antibody test. 
 
Representative formalin-fixed, paraffin embedded (FFPE) tumor specimen from surgical 
resection in paraffin blocks (preferred) or approximately 25 unstained slides (minimum of 
20 slides), with an associated pathology report documenting locally assessed ER, PgR, 
and HER2 negativity.   
– 
Tumor tissue should be of good quality based on total and viable tumor content and 
must be evaluated centrally for PD-L1 expression prior to enrollment.  
Fine-needle aspiration, brushing, cell pellet from cytology specimens are not 
acceptable.  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. 


 
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 
For women of childbearing potential:  agreement to remain abstinent (refrain from 
heterosexual intercourse) or use contraceptive measures, and agreement to refrain from 
donating eggs, as defined below: 
– 
Women must remain abstinent or use contraceptive methods with a failure rate of 
 1% per year during the treatment period and for at least 5 months after the last dose 
of atezolizumab, or 6 months after the last dose of paclitaxel or doxorubicin/epirubicin, 
or 12 months after the last dose of cyclophosphamide, whichever is later.  Women must 
refrain from donating eggs during the same period. 
– 
A woman is considered to be of childbearing potential if she is postmenarcheal, has not 
reached a postmenopausal state ( 12 continuous months of amenorrhea with no 
identified cause other than menopause), and has not undergone surgical sterilization 
(removal of ovaries and/or uterus). 
– 
Examples of contraceptive methods with a failure rate of  1% per year include bilateral 
tubal ligation, male sterilization, and copper intrauterine devices. 
– 
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 adequate 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 
paclitaxel, or doxorubicin/epirubicin or 12 months after the last dose of 
cyclophosphamide, whichever is later.  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 paclitaxel, or 
doxorubicin/epirubicin or 12 months after the last dose of cyclophosphamide, whichever 
is later 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 adequate methods of contraception. 
 
Women who are not postmenopausal ( 12 months of non-therapy-induced amenorrhea) 
and have not 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 
 
Any T4 tumor as defined by tumor-node metastasis classification in UICC/AJCC, 
8th edition, including inflammatory breast cancer 
 
For the currently diagnosed breast cancer, any previous systemic anti-cancer treatment 
(e.g., neoadjuvant or adjuvant), including, but not limited to, chemotherapy, anti-HER2 
therapy (e.g., trastuzumab, trastuzumab emtansine, pertuzumab, lapatinib, neratinib, or 
other tyrosine kinase inhibitors), hormonal therapy, or anti-cancer RT other than planned in 
the context of this study 
 
Previous therapy with anthracyclines or taxanes for any malignancy 
 
History of DCIS and/or LCIS that was treated with any form of systemic, hormonal therapy, 
or RT to the ipsilateral breast where invasive cancer subsequently developed 


 
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– 
Patients who had their DCIS/LCIS treated only with surgery and/or contralateral 
DCIS treated with RT are allowed to enter the study. 
 
Contraindication to RT when adjuvant RT is clinically indicated 
 
Cardiopulmonary and/or cerebrovascular dysfunction as defined by any of the following 
prior to randomization 
– 
History of NCI CTCAE (v5.0) Grade  2 symptomatic congestive heart failure or 
New York Heart Association (NYHA) 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  160 mmHg and/or 
diastolic blood pressure  100 mmHg) 
– 
Evidence of transmural infarction on ECG 
– 
Requirement for oxygen therapy 
– 
Cerebrovascular ischemic event (e.g., ischemic within 12 months prior to 
randomization) 
 
Prior malignancies within 5 years prior to randomization, with the exception of those with a 
negligible risk of metastasis or death and treated with expected curative outcome 
(i.e., adequately treated carcinoma in situ of the cervix or basal or squamous cell skin 
cancer) 
 
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 any component of the atezolizumab formulation 
 
Known allergy or hypersensitivity to any component of the paclitaxel 
(e.g., polyoxyl 35 castor oil), cyclophosphamide, or doxorubicin/epirubicin formulations 
 
Known allergy or hypersensitivity to G-CSF or GM-CSF 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’s 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 are eligible for this study. 
– 
Patients with controlled Type I diabetes mellitus who are on an 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 
eligible for the study provided all the 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. 


 
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There has been 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. 
 
Current treatment with anti-viral therapy for HBV 
 
Urinary outflow obstruction 
 
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. 
 
Major surgical procedure other than for diagnosis within 4 weeks prior to initiation of 
study treatment or anticipation of need for a major surgical procedure during 
study treatment 
 
Prior allogeneic stem cell or solid organ transplant 
 
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 study or within 
5 months after the last dose of atezolizumab 
– 
Patients must agree not to receive live, attenuated influenza vaccine (e.g., FluMist) 
within 28 days prior to initiation of study treatment, 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 that contraindicates the use of an investigational drug, may affect the 
interpretation of the results, or may render the patient at high risk from treatment 
complications 
 
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, interleukin-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 factor [anti-TNF] alpha agents) within 2 weeks prior to initiation of 
study treatment or anticipation of need for systemic immunosuppressive medication 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 
based on investigator’s assessment of benefitrisk. The Medical Monitor is 
available to advise as needed. 
– 
The use of inhaled corticosteroids and mineralocorticoids (e.g., fludrocortisone) 
is allowed. 
 
Pregnant or lactating, or intending to become pregnant during the study 
 
Known clinically significant liver disease, including alcoholic hepatitis, cirrhosis, and 
inherited liver disease 
 
Under any legal protection (tutorship/curatorship). 


 
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END OF STUDY 
The study is planned to end after approximately 298 deaths have been observed for the 
analysis of OS. 
LENGTH OF STUDY 
The total duration of the study is expected to be approximately 7 years after the first patient is 
randomized. 
INVESTIGATIONAL MEDICINAL PRODUCTS 
The investigational medicinal products (IMPs) for this study are atezolizumab, paclitaxel, 
doxorubicin, epirubicin, and cyclophosphamide. 
ATEZOLIZUMAB (ARM A ONLY) 
Atezolizumab will be administered by IV infusion at a fixed dose of 840 mg Q2W (14 [ 3] days) 
in combination with T-AC/EC chemotherapy.  Upon completion of chemotherapy, atezolizumab 
will be continued as maintenance therapy at a dose of 1200 mg administered by IV infusion 
Q3W (21 [ 3] days) to complete 1 year of treatment (i.e., approximately 1 year total duration of 
atezolizumab therapy from first administration of atezolizumab). 
BACKGROUND TREATMENT 
Patients will receive paclitaxel (80 mg/m2) administered via IV infusion QW for 12 weeks 
followed by dose-dense doxorubicin (60 mg/m2) or dose-dense epirubicin (90 mg/m2) IV 
(investigator’s choice)  cyclophosphamide (600 mg/m2) administered via IV infusion Q2W with 
G-CSF/GM-CSF support for 4 cycles (i.e., a total of 4 doses of doxorubicin/epirubicin and 
cyclophosphamide). 
STATISTICAL METHODS 
PRIMARY ANALYSIS 
The primary efficacy variable is invasive disease-free survival (iDFS), defined as the time 
between randomization and date of first occurrence of an iDFS event as described in the 
protocol.  Data from patients who have not had an event at the time of data 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 of the respective analysis. 
Patients with no postbaseline information will be censored on the date of randomization. 
The log-rank test, stratified by the protocol-defined stratification factors, will be used to compare 
iDFS between the two treatment arms.  The hazard ratio (HR) for iDFS will be estimated with 
use of a stratified Cox proportional hazards model.  The Kaplan-Meier approach will be used to 
estimate 3-year iDFS rates, and corresponding 95% Cis for each treatment arm will be used to 
describe iDFS in addition to the HR. 
DETERMINATION OF SAMPLE SIZE 
The final analysis of the primary endpoint of iDFS will take place when approximately 
390 iDFS events have occurred in the intent-to-treat (ITT) population (approximately 17% of 
the planned enrollment of 2300 patients experiencing an iDFS event).  This sample size is 
computed on the basis of the following assumptions: 
 
Primary statistical test:  two-sided, stratified log-rank test at the 0.05 significance level in the 
ITT population 
 
Approximately 80% power for iDFS 
 
A HR of 0.75  
 
Annual hazard rates of 0.047, 0.108, 0.035, 0.038, 0.029, and 0.014 in Years 1, 2, 3, 4, 
56, and 7 and thereafter are assumed for the T-AC/EC arm based on the adjuvant 
TNBC trials ECOG E1199, BEATRICE, and IBCSG 22-00  
 
Based on the piecewise hazard rates given above for the control arm, and the assumed 
HR of 0.75 (thus reducing the risk of an iDFS event by 25% at each piecewise interval), the 
3 year iDFS rate (probability of not having any iDFS event in the first 3 years) will be 
82.7% in the T-AC/EC arm and 86.7% in the atezolizumab    T-AC/EC arm 
 
2.5% annual loss to follow-up for iDFS 


 
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 
Two interim analyses for iDFS in the ITT population (see below) 
 
One futility analysis for iDFS in the ITT population at the same time of the first interim 
analysis 
 
Accrual is projected to occur over 51 months.  The required number of iDFS events in the ITT 
population is projected to occur 73 months after first patient in.  Also, on the basis of these 
assumptions, an observed HR of 0.81 or better will result in a statistically significant difference 
between the treatment arms (i.e., HR  0.81 will be the minimally detectable difference for the 
analysis; this corresponds to an improvement in 3-year iDFS from 82.7% in the T-AC/EC arm to 
85.7% in the atezolizumab      T-AC/EC arm). 
The study duration for the secondary endpoint, OS, was determined on the basis of the number 
of events required to demonstrate efficacy with regard to OS.  A total of 300 deaths are required 
to achieve 80% power at a two-sided alpha level of 5% to detect an HR of 0.72, corresponding 
to an improvement in 5-year OS rate from 84% in the T-AC/EC arm to 88.2% in the 
atezolizumab      T-AC/EC arm assuming a constant hazard.  An annual loss to follow-up of 
2.5% and two interim analyses of OS are assumed.  The final analysis of OS is planned to take 
place approximately 7 years after the first patient has been randomized. 
INTERIM ANALYSES 
One interim efficacy analysis of iDFS will be performed when approximately 80% of the 
total planned number of iDFS events have occurred.  On the basis of the assumption presented 
above, it is projected that 80% (310) iDFS events will have been observed approximately 
59 months after the first patient randomized. 
The interim analysis boundary for statistical significance will be determined based on the 
Lan-DeMets -spending function with an O’Brien-Fleming boundary.  Statistical significance will 
be declared if the p-value from the two-sided stratified log-rank test is  0.0244 (observed 
HR  0.77) depending on the actually observed number of events.  If the null hypothesis for 
iDFS is not rejected at the interim analysis and the study continues, the final analysis of 
iDFS will be performed when approximately 388 iDFS events have occurred; statistical 
significance will be declared if the p-value from the two-sided stratified log-rank test is 
p  0.0429 (observed HR  0.81). 
 






 
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Appendix 2 Schedule of Activities (cont.)  
 
Screening a 
Treatment b 
Treatment 
Discontinuation c 
≤ 30 days after 
Last Dose 
(Arm A) or Last 
Monitoring Visit 
(Arm B) 
Follow−Up d 
Induction 
(28−day Cycles) 
(Cycles 1−5; 
Weeks 1−20) 
Arm A: Maintenance 
Arm B: Monitoring 
(21−day Cycles) 
(Cycles 6−16; 
Weeks 21−53) 
Days − 28 
to − 1 
Day 1 of each cycle 
(± 3 days) 
Arm A: Day 1 of each 
cycle (± 3 days);  
Arm B: Day 1 of every 
other cycle (± 7 days) 
Hematology p 
x 
On each infusion day 
Arm A: Day 1 of each 
cycle 
Arm B: Day 1 of every 
other cycle (starting 
with Cycle 6) 
x 
 
Chemistry q 
x  
On each infusion day 
Arm A: Day 1 of each 
cycle 
Arm B: Day 1 of every 
other cycle (starting 
with Cycle 6) 
x 
 
Menopausal status 
x 
 
 
x 
1 year after 
treatment 
discontinuation 
at closest visit 
Pregnancy test r 
x s 
x r 
x r 
x r 
x r 
Coagulation (INR, aPTT) 
x 
 
 
x 
 
TSH, free T3 (or total T3 t), free T4 
x 
x t 
x 
 
Viral serology u 
x 
 
 
 
 
 


 
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Appendix 2 Schedule of Activities (cont.)  
 
Screening a 
Treatment b 
Treatment 
Discontinuation c 
≤ 30 days after 
Last Dose 
(Arm A) or Last 
Monitoring Visit 
(Arm B) 
Follow−Up d 
Induction 
(28−day Cycles) 
(Cycles 1−5; 
Weeks 1−20) 
Arm A: Maintenance 
Arm B: Monitoring 
(21−day Cycles) 
(Cycles 6−16; 
Weeks 21−53) 
Days − 28 
to − 1 
Day 1 of each cycle 
(± 3 days) 
Arm A: Day 1 of each 
cycle (± 3 days);  
Arm B: Day 1 of every 
other cycle (± 7 days) 
Urinalysis v 
x  
x w 
 
 
Serum autoantibody sample 
 
See Appendix 2 of the Protocol for detailed schedule. 
Serum PK sample for atezolizumab 
 
See Appendix 2 of the Protocol for detailed schedule (Arm A only). 
Serum ADA sample for atezolizumab 
 
See Appendix 2 of the Protocol for detailed schedule (Arm A only). 
Plasma samples for biomarkers 
 
See Appendix 2 of the Protocol for detailed schedule. 
Blood sample for RPBS (optional) x 
 
x 
 
 
 
Radiographic assessments (e.g., CT, MRI, PET) 
x y,z 
As clinically indicated 
Bilateral mammogram/breast MRI 
x y 
 
x aa 
 
x aa 
Tumor biopsy/tumor tissue at relapse, if clinically 
feasible 
 
At time of recurrence bb 
Concomitant medications ii 
x cc 
x 
Arm A: Day 1 of each 
cycle 
Arm B: Day 1 of every 
other cycle (starting 
with Cycle 6) 
x 
x dd 
 


 
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Appendix 2 Schedule of Activities (cont.)  
 
Screening a 
Treatment b 
Treatment 
Discontinuation c 
≤ 30 days after 
Last Dose 
(Arm A) or Last 
Monitoring Visit 
(Arm B) 
Follow−Up d 
Induction 
(28−day Cycles) 
(Cycles 1−5; 
Weeks 1−20) 
Arm A: Maintenance 
Arm B: Monitoring 
(21−day Cycles) 
(Cycles 6−16; 
Weeks 21−53) 
Days − 28 
to − 1 
Day 1 of each cycle 
(± 3 days) 
Arm A: Day 1 of each 
cycle (± 3 days);  
Arm B: Day 1 of every 
other cycle (± 7 days) 
Adverse events ee 
x ee 
x ee 
Arm A: Day 1 of each 
cycle 
Arm B: Day 1 of every 
other cycle (starting 
with Cycle 6) 
x 
x ee 
Study treatment administration ff 
 
xff 
(± 1 day for weekly 
paclitaxel) 
x gg 
 
 
Survival follow-up and anti-cancer treatment 
 
 
 
 
x d,hh 
AC = dose-dense doxorubicin + cyclophosphamide; AC/EC = dose-dense doxorubicin/epirubicin + cyclophosphamide; ADA = anti-drug antibody; 
CT = computed tomography; EC = dose-dense epirubicin + cyclophosphamide; 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; FACT-G = Functional Assessment of Cancer Therapy−General; 
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; HR = hormone receptor; MRI = magnetic resonance imaging; MUGA = multiple-gated 
acquisition; PET = positron emission tomography; PK = pharmacokinetic; RPBS = Research Project Biological Samples; Q2W = every 2 weeks; 
T3 = triiodothyronine; T4 = thyroxine; TSH = thyroid-stimulating hormone. 
 


 
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Appendix 2 Schedule of Activities (cont.)  
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). 
a Results of standard-of-care tests or examinations performed prior to obtaining informed consent and within 28 days prior to randomization may 
be used; such tests do not need to be repeated for screening. 
b  In the event of treatment delay, study visits should continue as scheduled, if feasible.  Patients (both in Arm A and on Arm B) who discontinue 
study treatment prematurely due to an adverse event should conduct a treatment discontinuation visit and move to the follow-up.  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, including during the follow-up period.  Additional tests can be performed, if needed, according to standard medical practice. 
c Patients will return to the clinic for a treatment discontinuation visit not more than 30 days after the last dose of study treatment (Arm A) or within 
30 days after the last monitoring visit (Arm B). 
d The follow-up period begins from the date of treatment phase completion/early termination visit with a duration of up to 7 years from the date of 
randomization of the first patient.  Visit windows are ± 28 days for quarterly, semiannual, and annual 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, submission of tumor tissue sample to central laboratory can occur.  Tumor tissue, which can be 
obtained outside the 28-day screening period, 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 approximately 25 unstained slides 
(minimum of 20 slides) should be provided from the surgical resection specimen. Biomarker samples should not be collected for patients 
enrolling from China prior to the approval from Human Genetic Resources Administration of China. 
g Disease status based on all available clinical assessments should be documented from the date of randomization at the following timepoints 
(± 28 days):  every 3 months during study treatment and up to 3 years, every 6 months from 3 to 5 years, and annually thereafter unless a 
recurrence as defined in Section 4.6.6 of the Protocol has occurred.  In addition to physical examinations and mammograms, liver function tests, 
bone scans, chest X-rays/diagnostic CT, liver imaging, or other radiographic modality may be considered when clinically indicated to exclude 
metastatic disease and within a timeline as per current local standard of practice.  Disease recurrence must be confirmed pathologically if 
clinically feasible.  In cases of disease recurrence diagnosed at any time during the study, patients will be out of the study schedule and will be 
followed once a year (starting 1 year after first relapse) until end of study for survival, anti-cancer medications, and new relapse events. 


 
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Appendix 2 Schedule of Activities (cont.)  
h 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, laboratory results or health 
record, before administration of study treatment, and/or prior to the performance of any other study assessments that could bias patients’ 
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) (± 3 days); on Cycle 4, Day 1 (± 3 days); on Day 1 
of every other cycle thereafter until Cycle 16 (Arm A [± 3 days], Arm B  [± 7days]); and at the end of treatment/monitoring visit.  In case the 
treatment is interrupted/delayed, the patient should repeat the PRO assessment at the next visit, corresponding to the treatment administration 
day. 
i Patients who discontinue the study treatment phase (e.g., Arm A Maintenance and Arm B Monitoring) 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 follow-up period at the following timepoints: 
every 3 months (± 28 days) for the first year, every 6 months (± 28 days) for Years 2−3, and then annually (± 28 days) thereafter.  
j While on study treatment, all patients will complete the FACT-G, single item GP5 beginning on Cycle 4, Day 1 (± 3 days); at Day 1 of every other 
cycle thereafter until Cycle 16 (Arm A [± 3 days], Arm B  [± 7days]); and at the end of treatment/monitoring visit.  In case the treatment is 
interrupted/delayed, the patient should repeat the PRO assessment at the next visit, corresponding to the treatment administration day. 
k Includes respiratory rate, pulse rate, and systolic and diastolic blood pressure while the patient is in a seated position, and temperature.  Record 
vital signs at baseline in the 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. 
l Includes evaluation of the head, eyes, ears, nose, and throat, and the cardiovascular, dermatological, musculoskeletal, respiratory, 
gastrointestinal, and neurological systems.  Special attention should be paid to cardiovascular symptoms (e.g., abnormally low or irregular pulse, 
chest pain, tachycardia, swollen legs).  Record abnormalities observed at baseline in the eCRF.  At subsequent visits, record new or worsened 
clinically significant abnormalities on the Adverse Event eCRF. 
m Perform a limited, symptom-directed examination at specified timepoints and as clinically indicated at other timepoints.  Special attention should 
be paid to cardiovascular symptoms (e.g., abnormally low or irregular pulse, chest pain, tachycardia, swollen legs).  Record new or worsened 
clinically significant abnormalities on the Adverse Event eCRF. 
n ECG recordings will be obtained during screening and as clinically indicated at other timepoints.  It is recommended that patients be resting in a 
supine position for at least 10 minutes or as per local practice prior to ECG recording. 
o Cardiac monitoring (ECHO/MUGA scans) will be performed in 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. 


 
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Appendix 2 Schedule of Activities (cont.)  
For both Arms A and B, ECHO/MUGA scans should be obtained at baseline (i.e., screening ECHO/MUGA), between the second dose of AC/EC 
and the third dose of AC/EC (which should usually occur approximately between Week 16 and Week 18 if no treatment delays), and then every 
3 months [i.e., at Week 26 (± 14 days), at Week 39 (± 14 days), and at Week 52 (± 14 days) if no treatment delays].  ECHO/MUGA scans should 
be obtained at the early termination visit if not performed within the previous 6 weeks.  During the survival follow-up period, ECHO/MUGA scans 
should be obtained annually until the end of study. 
During the follow-up period, ECHO/MUGA scans should be obtained annually until the end of study (except for patients who experienced a 
recurrence of disease). 
p Hematology includes WBC count, RBC count, hemoglobin, hematocrit, platelet count, differential count (neutrophils, eosinophils, basophils, 
monocytes, lymphocytes, other cells). 
q Chemistry panel (serum or plasma) includes sodium, potassium, chloride, 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.  Lipase and amylase levels should be determined if clinically indicated by the presence of abdominal symptoms (e.g., 
abdominal pain, digestive disorders) suggestive of pancreatitis.  Bicarbonate/total CO2 should be determined if clinically indicated or considered 
standard of care. 
r 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 childbearing potential (including premenopausal women who have had tubal ligation) and women not 
meeting the definition of postmenopausal:  For Arm A at Day 1 of Cycles 1−16, at treatment discontinuation visit, and every 4 weeks until 
6 months after treatment discontinuation (last administered dose of study treatment) including for patients who experienced a disease 
recurrence.  For Arm B at Day 1 of Cycles 1−5, at treatment discontinuation visit, and every 4 weeks until 6 months after last administered dose 
of study treatment including for patients who experienced a disease recurrence.  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. 
s Screening pregnancy test results must be obtained within 14 days prior to initiation of study treatment. 
t 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.  Patients in Arm B can have thyroid function tests at Cycle 1, Cycle 4, and Cycle 8 and then continue being tested every fourth cycle. 
u 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 must also be performed to determine if the patient has an HBV infection.  If a patient 
has a positive HCV antibody test at screening, an HCV RNA test must also be performed to determine if the patient has an HCV infection. 
v Includes pH, specific gravity, glucose, protein, ketones, and blood; dipstick permitted. 


 
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Appendix 2 Schedule of Activities (cont.)  
w Urinalysis should be performed as clinically indicated during study treatment. 
x Not applicable for a site that has not been granted approval for RPBS.  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 RPBS at 
Week 1, Day 1 (Cycle 1, Day 1).  If, however, the RPBS 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. 
y Within 6 months prior to randomization (except for patients who do not have any remaining breast tissue due to prior prophylactic 
breast surgery). 
z Per local standard practice 
aa Mammograms of any remaining tissue should be performed at least annually (± 3 months) from the date of the mammogram performed at 
screening/surgery and as clinically indicated based on findings from physical examinations. 
bb Patients are required to undergo tumor biopsy sample collection, if deemed clinically feasible by the investigator, at the time of first evidence of 
radiographic disease relapse.  Examples of when tumor biopsy sample collection may be considered not clinically feasible include, but are not 
limited to, cases where the location of the tumor renders tumor biopsy unsafe or not clinically feasible per the investigator due to patient 
concerns or is prohibited by the institution or country. Biomarker samples should not be collected for patients enrolling from China prior to the 
approval from Human Genetic Resources Administration of China.Biopsies should be performed within 40 days after recurrence.  An FFPE block 
or at least 20 unstained slides should be provided.  Fine-needle aspiration, brushing, cell pellets from pleural effusion, bone metastases, and 
lavage samples are not acceptable.  For core needle biopsy specimens, at least two cores should be submitted for evaluation.  See 
Section 4.6.7 of the Protocol for tissue sample requirements. 
cc Includes any medication (e.g., prescription drugs, over-the-counter drugs, vaccines, herbal or homeopathic remedies, nutritional supplements) 
used by a patient in addition to protocol-mandated study treatment from 7 days prior to initiation of study treatment until the treatment 
discontinuation visit.  Record all prior anti-cancer therapies. 
dd All new anti-cancer treatments are to be reported during the follow-up period. 
ee 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 of the Protocol).  
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. 
 


 
Atezolizumab — F. Hoffmann-La Roche Ltd 
Statistical Analysis Plan BIG 16-05/AFT-27/WO39391 
49 
Appendix 2 Schedule of Activities (cont.)  
ff 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.  Paclitaxel should be administered as an IV infusion QW (7 [± 1] days).  During the 
induction treatment phase, the interval between the end of the weekly paclitaxel (Cycle 3 Visit 4) and the initiation of AC or EC Q2W (Cycle 4 
Visit 1) should be 7 days (± 1 day), (i.e., Cycle 4 Visit 1 should be performed at maximum 8 days from Cycle 3 Visit 4, as shown in the study 
schema [see Figure 1 of the Protocol]). Cyclophosphamide and doxorubicin/epirubicin will be administered Q2W (14 [± 3] days).  The 14-days 
interval only starts after Cycle 4 Visit 1 and the respective ± 3 days window allowed per protocol is only applicable from Cycle 4 Visit 2. 
gg Study drug administration during the maintenance phase for the atezolizumab-containing arm only  
hh 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 study is terminated).  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 (if allowed 
per country regulation). Every effort should be made to obtain information on patients who withdraw from the study treatment and/or 
assessments but have agreed to be contacted for further information (i.e., partial withdrawal).   Partial withdrawal from the study, with consent to 
allow collection of information regarding disease recurrence, survival status, and reportable toxicity should be documented in both the medical 
records and in the eCRF (i.e., the patient accepted to be contacted for collection of these data despite she/he withdrew consent from the study 
treatment and/or procedures). 
ii For patients in Arm B (Monitoring), only medications given for reportable adverse events as per protocol (see Section 5.3.1 of the Protocol) as 
well as new anti-cancer treatments should be collected.


 
Atezolizumab — F. Hoffmann-La Roche Ltd 
Statistical Analysis Plan BIG 16-05/AFT-27/WO39391 
50 
Appendix 3 Study Schema 
eTNBC 
Stage II-III
S
U
R
G
E
R
Y
Follow-up
50% Node+
n=2300
21
Week 1
3
5
13
24
27
51
33
Induction Treatment
Maintenance Treatment
Paclitaxel QW for 12 weeks
AC or EC Q2W for 4 doses supported with 
G-CSF/GM-CSF
Atezolizumab
Induction: 840 mg Q2W for 10 doses
Maintenance: 1200 mg Q3W to complete 1 year
42
9
1:1
Rand.a
Arm B
Arm A
19
Cycle 1
2
6
4
7
8
10
13
3
5
16
 
AC  dose-dense doxorubicin  cyclophosphamide; 
EC  dose-dense epirubicin  cyclophosphamide; eTNBC  early triple-negative breast cancer; 
G-CSF  granulocyte colony-stimulating factor; GM-CSF  granulocyte-macrophage 
colony-stimulating factor; QW  weekly; Q2W  every 2 weeks; Q3W  every 3 weeks; 
Rand  randomization. 
Notes:  The study population will be enriched for patients with node-positive disease such that 
the final population will contain no more than 50% of node-negative patients.  
Node-negative patients with tumors  2 cm in size are not eligible to participate in this study. 
G-CSF/pegylated G-CSF/GM-CSF will be used with each dose of AC/EC. 
In the induction period, 1 cycle  4 weeks; in the maintenance period, 1 cycle  3 weeks. 
a Randomization should occur no more than 8 weeks after definite surgery, and study drug 
administration should begin within 1 week after randomization but no sooner than 2 weeks 
after surgery. 
 


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