A Randomized, Double-Blind, Phase III Trial of Taxane/Trastuzumab/Pertuzumab With Atezolizumab or Placebo in First-Line HER2-Positive Metastatic Breast Cancer
Phase: PHASE3
Conditions: Metastatic Breast Adenocarcinoma, Metastatic HER2-Positive Breast Carcinoma, Recurrent Breast Adenocarcinoma, Recurrent HER2-Positive Breast Carcinoma, Stage III Breast Cancer AJCC v7, Stage IV Breast Cancer AJCC v6 and v7, Unresectable Breast Carcinoma, Unresectable HER2-Positive Breast Carcinoma
Sponsor: National Cancer Institute (NCI)

NRG-BR004 
NCI Version Date: August 15, 2022 
 
i 
Response to CTEP Approval Letter with Recommendations from Review of Amendment #10 of 
Protocol #NRG-BR004 (NRG Oncology Amendment #6) dated 8/5/2022 
 
I. Recommendations: 
# 
Section 
Comments 
1. 
Cover 
Page 
Study 
Data 
Submissi
on 
Please delete the highlighted language below: 
Data collection for this study will be done exclusively through Medidata Rave.  Refer to 
the data submission section of the protocol for further instructions. 
Do not submit study data or forms to the CTSU.  Do not copy the CTSU on data 
submissions. 
PI Response: The change was made as requested. 
2. 
8.2.1 
IRB 
Approval 
Please revise the following, as indicated:  
Sites participating with the NCI CIRB must submit the Study Specific Worksheet 
(SSW) for Local Context  to the CIRB using IRBManager to indicate their intent to 
open the study locally.  The NCI CIRB’s approval of the SSW is automatically 
communicated to the CTSU Regulatory Office, but sites are required to contact the 
CTSU Regulatory Office at CTSURegPref@ctsu.coccg.org to establish site 
preferences for applying NCI CIRB approvals across their Signatory Network.  Site 
preferences can be set at the network or protocol level.  Questions about establishing 
site preferences can be addressed to the CTSU Regulatory Office by email or calling 1-
888-651-CTSU (2878). 
PI Response: The change was made as requested. 
3. 
8.2.1 
IRB 
Approval 
It is indicated that this study is open to international sites. Therefore, please include the 
following language in this section: 
Sites using their local IRB or REB, must submit their approval to the CTSU Regulatory 
Office using the Regulatory Submission Portal located in the Regulatory section of the 
CTSU website. Acceptable documentation of local IRB/REB approval includes: 
Local IRB documentation; 
IRB-signed CTSU IRB Certification Form; and/or 
Protocol of Human Subjects Assurance Identification/IRB Certification/Declaration of 
Exemption Form. 
PI Response: The change was made as requested. 
4. 
8.2.4 
Downloa
ding Site 
Registrati
on 
Documen
ts 
Please revise the following language: 
Download the site registration forms from the protocol-specific page located on the 
CTSU members’ website.  Permission to view and download this protocol and its 
supporting documents is restricted to institutions and its associated investigators and 
staff on a participating roster.  To view/download stie registration forms: 
Use of this document is governed by the terms of use on the first page of this document.

NRG-BR004 
NCI Version Date: August 15, 2022 
 
ii 
# 
Section 
Comments 
Log in to the CTSU members' website (https://www.ctsu.org) using your CTEP-IAM 
username and password; 
Click on Protocols in the upper left of the screen 
Enter the protocol number in the search field at the top of the protocol tree, or 
Click on the By Lead Organization folder to expand, then select NRG Oncology, and 
protocol number (NRG-BR004); 
Click on Documents, Protocol Related Documents, and use the Document Type filter 
and select Site Registration and download and complete the forms provided.  (Note: For 
sites under the CIRB, IRB data will load automatically to the CTSU.) 
PI Response: The change was made as requested. 
5. 
8.2.6 
Delegatio
n of 
Tasks 
Log 
Please revise the following language: 
To maintain an approved site registration status, the CI must re-sign the DTL at least 
annually and when a new version of the DTL is released; and to activate new task 
assignments requiring CI sign-off.   
PI Response: The change was made as requested. 
6. 
13.4 
Data 
Quality 
Portal 
Please delete the following highlighted text in this section:  
Data Quality Portal 
The Data Quality Portal (DQP) provides a central location for site staff to manage 
unanswered queries and form delinquencies, monitor data quality and timeliness, 
generate reports, and review metrics.  
The DQP is located on the CTSU members’ website under Data Management.  The 
Rave Home section displays a table providing summary counts of Total Delinquencies 
and Total Queries.  DQP Queries, DQP Delinquent Forms, DQP Form Status and the 
DQP Reports modules are available to access details and reports of unanswered queries, 
delinquent forms, and forms with current status and timeliness reports.  Review the 
DQP modules on a regular basis to manage specified queries and delinquent forms. 
The DQP is accessible by site staff that are rostered to a site and have access to the 
CTSU website.  Staff that have Rave study access can access the Rave study data using 
a direct link on the DQP. 
To learn more about DQP use and access, click on the Help icon displayed on the Rave 
Home, DQP Queries, DQP Delinquent Forms, DQP Forms Status, and DQP Reports 
modules. 
Note: Some Rave protocols may not have delinquent form details or reports specified on 
the DQP.  A protocol must have the Calendar functionality implemented in Rave by the 
Lead Protocol Organization (LPO) for delinquent form details and reports to be 
available on the DQP.  Site staff should contact the LPO Data Manager for their 
protocol regarding questions about Rave Calendaring functionality. 
PI Response: The change was made as requested. 
 
 
Use of this document is governed by the terms of use on the first page of this document.

NRG-BR004 
NCI Version Date: August 15, 2022 
 
iii 
 
II. Company Comments – Recommendations (no response required):  
# 
Section 
Comments 
7. 
14.8.3.3 
Minor suggestions: 
Type I error rate of 0.05 “(2-sided)”. 
The last sentence: 43% at the primary analysis. What does it mean? 
PI Response: The type 1 error rate of 0.05 was clarified to indicate that it is a two-
sided test.  Under the original design, we would have 80% power to detect a PFS 
HR=0.733.  Under the amended design, we would have 80% power to detect a PFS 
HR=0.6.  In this statement: “The chance to detect a PFS hazard ratio at 0.733, as 
originally designed, would be about 43% at the primary analysis,” we basically 
stated that the power to detect a PFS HR=0.733 under the amended design would be 
about 43%. 
 
III. Additional Change 
# 
Section 
Comments 
8. 
ICD 
The date has been changed to match the most recent version of the protocol. 
 
 
Use of this document is governed by the terms of use on the first page of this document.

Use of this document is governed by the terms of use on the first page of this document.

Use of this document is governed by the terms of use on the first page of this document.

 
NRG-BR004 
3 
NCI Version Date: August 15, 2022 
Protocol Agents 
NCI-Supplied Agents: Atezolizumab/Placebo (NSC 783608) 
Trastuzumab (NSC 688097) – commercial agent supplied to U.S. sites only 
 
Commercial Agents:  Paclitaxel (NSC 673089) 
Docetaxel (NSC 628503) 
Pertuzumab (NSC 740102) 
 
IND #: 
 
IND Sponsor: DCTD, NCI 
 
Participating Sites 
܈ U.S. 
܈ Canada  
܆ Approved International Member Sites 
Document History 
 
Version/Date 
Amendment 7 
August 15, 2022 
Amendment 6 
July 14, 2022 
Amendment 5 
January 14, 2022 
Amendment 4 
June 28, 2021 
Amendment 3 
March 30, 2021 
Amendment 2 
March 9, 2020 
Amendment 1 
August 5, 2019 
Pre-Activation Revision 
February 14, 2019 
Initial 
October 11, 2018 
 
This protocol was designed and developed by NRG Oncology.  It is intended to be used only in 
conjunction with institution-specific IRB approval for study entry.  No other use or reproduction is 
authorized by NRG Oncology nor does NRG Oncology assume any responsibility for unauthorized 
use of this protocol. 
Use of this document is governed by the terms of use on the first page of this document.

 
NRG-BR004 
4 
NCI Version Date: August 15, 2022 
CANCER TRIALS SUPPORT UNIT (CTSU) ADDRESS AND CONTACT INFORMATION 
For regulatory requirements: 
For patient enrollments: 
For study data submission: 
Regulatory documentation 
must be submitted to the 
Cancer Trials Support Unit 
(CTSU) via the Regulatory 
Submission Portal. 
(Sign in at www.ctsu.org, and 
select the Regulatory > 
Regulatory Submission.) 
Institutions with patients 
waiting that are unable to use 
the Portal should alert the 
CTSU Regulatory Office 
immediately by phone or 
email: 1-866-651-CTSU 
(2878), or 
CTSURegHelp@coccg.org to 
receive further instruction and 
support. 
Contact the CTSU Regulatory 
Help Desk at 1-866-651-CTSU 
(2878) for regulatory 
assistance. 
Refer to the patient enrollment 
section of the protocol for 
instructions on using the 
Oncology Patient Enrollment 
Network (OPEN).  OPEN is 
accessed at https://www.ctsu.org/ 
OPEN SYSTEM/ or 
https://OPEN.ctsu.org. 
Contact the CTSU Help Desk with 
any OPEN-related questions by 
phone or email: 1-888-823-5923, or 
ctsucontact@westat.com. 
Data collection for this study 
will be done exclusively 
through Medidata Rave.  Refer 
to the data submission section of 
the protocol for further 
instructions. 
 
The most current version of the study protocol and all supporting documents must be downloaded 
from the protocol-specific Web page of the CTSU Members' website located at https://www.ctsu.org.  
Access to the CTSU Members' website is managed through the Cancer Therapy and Evaluation 
Program - Identity and Access Management (CTEP-IAM) registration system and requires user log on 
with CTEP-IAM username and password. 
Permission to view and download this protocol and its supporting documents is restricted and is based 
on person and site roster assignment housed in the CTSU Regulatory Support System (RSS). 
For clinical questions (i.e., patient eligibility or treatment-related), contact the Clinical 
Coordinating Department at NRG Oncology at 1-800-477-7227 or by e-mail at 
ccdPGH@NRGOncology.org. 
For non-clinical questions (i.e., unrelated to patient eligibility, treatment, or clinical data 
submission), contact the CTSU Help Desk by phone or email: 
CTSU General Information Line – 1-888-823-5923 or ctsucontact@westat.com.  All calls and 
correspondence will be triaged to the appropriate CTSU representative. 
The CTSU website is located at https://www.ctsu.org. 
 
 
Use of this document is governed by the terms of use on the first page of this document.

 
NRG-BR004 
5 
NCI Version Date: August 15, 2022 
TABLE OF CONTENTS 
Cancer Trials Support Unit (CTSU) Address and Contact Information .......................................... 4 
 
1.0 
OBJECTIVES ................................................................................................................................ 10 
1.1 
Primary Objective ............................................................................................................. 10 
1.2 
Secondary Objectives ....................................................................................................... 10 
1.3 
Exploratory Objectives ..................................................................................................... 10 
2.0 
BACKGROUND ........................................................................................................................... 11 
2.1 
Introduction ....................................................................................................................... 11 
2.2 
HER2-Positive Metastatic Breast Cancer ......................................................................... 13 
2.3 
Immune System and HER2-Targeted Treatment in Breast Cancer .................................. 14 
2.4 
Atezolizumab .................................................................................................................... 15 
2.5 
Atezolizumab in Breast Cancer ........................................................................................ 18 
2.6 
Rationale for Dose Selection/Regimen/Modification ....................................................... 19 
2.7 
Rationale for Amendment #3 to Allow Investigator Discretion on Choice of Taxane ..... 20 
2.8 
Early Closure to Accrual of NRG-BR004 ........................................................................ 21 
3.0 
PATIENT SELECTION, ELIGIBILITY, AND INELIGIBILITY CRITERIA ............................ 24 
3.1 
Patient Selection Guidelines ............................................................................................. 24 
3.2 
Patient Entry and Randomization ..................................................................................... 24 
3.3 
Eligibility Criteria ............................................................................................................. 25 
3.4 
Ineligibility Criteria .......................................................................................................... 27 
4.0 
REQUIREMENTS FOR STUDY ENTRY, TREATMENT, AND FOLLOW-UP ....................... 31 
5.0 
TREATMENT REGIMENS .......................................................................................................... 38 
5.1 
Treatment Regimen for Arm 1 and Arm 2 ........................................................................ 38 
5.2 
Endocrine Therapy Following Paclitaxel and Docetaxel .................................................. 41 
5.3 
Dose Determinations ......................................................................................................... 41 
5.4 
General Concomitant Medication and Supportive Care Guidelines ................................. 41 
5.5 
Duration of Therapy .......................................................................................................... 43 
6.0 
TREATMENT MODIFICATIONS/MANAGEMENT ................................................................. 44 
6.1 
General Instructions .......................................................................................................... 44 
6.2 
Tumor Progression ............................................................................................................ 44 
6.3 
Treatment Decisions When Components of Therapy Must Be Held or Discontinued ..... 44 
6.4 
Management of Atezolizumab/Placebo Immune-Mediated Toxicities and Potential 
Unblinding ........................................................................................................................ 45 
6.5 
Management of Diarrhea Potentially Related to Study Therapy ...................................... 47 
6.6 
Management of Cardiac Toxicity Related to Study Therapy ........................................... 59 
6.7 
Treatment Modifications for Other Toxicities Related to Trastuzumab and Pertuzumab 64 
6.8 
Pulmonary Events ............................................................................................................. 66 
6.9 
Hepatic Events .................................................................................................................. 67 
6.10 
Endocrine Events .............................................................................................................. 68 
6.11 
Ocular Events .................................................................................................................... 71 
6.12 
Infusion-Related Reaction and Cytokine-Release Syndrome ........................................... 71 
6.13 
Management of Pancreatic Events .................................................................................... 76 
6.14 
Dermatologic Events ......................................................................................................... 78 
6.15 
Neurological Disorders ..................................................................................................... 78 
6.16 
Immune-mediated meningoencephalitis ........................................................................... 80 
6.17 
Immune-Mediated Renal Events ....................................................................................... 81 
Use of this document is governed by the terms of use on the first page of this document.

 
NRG-BR004 
6 
NCI Version Date: August 15, 2022 
6.18 
Immune-mediated myositis ............................................................................................... 81 
6.19 
Hemophagocytic lymphohistiocytosis and macrophage activation syndrome ................. 83 
6.20 
Management Guidelines for Other Immune-Mediated Toxicities Potentially Related to 
Atezolizumab/Placebo ...................................................................................................... 84 
6.21 
Liver dysfunction (Hy's Law) ........................................................................................... 85 
6.22 
Treatment Management for Paclitaxel and Docetaxel for Arms 1 and 2 .......................... 85 
7.0 
ADVERSE EVENTS REPORTING REQUIREMENTS .............................................................. 92 
7.1 
Study Agents ..................................................................................................................... 92 
7.2 
Adverse Events and Serious Adverse Events ................................................................... 92 
7.3 
Adverse Events for Study Agents ..................................................................................... 93 
7.4 
PRO-CTCAE Assessment Items ..................................................................................... 105 
7.5 
Expedited Reporting of Adverse Events ......................................................................... 106 
7.6 
Routine Reporting of Adverse Events ............................................................................ 111 
7.7 
Reporting Breast Cancer Progression and Second Primary Cancer................................ 112 
8.0 
REGISTRATION, STUDY ENTRY, AND WITHDRAWAL PROCEDURES ........................ 113 
8.1 
CTEP Registration Procedures ....................................................................................... 113 
8.2 
Cancer Trials Support Unit Registration Procedures ...................................................... 114 
8.3 
Patient Enrollment .......................................................................................................... 116 
8.4 
Oncology Patient Enrollment Network (OPEN) ............................................................. 116 
8.5 
ePRO Registration Process ............................................................................................. 117 
8.6 
Reimbursement ............................................................................................................... 118 
8.7 
Investigator-Initiated Discontinuation of Study Therapy ............................................... 118 
8.8 
Patient-Initiated Discontinuation of Study Therapy ....................................................... 119 
8.9 
Patient-Initiated Consent Withdrawal from the Study .................................................... 119 
9.0 
DRUG INFORMATION ............................................................................................................. 120 
9.1 
Atezolizumab (IND #
 NSC #783608) ................................................................ 120 
9.2 
Paclitaxel (NSC #673089) .............................................................................................. 124 
9.3 
Docetaxel (NSC #628503) .............................................................................................. 124 
9.4 
Pertuzumab (NSC #740102) ........................................................................................... 125 
9.5 
Trastuzumab (NSC #688097) ......................................................................................... 125 
9.6 
Unblinding ...................................................................................................................... 127 
10.0 
BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES ................................................... 128 
10.1 
Overview of Tumor Specimen Submissions ................................................................... 128 
10.2 
Specimen Submission Information ................................................................................. 130 
10.3 
Integral Marker Testing .................................................................................................. 130 
10.4 
Exploratory Analyses ...................................................................................................... 131 
11.0 
SPECIAL STUDIES (NON-TISSUE) ......................................................................................... 132 
11.1 
Quality of Life (QOL) Background ................................................................................ 132 
11.2 
Aims and Hypotheses ..................................................................................................... 134 
11.3 
Administration of BR004 Patient-Completed Questionnaires ........................................ 135 
11.4 
Administration Instructions ............................................................................................ 135 
11.5 
QOL Patient Population .................................................................................................. 136 
11.6 
Additional Toxicity Monitoring with PRO-CTCAE ...................................................... 136 
11.7 
Administration of PRO-CTCAE ..................................................................................... 137 
11.8 
Administration Instructions ............................................................................................ 137 
11.9 
PRO-CTCAE Patient Population .................................................................................... 138 
12.0 
MEASUREMENT OF EFFECT .................................................................................................. 139 
12.1 
Definitions ...................................................................................................................... 139 
Use of this document is governed by the terms of use on the first page of this document.

 
NRG-BR004 
7 
NCI Version Date: August 15, 2022 
12.2 
Disease Parameters ......................................................................................................... 139 
12.3 
Response Criteria ............................................................................................................ 141 
12.4 
Evaluation of Best Overall Response ............................................................................. 142 
12.5 
Symptomatic Deterioration ............................................................................................. 143 
12.6 
Duration of Response ...................................................................................................... 143 
12.7 
Progression-Free Survival ............................................................................................... 143 
13.0 
DATA AND RECORDS ............................................................................................................. 144 
13.1 
Data Management/Collection ......................................................................................... 144 
13.2 
Summary of Data Submission ........................................................................................ 145 
13.3 
Enhanced Centralized Data Monitoring .......................................................................... 145 
13.4 
Data Quality Portal ......................................................................................................... 148 
13.5 
Rave-CTEP-AERS Integration ....................................................................................... 148 
13.6 
Global Reporting/Monitoring ......................................................................................... 149 
14.0 
STATISTICAL CONSIDERATIONS ......................................................................................... 150 
14.1 
Study Design ................................................................................................................... 150 
14.2 
Study Endpoints .............................................................................................................. 150 
14.3 
Primary Objective and Primary Hypothesis ................................................................... 151 
14.4 
Statistical Analyses ......................................................................................................... 151 
14.5 
Study Monitoring ............................................................................................................ 156 
14.6 
Statistical Consideration for QOL Study ........................................................................ 158 
14.7 
Gender/Ethnicity/Race Distribution ................................................................................ 160 
14.8 
Amended Statistical Considerations ............................................................................... 162 
15.0 
PUBLICATION INFORMATION AND ADMINISTRATIVE AGREEMENTS ..................... 169 
16.0 
REFERENCES ............................................................................................................................ 171 
Appendix A 
Assessment of Performance Status and Activities of Daily Living ................................ 179 
Appendix B 
Medidata Patient Cloud ePRO Operational Procedures ................................................. 180 
 
Figure 1. 
NRG-BR004 Schema .......................................................................................................... 9 
Figure 2. 
Key mechanisms of involvement of the immune system in response to trastuzumab and 
other HER2-targeted monoclonal antibodies .................................................................... 14 
Table 1. 
Tests, exams, and other requirements prior to study entry and randomization ................. 31 
Table 2. 
Tests, exams, and other requirements during therapy and through Year 10 for  
Arm 1 and Arm 2 .............................................................................................................. 34 
Table 2A. 
Required status updates after study closure through April 2024 for Arm 1  
and Arm 2 ......................................................................................................................... 37 
Table 3. 
Treatment regimen for Arm 1 and Arm 2 ......................................................................... 38 
Table 4. 
Dose modifications and instructions for atezolizumab/placebo for treatment-related 
diarrhea or colitis .............................................................................................................. 49 
Table 5. 
Dose modifications and instructions for trastuzumab, pertuzumab, and paclitaxel for  
treatment-related diarrhea or colitis during paclitaxel administration .............................. 51 
Table 6. 
Dose modifications and instructions for trastuzumab, pertuzumab, and docetaxel for 
treatment-related diarrhea or colitis during docetaxel administration .............................. 54 
Table 7. 
Dose modifications and instructions for trastuzumab and pertuzumab for treatment-
related diarrhea or colitis following completion of chemotherapy administration ........... 57 
Table 8. 
Treatment modifications and instructions for cardiac toxicities related to trastuzumab, 
pertuzumab, or atezolizumab/placebo .............................................................................. 60 
Table 9. 
CTCAE Grade 2 Other Cardiac Disorders ........................................................................ 63 
Use of this document is governed by the terms of use on the first page of this document.

 
NRG-BR004 
8 
NCI Version Date: August 15, 2022 
Table 10. 
Trastuzumab, pertuzumab, and atezolizumab/placebo management based on LVEF 
assessments ....................................................................................................................... 64 
Table 11. 
Treatment modifications and instructions for other toxicities related to trastuzumab  
and pertuzumab ................................................................................................................. 64 
Table 12. 
Management guidelines for pulmonary events, including pneumonitis, related to 
atezolizumab/placebo ........................................................................................................ 67 
Table 13. 
Management guidelines for hepatic events related to atezolizumab/placebo ................... 68 
Table 14. 
Management guidelines for endocrine events related to atezolizumab/placebo ............... 69 
Table 15. 
Management guidelines for ocular events related to atezolizumab/placebo ..................... 71 
Table 16. 
Management guidelines for infusion-related reactions and cytokine-release syndrome 
related to atezolizumab/placebo ........................................................................................ 72 
Table 17. 
Management guidelines for pancreatic events, including pancreatitis, related to 
atezolizumab/placebo ........................................................................................................ 76 
Table 18. 
Management for dermatologic events related to atezolizumab/placebo ........................... 78 
Table 19. 
Treatment management guidelines for neurological disorders related to 
atezolizumab/placebo ........................................................................................................ 79 
Table 20. 
Management guidelines for immune-mediated meningoencephalitis related to 
atezolizumab/placebo ........................................................................................................ 80 
Table 21. 
Management and evaluation of immune-mediated renal events (potential immune-
mediated nephritis) ........................................................................................................... 81 
Table 22. 
Management and evaluation of immune-mediated myositis ............................................ 82 
Table 23. 
Management and evaluation of hemophagocytic lymphohistiocytosis and macrophage 
activation syndrome .......................................................................................................... 84 
Table 24. 
Management guidelines for other immune-mediated toxicities potentially related to 
atezolizumab/placebo not covered on other tables ........................................................... 84 
Table 25. 
Dose levels for paclitaxel and docetaxel (Arm 1 and Arm 2) ........................................... 86 
Table 26. 
Dose modifications and instructions for paclitaxel (Arm 1 and Arm 2) ........................... 87 
Table 27. 
Dose modifications and instructions for docetaxel (Arm 1 and Arm 2) ........................... 89 
Table 28. 
Treatment management for taxane-related neuropathy (Arm 1 and Arm 2)..................... 90 
Table 29. 
Treatment management for taxane-related musculoskeletal pain (Arm 1 and  Arm 2) .... 91 
Table 30. 
Comprehensive adverse events and potential risks list (CAEPR) for Pertuzumab   
(NSC 740102) ................................................................................................................... 94 
Table 31. 
Comprehensive adverse events and potential risks list (CAEPR) for Trastuzumab 
(Herceptin, NSC 688097) and Herceptin Hylecta™ (SQ trastuzumab, NSC 827797) ..... 97 
Table 32. 
 Comprehensive adverse events and potential risks list (CAEPR) for Atezolizumab 
(MPDL 3280A, NSC 783608) ........................................................................................ 101 
Table 33. 
Expedited reporting requirements for adverse events that occur on studies under an  
IND within 30 days of the last administration of the investigational agent 
atezolizumab/placebo and/or commercial agents 
(trastuzumab/pertuzumab/paclitaxel/docetaxel) ............................................................. 108 
Table 34. 
Mandatory and optional sample requirements ................................................................ 128 
Table 35. 
Time point response: patients with target (r non-target) disease ................................... 142 
Table 36. 
Time point response: patients with non-target disease only ........................................... 142 
Table 37. 
Expected racial and ethnic composition of NRG-BR004 ............................................... 161 
Table 38. 
Racial and ethnic composition of NRG-BR004 .............................................................. 167 
Use of this document is governed by the terms of use on the first page of this document.

 
NRG-BR004 
10 
NCI Version Date: August 15, 2022 
1.0 
OBJECTIVES 
1.1 
Primary Objective 
To determine whether the addition of atezolizumab to a regimen of pertuzumab and trastuzumab 
combined with a taxane (paclitaxel or docetaxel) will improve the progression-free survival 
(PFS), assessed by investigator using RECIST 1.1 criteria, relative to the addition of a placebo to 
a regimen of pertuzumab and trastuzumab combined with a taxane (paclitaxel or docetaxel) in 
patients with newly documented HER2-positive measurable metastatic breast cancer. 
1.2 
Secondary Objectives 
1.2.1 
To determine whether the addition of atezolizumab to a regimen of pertuzumab and trastuzumab 
combined with a taxane (paclitaxel or docetaxel) will improve the overall survival (OS) relative 
to the addition of placebo to a regimen of pertuzumab and trastuzumab, combined with a taxane 
(paclitaxel or docetaxel). 
1.2.2 
To determine whether the addition of atezolizumab to a regimen of pertuzumab and trastuzumab 
combined with a taxane (paclitaxel or docetaxel) will improve the overall objective response 
(OR) in the cohort of patients randomized 6 months or more prior to study accrual closure 
assessed by investigator using RECIST 1.1 criteria, relative to the addition of placebo to a 
regimen of pertuzumab and trastuzumab combined with a taxane (paclitaxel or docetaxel). 
1.2.3 
To determine the immune-related toxicity profile of the two treatment regimens. 
1.2.4 
To determine the cardiac safety profile of the two treatment regimens. 
1.3 
Exploratory Objectives 
1.3.1 
To determine whether the addition of atezolizumab to a regimen of pertuzumab and trastuzumab 
combined with a taxane (paclitaxel or docetaxel) will decrease the incidence of subsequent brain 
metastases in patients without known brain metastases at study entry relative to the addition of 
placebo to a regimen of pertuzumab and trastuzumab combined with a taxane (paclitaxel or 
docetaxel). 
1.3.2 
To determine the utility of PD-L1 IHC staining as a predictive and prognostic biomarker 
associated with clinical response, as assessed by investigator using RECIST 1.1 criteria, to 
atezolizumab in combination with trastuzumab and pertuzumab combined with a taxane 
(paclitaxel or docetaxel). 
1.3.3 
To identify potential biomarkers that can predict benefit from the addition of atezolizumab in 
patients with newly documented HER2-positive measurable metastatic breast cancer treated with 
a regimen of pertuzumab and trastuzumab combined with a taxane (paclitaxel or docetaxel). 
1.3.4 
To explore the toxicity profile of the two treatment regimens using patient-reported symptomatic 
adverse events in addition to standard adverse event reports. 
1.3.5 
To determine the feasibility and added value of frequent assessment of toxicity using PRO-
CTCAE with ePRO reporting. 
1.3.6 
To explore whether the addition of atezolizumab to a regimen of pertuzumab and trastuzumab 
combined with a taxane (paclitaxel or docetaxel) will contribute to increased patient-reported 
fatigue in comparison to the addition of placebo to a regimen of pertuzumab and trastuzumab 
combined with a taxane (paclitaxel or docetaxel). 
 
 
Use of this document is governed by the terms of use on the first page of this document.

 
NRG-BR004 
11 
NCI Version Date: August 15, 2022 
2.0 
BACKGROUND 
2.1 
Introduction 
The Clinical Evaluation of Pertuzumab and Trastuzumab (CLEOPATRA) study demonstrated 
substantial improvement in long-term outcomes with the addition of pertuzumab to trastuzumab 
and docetaxel as first-line treatment for patients with HER2-positive metastatic breast cancer 
(MBC).  While median progression-free survival (PFS) was improved by 6 months and median 
overall survival (OS) by an impressive 16 months with the addition of pertuzumab, two-thirds of 
patients receiving the 3-drug combination had disease progression by 3 years, and one third had 
died by that time (Baselga 2012, Swain 2015).  Over half of the patients receiving dual HER-
targeted therapy had expired by 5 years with most deaths due to progressive breast cancer.  Novel 
approaches for treatment continue to need to be explored for these patients.   
One approach is to continue efforts to understand the multiple mechanisms of resistance to the 
disruption of oncogenic signaling pathways that evolve while patients are on prolonged therapy 
with trastuzumab and pertuzumab.  Identification and understanding of these mechanisms may 
help develop additional therapies that can provide benefit for the subsets of patients with specific 
resistance mechanisms.  However, this approach will require development of an array of agents to 
inhibit a variety of evolving resistance mechanisms and, ultimately, resistance to the additional 
therapies seems probable.  If a promising alternative approach is available for study that offers 
potential for managing the problem of evolving resistance in an innovative manner, it should be 
aggressively pursued.  
The mechanisms of action for the therapeutic HER2-targeted monoclonal antibodies in 
combination with chemotherapy are complex, but a rapidly evolving body of literature indicates 
an important component of the activity is mediated through the adaptive immune system initially 
by antibody-dependent cell-mediated cytotoxicity (ADCC) (Bianchini 2014).  Cross-priming of 
antigen specific cytotoxic T-cells following ADCC also occurs, but the impact of T-cell 
activation may be abrogated by upregulation and interaction of normal checkpoint inhibitors of 
cytotoxic T-cell function such as programmed death-1 (PD-1) and programmed death-ligand 1 
(PD-L1).  Suppression of these inhibitors with monoclonal antibodies co-administered with dual 
HER2-targeted monoclonal antibodies and chemotherapy could improve the long-term efficacy of 
the therapy.  The safety and activity of the PD-1 and PD-L1 inhibitors have been demonstrated in 
a wide range of cancers, and justify evaluation in patients with newly documented metastatic 
HER2-positive breast cancer, many of whom will have developed recurrent disease after 
receiving HER2-targeted monoclonal antibodies in the neoadjuvant and adjuvant settings.  We 
propose a randomized Phase III clinical trial to evaluate the efficacy and the safety of the addition 
of the PD-L1 inhibitor, atezolizumab, to a regimen of paclitaxel, trastuzumab, and pertuzumab 
versus a regimen of paclitaxel, trastuzumab, and pertuzumab in HER2-positive MBC in the first-
line setting.   
The development of trastuzumab and the incorporation of the monoclonal antibody as the core 
therapy of HER2-positive MBC have been transformative (Slamon 2001).  Binding of the 
antibody to the overexpressed HER2 receptors that occur as a result of amplification of the HER2 
gene, substantially enhances the efficacy of numerous chemotherapeutic agents through inhibition 
of the aberrantly activated downstream pathways impacted by the HER family of receptors.  
These activated pathways drive the aggressive phenotype of HER2-positive breast cancer and 
promote resistance to chemotherapy and endocrine therapy.  This landmark advancement in the 
treatment of this aggressive phenotype of breast cancer has been of even greater clinical relevance 
because of the remarkable safety profile of trastuzumab.   
Use of this document is governed by the terms of use on the first page of this document.

 
NRG-BR004 
12 
NCI Version Date: August 15, 2022 
However, primary resistance to trastuzumab is present in an important minority of the  
HER2-positive cancers in these patients and the large majority eventually develop resistance to 
trastuzumab.  Efforts to understand mechanisms of resistance to trastuzumab and identify 
therapies to address those mechanisms have met with some notable success.  The  
co-administration of a second monoclonal antibody, pertuzumab, targeting the dimerization 
domain of the HER2 protein, with trastuzumab and docetaxel in the CLEOPATRA trial improved 
median PFS by 6 months and resulted in an unprecedented improvement in median OS of  
16 months to almost 5 years (Baselga 2012, Swain 2015).  Again, this substantive improvement 
in outcomes was achieved without the addition of substantial toxicities.  However, these patients 
require prolonged administration of these therapies and, ultimately, the large majority still 
develop resistant disease and eventually succumb to their cancer.  Efforts to understand the 
mechanism of resistance may identify additional therapies that can further prolong survival, but to 
date efforts to target key downstream proteins thought to play a role in resistance have not been 
very effective and have been associated with substantial additional toxicities (André 2015, 
Hurvitz 2015).  Alternative strategies that cannot be overcome by the complex pathway resistance 
mechanisms need to be identified and aggressively evaluated. 
Fortunately, the activity of trastuzumab and pertuzumab is not limited to the ability of the drugs 
to interrupt oncogenic signaling pathways.  The antibodies were developed with functional Fc 
receptors to provide opportunity for development of adaptive immunity through ADCC.  
Following cell death through ADCC, presentation of tumor antigens and tumor antigens 
complexed with the antibodies to antigen processing cells can activate an adaptive immune 
response generating cytotoxic memory CD8+ T cells.  Recognition of the increased activity of 
trastuzumab in the presence of CD8+ tumor infiltrating lymphocytes (TILs) supports active 
investigation of therapies that can enhance the adaptive immune response (Bianchini 2014).  
Preclinical studies have demonstrated the therapeutic effect of trastuzumab depends on both 
innate and adaptive immunity.  An important new group of therapeutic agents are the checkpoint 
inhibitor monoclonal antibodies, particularly those that can abrogate the inhibitory signals of 
cancer cells through PD-L1 and PD-1 interactions with cytotoxic T cells in the tumor 
microenvironment.  These new therapeutics have demonstrated remarkable activity and 
manageable toxicity in patients with melanoma, non-small cell lung, bladder, and head and neck 
cancer.  Pilot studies in triple-negative breast cancer (TNBC) and colon cancer in patients with 
mismatch repair defects have demonstrated efficacy and a favorable toxicity profile (Nanda 2014, 
Emens 2015, Powles 2014, Le 2015).  While only a minority of patients respond to monotherapy 
with these agents, responses are often prolonged.  This data suggests that efforts to augment the 
immune-based components of trastuzumab therapy with these agents may be more productive 
than efforts to address the resistance mechanisms that evolve to overcome the interruption of 
oncogenic signaling. 
Pertuzumab also promotes ADCC and may augment the ADCC of trastuzumab (El-Sahwi 2010).  
These two well-tolerated monoclonal antibodies initially interrupt oncogenic signaling in a 
majority of patients and provide for ongoing ADCC with potential development of adaptive 
immunity.  An important minority of patients receiving HER2-targeted monoclonal antibody 
therapy and chemotherapy for first-line treatment of HER2-positive MBC continue to enjoy 
freedom from progression even after discontinuing the medications following years of therapy.  
One explanation could be that the adaptive immune response in some of these patients was 
sufficient to eradicate their metastatic disease.  The failure of the adaptive immunity to eliminate 
the cancer in the large majority of patients could be explained in part by upregulation of PD-1 in 
the tumor microenvironment, as well as expression of PD-L1 in the cancer cells surviving the 
initial therapy.  Inhibition of the local immunosuppressive effects of PD-L1 expression by co-
administration of an anti-PD-1 monoclonal antibody may overcome a potential major mechanism 
Use of this document is governed by the terms of use on the first page of this document.

 
NRG-BR004 
13 
NCI Version Date: August 15, 2022 
of resistance independent of signaling pathway resistant mechanisms.  Demonstration of 
therapeutic synergy between the ADCC inducing monoclonal antibodies trastuzumab and 
pertuzumab, which target a cancer-specific antigen (HER2), and a PD-1 checkpoint inhibitor 
could represent another transformative change for patients with HER2-positive breast cancer.  It 
could also have broad potential implications for the field of immuno-oncology.  
2.2 
HER2-Positive Metastatic Breast Cancer 
Pertuzumab and trastuzumab bind to different HER2 epitopes and have complementary 
mechanisms of action.  Combining them has been an effective therapeutic strategy for potent 
inhibition of HER2 signaling and stimulation of adaptive immunity through ADCC.  The anti-
tumor effects of the combination are greater than either agent alone in breast cancer cell lines and 
HER2-positive tumor models (Scheuer 2009, Nahta 2004, Lee-Hoeflich 2008, Arpino 2007). 
The combination of pertuzumab and trastuzumab has demonstrated activity in patients with 
HER2-positive MBC (Baselga 2010, Baselga 2012, Portera 2008).  A Phase II study of 
pertuzumab in combination with trastuzumab demonstrated an objective response rate (ORR) of 
24.2% in patients with MBC progressing after prior trastuzumab therapy.  The clinical benefit 
rate (CBR) was 50% and was well-tolerated (Baselga 2010). 
The CLEOPATRA study evaluated docetaxel/trastuzumab (control group) compared to 
docetaxel/trastuzumab plus pertuzumab (pertuzumab group) as first-line treatment for patients 
with HER2-positive MBC (Baselga 2012).  Women received the standard every-3-week dose of 
trastuzumab (loading dose of 8 mg/kg followed by 6 mg/kg) and pertuzumab (loading dose of 
840 mg followed by 420 mg) until progression.  Women also received docetaxel 75 mg/m2 every 
3 weeks; at the investigator's discretion, the dose could be increased to 100 mg/m2.  It was 
recommended that patients receive at least six cycles of chemotherapy.  The primary endpoint, 
median PFS (independently assessed), was improved by 6.1 months from 12.4 months in the 
control group to 18.5 months in the pertuzumab group (HR 0.62; 95% CI 0.51-0.75; p0.001).  
The ORR was 69.3% in the control group compared to 80.2% in the pertuzumab group (Baselga 
2012). 
The median OS was improved by a remarkable 15.7 months from 40.8 months in the control 
group to 56.5 months in the pertuzumab group (HR 0.68; 95% CI, 0.56-0.84; p0.001).  The 
estimated Kaplan-Meier overall survival rate at 3 years in the pertuzumab group was 68.2%  
(95% CI, 63.4-72.9) and 57.6% (95% CI, 52.4-62.7) at 4 years (Swain 2015).  The incidences of 
the following adverse events (any grade) were at least 5% higher in the pertuzumab group 
compared to the control group: diarrhea (68.4% vs. 48.7%), rash (37.5% vs. 24%), mucosal 
inflammation (27.2% vs. 19.9%), headache (25.7% vs. 19.2%), upper respiratory infection 
(20.8% vs. 14.4%), febrile neutropenia (13.7% vs. 7.6%), dry skin (11.3% vs. 6.1%), and muscle 
spasms (10.3% vs. 5.1%).  However, the adverse events were mostly grade 1 or 2.  The 
incidences of grade 3 or higher diarrhea and febrile neutropenia were only slightly increased in 
the pertuzumab group compared to the control group, respectively (9.3% vs. 5.1% and 13.7% vs. 
7.6%) (Swain 2015).  The pertuzumab regimen did not increase the rate of cardiac dysfunction, 
and in fact, left ventricular systolic dysfunction (any grade) was reported less frequently in the 
pertuzumab group compared to the control group (6.6% vs. 8.6%) (Swain 2015). 
A Phase II study evaluated the efficacy and safety of weekly paclitaxel with trastuzumab and 
pertuzumab in patients treated in the first- or second-line metastatic setting.  The median PFS for 
the entire study cohort was 19.5 months (95% CI, 14-26 months).  The PFS was 24.2 months 
(95% CI, 14 months-not reached) for those without prior treatment and 16.4 months (95% CI,  
8.5 months-not reached) for those with prior treatment.  Grade 3/4 adverse events included 
fatigue (6%), diarrhea (3%), sensory neuropathy (3%), palmar-plantar erythrodysesthesia (3%), 
Use of this document is governed by the terms of use on the first page of this document.

Use of this document is governed by the terms of use on the first page of this document.

 
NRG-BR004 
15 
NCI Version Date: August 15, 2022 
Preclinical and clinical studies have demonstrated that ADCC is one of the mechanisms 
underlying the clinical efficacy of trastuzumab (Barok 2007, Kute 2009, Gennari 2004).  The 
JIMT-1 HER2-positive human breast cancer cell line is intrinsically resistant to trastuzumab in 
vitro.  However, trastuzumab caused significant growth inhibition of JIMT-1 cells in an 
immunocompetent xenograft model.  Trastuzumab-F(ab')2 which does not contain the Fc portion 
of trastuzumab IgG was not an effective treatment in this model, indicating the activity occurred 
through FcR activated ADCC (Barok 2007). 
A pilot study of neoadjuvant trastuzumab showed a correlation between response to trastuzumab 
and ADCC activity of peripheral blood leukocytes.  Treatment with trastuzumab has also been 
shown to increase NK cell activity and response correlates with the intensity of ADCC (Gennari 
2004, Varchetta 2007).   
Trastuzumab treatment appears to require an adaptive immune response to achieve maximal 
therapeutic effects.  Data from Park et al. provide evidence that T cells are necessary for tumor 
regression with single agent trastuzumab.  The effect of the monoclonal antibody was greatly 
reduced in murine models in which T-cells and B-cells were deficient and in murine models 
depleted of CD8-positive T cells.  In both of these models, there was an initial response followed 
by a rapid relapse of tumor (Park S 2010).   
Augmentation of the immune response produced by ADCC occurs through cross-priming of 
cytotoxic T cells.  Dendritic cells present tumor antigens and immune complexes to the cell 
surface of T cells of the immune system that become HER2-specific cytotoxic T cells and 
undergo clonal expansion.  Cross talk between NK cells and dendritic cells can be induced by 
monoclonal antibodies and contributes to tumor antigen specific T-cell immunity (Lee 2011). 
The activity of HER2-specific cytotoxic T cells might be inhibited by the expression of PD-L1 on 
the surface of HER2-positive cells that were not eliminated by inhibition of oncogenic signaling 
or ADCC.  This immune tolerance could provide a survival mechanism that allows cells time to 
acquire resistance to the oncogenic signaling inhibition.  Recently, Bianchini and Gianni et al. 
demonstrated in the NeoSphere trial that increased PD-L1 expression was associated with 
reduced pathologic complete response (pCR) (Bianchini 2015).   
In a preclinical study, an anti-PD-1 monoclonal antibody significantly improved the activity of 
anti-ErbB-2 antibody (Stagg 2011).  Two multicenter neoadjuvant trials enrolled patients with 
HER2-positive breast cancer.  Core biopsies were obtained at baseline and after a brief exposure 
to single agent trastuzumab or nab-paclitaxel.  Significant increases in a signature of immune 
cells (Immune Index) was seen following a brief exposure to trastuzumab in HER2-enriched 
tumors (Trial 03-311[Discovery], p=0.05: Trial 211B [Validation], p=0.02).  The increased 
Immune Index was also predictive of response after exposure to trastuzumab (Trial 03-311, 
p=0.03; Trial 211B, p=0.04).  These results demonstrate immune cell function is upregulated in 
patients following one dose of trastuzumab and is associated with response to subsequent therapy 
(Varadan 2016). 
In aggregate, these studies suggest that therapies which inhibit PD-1/PD-L1 could augment the 
immune-mediated effects of trastuzumab and pertuzumab. 
2.4 
Atezolizumab 
Binding of PD-L1 to its receptors suppresses T-cell migration, proliferation, secretion of 
cytotoxic mediators, and restricts tumor cell killing (Park JJ 2010, Yang 2011, Paterson 2011, 
Butte 2007, Dong 1999).  Inhibiting PD-L1/PD-1 interaction restores antitumor T-cell activity 
(Akbari 2010, Matsumoto 2008). 
Use of this document is governed by the terms of use on the first page of this document.

 
NRG-BR004 
16 
NCI Version Date: August 15, 2022 
Atezolizumab is a human immunoglobulin (Ig) G1 monoclonal antibody consisting of two heavy 
chains (448 amino acids) and two light chains (214 amino acids) and is produced in Chinese 
hamster ovary cells (Investigator’s Brochure 2016).  Atezolizumab was engineered to eliminate 
Fc-effector function via a single amino acid substitution (asparagine to alanine) at position 298 on 
the heavy chain, which results in a non-glycosylated antibody that has minimal binding to Fc 
receptors, thus eliminating detectable Fc-effector function and associated antibody-mediated 
clearance of activated effector T cells.  Atezolizumab targets human programmed death-ligand 1 
(PD-L1) and inhibits the interaction with its PD-L1 and its receptors, PD-1 and B7-1 (also known 
as CD80), both of which function as inhibitory receptors expressed on T cells. 
Atezolizumab shows anti-tumor activity in both nonclinical models and cancer patients and is 
being investigated as a potential therapy in a wide variety of malignancies.  Atezolizumab is 
being studied as a single agent in the advanced cancer and adjuvant therapy settings, as well as in 
combination with chemotherapy, targeted therapy, and cancer immunotherapy. 
Atezolizumab is approved in the United States for the treatment of locally advanced or metastatic 
urothelial carcinoma and as well as metastatic non-small cell lung carcinoma. 
2.4.1 
Mechanism of Action 
PD-L1 expression is prevalent in many human tumors (e.g., lung, bladder, ovarian, melanoma, 
colon carcinoma), and its overexpression has been associated with poor prognosis in patients with 
several cancers (Thompson 2006, Hamanashi 2007, Okazaki 2007, Hino 2010).  PD-L1 binds to 
two known inhibitory receptors expressed on activated T cells (PD-1 and B7.1), and receptor 
expression is sustained in states of chronic stimulation such as chronic infection or cancer (Blank 
2005, Keir 2008).  Ligation of PD-L1 with PD-1 or B7.1 inhibits T-cell proliferation, cytokine 
production, and cytolytic activity, leading to the functional inactivation or inhibition of T cells.  
Aberrant expression of PD-L1 on tumor cells has been reported to impede anti-tumor immunity, 
resulting in immune evasion (Blank 2007).  Therefore, interruption of the PD-L1/PD-1 and PD-
L1/B7.1 pathway represents an attractive strategy to reinvigorate tumor-specific T-cell immunity. 
Blockade of PD-L1 or PD-1 with monoclonal antibodies has been reported to result in strong and 
often rapid antitumor effects in several mouse tumor models (Iwai 2002, Strome 2003).  These 
data suggest that tumor-specific T cells may be present in the tumor microenvironment in an 
inactive or inhibited state, and blockade of the PD-L1/PD-1 pathway can reinvigorate tumor-
specific T-cell responses. 
Collectively, these data establish the PD-L1/PD-1 pathway as a promising new therapeutic target 
in patients with advanced tumors.  Immune-related adverse events (AEs) reported from the two 
recent studies were consistent with the role of the PD-L1/PD-1 pathway in regulating peripheral 
tolerance. 
2.4.2 
Summary of Nonclinical Experience 
The safety, pharmacokinetics (PK), and toxicokinetics of atezolizumab were investigated in mice 
and cynomolgus monkeys to support intravenous (IV) administration and to aid in projecting the 
appropriate starting dose in humans.  Given the similar binding of atezolizumab for cynomolgus 
monkey and human PD-L1, the cynomolgus monkey was selected as the primary and relevant 
nonclinical model for understanding the safety, PK, and toxicokinetics of atezolizumab.  
Overall, the nonclinical PK and toxicokinetics observed for atezolizumab supported entry into 
clinical studies, including providing adequate safety factors for the proposed phase 1 starting 
doses.  The results of the toxicology program were consistent with the anticipated pharmacologic 
Use of this document is governed by the terms of use on the first page of this document.

 
NRG-BR004 
17 
NCI Version Date: August 15, 2022 
activity of down-modulating the PD-L1/PD-1 pathway and supported entry into clinical trials in 
patients. 
Refer to the Atezolizumab Investigator’s Brochure for details on the nonclinical studies. 
2.4.3 
Summary of Clinical Experience 
A summary of clinical data from company-sponsored atezolizumab trials is presented below.  
Details of all ongoing studies can be found in the Atezolizumab Investigator’s Brochure. 
2.4.4 
Clinical PK and Immunogenicity 
On the basis of available preliminary PK data (0.03-20 mg/kg), atezolizumab shows linear PK at 
doses t1 mg/kg (Investigator’s Brochure 2016).  Based on an analysis of exposure, safety, and 
efficacy data, the following factors had no clinically relevant effect: age (21í89 years), body
weight, gender, positive ATA status, albumin levels, tumor burden, region or ethnicity, renal 
impairment, mild hepatic impairment, level of PD-L1 expression, or ECOG status.  No formal PK 
drug-drug interaction studies have been conducted with atezolizumab, and the interaction 
potential is unknown.  Further details can be found in the current Investigator’s Brochure.   
The development of anti-therapeutic antibodies (ATAs) has been observed in patients in all dose 
cohorts and was associated with changes in PK for some patients in the lower dose cohorts (0.3, 
1, and 3 mg/kg) (Investigator’s Brochure 2016).  Patients dosed at t 10 mg/kg maintained Cmin 
values well above the target serum concentration of 6 mcg/mL despite the detection of ATAs.  
Accordingly, the development of detectable ATAs does not appear to have a clinically significant 
impact on PK for doses above 10 mg/kg.  To date, no relationship between the development of 
measurable ATAs and safety or efficacy has been observed. 
2.4.5 
Clinical Safety Summary 
As of May 10, 2016, atezolizumab has been administered (alone or in combination with other 
agents) to approximately 6053 patients with solid tumors and hematologic malignancies 
(Investigator’s Brochure 2016).  The first-in-human monotherapy study PCD4989g (in patients 
with locally advanced or metastatic solid tumors or hematologic malignancies) provides the 
majority of monotherapy safety data, with 629 safety-evaluable patients as of the data extraction 
date.  Currently, no maximum tolerated dose (MTD), no dose-limiting toxicities (DLTs), and no 
clear dose-related trends in the incidence of AEs have been determined. 
Fatigue, decreased appetite, nausea, diarrhea, constipation, and cough were commonly reported 
AEs in single and combination therapy (Investigator’s Brochure 2016).  AE profiles are similar 
across tumor types studied, including non-small cell lung cancer (NSCLC), renal cell carcinoma 
(RCC), triple-negative breast cancer (TNBC), and urothelial carcinoma (UC), and are consistent 
with the mechanism of action of atezolizumab.  The overall immune-mediated AEs reported were 
considered moderate in severity, and the majority of patients were able to continue on 
atezolizumab therapy. 
As of the data extraction date of December 15, 2015, there were 629 safety-evaluable patients 
from the first-in-human phase 1a study PCD4989g (Investigator’s Brochure 2016).  The median 
age was 61 years.  Of the 629 patients, 619 patients (98.4%) reported at least one AE of any grade 
or attribution to atezolizumab, and 316 patients (50.2%) experienced at least one grade 3 or 4 AE 
of any attribution.  A total of 444 patients (70.6%) reported at least one treatment-related AE, and 
86 patients (13.7%) experienced at least one treatment-related grade 3 or 4 AE.  The most 
frequently observed AEs of any grade and attribution (occurring in t 10% of treated patients) 
Use of this document is governed by the terms of use on the first page of this document.

 
NRG-BR004 
18 
NCI Version Date: August 15, 2022 
include fatigue, decreased appetite, nausea, pyrexia, constipation, cough, dyspnea, diarrhea, 
anemia, vomiting, asthenia, back pain, headache, arthralgia, pruritus, rash, abdominal pain, 
insomnia, peripheral edema, and dizziness. 
Serious AEs (SAEs) have been reported in 261 patients (41.5%) in study PCD4989g 
(Investigator’s Brochure 2016).  Reported SAEs were consistent with the underlying disease.  
Treatment-related SAEs (57 patients [9.1%]) included pyrexia, dyspnea, pneumonitis, malaise, 
fatigue, hypoxia, colitis, and bone pain.  Pooled single-agent safety data from 1978 patients with 
UC, NSCLC, and other indications (including trial PCD4989g) indicate that the most frequent 
(>1% of patients) serious adverse drug reactions (regardless of grade) include dyspnea (3.0%), 
back pain (1.2%), and abdominal pain (1.1%).  A list of AEs considered “expected” for 
atezolizumab is presented in Section 7.3.2. 
2.4.6 
Immune-Related Adverse Events 
Given the mechanism of action of atezolizumab, events associated with inflammation and/or 
immune-mediated AEs have been closely monitored during the atezolizumab clinical program 
(Investigator’s Brochure 2016).  To date, immune-related adverse events associated with 
atezolizumab include hepatitis, pneumonitis, colitis, pancreatitis, nephritis, diabetes mellitus, 
hypothyroidism, hyperthyroidism, adrenal insufficiency, Guillain-Barré syndrome, myasthenic 
syndrome/myasthenia gravis, and meningoencephalitis. 
Cases of myocarditis have been reported in patients receiving atezolizumab treatment in clinical 
trials.  As of 17 May 2018, approximately 16,815 clinical trial patients and 20,783 post-marketing 
patients have been exposed to atezolizumab.  A cumulative analysis of the Genentech safety 
database (data cut-off date 17 May 2017) identified two cases of myocarditis (Genentech 2018).  
Immune-mediated myocarditis has been reported in patients treated with other immune 
checkpoint inhibitor therapy. 
For further details, see the most recent Atezolizumab Investigator’s Brochure. 
2.4.7 
Clinical Efficacy Summary 
Patients with multiple tumor types were included in study PCD4989g, with the largest cohorts 
consisting of patients with NSCLC, RCC, and UC (Investigator’s Brochure 2016).  Objective 
responses with atezolizumab monotherapy were observed in a broad range of malignancies, 
including NSCLC, RCC, melanoma, UC, colorectal cancer, head and neck cancer, gastric cancer, 
breast cancer, and sarcoma.  Both the preliminary and more mature efficacy data available 
suggest that treatment with atezolizumab as a single agent or in combination with other 
therapeutic agents results in anti-tumor activity across a range of tumor types and hematologic 
malignancies (UC, NSCLC, RCC, TNBC, melanoma, CRC, and NHL) and across lines of 
therapy.  Clinical benefit was observed in terms of objective responses, durability of responses, 
and overall survival (OS).  Improved efficacy of atezolizumab was observed in the unselected 
patient population, as well as in patients with higher PD-L1 expression on TCs or ICs  
(e.g., NSCLC) or on ICs only (e.g., mUC, RCC). 
2.5 
Atezolizumab in Breast Cancer 
Atezolizumab (MPDL3280A) is a monoclonal anti-PD-L1 antibody that was evaluated in a 
cohort of 115 women with metastatic TNBC (Emens 2015, Schmid 2017).  This included 63% of 
women initially selected for high PD-L1 expression levels (at least 5% of tumor-infiltrating 
immune cells were PD-L1 positive) and 33% of patients with TNBC regardless of PD-L1 
expression.  Four percent of patients had unknown PD-L1 expression levels.  Efficacy was 
evaluated in 112 patients and safety was evaluated in 115 patients.  PD-L1 expression was 
Use of this document is governed by the terms of use on the first page of this document.

 
NRG-BR004 
19 
NCI Version Date: August 15, 2022 
centrally evaluated on tumor-infiltrating immune cells based on an IHC assay.  Atezolizumab was 
administered at 15 mg/kg, 20 mg/kg, or 1200 mg IV every 3 weeks.  The objective response rate 
(ORR) was 10% (95% CI, 5-17) among the 112 evaluable patients.  The one and two year overall 
survival rates for these responders were 100% and for non-responders, the overall survival rates 
were 33% and 11%, respectively.  The median duration of response was 21 months (2.8 to 
26.5+).  Atezolizumab was generally well-tolerated.  Treatment-related Grade 3 or 4 adverse 
events were reported in 11% of patients and adverse events leading to treatment discontinuation 
occurred in 3% of the cases.  Two treatment related Grade 5 adverse events, pulmonary 
hypertension and death (unspecified) were reported in a hospitalized patient. 
Preliminary results of a Phase 1b study evaluating the combination of atezolizumab in 
combination with nab-paclitaxel at 125 mg/m2 demonstrated activity in patients with metastatic 
TNBC.  A total of 32 patients were evaluable for efficacy.  The confirmed ORR for patients 
receiving any line of therapy was 38% (95% CI 21,56) [46% (19,75) in first line, 22% (3,60) in 
second line, and 40% (12,74) in third line].  The stable disease rate was 44%.  Safety information 
was available for all 32 patients with a median follow-up of 6.1 months.  Treatment-related Grade 
3/4 AEs occurred in 69% of patients which included neutropenia (47%), thrombocytopenia (9%), 
anemia (6%), decreased WBC (6%), and diarrhea (6%).  Six patients discontinued nab-paclitaxel 
due to an adverse event.  Treatment discontinuations were related to fatigue (n=1; grade 2), 
asthenia (n=1; Grade 2), peripheral neuropathy (n=3; Grade 1, 2, and 3), and pneumonia (n=1; 
Grade 3).  The combination of nab-paclitaxel and atezolizumab showed high response rates and 
was well-tolerated (Adams 2016). 
2.6 
Rationale for Dose Selection/Regimen/Modification 
Atezolizumab/placebo will be administered at a fixed dose of 1200 mg Q3W by IV infusion with 
taxane (paclitaxel or docetaxel)/trastuzumab/pertuzumab until the taxane has been completed.  
Atezolizumab/placebo will then be administered at a fixed dose of 1200 mg Q3W by IV infusion 
with trastuzumab and pertuzumab every 3 weeks until progression or for 2 years.   
Anti-tumor activity has been observed across doses ranging from 1 mg/kg to 20 mg/kg Q3W.  In 
Study PCD4989g, the maximum tolerated dose of atezolizumab was not reached and no dose-
limiting toxicities were observed at any dose.  The fixed dose of 1200 mg Q3W (equivalent to an 
average body weightíbased dose of 15 mg/kg Q3W) was selected on the basis of both nonclinical
studies (Deng 2016).  A fixed dose regimen will simplify the dosing regimen to be more 
convenient for physicians, reduces potential for dosing errors, reduces complexity in the logistical 
chain at treatment facilities, and reduces wastage.  
The NRG-BR004 clinical trial will evaluate a standard of care regimen of either weekly paclitaxel 
or every 3-week docetaxel, in combination with trastuzumab and pertuzumab administered with 
atezolizumab or placebo, in HER2-positive MBC in the first-line setting.  A minimum of  
18 weeks of taxane chemotherapy will be administered, with trastuzumab and pertuzumab 
continuing until progression.  Atezolizumab/placebo will be administered for 24 months or until 
progression to provide exposure to atezolizumab/placebo combined with the HER2-targeted 
monoclonal antibodies for 6 months beyond the median PFS in the CLEOPATRA trial.  
The definitive analysis for PFS will occur at about 41 months after the study has initiated.  
Following first progression, patients will be assessed for survival, late immune toxicities, and 
subsequent immuno-oncology therapy.  Since the median OS was almost 5 years in patients 
receiving docetaxel/trastuzumab/pertuzumab, we propose that patients will be followed for up to 
8.5 years to determine the possible impact of the therapy on OS.  There are no trials currently 
being conducted in this setting to evaluate the addition of atezolizumab or other checkpoint 
inhibitors to standard first-line therapy of metastatic HER2-positive breast cancer. 
Use of this document is governed by the terms of use on the first page of this document.

 
NRG-BR004 
20 
NCI Version Date: August 15, 2022 
2.7 
Rationale for Amendment #3 to Allow Investigator Discretion on Choice of Taxane 
Since accrual remained below projections one year after activation, an investigator survey was 
released to identify barriers to accrual and trial participation among NCTN sites.  The information 
supplemented information we had received from investigators during the activation and the first 
year of accrual.  Three major barriers were identified.  First, central testing can take 5-7 days to 
confirm eligibility and drug shipment following randomization can also take up to 7 days; 
therefore, patients entering BR004 may have a delay of 2-3 weeks before therapy can be initiated.  
In some instances, an extensive burden of disease at presentation has precluded participation in 
the trial because of the need to begin therapy on an urgent basis.  Second, the weekly paclitaxel 
regimen is problematic for patients living at a distance from their cancer center, particularly in 
areas with large rural populations, and this issue has been magnified by the COVID-19 pandemic.  
Investigators have indicated the option of every-3-week docetaxel would be helpful in addressing 
this barrier.  Finally, the exclusion of biosimilar trastuzumab was beginning to be problematic as 
some insurance policies began to require use of biosimilars and an increasing number of cancer 
centers began to preferentially use biosimilars to reduce costs.   
The biosimilar issue will be addressed by provision of trastuzumab by Genentech distributed by 
the Pharmaceutical Management Branch (PMB) for randomized patients throughout their 
treatment period while on the medication.  The other two issues related to the delay in initiating 
therapy due to the requirement for central testing and the frequency of administration required for 
the paclitaxel administration will be addressed by amending the protocol to enroll patients and 
administer Cycle 1 based on local testing results, while tissue is sent for central testing for 
confirmation of HER2-positive status and determination of PD-L1 status required for 
stratification prior to randomization.  Upon receipt of confirmation of HER2-positive status and 
determination of PD-L1 status, patients will be randomized in time for atezolizumab/placebo and 
trastuzumab to be shipped from the PMB to be available for initiation of atezolizumab/placebo on 
Day 22 of Cycle 1 along with the continuation of trastuzumab provided by the PMB and 
pertuzumab and chemotherapy that will continue to be provided as part of routine care.  With this 
process, patients will not have to delay starting therapy while central testing and post-
randomization drug shipment occurs.  This approach will also allow for assessment of tolerance 
to the standard components of the treatment regimen prior to initiation of atezolizumab/placebo, 
which will be important in evaluating and managing treatment-related diarrhea. 
Finally, results of two double blind, placebo-controlled Phase III studies evaluating atezolizumab 
in patients with untreated metastatic TNBC have been reported since BR004 was developed.  The 
first of the studies to report was the IMpassion-130 study, which randomized patients 1:1 to 
receive atezolizumab/placebo Days 1 and 15 in combination with nab-paclitaxel 100 mg/m2 Days 
1, 8, and 15 in 28-day cycles (Schmid 2018).  Median PFS was 7.2 months with atezolizumab 
plus nab-paclitaxel, as compared with 5.5 months with placebo plus nab-paclitaxel (HR 0.80; 
95% confidence interval [CI], 0.69-0.92; P = 0.002).  Among the cohort of patients with PD-L1-
positive tumors, median PFS was 7.5 months and 5.0 months, respectively (HR, 0.62; 95% CI, 
0.49 to 0.78; P<0.001).  Among patients with PD-L1-positive tumors, median OS was improved 
from 15.5 months to 25.0 months, respectively (hazard ratio, 0.62; 95% CI, 0.45 to 0.86).  No 
new adverse effects were identified.  Based on these results and an acceptable safety profile the 
combination was approved by the FDA on March 11, 2019, in patients with PD-L1-positive 
untreated metastatic TNBC.  
More recently, results from the IMpassion-131 study were presented at the European Society of 
Medical Oncology.  IMpassion-131 randomized patients with untreated metastatic TNBC to 
receive atezolizumab/placebo 2:1 in combination with paclitaxel 80 mg/m2 Days 1, 8, and 15 in 
21-day cycles.  Atezolizumab + paclitaxel did not improve PFS compared with placebo + 
Use of this document is governed by the terms of use on the first page of this document.

 
NRG-BR004 
21 
NCI Version Date: August 15, 2022 
paclitaxel in the PD-L1-positive population with a stratified HR of 0.82, (95% CI 0.60 - 1.12,  
p = 0.20, stratified log-rank test).  Median PFS was 6.0 months in the atezolizumab arm and  
5.7 months in the placebo arm.  In the intent-to-treat (ITT) population, the median PFS was  
5.7 months in the atezolizumab arm and 5.6 months in the placebo arm (stratified HR: 0.86 [0.70 
- 1.05], p= 0.1343 stratified log-rank test [not formally tested due to the hierarchy]).  An interim 
analysis of OS was also planned at the time of the formal analysis of PFS.  At that time with 
deaths in only 27% of the ITT population, OS showed a negative trend for atezolizumab in the 
PD-L1-positive population (stratified HR: 1.55, 95% CI [0.86, 2.80]).  A similar trend was 
observed in the ITT population (stratified HR: 1.31, 95% CI [0.94 - 1.82]).  An update of OS with 
9 months of additional follow-up with deaths in 47% of the ITT population, was included in the 
ESMO presentation and demonstrated a HR of 1.12 (95% CI [0.76, 1.65]) for OS in the PD-L1 
positive cohort with a 2-year OS rate of 51% in the placebo arm and 49% in the atezolizumab 
arm.  A similar trend was observed in the ITT population (stratified HR: 1.11, 95% CI [0.87, 
1.42]), with 2-year OS rates of 45% vs 42%, respectively (Miles 2020). 
The safety of atezolizumab in combination with paclitaxel appeared consistent with the known 
safety profiles of the individual medicines, and no new safety signal was identified.  The rates of 
AEs with fatal outcomes were balanced (1.8% vs 2.1%, respectively, in the placebo arm vs 
atezolizumab arm) with no discernable pattern.  Infection-related events were the most common 
cause of fatal AEs for both arms and were balanced between arms.  SAEs were higher in the 
atezolizumab arm (16.1% vs 22.7%), with pneumonia being the only event occurring in > 2% of 
patients.  Grade 3-4 events were also higher in the atezolizumab arm (43.1% vs 49.4%) with 
neutropenia, neutrophil count increase, and peripheral neuropathy occurring in  5% of patients. 
BR004 is evaluating atezolizumab as an additional component to the highly effective regimen of 
trastuzumab and pertuzumab in combination with a taxane in HER2-positive metastatic breast 
cancer with an expected median PFS of 18-19 months.  This represents a very different patient 
population from the first-line TNBC population evaluated in IMpassion-130 and IMpassion-131, 
which reported a median PFS of 5.5 months and 5.6 months in the control arms of those trials 
when treated with single agent nab-paclitaxel and paclitaxel, respectively.  Thus, the results of the 
IMpassion-131 and IMpassion-130 studies do not warrant removal of paclitaxel from the BR004 
study.  Therefore, BR004 will retain use of weekly paclitaxel as an option for the choice of 
standard chemotherapy but as noted will be amended to allow the option of docetaxel.   
2.8 
Early Closure to Accrual of NRG-BR004 
On 05/20/2022, the NRG BR004 study was permanently closed to further accrual, and patients 
receiving atezolizumab/placebo discontinued experimental treatment.  Patients were to continue 
to receive trastuzumab in combination with pertuzumab and taxane where appropriate.  This 
decision was made in consultation between NRG Oncology leadership, the study team, the Data 
Monitoring Committee (DMC), and NCI CTEP when an imbalance in deaths between the study 
arms while on-treatment became evident on April 27, 2022, following report of a 6th on-
treatment death in one of the study arms compared with no on-treatment deaths reported in the 
other arm. 
A potential imbalance was noted during the DMC review of the BR004 safety data in February 
2022, when it was seen that the 4 reported deaths on treatment had all on occurred on one arm of 
the study.  However, there was no consistent pattern of toxicities among the four Grade 5 events 
and there were no imbalances in Grade 3 or Grade 4 toxicities or drug delivery between the two 
arms.  Therefore, the NRG BR004 team remained blinded to the treatment, and the study was 
continued without modification.  Subsequently, 2 additional on-treatment deaths were reported, 
the first on 
 and the second on 
.  Since the deaths were again on the same study 
Use of this document is governed by the terms of use on the first page of this document.

 
NRG-BR004 
22 
NCI Version Date: August 15, 2022 
arm, accrual was halted until the DMC could review unblinded safety data, narratives of the 
deaths, and the overall context of the trial. 
The DMC met on May 10, 2022, and reviewed the unblinded safety data in detail, including the 
narratives from the six deaths which had occurred on the atezolizumab arm.  The analysis and 
interpretation of the narratives by the DMC follows: 
Case 
Number 
Event Analysis 
Interpretation by DMC 
1 
Rapid progression of hepatic metastases in days after 
starting protocol-based therapy 
Unrelated to treatment 
2 
Diarrhea attributed to pertuzumab, with malnutrition, 
admitted for non-neutropenic sepsis, then with 
progressive pneumonic infiltrates and liver failure, 
also complicated by tumor progression. 
Probably related to 
treatment 
3 
Evidence for immune-related side effects (elevated 
TSH, low cortisol), with subsequent admission for 
nausea, vomiting, diarrhea, hypotension, and later 
pneumonia. 
Related to treatment 
4 
Non-neutropenic fever with diarrhea, and tissue 
evidence for immune mediated colitis, with 
subsequent re-admission for fever, colitis, and 
diarrhea, found unexpectedly deceased at home two 
days after hospital discharge.  
Related to treatment 
5 
Non-neutropenic sepsis complicated by pulmonary 
edema and cardiac injury 
Related to treatment 
6 
Elderly patient with history of atrial fibrillation, 
admitted to hospital with atrial fibrillation and rapid 
ventricular response/dyspnea, developed progressive 
multi-system organ failure in setting of worsening 
congestive heart failure and mitral valve regurgitation. 
Not directly related to 
treatment though 
possibly aggravated by 
treatment 
 
The DMC also evaluated the persistent low accrual since activation and the lack of meaningful 
increase in accrual following an extensive protocol revision in the summer of 2021 designed to 
address identified barriers to accrual, the context of a similar pattern of imbalance in on-treatment 
deaths seen in the IMpassion050 study in HER2-positive early breast cancer which evaluated the 
addition of atezolizumab/placebo added to trastuzumab and pertuzumab in combination with 
sequential anthracycline/taxane neoadjuvant chemotherapy reported in June of 2021 in an ESMO 
Virtual Plenary session (Huober 2021, Huober 2022), and the current landscape of metastatic 
therapies for HER2-positive disease.  The DMC recommended that based on 1) the presence of an 
uncertain but material signal regarding the adverse event risk, 2) the continuing accrual 
challenges, and 3) a determination that the clinical question being addressed in BR004, while 
potentially important, is no longer sufficiently compelling to incur the risk of either severe 
adverse events or an uninformative result due to low accrual, the trial should be permanently 
closed to further enrollment.  Since only 190 of the planned 600 patients (32%) had been accrued, 
the ability to detect a clinically relevant improvement in outcomes effectively precluded closure 
to further accrual, continued exposure of first line HER2-positive patients to potential risks of 
atezolizumab was difficult to justify as these patients generally derive substantial benefit from 
Use of this document is governed by the terms of use on the first page of this document.

 
NRG-BR004 
23 
NCI Version Date: August 15, 2022 
dual HER2 targeted therapy in combination with a taxane.  Based on these considerations, a 
decision was made to also discontinue atezolizumab/placebo in patients who were receiving the 
investigational component of the trial therapy and unblind investigators and patients so that 
investigators know which patients should be monitored for possible immune-related adverse 
events that can occur after stopping atezolizumab. 
With Amendment #6, the BR004 protocol is being amended to provide for continued follow-up 
for the primary endpoint of PFS and the secondary endpoint of OS through April 2024.  While it 
is unlikely that statistically significant improvement in PFS can be demonstrated with the reduced 
sample size, it is important to assess the primary endpoint in the two arms with reasonable 
follow-up, and to assess the numerical differences in survival as a predefined endpoint.  The 
follow-up period will also provide opportunity to continue to monitor for post therapy immune-
related adverse events.  Secondary endpoints requiring central review, the original larger sample 
size or extended follow-up are being removed with this amendment, as are requirements for 
submission of scans for independent review of response, which had been a secondary endpoint of 
the trial.  The secondary endpoint of overall response is being modified to be evaluated in the 
cohort of patients randomized 6 months or more prior to study accrual closure.  Follow-up 
requirements will also be limited to investigator determined assessment of disease status to 
encourage patients to allow continued submission of follow-up information until closure to 
follow-up in 2024. 
 
 
Use of this document is governed by the terms of use on the first page of this document.

 
NRG-BR004 
24 
NCI Version Date: August 15, 2022 
3.0 
PATIENT SELECTION, ELIGIBILITY, AND INELIGIBILITY CRITERIA 
The NRG-BR004 study was permanently closed to accrual on May 20, 2022.  Modified scheduled 
status updates, as outlined on Table 2A, will be completed for patients enrolled prior to study 
accrual closure. 
Note: Per NCI guidelines, exceptions to inclusion and exclusion criteria are not permitted.  
For questions concerning eligibility, please contact the Clinical Coordinating Department (CCD). 
3.1 
Patient Selection Guidelines 
Investigators should consider all relevant factors (medical and non-medical), as well as the risks 
and benefits of the study therapy, when deciding if an individual patient is an appropriate 
candidate for this trial. 
Submission of tumor tissue obtained at the time of diagnosis of de novo metastatic disease or 
locally recurrent or metastatic disease is required for all patients.  (see Section 3.3.5 and Section 
10.0).  Investigators should check with their site Pathology department regarding release of tumor 
tissue before approaching patients about participation in the trial.   
3.2 
Patient Entry and Randomization  
The following sections outline procedures for Study Entry, Randomization, and ordering Study 
Drug at randomization. 
3.2.1 
Step 1 Study Entry and Initiation of Study Therapy: Begin Cycle 1 and provide tissue for central 
confirmation of HER2-positive status 
x 
The authorized site staff must obtain signed informed consent from the potential patient 
before any study specific procedures are performed. 
x 
The authorized site staff must determine patient eligibility.  See Sections 3.3 and 3.4. 
x 
Entry in OPEN:  Patients will be assigned a unique patient identifier which will be used to 
identify the samples used for central confirmation of HER2 and ER/PgR and for PD-L1 
testing, the eCRFs in Medidata RAVE, and any other trial-related communications. 
x 
Preferentially send tissue that is HER2-positive per local testing for central confirmation of 
HER2 and ER/PgR and PD-L1 testing.  See Section 10.0 if insufficient material available. 
x 
Once potential eligibility has been confirmed and consent signed, initiate Cycle 1 treatment 
with standard loading doses of trastuzumab and pertuzumab obtained by the investigator from 
commercial supply and paclitaxel or docetaxel per institutional standards while waiting on 
results of central testing.  When HER2-positive is confirmed on central testing, patient should 
be randomized.  Patients who are not confirmed to be HER2-positive by central confirmation 
testing will not be randomized, will be taken off study, treated per investigator discretion, and 
will not be followed on BR004. 
3.2.2 
Step 2 Randomization 
x 
Following central confirmation of a positive HER2 status and central testing of ER/PgR and 
PD-L1, the authorized site staff will randomize the patient using OPEN.  For the purposes of 
stratification, the PD-L1 results will be provided to the NRG Oncology SDMC.  Results will 
not be provided to the investigator or the patient.  Randomization within 14 days from 
study entry will ensure that the PMB-supplied agents will be received at the site for 
treatment on Day 22 of Cycle 1. 
Use of this document is governed by the terms of use on the first page of this document.

 
NRG-BR004 
25 
NCI Version Date: August 15, 2022 
x 
OPEN will randomly assign treatment (atezolizumab or placebo).  The treatment allocation 
will be blinded for the Investigator and the patient. 
x 
Randomization will automatically trigger study drug shipment to the site in time to begin 
atezolizumab/placebo on Day 22 of Cycle 1.  Details of drug ordering procedures can be 
found in Section 9.1.2. 
3.3 
Eligibility Criteria 
A patient cannot be considered eligible for this study unless ALL of the following conditions 
are met. 
3.3.1 
The patient must have signed and dated an IRB-approved consent form that conforms to federal 
and institutional guidelines. 
3.3.2 
The trial is open to female and male patients. 
3.3.3 
Patients must be t 18 years old. 
3.3.4 
Patient must have an ECOG Performance Status of 0 or 1 (see Appendix A).  
3.3.5 
Histologically confirmed adenocarcinoma of the breast with locally recurrent, unresectable 
disease or metastatic disease outside the CNS confirmed as described below.  Eligible patients 
include those with either: 
x 
De novo metastatic disease presenting without prior history of HER2-positive breast cancer: 
 
Diagnosis should have been made from a biopsy of a metastatic disease site, but biopsy 
from the breast primary or involved regional lymph nodes is acceptable if biopsy of the 
metastatic sites was thought to carry excessive risk for the patient. 
x 
Locally recurrent or metastatic disease following prior therapy for early breast cancer: 
 
Diagnosis must have been made from the biopsy of the locally recurrent or metastatic 
disease.  
 
There must be an interval of t 6 months between completion of neoadjuvant/adjuvant 
HER2-targeted therapy and documentation of locally recurrent or metastatic HER2-
positive disease by biopsy. 
3.3.6 
Patients must have measurable disease based on RECIST 1.1, as determined by the site, which 
has not been irradiated to be eligible. 
3.3.7 
Patients with brain metastases are eligible if they meet ALL the following criteria: 
x 
Four or fewer metastatic sites to CNS 
x 
Largest unexcised tumor does not exceed 3 cm 
x 
No metastases to brain stem, midbrain, pons, medulla or the optic nerves and chiasm 
x 
Must have measurable disease outside the CNS, based on RECIST 1.1, as determined by the 
site, which has not been irradiated. 
x 
If patient presented with symptoms from CNS metastases, the symptoms must have resolved 
with initiation of steroids and initial local therapy (surgery, radiation therapy, or both). 
x 
Must have been evaluated by Medical Oncologist and plan is to administer trastuzumab, 
pertuzumab, and a taxane as first-line systemic therapy. 
x 
May have received administration of trastuzumab OR lapatinib concurrently with radiation 
therapy for brain metastases.  Toxicities related to lapatinib if administered, should be  
 grade 1 per the CTCAE v5.0, and the lapatinib must have been completed at least 2 weeks 
prior to study entry. 
x 
No history of intracranial hemorrhage or spinal cord hemorrhage. 
x 
No neurosurgical resection or brain biopsy within 10 days prior to study entry. 
Use of this document is governed by the terms of use on the first page of this document.

 
NRG-BR004 
26 
NCI Version Date: August 15, 2022 
3.3.8 
After study entry and before randomization, send tissue for central HER2 confirmation.  A tumor 
specimen obtained at the time of diagnosis of locally recurrent or metastatic disease must have 
been determined to be HER2-positive based on local testing according to ASCO/CAP guidelines 
(Wolff 2018).  HER2 status should initially be assessed using a FDA-cleared IHC assay.  Positive 
is defined as IHC 3+ staining intensity.  If HER2 IHC results are equivocal (2+), then HER2 
status will be determined using an FDA-cleared HER2 ISH test according to ASCO/CAP 
guidelines.  Note: Once HER2-positive is confirmed on central testing, patients will be 
randomized to atezolizumab/placebo.  Randomization within 14 days from study entry will 
ensure that the PMB-supplied agents will be received at the site for treatment on Day 22 of 
Cycle 1. 
3.3.9 
The tumor specimen obtained at the time of diagnosis used for HER2 testing must also have 
central testing for PD-L1 status.  Patients will be eligible irrespective of PD-L1 testing result 
including PD-L1 indeterminant. 
3.3.10 The tumor specimen obtained at the time of diagnosis used for HER2 and PD-L1 testing should 
also have central testing for ER and PgR according to current ASCO/CAP Guideline 
Recommendations for hormone receptor testing (http://www.asco.org).  Patients with  1% ER 
and PgR staining by IHC will be classified as negative.  If enough material for central 
confirmation of ER and PgR is unavailable, local testing results for ER and PgR may be used for 
eligibility. 
3.3.11 Localized palliative radiation therapy to sites of non-measurable disease is allowed for symptom 
management and may begin prior to study entry and continue following study entry while 
receiving study therapy. 
3.3.12 Patients must have imaging of the chest/abdomen/pelvis, preferably with a CT scan, and a bone 
scan within 5 weeks prior to study entry.  (Note: If a patient is unable to receive CT contrast, a 
MRI of the abdomen/pelvis and non-contrast chest CT should be performed.  PET/CT is not an 
acceptable alternative.) 
3.3.13 MRI of the brain (or contrast CT scan of the brain if patients are unable to undergo MRI) must be 
obtained in patients with symptoms suggesting possible central nervous system (CNS) metastatic 
disease.  Neuroimaging is recommended but not required in asymptomatic patients. 
3.3.14 Adequate hematologic function within 14 days prior to study entry defined as follows: 
x 
ANC must be t 1200/mm3;  
x 
Platelet count must be t 100,000/mm3; 
x 
Hemoglobin must be t 8 g/dL. 
3.3.15 Adequate hepatic function within 14 days prior to study entry: 
x 
total bilirubin must be d 1.5 x ULN for the lab or direct bilirubin d ULN for patients with 
bilirubin levels ! 1.5 x ULN; 
x 
AST and ALT must be d 2.5 x ULN for the lab or d 5 x ULN for patients with liver 
metastases. 
3.3.16 Adequate renal function determined within 14 days prior to study entry defined as the most recent 
serum creatinine d 1.5 x ULN or measured or calculated creatinine clearance t 50 mL/min using 
the Cockroft-Gault formula for patients with creatinine levels ! 1.5 x ULN for the lab. 
For Women 
Creatinine Clearance (mL/min)  =  (140 – age) x weight (kg) x 0.85 
72 x serum creatinine (mg/dL) 
 
Use of this document is governed by the terms of use on the first page of this document.

 
NRG-BR004 
27 
NCI Version Date: August 15, 2022 
 
For Men 
Creatinine Clearance (mL/min)  =  (140 – age) x weight (kg) 
72 x serum creatinine (mg/dL) 
3.3.17 Patients not receiving anti-coagulant therapy must have PT and INR d 1.5 x ULN within 14 days 
prior to study entry.  For laboratories that do not report an ULN for the INR assay, use d 1.5 as 
the value for the ULN.  Patients receiving anti-coagulants should have a baseline INR assessed, 
but the value does not affect eligibility. 
3.3.18 A serum TSH and AM (preferably in morning) cortisol must be obtained within 14 days prior to 
study entry to obtain a baseline value.  Patients with abnormal TSH or AM cortisol baseline 
levels should be further evaluated and managed per institutional standards.  Asymptomatic 
patients who require initiation or adjustment of medication or are followed without initiating 
treatment based on endocrinologist’s recommendations are eligible. 
3.3.19 LVEF assessment must be performed within 6 weeks prior to study entry.  (LVEF assessment 
performed by echocardiogram is preferred; however, MUGA scan may be substituted based on 
institutional preferences.)  The LVEF must be  50% regardless of the cardiac imaging facility's 
lower limit of normal.  
3.3.20 Administration of atezolizumab may have an adverse effect on pregnancy and poses a risk to the 
human fetus, including embryo-lethality.  Women of child-bearing potential and men must agree 
to use adequate contraception (non-hormonal or barrier method of birth control; abstinence) prior 
to study entry, for the duration of study participation, and for 5 months (150 days) after the last 
dose of atezolizumab/placebo and 7 months after the last dose of trastuzumab and pertuzumab.  
Should a woman become pregnant or suspect she is pregnant while she or her partner is 
participating in this study, she should inform her treating physician immediately.  
3.3.21 
HIV-infected patients on effective anti-retroviral therapy with undetectable viral load within  
6 months of study entry are eligible for this trial. 
3.4 
Ineligibility Criteria 
Patients with one or more of the following conditions are NOT eligible for this study. 
3.4.1 
Patients with brain metastases are excluded if they meet ANY of the following criteria: 
x 
Symptoms from brain metastases have not resolved prior to study entry 
x 
Five or more clearly identified foci of metastases to the brain 
x 
Largest unexcised tumor exceeds 3 cm 
x 
Spinal cord metastases 
x 
Medical Oncologist plans to employ HER2-directed tyrosine kinase inhibitor as component 
of systemic therapy 
x 
Metastatic disease limited to CNS 
3.4.2 
Leptomeningeal carcinomatosis. 
3.4.3 
History of systemic anti-cancer therapy (e.g., chemotherapy, targeted therapy) for MBC except as 
described in Eligibility Criterion 3.3.7. 
3.4.4 
History of exposure to cumulative doses of doxorubicin greater than 360 mg per square meter of 
body-surface area or its equivalent. 
3.4.5 
Prior treatment with mTOR inhibitors or CDK 4/6 inhibitors in combination with endocrine 
therapy for treatment of metastatic disease. 
Use of this document is governed by the terms of use on the first page of this document.

 
NRG-BR004 
28 
NCI Version Date: August 15, 2022 
3.4.6 
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. 
3.4.7 
History of non-breast malignancies (except for in situ cancers treated only by local excision and 
basal cell and squamous cell carcinomas of the skin) within 5 years prior to study entry. 
3.4.8 
Uncontrolled hypertension defined as sustained systolic BP ! 150 mmHg or diastolic BP  
! 90 mmHg.  (Patients with initial BP elevations are eligible if initiation or adjustment of BP 
medication lowers pressure to meet entry criteria.) 
3.4.9 
History of asymptomatic LVEF decline to < 40% during or after prior HER2-targeted therapy 
even if the current LVEF is 50%. 
3.4.10 Cardiac disease (history of and/or active disease) that would preclude the use of the drugs 
included in the treatment regimens.  This includes but is not confined to: 
Active cardiac disease 
x 
angina pectoris that requires the current use of anti-anginal medication; 
x 
ventricular arrhythmias except for benign premature ventricular contractions; 
x 
supraventricular and nodal arrhythmias requiring a pacemaker or not controlled with 
medication; 
x 
conduction abnormality requiring a pacemaker; 
valvular disease with documented compromise in cardiac function; or 
x 
symptomatic pericarditis. 
History of cardiac disease 
x 
prior myocardial infarction documented by elevated cardiac enzymes or persistent regional 
wall abnormalities on assessment of LV function; 
x 
history of documented CHF defined as symptomatic heart failure with an LVEF  40%; or 
x 
documented cardiomyopathy. 
3.4.11 Nervous system disorder (paresthesia, peripheral motor neuropathy, or peripheral sensory 
neuropathy) t grade 2, per the CTCAE v5.0. 
3.4.12 History of severe allergic, anaphylactic, or other hypersensitivity reactions to pertuzumab or 
trastuzumab or to any of its excipients, as well as any chimeric or humanized antibodies or fusion 
proteins. 
3.4.13 Known hypersensitivity to biopharmaceuticals produced in Chinese hamster ovary cells or other 
recombinant antibodies. 
3.4.14 Known allergy or hypersensitivity to the components of the atezolizumab formulation or to any of 
the study drugs or excipients, (e.g., Cremophor® EL, polysorbate 80).  
3.4.15 History or risk of autoimmune disease, including, but not limited to, systemic lupus 
erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular thrombosis associated 
with antiphospholipid syndrome, Wegener’s granulomatosis, Sjögren’s syndrome, Bell’s palsy, 
Guillain-Barré syndrome, multiple sclerosis, autoimmune thyroid disease, vasculitis, or 
glomerulonephritis. 
x 
Patients with a history of autoimmune hypothyroidism on a stable dose of thyroid 
replacement hormone may be eligible. 
x 
Patients with controlled Type 1 diabetes mellitus on a stable insulin regimen may be eligible. 
x 
Patients with eczema, psoriasis, lichen simplex chronicus of vitiligo with dermatologic 
manifestations only (e.g., patients with psoriatic arthritis would be excluded) are permitted 
provided that they meet the following conditions: 
Use of this document is governed by the terms of use on the first page of this document.

 
NRG-BR004 
29 
NCI Version Date: August 15, 2022 
 
Patients with psoriasis must have a baseline ophthalmologic exam to rule out ocular 
manifestations 
 
Rash must cover less than 10% of body surface area (BSA)  
 
Disease is well controlled at baseline and only requiring low-potency topical steroids 
(e.g., hydrocortisone 2.5%, hydrocortisone butyrate 0.1%, flucinolone 0.01%, desonide 
0.05%, aclometasone dipropionate 0.05%)  
 
No acute exacerbations of underlying conditions within the last 12 months (not requiring 
psoralen plus ultraviolet A radiation [PUVA], methotrexate, retinoids, biologic agents, 
oral calcineurin inhibitors; high potency or oral steroids) 
3.4.16 Treatment with systemic immunomodulatory medications (including but not limited to 
interferons, IL-2) within 4 weeks or 5 half-lives of the drug, whichever is longer, prior to study 
entry. 
3.4.17 Treatment with systemic immunosuppressive medications (including but not limited to 
prednisone, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor necrosis 
[anti-TNF] factor agents) within 14 days prior to study entry or anticipation of need for systemic 
immunosuppressive medications during the study.  Note: Intranasal and inhaled corticosteroids or 
systemic corticosteroids at doses that do not exceed 10 mg/day of prednisone or an equivalent 
corticosteroid are allowed. 
3.4.18 Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form 
of immunosuppressive therapy within 2 weeks prior to study entry.   
3.4.19 Active hepatitis B virus (HBV) infection, defined as having a positive hepatitis B surface antigen 
(HBsAg) test at screening. 
Patients with a past or resolved HBV infection, defined as having a negative HBsAg test and a 
positive total hepatitis B core antibody (HBcAb) test at screening, are eligible for the study if 
active HBV infection is ruled out on the basis of HBV DNA viral load per local guidelines. 
3.4.20 Active hepatitis C virus (HCV) infection, defined as having a positive HCV antibody test at 
screening confirmed by a polymerase chain reaction (PCR) positive for HCV RNA. 
3.4.21 Patients with clinically active tuberculosis. 
3.4.22 Severe infection within 4 weeks prior to study entry, including but not limited to hospitalization 
for complications of infection, bacteremia, or severe pneumonia. 
3.4.23 Prior allogeneic stem cell or solid organ transplantation. 
3.4.24 Symptomatic peripheral ischemia. 
3.4.25 History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis obliterans), 
drug-induced pneumonitis, idiopathic pneumonitis, or evidence of active pneumonitis or t grade 
1 pulmonary fibrosis, per the CTCAE v5.0, on screening chest CT scan. 
3.4.26 Administration of a live, attenuated vaccine within 4 weeks prior to study entry or anticipation 
that such vaccine will be required during the study. 
Patients must agree not to receive live, attenuated influenza vaccine (e.g., FluMist) within  
4 weeks prior to study entry, during treatment or within 5 months following the last dose of 
atezolizumab/placebo. 
3.4.27 Any other disease, metabolic dysfunction, physical examination finding, or clinical laboratory 
finding giving reasonable suspicion of a disease or condition that contraindicates the use of an 
investigational drug or that may affect the interpretation of the results or render the patient at high 
risk from treatment complications. 
Use of this document is governed by the terms of use on the first page of this document.

 
NRG-BR004 
30 
NCI Version Date: August 15, 2022 
3.4.28 Psychiatric or addictive disorders or other conditions that, in the opinion of the investigator, 
would preclude the patient from meeting the study requirements or interfere with interpretation of 
study results. 
3.4.29 Pregnancy or lactation at the time of study entry or intention to become pregnant during the 
study.  (Note: Pregnancy testing according to institutional standards for women of 
childbearing potential must be performed within 3 days prior to study entry.) 
3.4.30 Use of any investigational product within 4 weeks prior to study entry. 
 
 
Use of this document is governed by the terms of use on the first page of this document.

 
NRG-BR004 
31 
NCI Version Date: August 15, 2022 
4.0 
REQUIREMENTS FOR STUDY ENTRY, TREATMENT, AND FOLLOW-UP 
The NRG-BR004 study was permanently closed to accrual on May 20, 2022.  Modified scheduled 
status updates, as outlined on Table 2A, will be completed for patients enrolled prior to study 
accrual closure. 
With Amendment #3, accrual to the PRO-CTCAE substudy is closed.  Patients enrolled on the 
PRO-CTCAE substudy prior to Amendment #3 will continue to complete the scheduled 
assessments as outlined on Table 2.  Accrual to the QOL substudy will continue. 
Tests, exams, and other studies required prior to study entry and randomization are listed on  
Table 1.  Requirements following randomization are outlined on Table 2. 
Table 1.  Tests, exams, and other requirements prior to study entry and randomization 
Required Assessments 
Prior to study entry 
Prior to 
randomization 
Consent form signed by the patient 
X 
 
Local determination of HER2 status (see 
Section 3.3.8) 
X 
 
Central determination of HER2 and hormone 
receptor status and PD-L1 status (see Sections 
3.3.8, 3.3.9, 3.3.10, 10.0) 
 
Xa 
History & physical exam 
  Xb 
Within 4 weeks 
 
Performance status (see Appendix A) 
X 
 
Height & weight 
X 
 
Assessment of BP and BP meds 
X 
 
Assessment of concomitant medications 
  Xc 
 
CBC/differential/platelet count 
X 
Within 14 days 
 
Total bilirubin/AST/ALT/Alkaline phosphatase 
X 
 
Calcium, fasting blood glucose, albumin, 
sodium, potassium 
X 
 
Creatinine or creatinine clearance (calculated 
or measured) 
X 
 
TSH and AM (preferably drawn in morning) 
Cortisol 
X 
 
PT/INR 
X 
 
Hepatitis B Surface Antigen, Hepatitis B Core 
Antibody, Hepatitis C Antibody 
  Xd 
 
Pregnancy test 
  Xe 
Within 3 days 
 
Echocardiogram (or MUGA scan) 
  Xf 
Within 6 weeks 
 
12-Lead ECG 
X 
 
Imaging of chest/abdomen/pelvis  
  Xg 
Within 5 weeks 
 
Bone scan 
  Xh 
 
Neuroimaging 
 Xi 
 
Table continued on next page. 
 
Use of this document is governed by the terms of use on the first page of this document.

 
NRG-BR004 
32 
NCI Version Date: August 15, 2022 
Table 1.  Tests, exams, and other requirements prior to study entry and randomization (continued) 
Required Assessments 
Prior to study entry 
Prior to 
randomization 
Optional submission of unstained slides (see 
Section 10.0) 
Xj 
Optional submission of blood sample for 
ctDNA 
  Xk 
(before atezolizumab/placebo therapy begins) 
Quality of Life (QOL) questionnaire  
  Xl 
 
If patient not randomized, an adverse event 
assessment is to be performed 30 days after last 
treatment received after study entry and prior 
to randomization  
 
Xm 
a 
Submission of unstained slides for central confirmation of HER2 and ER/PgR and PD-L1 
testing after study entry but prior to randomization is mandatory.  For patients presenting with de 
novo metastatic disease, unstained slides from metastatic disease are preferred, but unstained slides 
from breast primary or involved regional lymph nodes may be submitted as an alternative.  For 
patients presenting with locally recurrent or metastatic disease following prior therapy for early 
breast cancer, unstained slides from the metastatic disease or locally recurrent disease must be 
submitted.  A "Notice of HER2 Eligibility" must appear in Medidata Rave to confirm testing for 
HER2, ER/PgR, and PD-L1 has been completed before a patient can be randomized.  See Section 
10.0 and the NRG-BR004 Pathology, Correlative Science, and Imaging Submission Instructions. 
b History and physical by a physician or other healthcare professional. 
c 
Include all prescribed and over-the-counter medications, supplements, herbal therapies (see Section 
5.4.3) 
d Hepatitis B virus DNA must be collected in patients who have negative serology for Hepatitis B 
surface antigen and positive serology for antibody to hepatitis B core antigen. 
e 
For women of childbearing potential: Pregnancy testing should be performed according to 
institutional standards within 3 days prior to study entry. 
f 
Echocardiogram is the preferred method for assessment of LVEF.  However, LVEF assessment 
by MUGA scan is permitted.  All subsequent LVEF assessments should be performed by the same 
method (echocardiogram or MUGA scan) that was performed at baseline. 
g 
The same method (CT or MRI) used for baseline tumor measurements should be used at all other 
tumor measurement time points.  If patient is unable to receive CT contrast, a MRI of the 
abdomen/pelvis and non-contrast chest CT should be performed.  PET/CT is not an acceptable 
alternative contrast enhanced imaging method.  Note: Copies of all disease imaging scans are to be 
submitted to Bioclinica for retrospective central independent review (see the NRG-BR004 
Pathology, Correlative Science, and Imaging Submission Instructions and the BR004 Bioclinica 
site manual).  See Section 13.1 for submission of disease imaging scan reports. 
h If PET/CT was previously performed within the 5 weeks prior to study entry and demonstrated no 
evidence of bone metastases, baseline bone scan is recommended but not required. 
i 
MRI of the brain (or contrast CT scan of the brain if patients are unable to undergo MRI) is 
required if symptoms suggest possible CNS metastatic disease.  However, neuroimaging is also 
recommended in asymptomatic patients. 
j 
Submission of unstained slides within 45 days following study entry is required for all patients 
who agreed to optional tissue submission in the consent form.  See Section 10.0 and the NRG-
BR004 Pathology, Correlative Science, and Imaging Submission Instructions. 
Table continued on next page. 
 
Use of this document is governed by the terms of use on the first page of this document.

 
NRG-BR004 
33 
NCI Version Date: August 15, 2022 
Table 1.  Tests, exams, and other requirements prior to study entry and randomization (continued) 
k Requirement for all patients who agreed to optional blood collection and submission in the 
consent form.  See Section 10.0 and the NRG-BR004 Pathology, Correlative Science, and Imaging 
Submission Instructions for ctDNA kit ordering instructions. 
l 
The QOL questionnaire must be administered after the informed consent is signed (see Section 
11.0).  For QOL reporting, this study uses Medidata Patient Cloud ePRO.  Remember to register 
the patient to the Patient Cloud.  For instructions on registering the patient, please refer to Section 
8.5 and Appendix B.  The study-specific QOL items for this protocol can be found on the CIRB 
Documents>Amendment Reviews section of the CTSU protocol webpage (https://www.ctsu.org). 
m Patients who are not confirmed to be HER2-positive by central confirmation testing will not be 
randomized and will be taken off study and treated per investigator discretion.  Patients will not be 
followed on BR004. 
 
 
Use of this document is governed by the terms of use on the first page of this document.

 
NRG-BR004 
 
34 
NCI Version Date: August 15, 2022 
Table 2.  Tests, exams, and other requirements during therapy and through Year 10 for Arm 1 and Arm 2 
The NRG-BR004 study was permanently closed to accrual on May 20, 2022.  Modified scheduled status updates, as outlined on Table 2A, will be 
completed for patients enrolled prior to study accrual closure. 
With Amendment #3, accrual to the PRO-CTCAE substudy is closed.  Patients enrolled on the PRO-CTCAE substudy prior to Amendment #3 will 
continue to complete the scheduled assessments as outlined on Table 2.  Accrual to the QOL substudy will continue. 
Required assessments 
(See footnotes a, b, and c) 
During Paclitaxel or 
Docetaxel Therapy 
(Within 3 days of  
Days 1 and 22 of each  
6-week cycle) 
During Trastuzumab, 
Pertuzumab, 
Atezolizumab/Placebo 
(Within 3 days of Day 1 
of each 6-week cycle  
through Year 2) 
30 to 45 days after the 
last dose of  
atezolizumab/placebo 
Years 3 through 5 
(from study entry) 
Years 6 through 
10 (from study 
entry) 
History & physical examd 
X 
(every 3 weeks) 
X 
(every 6 weeks) 
 
X 
(every 3 months) 
X 
(every 6 months) 
Vital signs 
X 
(every 3 weeks) 
X 
(every 6 weeks) 
 
X 
(every 3 months) 
X 
(every 6 months) 
Adverse event assessmente 
X 
(every 3 weeks) 
X 
(every 6 weeks) 
X 
X 
(every 3 months) 
X 
(every 6 months) 
Concomitant medication 
assessmentf 
X 
X 
X 
 
 
CBC/differential/platelet 
countg 
X 
(every 3 weeks) 
X 
(every 6 weeks) 
X 
X 
(every 6 months) 
X 
(every 6 months) 
Total bilirubin/AST/ALT/Alk 
phos 
X 
(every 3 weeks) 
X 
(every 6 weeks) 
X 
X 
(every 6 months) 
X 
(every 6 months) 
Creatinine, calcium, glucose, 
albumin, sodium, potassium 
X 
(every 3 weeks) 
X 
(every 6 weeks) 
X 
X 
(every 6 months) 
X 
(every 6 months) 
TSH and Cortisolh 
X 
(every 6 weeks while on atezolizumab/placebo) 
X 
 
 
Imaging of 
chest/abdomen/pelvis for 
disease assessmenti,j 
X 
(prior to Weeks 10, 19, and 28 and then at 9, 12, 15, 18, 
21, and 24 months from study entry) 
 
X 
(every 3 months 
through Year 3 and 
every 6 months for 
Years 4 and 5) 
X 
(every 6 months) 
MRI of braink 
(only if metastatic brain 
disease present at study entry) 
X 
(prior to Weeks 10, 19, and 28 and then at 9, 12, 15, 18, 
21, and 24 months from study entry) 
 
X 
(every 3 months 
through Year 3 and 
every 6 months for 
Years 4 and 5) 
X 
(every 6 months) 
Table continued next page. 
 
Use of this document is governed by the terms of use on the first page of this document.

 
NRG-BR004 
 
35 
NCI Version Date: August 15, 2022 
Table 2.  Tests, exams, and other requirements during therapy and through Year 10 for Arm 1 and Arm 2 (continued) 
Required assessments 
(See footnotes a, b, and c) 
During Paclitaxel or 
Docetaxel Therapy 
(Within 3 days of  
Days 1 and 22 of each  
6-week cycle) 
During Trastuzumab, 
Pertuzumab, 
Atezolizumab/Placebo 
(Within 3 days of Day 1 of 
each 6-week cycle  
through Year 2) 
30 to 45 days after 
the last dose of  
atezolizumab/placebo 
Years 3 through 5 
(from study entry) 
Years 6 through 
10 (from study 
entry) 
MRI of braink 
(only if metastatic brain 
disease present at study entry) 
X 
(prior to Weeks 10, 19, and 28 and then at 9, 12, 15, 18, 
21, and 24 months from study entry) 
 
X 
(every 3 months 
through Year 3 and 
every 6 months for 
Years 4 and 5) 
X 
(every 6 months) 
Echocardiogram (or MUGA 
scan)l 
X 
(every 12 weeks from study entry) 
 
X 
(every 6 months) 
X 
(every 12 months) 
Bone scan 
X 
(every 6 months from study entry) 
 
X  
(every 6 months 
through Year 3 and 
every 12 months 
for Years 4 and 5) 
 
Quality of Life (QOL) 
questionnairem 
X 
(at 12 and 24 weeks from 
study entry) 
X 
(12, 18, and 24 months 
from study entry) 
 
X 
(at 30 months 
only) 
 
PRO-CTCAE assessmentm 
X 
(weekly Cycles 1-2; 
every 3 weeks Cycles 3-4) 
X 
(every 6 weeks) 
 
X 
(at 30 months 
only) 
 
Submission of blood sample 
for ctDNAn 
X 
(prior to Weeks 10, 19, and 28 and then at 9, 12, 18, and 
24 months from study entry) 
 
X 
(every 6 months) 
 
Submission of unstained 
slides at time of progressiono 
X 
a 
History and physical, blood tests, x-rays, scans, and other testing may be performed more frequently at the discretion of the investigator. 
b Patients who discontinue all protocol therapy for reasons other than disease progression must follow the exams, assessments, and tissue sample 
submissions outlined on Table 2.  Further therapy will be at the investigator's discretion and treatments administered prior to progression must be 
reported in eCRF.  
c While tests, exams, and assessments, are not required following disease progression, follow-up for subsequent cancer events and immune-related 
events, post progression therapies with immune therapy, and for survival continues to be required every 6 months through Year 10.  (See Section 7.0 
for adverse event reporting requirements.) 
Table continued on next page. 
 
Use of this document is governed by the terms of use on the first page of this document.

 
NRG-BR004 
 
36 
NCI Version Date: August 15, 2022 
Table 2.  Tests, exams, and other requirements during therapy and through Year 10 for Arm 1 and Arm 2 (continued) 
d History and physical with exams (by physician or other healthcare professional) appropriate for therapy-related assessments and follow-up 
evaluations. 
e See Section 7.6 for instructions regarding adverse event reporting. 
f 
Include all prescribed and over-the-counter medications, supplements, herbal therapies (see Section 5.4.3). 
g 
CBC/differential/platelet count may be checked more frequently per institutional policy.  If obtained, the results must be reviewed prior to 
administration of paclitaxel or docetaxel.  The trastuzumab and pertuzumab may be started prior to obtaining results. 
h Cortisol should be collected preferably in the morning.  After atezolizumab/placebo is discontinued, patients should be monitored for signs and 
symptoms of endocrinopathies (e.g., fatigue) and testing considered for TSH and cortisol as clinically indicated.  
i 
The same method (CT or MRI) used for baseline tumor measurements should be used at all other tumor measurement time points.  Scans may be 
performed within 14 days of the scheduled scan assessment through Year 2.  Scans may be performed +/- 3 weeks for scans done in Years 3 through 
10.  Follow the scan schedule until documented progression.  If therapy with atezolizumab/placebo is continued in the setting of possible 
pseudoprogression, repeat scans are required in 4 to 6 weeks (see Section 12.2.8).  If patients discontinue protocol therapy in the absence of disease 
progression, tumor assessments should continue unless they have started alternative (non-protocol) anti-cancer therapy, withdraw consent, or the 
study is terminated by the sponsor, whichever occurs first.  Note: Copies of all disease imaging scans are to be submitted to Bioclinica for 
retrospective central independent review (see the NRG-BR004 Pathology, Correlative Science, and Imaging Submission Instructions and the BR004 
Bioclinica site manual).  See Section 13.1 for submission of disease imaging scan reports. 
j 
Beginning in Year 2 the following substitutions for disease assessment scans of regions of the body not previously involved with malignancy on 
imaging may be made at investigator discretion to reduce radiation or gadolinium exposure: 
x 
No disease in the chest at entry – A chest x-ray may be substituted for a CT scan of the chest. 
x 
No disease in the abdomen at entry – An ultrasound of the abdomen may be substituted for a CT scan of the abdomen. 
x 
No disease in the pelvis at entry – An ultrasound of the pelvis may be substituted for a CT scan of the pelvis. 
At the time of progression, patients should have imaging of the chest/abdomen/pelvis, preferably with a CT scan, and a bone scan performed to 
document extent of disease. 
Note: In the event of declining renal function or dye allergy, chest CT may be performed without contrast and MRI of abdomen and pelvis may be 
substituted for CT scan. 
k Any patient with worsening and/or new neurological symptoms will be evaluated per institutional standards. 
l 
Echocardiogram is the preferred method for assessment of LVEF.  However, LVEF assessment by MUGA scan is permitted.  All LVEF 
assessments should be performed by the same method (echocardiogram or MUGA scan) that was performed at baseline. 
m PRO-CTCAE assessments are expected from only those patients who completed the baseline PRO-CTCAE prior to Amendment #3.  This study uses 
Medidata Patient Cloud ePRO for QOL and PRO-CTCAE reporting.  Remember to register the patient to the Patient Cloud.  For instructions on 
registering the patient, please refer to Section 8.5 and Appendix B.  The study-specific QOL and PRO-CTCAE items for this protocol can be found 
on the CIRB Documents>Amendment Reviews section of the CTSU protocol webpage (https://www.ctsu.org). 
Table continued on next page. 
 
Use of this document is governed by the terms of use on the first page of this document.

 
NRG-BR004 
 
37 
NCI Version Date: August 15, 2022 
Table 2.  Tests, exams, and other requirements during therapy and through Year 10 for Arm 1 and Arm 2 (continued) 
n Requirement for all patients who agreed to optional blood collection and submission in the consent form.  See Section 10.0 and the NRG-BR004 
Pathology, Correlative Science, and Imaging Submission Instructions for ctDNA kit ordering instructions.  A blood sample must also be collected at 
the time of tumor recurrence (see Section 10.0). 
o 
Submission of unstained slides at the time of tumor progression (if biopsy was performed) is only required for patients who have agreed to the 
optional tumor sample submission when signing the consent form (see Section 10.0 and the NRG-BR004 Pathology, Correlative Science, and 
Imaging Submission Instructions). 
 
Table 2A.  Required status updates after study closure through April 2024 for Arm 1 and Arm 2 
The NRG-BR004 study was permanently closed to accrual on May 20, 2022.  Modified scheduled status updates, as outlined on Table 2A, will be 
completed for patients enrolled prior to study accrual closure. 
 
Required status updates 
First follow-up visit post-activation 
of Amendment #6a 
Subsequent follow-up visits 
(every 6 months)b 
Vital status 
X 
X 
Adverse events of special interest assessmentc  
X 
X 
Monitoring for initial disease progression and 
survival statusc 
X 
X 
a After activation of Amendment #6, the first follow-up visit will occur 3 months from the last scheduled follow-up visit. 
b After the first follow-up visit post-activation of Amendment #6, patient follow-up visits will change to an every-6-month 
schedule through April 2024. 
c 
Follow-up for breast cancer progression, second malignancies, adverse events of special interest, and survival continues to 
be required every 6 months through April 2024.  (See Section 7.5.4 and Section 7.7 for reporting requirements.)   
 
 
Use of this document is governed by the terms of use on the first page of this document.

 
NRG-BR004 
38 
NCI Version Date: August 15, 2022 
5.0 
TREATMENT REGIMENS 
5.1 
Treatment Regimen for Arm 1 and Arm 2 
This is a double-blind trial; neither the patient nor the investigator/healthcare providers will know 
the treatment assigned. 
x 
Once potential eligibility has been confirmed and consent signed, initiate Cycle 1 treatment 
with standard loading doses of trastuzumab and pertuzumab obtained by the investigator from 
commercial supply and paclitaxel or docetaxel per institutional standards while waiting on 
results of central testing.  Once eligibility has been confirmed by central testing and the 
patient has been randomized, the first dose of atezolizumab/placebo should be administered 
on Day 22 of Cycle 1.   
x 
After study entry, a tumor specimen must be submitted for central testing so that results are 
received in time for patient randomization within 14 days from study entry.  This will ensure 
that the PMB-supplied agents will be received at the site for treatment on Day 22 of Cycle 1. 
x 
Patients who are not confirmed to be HER2-positive by central testing will not be randomized 
and will be taken off study and treated per investigator discretion.  A final adverse event 
assessment should be performed at 30 days after the last treatment received after study entry 
and prior to randomization.  Patients will not continue to be followed on BR004. 
x 
Atezolizumab/placebo should begin within 7 days following randomization. 
x 
Adverse events and results of laboratory safety assessments are to be reviewed prior to 
administration of components of study therapy pertinent to that parameter. 
x 
Central venous access is strongly recommended. 
Table 3.  Treatment regimen for Arm 1 and Arm 2 
Drug 
Dose 
Dosing Interval 
Planned Duration 
Pertuzumab (P)a 
(Use of premeds is at 
the investigator’s 
discretion or 
institutional policy.) 
First dose (loading dose): 
840 mg IV over 60 minutes (r10 
minutes)b,c 
Subsequent doses: 
420 mg IV over 30-60 minutesc,d 
Days 1 and 22 
every 6 weeks 
Until progression 
Trastuzumab (T)a 
(Use of premeds is at 
the investigator’s 
discretion or 
institutional policy.) 
First dose (loading dose): 
8 mg/kg IV over 90 minutes  
(r10 minutes)b,c 
Subsequent doses: 
6 mg/kg IV over 30-60 minutesc,d 
Days 1 and 22 
every 6 weeks 
Until progression 
Paclitaxel (WP)b,e 
OR 
Docetaxel (D)b,f 
(Premeds may be 
modified at the 
investigator’s 
discretion or 
institutional policy.) 
Paclitaxel (WP)b,e 
80 mg/m2 IV over 60 minutes  
(-5 or +10 minutes) 
See footnote f for premedications 
Days 1, 8, 15, 
22, 29, and 36 
every 6 weeks 
Minimum of 3 
cycles with 
additional cycles 
allowed in absence 
of progression or 
toxicity at the 
investigator's 
discretion 
Docetaxel (D)b,f 
75 mg/m2 IV over 60 minutes  
(-5 or +10 minutes) 
See footnote f for premedications 
Days 1 and 22 
every 6 weeks 
Table continued on next page. 
 
Use of this document is governed by the terms of use on the first page of this document.

 
NRG-BR004 
39 
NCI Version Date: August 15, 2022 
Table 3.  Treatment regimen for Arm 1 and Arm 2 (continued) 
Drug 
Dose 
Dosing 
Interval 
Planned Duration 
Atezolizumab/ 
Placebo 
1200 mg IV diluted in 250 mL 
polyvinyl chloride (PVC), 
polyethylene (PE), or polyolefin 
(PO) infusion bag containing 0.9% 
NaCl solution (NSS) or placebo 
IV.  
Administer through an intravenous 
line with a sterile, non-pyrogenic, 
low-protein binding in-line filter 
(pore size of 0.2 – 0.22 micron)g,h 
Day 22 of 
Cycle 1 and 
then Days 1 
and 22 every  
6 weeks 
Two years in 
absence of 
progression  
First Infusion 
Subsequent Infusions 
• 
No premedication for 
atezolizumab/placebo is 
permitted prior to the 
atezolizumab/placebo infusion. 
• 
Vital signs (pulse rate, 
respiratory rate, blood pressure, 
and temperature) should be 
measured within 60 minutes 
prior to the infusion. 
• 
Atezolizumab/placebo 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/placebo 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. 
Table continued on next page. 
 
Use of this document is governed by the terms of use on the first page of this document.

 
NRG-BR004 
40 
NCI Version Date: August 15, 2022 
Table 3.  Treatment regimen for Arm 1 and Arm 2 (continued) 
Atezolizumab/ 
Placebo 
Because of the risk of an anaphylactic reaction, it is important to have the 
following equipment available: 
Equipment Needed 
x 
Monitoring devices: ECG monitor, blood pressure monitor, oxygen 
saturation monitor, and thermometer 
x 
Oxygen 
x 
Epinephrine for subcutaneous, intravenous, and/or endotracheal use 
in accordance with standard practice  
x 
Antihistamines 
x 
Corticosteroids 
x 
IV infusion solutions, tubing, catheters, and tape 
Note: During paclitaxel or docetaxel therapy, patients are to be assessed every 3 weeks during the  
6-week cycle.  While on antibody therapies alone, patients are to be assessed every 6 weeks.  In 
order to keep the AE reporting cycles consistent for the first 2 years of study therapy, a 
treatment cycle will be 6 weeks (see Table 2). 
a 
Initiate Cycle 1 treatment with standard loading doses of trastuzumab and pertuzumab obtained by 
the investigator from commercial supply. 
b 
Pertuzumab, trastuzumab, paclitaxel or docetaxel should be administered sequentially.  Paclitaxel 
or docetaxel should be administered after pertuzumab and trastuzumab.  An observation period of 
30 to 60 minutes is recommended after each pertuzumab infusion and before starting any 
subsequent infusion of trastuzumab or paclitaxel but may be adjusted by institutional standards.   
c 
See Table 10 for LVEF requirements for continuation of trastuzumab and pertuzumab, and 
atezolizumab/placebo.  
d See Table 11 for instructions regarding trastuzumab and pertuzumab infusion-related and allergic 
reactions. 
e 
Patients should receive premedications as follows for initial paclitaxel dose. 
x 
Dexamethasone 8-12 mg IV, completed 30 minutes before paclitaxel administration. 
x 
Diphenhydramine hydrochloride 25-50 mg IV or PO and an H-2 blocker IV or PO (cimetidine 
300 mg, ranitidine 50 mg, or famotidine 20 mg) before paclitaxel administration. 
x 
Dexamethasone should be tapered and discontinued for subsequent paclitaxel cycles if tolerated 
and may be discontinued per investigator discretion. 
x 
Diphenhydramine hydrochloride 25-50 mg and the H-2 blocker may also be tapered and 
discontinue per investigator discretion. 
Table continued on next page. 
 
Use of this document is governed by the terms of use on the first page of this document.

 
NRG-BR004 
41 
NCI Version Date: August 15, 2022 
Table 3.  Treatment regimen for Arm 1 and Arm 2 (continued) 
f 
Patients should receive premedications as follows before initial docetaxel dose. 
x 
Dexamethasone 8 mg BID the day before and the day of chemotherapy.  At investigator 
discretion, dexamethasone may be continued on the day after chemotherapy.  An equivalent 
dose of other corticosteroids may be substituted (dexamethasone 8 mg = methylprednisolone 40 
mg = prednisone 50 mg = prednisolone 50 mg). 
x 
Administration of IV dexamethasone as a substitute for oral dexamethasone prior to 
chemotherapy is at the investigator's discretion. 
x 
Dexamethasone dose and duration may be tapered for subsequent docetaxel cycles per 
investigator discretion. 
At the investigator's discretion, other non-steroidal premedications, e.g., diphenhydramine 
hydrochloride 50 mg IV and H-2 blocker IV (cimetidine 300 mg, ranitidine 50 mg, or famotidine 
20 mg) may be given in addition to dexamethasone. 
g 
If an infusion-related reaction, cytokine-release syndrome, or anaphylactic reaction occurs, see 
Section 6.12 for additional treatment management information. 
h Refer to Section 9.1.1 for compatible infusion set materials including inline filter. 
 
5.2 
Endocrine Therapy Following Paclitaxel and Docetaxel 
Initiation of endocrine therapy for patients who are ER-positive or PgR-positive is not 
recommended until progression but may be initiated per investigator discretion following 
completion of paclitaxel or docetaxel.  The endocrine therapies that may be administered after 
completing paclitaxel or docetaxel include tamoxifen, aromatase inhibitors, fulvestrant, and 
luteinizing hormone-releasing hormone agonists.  Co-administration of everolimus or CDK 4/6 
inhibitors is not permitted.  Patients should continue to follow the study calendar (see Table 2). 
5.3 
Dose Determinations 
5.3.1 
Calculations of BSA and Chemotherapy Doses 
x 
Recommended chemotherapy doses will be provided at the time of study entry.    
x 
Recalculations of BSA and chemotherapy doses are required if the patient has a 10% or 
greater weight change (+/-) from baseline or from the last weight used to calculate BSA and 
drug doses.  At investigator discretion and institutional practice, the BSA and chemotherapy 
doses may be recalculated prior to each treatment. 
5.3.2 
Rounding Doses 
Follow institutional practice for standard drug rounding. 
5.4 
General Concomitant Medication and Supportive Care Guidelines 
5.4.1 
Bone-directed therapy 
Bisphosphonates and denosumab are allowed. 
5.4.2 
Antiemetic Therapy 
Antiemetic therapy should be administered according to National Comprehensive Cancer 
Network (NCCN) (https://www.nccn.org) or American Society of Clinical Oncology (ASCO) 
(http://www.asco.org) clinical practice guidelines. 
Use of this document is governed by the terms of use on the first page of this document.

 
NRG-BR004 
42 
NCI Version Date: August 15, 2022 
5.4.3 
Concomitant Therapy Precautions 
Concomitant therapy includes any medication (e.g., prescription drugs, over-the-counter drugs, 
vaccines, herbal or homeopathic remedies, nutritional supplements) used by a patient in addition 
to protocol-mandated study treatment from 14 days prior to initiation of study entry to the 
treatment discontinuation visit.  Concomitant use of herbal therapies is not recommended because 
their pharmacokinetics, safety profiles, and potential drug-drug interactions are generally 
unknown. 
Patients who experience infusion-associated symptoms may be treated symptomatically with 
acetaminophen, ibuprofen, H1-receptor antagonists (e.g., 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 ȕ2-adrenergic 
agonists).  
Systemic corticosteroids are recommended, at the discretion of the investigator, for the treatment 
of specific immune-related adverse events when associated with atezolizumab or placebo therapy 
(refer to the Atezolizumab Investigator's Brochure for details). 
5.4.4 
Prohibited Therapies 
The following types of treatment, in addition to any cancer therapy other than the therapy 
specified in this protocol, are prohibited until the time of disease progression or discontinuation 
of protocol therapy. 
x 
Chemotherapy 
Administration of chemotherapy other than the chemotherapy specified in this protocol is 
prohibited. 
x 
Targeted therapy or immunotherapy 
Administration of targeted therapy or immunotherapy other than the targeted therapy and 
immunotherapy specified in the protocol is prohibited. 
x 
Live virus vaccines 
Live, attenuated vaccines (e.g., FluMist) are prohibited within 4 weeks prior to study entry, 
during study treatment, and for 5 months after the last dose of atezolizumab/placebo. 
x 
Systemic immunomodulatory or immunosuppressive medications 
 
Systemic immunomodulatory agents (including, but not limited to, interferons and IL-2) 
are prohibited within 4 weeks or 5 half-lives of the drug, whichever is longer, prior to 
study entry and during study treatment because these agents could potentially increase the 
risk for autoimmune conditions when given in combination with atezolizumab. 
 
Systemic immunosuppressive medications (including, but not limited to, azathioprine, 
methotrexate, and thalidomide) are prohibited during study treatment because these 
agents could potentially alter the efficacy and safety of atezolizumab. 
5.4.5 
Participation in Other Trials 
Patients are not permitted to participate in other therapeutic trials until after progression.  If a 
BR004 patient is considering participation in a supportive therapy trial, contact the NRG 
Oncology Clinical Coordinating Department.   
Use of this document is governed by the terms of use on the first page of this document.

 
NRG-BR004 
43 
NCI Version Date: August 15, 2022 
5.5 
Duration of Therapy 
In the absence of treatment delays due to adverse event(s), treatment should continue as specified 
in the above treatment modality sections until one of the following criteria applies: 
x 
Disease progression 
x 
Intercurrent illness that prevents further administration of treatment 
x 
Unacceptable adverse event(s) 
x 
Patient decides to withdraw from the study 
x 
General or specific changes in the patient's condition render the patient unacceptable for 
further treatment in the judgment of the investigator 
x 
Patient non-compliance 
x 
Pregnancy 
 
All women of child bearing potential should be instructed to contact the investigator 
immediately if they suspect they might be pregnant (e.g., missed or late menstrual period) 
at any time during study participation. 
 
The investigator must immediately notify CTEP in the event of a confirmed pregnancy in 
a female patient or the partner of a male patient participating in the study. 
x 
Termination of the study by sponsor 
x 
The drug manufacturer can no longer provide the study agent 
The reason(s) for protocol therapy discontinuation, the reason(s) for study removal, and the 
corresponding dates must be reported in the Case Report Form. 
 
Use of this document is governed by the terms of use on the first page of this document.

 
NRG-BR004 
44 
NCI Version Date: August 15, 2022 
6.0 
TREATMENT MODIFICATIONS/MANAGEMENT 
6.1 
General Instructions 
x 
The CTCAE v5.0 must be used to grade the severity of AEs.  Refer to 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
x 
PRO-CTCAE data should not be used for determining dose delays or dose modifications or 
any other protocol-directed action. 
x 
Dose reductions for paclitaxel and docetaxel must be based on the AE requiring the greatest 
modification. 
x 
Paclitaxel and docetaxel doses that have been reduced may not be escalated. 
x 
There are no dose reductions for trastuzumab, pertuzumab, and atezolizumab/placebo. 
x 
If necessary, the timing of a treatment may be adjusted to 2 days earlier or 2 days later than 
the scheduled date of treatment, though paclitaxel doses should not be administered within  
5 days of each other. 
x 
Atezolizumab/placebo must not be administered beyond 2 years after the first dose (Day 22) 
of the first treatment cycle regardless of any missed doses or treatment delays. 
x 
Dosing interruptions are permitted in the case of medical/surgical events or logistical reasons 
not related to study therapy (e.g., elective surgery, unrelated medical events, patient vacation, 
and/or holidays).  Patients should be placed back on study therapy within 21 days of the 
scheduled interruption.  The reason for interruption should be documented in the patient's 
study record. 
x 
When rescheduling study therapy for non-medical adjustments, refer to the memo 
"Scheduling Protocol Therapy during the Holidays."  This memo provides information 
regarding treatment over holidays/vacations and other non-medical delays (e.g., physician or 
patient schedules).  This memo is updated annually and is posted on the CTSU Web site 
under the specific protocol supplemental documents.   
6.2 
Tumor Progression 
Progression of disease is defined in Section 12.0, and study therapy should generally be 
discontinued at the time of initial documentation of RECIST 1.1 criteria for progression.  
However, in cases in which the investigator believes pseudoprogression may have occurred, 
protocol therapy may be continued, but repeat scans must be obtained in 4 to 6 weeks to 
determine if true progression has occurred.  If follow-up scans determine true progression has 
occurred, the date of progression will be considered the date of the initial scan meeting  
RECIST 1.1 criteria for analysis purposes.  If pseudoprogression is confirmed, the patient will 
continue therapy and follow-up per protocol until true progression is documented. 
6.3 
Treatment Decisions When Components of Therapy Must Be Held or Discontinued 
x 
If Cycle 1, Day 22 trastuzumab is held due to toxicity, delay initiation of 
atezolizumab/placebo until trastuzumab is resumed. 
x 
Trastuzumab, pertuzumab, and atezolizumab/placebo therapy should continue in the absence 
of progression if chemotherapy is discontinued before completion of all planned cycles. 
x 
If trastuzumab, pertuzumab, or atezolizumab/placebo is discontinued in the absence of 
progression, chemotherapy doses may be continued if the patient is benefitting from the 
therapy. 
Use of this document is governed by the terms of use on the first page of this document.

 
NRG-BR004 
45 
NCI Version Date: August 15, 2022 
x 
If trastuzumab and pertuzumab have been discontinued, atezolizumab/placebo must also be 
discontinued. 
x 
If trastuzumab, pertuzumab, and atezolizumab/placebo must be omitted for a cycle due to 
cardiac toxicities, maintain the chemotherapy schedule if clinically appropriate. 
x 
If trastuzumab must be omitted for a cycle for toxicities related to trastuzumab other than 
hypersensitivity, the pertuzumab and atezolizumab/placebo must also be held.  Maintain the 
chemotherapy schedule if clinically appropriate. 
x 
If criteria for administration of either pertuzumab or atezolizumab/placebo are not met when 
criteria for trastuzumab administration are met, the agent not meeting criteria should be 
omitted for that cycle and resumed once criteria for resumption are met with subsequent 
doses of trastuzumab. 
x 
A loading dose of trastuzumab or pertuzumab may be given at the investigator's discretion, if 
t 6 weeks have elapsed since the prior dose of trastuzumab or pertuzumab.  The maintenance 
dose will be administered for subsequent doses. 
x 
If atezolizumab/placebo must be held for ! 16 weeks for toxicities related to 
atezolizumab/placebo, atezolizumab/placebo must be discontinued. 
x 
If alternative (non-protocol) anti-cancer therapy is given at any time, protocol therapy must 
be discontinued. 
x 
If all protocol therapy is discontinued, further therapy is at the investigator's discretion.  
If protocol therapy has been discontinued for ANY reason other than disease 
progression, the study calendar for assessing response status should continue to be 
followed until first progression is documented.  This should occur even if non-protocol 
therapy has been initiated. 
6.4 
Management of Atezolizumab/Placebo Immune-Mediated Toxicities and Potential 
Unblinding 
6.4.1 
Supportive Care Guidelines 
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/placebo may not have an 
immediate therapeutic effect, and more severe immune-mediated toxicities may require acute 
management with topical corticosteroids, systemic corticosteroids, or other immunosuppressive 
agents.  Patients should receive appropriate supportive care measures as deemed necessary by the 
treating investigator.  Suggested supportive care measures for the management of adverse events 
with potential immunologic etiology are outlined in the following sections.  Where appropriate, 
these guidelines include the use of oral or intravenous treatment with corticosteroids as well as 
additional anti-inflammatory agents if symptoms do not improve with administration of 
corticosteroids.   
Toxicities associated or possibly associated with atezolizumab/placebo treatment should be 
managed according to standard medical practice.  Investigators are encouraged to review and 
refer to the American Society for Clinical Oncology Clinical Practice Guidelines for management 
of immune-mediated adverse events in patients treated with immune checkpoint inhibitors 
(Brahmer 2018), along with the dose modification guidelines provided in this protocol for 
evaluation and management of potential immune adverse events.  It may be necessary to perform 
conditional procedures such as bronchoscopy, endoscopy, or skin photography as part of 
evaluation of the event.  Additional tests, such as autoimmune serologies or biopsies, should be 
used to evaluate for a possible immunogenic etiology. 
Use of this document is governed by the terms of use on the first page of this document.

 
NRG-BR004 
46 
NCI Version Date: August 15, 2022 
For each disorder, attempts should be made to rule out other causes such as metastatic disease or 
bacterial or viral infection, which might require additional supportive care.  The treatment 
guidelines are intended to be applied when the investigator determines the events to be related to 
atezolizumab/placebo.   
Note: If after the evaluation the event is determined not to be related, the investigator does not 
need to follow the treatment guidance (as outlined in the following sections). 
6.4.2 
Overall Management for Immune-Mediated Adverse Events 
The following guidelines should be followed for management of immune-mediated 
reactions/immune-mediated adverse events (irAEs): 
x 
Patients should be thoroughly evaluated to rule out any alternative etiology (e.g., disease 
progression, concomitant medications, infections, etc.). 
x 
In the absence of a clear alternative etiology, events should be considered potentially 
immune-mediated. 
x 
Symptomatic or topical therapy should be considered for Grade 1 and mild or transient  
(d 3 days) Grade 2 irAEs, unless otherwise specified in each immune-mediated toxicity 
section.  
x 
For persistent (t 3 days) Grade 2 or Grade 3 irAEs, hold atezolizumab/placebo and 
promptly begin prednisone orally 1-2 mg/kg/day unless otherwise specified in each 
immune-mediated toxicity section. 
 
If toxicity does not improve within 5 days, hospitalize and treat as severe Grade 3 irAE. 
 
Begin steroid taper over no less than 4 weeks when toxicity improves to d Grade 1. 
 
If symptoms recur or worsen during corticosteroid tapering, contact the Protocol Officer. 
x 
For severe Grade 3 and Grade 4 irAEs, hospitalize and begin IV methylprednisolone  
2-4 mg/kg/day or equivalent. 
 
If no response within 3 days, consider additional immunosuppression (infliximab, 
cyclophosphamide).  Contact the Protocol Officer. 
 
If symptoms recur or worsen during corticosteroid tapering, contact the Protocol Officer.  
Consider increasing the corticosteroid dose (prednisone dose [e.g., up to 2-4 mg/kg/day 
or IV equivalent]) until stabilization or improvement of symptoms, then resume 
corticosteroid tapering at a slower rate. 
x 
Discontinuation of study drug is not mandated for grade 3 inflammatory reactions attributed 
to local tumor response (e.g., inflammatory reaction at sites of metastatic disease, lymph 
nodes, etc.).  Continuation of atezolizumab/placebo in this situation should be based upon a 
benefit/risk analysis for the patient. 
6.4.3 
Management of Atezolizumab/Placebo Immune-Mediated Toxicities and Potential Unblinding 
Management of certain AEs of concern, including immune-mediated pneumonitis, hepatitis, 
colitis, endocrinopathies, pancreatitis, neuropathies, meningoencephalitis, and potential ocular 
toxicities are presented in the Atezolizumab Investigator’s Brochure.  See the 
atezolizumab/placebo management guidelines in this document, administration of First and 
Subsequent Atezolizumab Infusions in Table 3, and guidelines for the management of infusion-
related reactions, cytokine-release syndrome, and anaphylaxis in Table 16. 
Atezolizumab has been associated with risks such as the following: IRRs and immune-mediated 
hepatitis, pneumonitis, colitis, pancreatitis, diabetes mellitus, hypothyroidism, hyperthyroidism, 
Use of this document is governed by the terms of use on the first page of this document.

 
NRG-BR004 
47 
NCI Version Date: August 15, 2022 
adrenal insufficiency, hypophysitis, Guillain-Barré syndrome, myasthenic syndrome or 
myasthenia gravis, meningoencephalitis, myocarditis, nephritis, myositis, and severe cutaneous 
adverse reactions.  Immune-mediated reactions may involve any organ system and may lead to 
hemophagocytic lymphohistiocytosis and macrophage activation syndrome. 
In general, for Grade 3 or 4 toxicities which have the potential for being immune-mediated, 
unblinding should be requested to determine if a patient had been receiving atezolizumab or 
placebo.  Management of patients with Grade 3 or 4 immune-mediated toxicities will require 
aggressive immunosuppressive therapies if a patient has been receiving atezolizumab.  If a patient 
had been receiving placebo, alternative therapies and additional diagnostic testing may be 
indicated.  Patients with Grade 2 toxicities may have atezolizumab/placebo held and observed 
without initiation of immunosuppressive therapy, with consideration of rechallenge without 
unblinding if medically appropriate.  However, if a decision is made to initiate 
immunosuppressive therapy, unblinding should be considered to determine if the patient was 
receiving atezolizumab or placebo to determine if the immunosuppressive therapy is appropriate.  
Unblinding is permitted for medical management of toxicity and to guide initiation of steroids 
and other immunosuppressives.  When the unblinding is requested, the date and reason for 
unblinding must be fully documented in source documents and recorded in the case report forms.  
If unblinding occurs, the site staff should make every effort to ensure that the treatment arm in 
which the unblinded patient was assigned is not communicated to any sponsor personnel or 
designee involved in the study.  If unblinding occurs, the atezolizumab/placebo must be 
permanently discontinued.  When this occurs, provision of trastuzumab is also discontinued.  
Patients will transition to trastuzumab and pertuzumab obtained by the investigator from 
commercial supply.  The institution is responsible for providing continued follow-up (for patients 
whose treatment assignment has been unblinded) on the same schedule as indicated in the study 
protocol for patients who have not been unblinded, unless otherwise specified (see Table 2).  See 
Section 9.6 for instructions on unblinding patient treatment. 
6.5 
Management of Diarrhea Potentially Related to Study Therapy 
6.5.1 
Evaluation and Management of Diarrhea 
Diarrhea is an expected potential toxicity with the use of trastuzumab, pertuzumab, and docetaxel 
in BR004, generally occurring shortly after initiation of the therapy.  Diarrhea may also occur at 
any time due to immune-colitis from atezolizumab/placebo at any time following initiation of 
therapy, though the incidence of early diarrhea is low.  Therefore, the timing of onset of the 
diarrhea should be taken into consideration when evaluating and managing diarrhea, particularly 
Grade 1 and Grade 2 diarrhea.  Evaluation and management of diarrhea will also be impacted by 
whether or not patients are receiving chemotherapy with trastuzumab and pertuzumab as well as 
co-administration of atezolizumab/placebo.  Investigators should also remember immune-colitis 
may occur subsequent to discontinuation of atezolizumab/placebo, so patients developing 
diarrhea following completion or discontinuation of atezolizumab/placebo should be evaluated 
for possible immune-mediated diarrhea/colitis.   
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. 
If immune-mediated diarrhea has not been documented and an alternative specific etiology for 
diarrhea is found that suggests it is not treatment-related, dose modifications for treatment-related 
Use of this document is governed by the terms of use on the first page of this document.

 
NRG-BR004 
48 
NCI Version Date: August 15, 2022 
diarrhea do not have to be followed, and investigators may continue portions or all of therapy 
without modifications per investigator discretion.  These decisions must be documented in the 
source documents. 
Patient education should include instructions regarding the importance of prompt 
reporting of diarrhea, early intervention with antidiarrheal medication such as loperamide, 
and non-pharmacologic interventions (e.g., increasing fluid intake, eating frequent small 
meals, avoiding foods that are high in lactose, etc.).  Refer to ASCO Recommended Guidelines 
for Treatment of Cancer Treatment-Induced Diarrhea for additional recommendations regarding 
diarrhea (Benson 2004). 
Patients should be carefully monitored for signs and symptoms of associated enterocolitis 
(such as abdominal pain, blood or mucus in stool, with or without fever in addition to the 
diarrhea) as well as bowel perforation (i.e., peritoneal signs and ileus).  This is essential in 
patients receiving docetaxel, particularly if associated with neutropenia.  Patients with 
diarrhea accompanied by abdominal pain or febrile neutropenia should be admitted to the 
hospital.   
x 
All patients who experience diarrhea should be advised to drink liberal quantities of clear 
fluids.  If sufficient oral fluid intake is not feasible, fluid and electrolytes should be 
administered via IV infusion. 
x 
Always evaluate for potential infectious causes of diarrhea. 
x 
At onset of diarrhea, promptly initiate loperamide. 
x 
Acceptable Grade 2 diarrhea will be determined by the investigator and patient but must 
also be characterized by ALL of the following: 
 
Maintenance of fluid and electrolyte balance with oral hydration. 
 
Absence of abdominal pain or no worsening of abdominal pain in patients with 
pre-existing abdominal pain due to metastatic disease. 
 
Absence of fever t 38q C. 
 
Absence of visible blood in the stool. 
x 
For Unacceptable Grade 2 diarrhea/colitis, consult GI for lower endoscopy or flexible 
sigmoidoscopy with biopsy to confirm or rule out immune-mediated colitis.  If a patient is 
experiencing abdominal pain or fever, particularly if associated with neutropenia, the patient 
should be admitted to the hospital. 
x 
For Grade 3 diarrhea/colitis, hospitalize and evaluate for both immune and non-immune 
etiologies of diarrhea/colitis.  Promptly consult GI for consideration of lower endoscopy.  If 
biopsy can be performed, initiate corticosteroids without unblinding, pending results of lower 
endoscopy biopsy.  If patient is too ill for lower endoscopic biopsy, promptly initiate steroids 
and request unblinding to help guide management.  For patients with Grade 3 diarrhea of  
d 3 days duration based solely on an increase in the number of stools to t 7 over baseline, 
who are maintaining fluid and electrolyte balance with oral hydration, are free of abdominal 
pain, are free of fever t 38qC and are free of blood in the stool may be evaluated as an 
outpatient per investigator discretion. 
x 
For Grade 4 diarrhea/colitis, hospitalize and evaluate for both immune and non-immune 
etiologies of diarrhea/colitis.  Promptly consult GI for consideration of lower endoscopy.  
Promptly initiate steroids and request unblinding to help guide further management.   
 
 
Use of this document is governed by the terms of use on the first page of this document.

 
NRG-BR004 
49 
NCI Version Date: August 15, 2022 
6.5.2 
Treatment Management and Dose Modifications for Treatment-Related Diarrhea or Colitis 
The following tables provide dose modifications for patients in Arm 1 and Arm 2 for the time 
patients are receiving study therapy. 
x 
Refer to Table 4 for management of atezolizumab/placebo for patients experiencing 
treatment-related diarrhea or colitis while on therapy.  If diarrhea occurs early following 
initiation of atezolizumab/placebo with trastuzumab and pertuzumab, atezolizumab/placebo 
should be held and not resumed until tolerance to trastuzumab and pertuzumab has been 
established. 
x 
Refer to Table 5 for management of trastuzumab, pertuzumab, and paclitaxel for patients 
experiencing treatment-related diarrhea or colitis while receiving paclitaxel. 
x 
Refer to Table 6 for management of trastuzumab, pertuzumab, and docetaxel for patients 
experiencing treatment-related diarrhea or colitis while receiving docetaxel. 
x 
Refer to Table 7 for management of trastuzumab and pertuzumab for patients experiencing 
treatment-related diarrhea or colitis following completion of chemotherapy. 
Table 4.  Dose modifications and instructions for atezolizumab/placebo for treatment-related diarrhea or 
colitis 
See Section 6.5.1 for management of diarrhea or colitis. 
CTCAE v5.0 
Adverse Event 
CTCAE 
Grade 
Management of atezolizumab/placebo 
Diarrhea, Colitis 
Grade 1 
Diarrhea 
x Initiate symptomatic treatment. 
x Continue atezolizumab/placebo. 
x Endoscopy is recommended if symptoms persist for > 7 days. 
x Monitor closely. 
Acceptable 
Grade 2 
Diarrhea 
x Initiate symptomatic treatment. 
x Continue atezolizumab/placebo. 
Unacceptable 
Grade 2 
Diarrhea or 
Grade 2 
Colitis 
x Initiate symptomatic treatment. 
x Hold atezolizumab/placebo.  
x Refer to GI specialist for evaluation and sigmoidoscopy. 
x Endoscopic evaluation should include random biopsy to look for 
lymphocytic infiltrate even if no clear visual evidence of colitis 
is seen by endoscopist. 
- If immune colitis documented, discontinue 
atezolizumab/placebo and request unblinding. 
- If receiving atezolizumab, initiate treatment with  
1-2 mg/kg/day oral prednisone or equivalent. 
- When event resolves to Grade 1 or better, taper 
corticosteroids over  1 month. 
x If immune colitis not documented, resume atezolizumab/placebo 
when tolerance to trastuzumab, pertuzumab, and chemotherapy 
has been established. 
Table continued on next page. 
 
Use of this document is governed by the terms of use on the first page of this document.

 
NRG-BR004 
50 
NCI Version Date: August 15, 2022 
Table 4.  Dose modifications and instructions for atezolizumab/placebo for treatment-related diarrhea or 
colitis (continued) 
CTCAE v5.0 
Adverse Event 
CTCAE 
Grade 
Management of atezolizumab/placebo 
Diarrhea, Colitis 
Grade 3 
Diarrhea and 
Colitis 
x Hospitalize for evaluation and management (patients with  
Grade 3 diarrhea of  3 days duration based solely on an 
increase in the number of stools to  7 over baseline with no 
evidence of colitis may be evaluated as an outpatient per 
investigator discretion). 
x Hold atezolizumab/placebo.   
x Consult GI specialist for urgent evaluation and consideration of 
endoscopy with possible biopsy. 
x If immune colitis documented or if patient too ill for lower 
endoscopy and biopsy, discontinue atezolizumab/placebo and 
request unblinding to guide further management. 
- Initiate treatment with 1-2 mg/kg/day intravenous 
methylprednisolone or equivalent and convert to  
1-2 mg/kg/day oral prednisone or equivalent upon 
improvement. 
- When event resolves to Grade 1 or better, taper 
corticosteroids over  1 month. 
- For patients with documented or presumed immune colitis 
who had received atezolizumab with progressive symptoms 
despite corticosteroid therapy, or who relapse following 
corticosteroid taper and do not improve with re-escalation of 
corticosteroids, administer infliximab 5 mg/kg.  Repeat dose 
in 2 weeks if symptoms not improved.  Maintain 
corticosteroid dosing during infliximab dosing period, taper 
once symptoms are improving. 
x If immune colitis not documented and patient was not 
unblinded, resume or discontinue atezolizumab/placebo per 
investigator discretion when tolerance to trastuzumab, 
pertuzumab, and chemotherapy has been established. 
Table continued on next page. 
 
Use of this document is governed by the terms of use on the first page of this document.

 
NRG-BR004 
51 
NCI Version Date: August 15, 2022 
Table 4.  Dose modifications and instructions for atezolizumab/placebo for treatment-related diarrhea or 
colitis (continued) 
CTCAE v5.0 
Adverse Event 
CTCAE 
Grade 
Management of atezolizumab/placebo 
Diarrhea, Colitis 
Grade 4 
Diarrhea and 
Colitis 
x Hospitalize for evaluation and management. 
x Consult GI specialist for urgent evaluation and consideration of 
lower endoscopy and biopsy. 
x Discontinue atezolizumab/placebo and request unblinding to 
guide further medical management. 
- Promptly initiate treatment with 1-2 mg/kg/day intravenous 
methylprednisolone or equivalent and convert to  
1-2 mg/kg/day oral prednisone or equivalent upon 
improvement. 
- When event resolves to Grade 1 or better, taper 
corticosteroids over  1 month. 
x For patients with documented or presumed immune colitis who 
had received atezolizumab, with progressive symptoms despite 
corticosteroid therapy and do not improve with re-escalation of 
corticosteroids, administer infliximab 5 mg/kg, repeat dose in  
2 weeks if symptoms not improved.  Maintain corticosteroid 
dosing during infliximab dosing period, taper once symptoms 
are improving.   
Table 5.  Dose modifications and instructions for trastuzumab, pertuzumab, and paclitaxel for treatment-
related diarrhea or colitis during paclitaxel administration 
See Section 6.5.1 for management of diarrhea. 
CTCAE v5.0 
Adverse Event 
CTCAE 
Grade 
Management of Trastuzumab, Pertuzumab, and Paclitaxel 
Diarrhea, Colitis 
Grade 1 
Diarrhea 
x Initiate symptomatic treatment. 
x Continue trastuzumab, pertuzumab, and paclitaxel. 
Acceptable 
Grade 2 
Diarrhea 
x Initiate symptomatic treatment. 
x Continue trastuzumab and paclitaxel.   
x Continue or hold pertuzumab per investigator discretion. 
Table continued on next page. 
 
Use of this document is governed by the terms of use on the first page of this document.

 
NRG-BR004 
52 
NCI Version Date: August 15, 2022 
Table 5.  Dose modifications and instructions for trastuzumab, pertuzumab, and paclitaxel for treatment-
related diarrhea or colitis during paclitaxel administration (continued) 
CTCAE v5.0 
Adverse Event 
CTCAE 
Grade 
Management of Trastuzumab, Pertuzumab, and Paclitaxel 
Diarrhea, Colitis 
Unacceptable 
Grade 2 
Diarrhea, 
Grade 2 
Colitis 
x Initiate symptomatic treatment. 
x Hold trastuzumab, pertuzumab, and paclitaxel pending results 
of endoscopic biopsy. 
- If immune colitis documented, resume paclitaxel at same 
dose level when d Grade 1.  Resume pertuzumab when 
tolerance to trastuzumab and paclitaxel established. 
- If immune colitis NOT documented, resume paclitaxel with 
one dose level reduction when d Grade 1.  Resume 
pertuzumab when tolerance to trastuzumab and paclitaxel 
established.  
x If Unacceptable Grade 2 diarrhea occurs a 2nd or 3rd time 
with co-administration of atezolizumab/placebo, hold 
trastuzumab, pertuzumab, and paclitaxel pending results of 
lower endoscopic biopsy.   
- If immune colitis documented, resume trastuzumab and 
paclitaxel at same dose level when d Grade 1.  Resume 
pertuzumab when tolerance to trastuzumab and paclitaxel 
established. 
- If immune colitis NOT documented, resume paclitaxel with 
one dose level reduction and trastuzumab when d Grade 1.  
Resume or discontinue pertuzumab when tolerance to 
trastuzumab and paclitaxel established. 
Unacceptable 
Grade 2 
Diarrhea, 
Grade 2 
Colitis 
x If Unacceptable Grade 2 diarrhea occurs a 2nd or 3rd time 
without co-administration of atezolizumab/placebo, hold 
trastuzumab, pertuzumab, and paclitaxel.   
- If diarrhea resolves to d Grade 1 within 1 week, resume 
paclitaxel with one dose level reduction and trastuzumab.  
Resume pertuzumab when tolerance to trastuzumab and 
paclitaxel established. 
- If diarrhea does not improve within 3 days refer for 
endoscopic biopsy. 
o If immune colitis documented, resume trastuzumab and 
paclitaxel at same dose level when d Grade 1.  Resume 
pertuzumab when tolerance to trastuzumab and paclitaxel 
established. 
o If immune colitis NOT documented, resume trastuzumab 
and paclitaxel with one dose level reduction when d 
Grade 1.  Discontinue or resume pertuzumab when 
tolerance to trastuzumab and paclitaxel established. 
x If Unacceptable Grade 2 diarrhea occurs a 4th time, continue 
trastuzumab but discontinue paclitaxel and pertuzumab. 
Table continued on next page. 
 
Use of this document is governed by the terms of use on the first page of this document.

 
NRG-BR004 
53 
NCI Version Date: August 15, 2022 
Table 5.  Dose modifications and instructions for trastuzumab, pertuzumab, and paclitaxel for treatment-
related diarrhea or colitis during paclitaxel administration (continued) 
CTCAE v5.0 
Adverse Event 
CTCAE 
Grade 
Management of Trastuzumab, Pertuzumab, and Paclitaxel 
Diarrhea, Colitis 
Grade 3 
Diarrhea, 
Colitis 
x Initiate symptomatic treatment. 
x Hold trastuzumab, pertuzumab and paclitaxel pending results of 
lower endoscopic biopsy.   
- If immune colitis documented, resume paclitaxel at same 
dose level and trastuzumab when d Grade 1.  Resume 
pertuzumab when tolerance to trastuzumab and paclitaxel 
established. 
- If immune colitis NOT documented, resume paclitaxel with 
one dose level reduction and trastuzumab when d Grade 1.  
Discontinue or resume pertuzumab when tolerance to 
trastuzumab and paclitaxel established. 
x If Grade 3 diarrhea occurs a 2nd time, hold trastuzumab, 
pertuzumab, and paclitaxel pending results of lower endoscopic 
biopsy.   
- If immune colitis documented, resume paclitaxel at same 
dose level and trastuzumab when d Grade 1.  Resume 
pertuzumab when tolerance to trastuzumab and paclitaxel 
established. 
- If immune colitis NOT documented, resume paclitaxel with 
one dose level reduction and trastuzumab when d Grade 1.  
Discontinue or resume pertuzumab when tolerance to 
trastuzumab and paclitaxel established. 
x If Grade 3 diarrhea occurs a 3rd time, hold trastuzumab, 
pertuzumab, and paclitaxel pending results of lower endoscopic 
biopsy. 
- If immune colitis documented, resume trastuzumab and 
discontinue or resume paclitaxel with one dose level 
reduction when d Grade 1.  Discontinue or resume 
pertuzumab when tolerance to trastuzumab and paclitaxel 
established. 
- If immune colitis NOT documented, resume trastuzumab 
when d Grade 1.  Discontinue or resume paclitaxel with one 
dose level reduction and resume or discontinue pertuzumab 
when tolerance to trastuzumab has been established. 
Grade 4 
Diarrhea, 
Colitis 
x Hold trastuzumab, pertuzumab, and paclitaxel pending results of 
lower endoscopic biopsy.   
- If immune colitis documented, resume paclitaxel at reduced 
dose level and trastuzumab when d Grade 1.  Resume or 
discontinue pertuzumab when tolerance to trastuzumab and 
paclitaxel established. 
- If immune colitis NOT documented, resume trastuzumab and 
discontinue or resume paclitaxel with one dose level 
reduction when d Grade 1.  Discontinue pertuzumab. 
Use of this document is governed by the terms of use on the first page of this document.

 
NRG-BR004 
54 
NCI Version Date: August 15, 2022 
Table 6.  Dose modifications and instructions for trastuzumab, pertuzumab, and docetaxel for treatment-
related diarrhea or colitis during docetaxel administration   
Note: If diarrhea management becomes persistently problematic, an alternative to dose reductions of 
docetaxel per investigator discretion would be conversion to paclitaxel for subsequent cycles.  See 
Section 6.5.1 for management of diarrhea. 
CTCAE v5.0 
Adverse Event 
CTCAE 
Grade 
Management of Trastuzumab, Pertuzumab, and Docetaxel 
Diarrhea, Colitis 
Grade 1 
Diarrhea 
x Initiate symptomatic treatment. 
x Continue trastuzumab, pertuzumab, and docetaxel. 
Acceptable 
Grade 2 
Diarrhea 
x Initiate symptomatic treatment. 
x Continue trastuzumab and docetaxel at same dose level or 
reduce one dose level per investigator discretion. 
x Continue or hold pertuzumab per investigator discretion. 
Unacceptable 
Grade 2 
Diarrhea, 
Grade 2 
Colitis 
x Initiate symptomatic treatment. 
x Hold trastuzumab, pertuzumab, and docetaxel pending results of 
endoscopic biopsy.  
- If immune colitis documented, resume docetaxel at same 
dose level and trastuzumab when d Grade 1.  Resume 
pertuzumab when tolerance to trastuzumab and docetaxel 
established.   
- If immune colitis NOT documented, resume docetaxel with 
one dose level reduction and trastuzumab when d Grade 1.  
Resume pertuzumab when tolerance to trastuzumab and 
docetaxel established. 
x If Unacceptable Grade 2 diarrhea occurs a 2nd or 3rd time 
with co-administration of atezolizumab/placebo, hold 
trastuzumab, pertuzumab, and docetaxel pending results of 
lower endoscopic biopsy.   
- If immune colitis documented, resume docetaxel at same 
dose level and trastuzumab when d Grade 1.  Resume 
pertuzumab when tolerance to trastuzumab and docetaxel 
established.  
- If immune colitis NOT documented, resume docetaxel with 
one dose level reduction and trastuzumab when d Grade 1.  
Resume or discontinue pertuzumab when tolerance to 
trastuzumab and docetaxel established. 
Table continued on next page. 
 
Use of this document is governed by the terms of use on the first page of this document.

 
NRG-BR004 
55 
NCI Version Date: August 15, 2022 
Table 6.  Dose modifications and instructions for trastuzumab, pertuzumab, and docetaxel for 
treatment-related diarrhea or colitis during docetaxel administration (continued) 
CTCAE v5.0 
Adverse Event 
CTCAE 
Grade 
Management of Trastuzumab, Pertuzumab, and Docetaxel 
Diarrhea, Colitis 
Unacceptable 
Grade 2 
Diarrhea, 
Grade 2 
Colitis 
x If Unacceptable Grade 2 diarrhea occurs a 2nd or 3rd time 
without co-administration of atezolizumab/placebo, hold 
trastuzumab, pertuzumab, and docetaxel. 
- 
If diarrhea resolves to d Grade 1 within 1 week, resume 
docetaxel with one dose level reduction and trastuzumab.  
Resume or discontinue pertuzumab when tolerance to 
trastuzumab and docetaxel established. 
- 
If diarrhea does not improve within 3 days refer for 
endoscopic biopsy.   
o If immune colitis documented, resume docetaxel at same 
dose level and trastuzumab when d Grade 1.  Resume or 
discontinue pertuzumab when tolerance to trastuzumab 
and docetaxel established.   
o If immune colitis NOT documented, resume docetaxel 
with one dose level reduction and trastuzumab when  
d Grade 1 following 2nd episode.  Resume trastuzumab and 
discontinue docetaxel following 3rd episode.  Resume or 
discontinue pertuzumab when tolerance to trastuzumab 
and docetaxel established. 
x If Unacceptable Grade 2 diarrhea occurs a 4th time, hold 
trastuzumab and resume when d Grade 1.  Discontinue 
pertuzumab. 
Grade 3 
Diarrhea, 
Colitis 
x Initiate symptomatic treatment. 
x Hold trastuzumab, pertuzumab, and docetaxel pending results of 
lower endoscopic biopsy. 
- If immune colitis documented, resume docetaxel at same 
dose level and trastuzumab when d Grade 1.  Resume 
pertuzumab when tolerance to trastuzumab and docetaxel 
established.   
- If immune colitis NOT documented, resume docetaxel with 
one dose level reduction and trastuzumab when d Grade 1.  
Resume pertuzumab when tolerance to trastuzumab and 
docetaxel established.  
Table continued in next page. 
 
Use of this document is governed by the terms of use on the first page of this document.

 
NRG-BR004 
56 
NCI Version Date: August 15, 2022 
Table 6.  Dose modifications and instructions for combination of trastuzumab, pertuzumab, and 
docetaxel for treatment-related diarrhea or colitis during docetaxel administration 
(continued) 
CTCAE v5.0 
Adverse Event 
CTCAE 
Grade 
Management of Trastuzumab, Pertuzumab, and Docetaxel 
Diarrhea, Colitis 
Grade 3 
Diarrhea, 
Colitis 
x If Grade 3 diarrhea occurs a 2nd time, hold trastuzumab, 
pertuzumab, and docetaxel pending results of lower endoscopic 
biopsy.   
- If immune colitis documented, resume docetaxel at same 
dose level or with one dose level reduction per investigator 
discretion and trastuzumab when d Grade 1.  Resume or 
discontinue pertuzumab when tolerance to trastuzumab and 
docetaxel established. 
- If immune colitis NOT documented, resume docetaxel with 
one dose level reduction and trastuzumab when d Grade 1.  
Resume or discontinue pertuzumab when tolerance to 
trastuzumab and docetaxel established. 
x If Grade 3 diarrhea occurs a 3rd time, hold trastuzumab, 
pertuzumab, and docetaxel pending results of lower endoscopic 
biopsy.   
- If immune colitis documented, resume trastuzumab and 
discontinue docetaxel or resume with one dose level reduction 
when d Grade 1.  Discontinue or resume pertuzumab when 
tolerance to trastuzumab and docetaxel established.   
- 
If immune colitis NOT documented, resume trastuzumab when 
d Grade 1.  Discontinue docetaxel and resume or discontinue 
pertuzumab when tolerance to trastuzumab established. 
Grade 4 
Diarrhea, 
Colitis 
x Hold trastuzumab, pertuzumab, and docetaxel pending results of 
lower endoscopic biopsy.   
- If immune colitis documented, resume docetaxel at reduced 
dose level and trastuzumab when d Grade 1.  Resume 
pertuzumab when tolerance to trastuzumab and docetaxel 
established.   
- If immune colitis NOT documented, resume trastuzumab and 
discontinue or reduce docetaxel one or two dose levels when d 
Grade 1.  Discontinue or resume pertuzumab when tolerance to 
trastuzumab and docetaxel established.   
 
 
Use of this document is governed by the terms of use on the first page of this document.

 
NRG-BR004 
57 
NCI Version Date: August 15, 2022 
Table 7.  Dose modifications and instructions for trastuzumab and pertuzumab for treatment-related 
diarrhea or colitis following completion of chemotherapy administration 
See Section 6.5.1 for management of diarrhea or colitis. 
CTCAE v5.0 
Adverse Event 
CTCAE 
Grade 
Management of Trastuzumab and Pertuzumab 
Diarrhea, Colitis 
Grade 1 
Diarrhea 
x Initiate symptomatic treatment. 
x Continue trastuzumab and pertuzumab. 
Acceptable 
Grade 2 
Diarrhea 
x Initiate symptomatic treatment. 
x Continue trastuzumab and pertuzumab. 
Unacceptable 
Grade 2 
Diarrhea, 
Grade 2 
Colitis 
x 
Initiate symptomatic treatment. 
x 
Refer to GI specialist for evaluation and sigmoidoscopy. 
x 
Hold trastuzumab and pertuzumab until  
d Grade 1 then resume trastuzumab and pertuzumab. 
x 
If Unacceptable Grade 2 diarrhea occurs a 2nd time with co-
administration of atezolizumab/placebo, hold trastuzumab 
and pertuzumab pending results of lower endoscopic biopsy.   
- 
If immune colitis documented, resume trastuzumab and 
pertuzumab when d Grade 1.   
- 
If immune colitis NOT documented, resume trastuzumab 
when d Grade 1.  Resume or discontinue pertuzumab 
when tolerance to trastuzumab established. 
x 
If Unacceptable Grade 2 diarrhea occurs a 2nd time without 
co-administration of atezolizumab/placebo, hold 
trastuzumab and pertuzumab.   
- 
If diarrhea resolves to d Grade 1 within 1 week, resume 
trastuzumab.  Resume pertuzumab when tolerance to 
trastuzumab established. 
- 
If diarrhea does not improve within 3 days refer for 
endoscopic biopsy. 
o If immune colitis documented, resume trastuzumab 
and pertuzumab when d Grade 1.  Resume pertuzumab 
when tolerance to trastuzumab established. 
o If immune colitis NOT documented, resume 
trastuzumab when d Grade 1 following 2nd episode.  
Resume or discontinue pertuzumab when tolerance to 
trastuzumab established. 
Table continued on next page. 
 
Use of this document is governed by the terms of use on the first page of this document.

 
NRG-BR004 
58 
NCI Version Date: August 15, 2022 
Table 7.  Dose modifications and instructions for trastuzumab and pertuzumab for treatment-related 
diarrhea or colitis following completion of chemotherapy administration (continued) 
CTCAE v5.0 
Adverse Event 
CTCAE 
Grade 
Management of Trastuzumab and Pertuzumab 
Diarrhea, Colitis 
Unacceptable 
Grade 2 
Diarrhea, 
Grade 2 
Colitis 
x 
If Unacceptable Grade 2 diarrhea occurs a 3rd time with co-
administration of atezolizumab/placebo, hold trastuzumab 
and pertuzumab pending results of lower endoscopic biopsy.   
- 
If immune colitis documented, resume trastuzumab when 
d Grade 1.  Resume or discontinue pertuzumab when 
tolerance to trastuzumab established.   
- 
If immune colitis NOT documented, resume trastuzumab 
when d Grade 1.  Discontinue pertuzumab. 
x 
If Unacceptable Grade 2 diarrhea occurs a 3rd time without 
co-administration of atezolizumab/placebo, hold 
trastuzumab and pertuzumab pending results of lower 
endoscopic biopsy. 
- 
If diarrhea resolves to d Grade 1 within 1 week, resume 
trastuzumab.  Resume pertuzumab when tolerance to 
trastuzumab established. 
- 
If diarrhea does not improve within 3 days refer for 
endoscopic biopsy. 
o If immune colitis documented, resume trastuzumab 
when d Grade 1.  Resume pertuzumab when tolerance 
to trastuzumab established. 
o If immune colitis NOT documented, resume 
trastuzumab when d Grade 1.  Discontinue 
pertuzumab. 
x 
If Unacceptable Grade 2 diarrhea occurs a 4th time, 
discontinue trastuzumab. 
Grade 3 
Diarrhea, 
Colitis 
x Initiate symptomatic treatment. 
x Hold trastuzumab and pertuzumab pending results of 
endoscopic biopsy. 
- If immune colitis documented, resume trastuzumab when d 
Grade 1.  Resume pertuzumab when tolerance to 
trastuzumab established. 
- If immune colitis NOT documented, resume trastuzumab   
when d Grade 1 and discontinue pertuzumab.   
x If Grade 3 diarrhea occurs a 2nd time, hold trastuzumab and 
pertuzumab.   
- If immune colitis documented, resume trastuzumab when d 
Grade 1.  Resume or discontinue pertuzumab when 
tolerance to trastuzumab established. 
- If immune colitis NOT documented, resume trastuzumab 
when d Grade 1.  Discontinue pertuzumab if still on 
medication. 
x 
If Grade 3 diarrhea occurs a 3rd time, discontinue 
trastuzumab. 
Table continued on next page. 
 
Use of this document is governed by the terms of use on the first page of this document.

 
NRG-BR004 
59 
NCI Version Date: August 15, 2022 
Table 7.  Dose modifications and instructions for trastuzumab and pertuzumab for treatment-related 
diarrhea or colitis following completion of chemotherapy administration (continued) 
CTCAE v5.0 
Adverse Event 
CTCAE 
Grade 
Management of Trastuzumab and Pertuzumab 
Diarrhea, Colitis 
Grade 4 
Diarrhea, 
Colitis 
x 
Admit to hospital and consider endoscopic biopsy of colon. 
- If immune colitis documented, resume trastuzumab when  
d Grade 1.  Resume or discontinue pertuzumab when 
tolerance to trastuzumab established. 
- 
If immune colitis NOT documented, resume trastuzumab 
when  Grade 1.  Discontinue pertuzumab.   
 
6.6 
Management of Cardiac Toxicity Related to Study Therapy 
6.6.1 
Evaluation and Management of Cardiac Toxicity 
x 
Cardiac toxicity, particularly left ventricular dysfunction is an expected potential toxicity 
with the use of trastuzumab and pertuzumab in BR004.  Because the potential exists for 
additive or synergistic toxicity, patients should be monitored for signs and symptoms of 
cardiotoxicity, including left ventricular dysfunction and cardiac arrhythmias.   
x 
For Grade 1 and 2 cardiac toxicities refer to cardiologist for evaluation.   
x 
For Grade 3 or Grade 4 cardiac toxicities, hospitalize on telemetry and obtain an urgent 
cardiology consult.  Promptly initiate high dose IV corticosteroid therapy. 
6.6.2 
Evaluation and Management of Immune-mediated Myocarditis 
Immune-mediated myocarditis has been associated with the administration of atezolizumab.  
Immune-mediated myocarditis should be suspected in any patient presenting with signs or 
symptoms suggestive of myocarditis, including, but not limited to, laboratory (e.g., B-NP [B-
Natriuretic Peptide]) or cardiac imaging abnormalities, dyspnea, chest pain, palpitations, fatigue, 
decreased exercise tolerance, or syncope.  
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 electrocardiogram (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 8. 
6.6.3 
Management of Trastuzumab, Pertuzumab, and Atezolizumab/Placebo during Episodes of 
Cardiac Toxicity  
Note: If both trastuzumab and pertuzumab are discontinued for non-immune cardiac toxicity, 
atezolizumab/placebo should also be discontinued. 
 
Use of this document is governed by the terms of use on the first page of this document.

 
NRG-BR004 
60 
NCI Version Date: August 15, 2022 
Table 8.  Treatment modifications and instructions for cardiac toxicities related to trastuzumab, 
pertuzumab, or atezolizumab/placebo 
Table continued on next page  
 
CTCAE v5.0 
Adverse Event 
CTCAE 
Grade 
Instructions for Each Agent Patient is Receiving 
Heart Failure 
1 
x 
Hold atezolizumab/placebo.  Consult Table 10 for management of 
trastuzumab and pertuzumab. 
x Consult cardiologist to conduct cardiac evaluation including LVEF 
assessment, troponin, BNP, and ECG.   
x If ventricular dysfunction confirmed, request unblinding for medical 
management. 
- If receiving atezolizumab, treat with 1-2 mg/kg/day oral 
prednisone or equivalent. 
– 
If steroids initiated, taper corticosteroids over 4-6 weeks. 
x 
If receiving atezolizumab, resume trastuzumab and pertuzumab if held 
when steroid taper completed and LVEF t 40%. 
x 
If receiving placebo, resume trastuzumab and pertuzumab if held when 
LVEF t 40%. 
Heart Failure, 
Ejection Fraction 
Decreased to 
LVEF of 40-
50%, or 
Myocarditis 
2 
x Hold atezolizumab/placebo.  
x Hold trastuzumab and pertuzumab.   
x Consult cardiologist to conduct cardiac evaluation including LVEF 
assessment, troponin, and EKG.   
x If ventricular dysfunction confirmed, admit to the hospital on 
telemetry and request unblinding for medical management. 
x If receiving atezolizumab, initiate treatment with  
1-2 mg/kg/day IV methylprednisolone or equivalent. 
– 
When improved to d Grade 1, taper corticosteroids over  
4-6 weeks. 
x If myocarditis confirmed, request unblinding for medical 
management. 
 
If receiving atezolizumab, initiate treatment with  
1-2 mg/kg/day IV methylprednisolone or equivalent. 
– 
When improved to d Grade 1, taper corticosteroids over  
4-6 weeks. 
x If receiving atezolizumab, resume trastuzumab and pertuzumab 
when steroid taper completed, symptoms have resolved, and LVEF 
t 40%. 
x If receiving placebo, resume trastuzumab and pertuzumab when 
symptoms have resolved and LVEF t 40%. 
Ejection Fraction 
Decreased when 
LVEF > 50% 
associated with a 
10-19% absolute 
drop from 
baseline 
2 
x 
Manage as per Table 10 based on LVEF value irrespective of value 
decline. 
Use of this document is governed by the terms of use on the first page of this document.

 
NRG-BR004 
61 
NCI Version Date: August 15, 2022 
Table 8.  Treatment modifications and instructions for cardiac toxicities related to trastuzumab, 
pertuzumab, or atezolizumab/placebo (continued) 
Table continued on next page  
 
CTCAE v5.0 
Adverse Event 
CTCAE 
Grade 
Instructions for Each Agent Patient is Receiving 
Heart Failure, 
Ejection 
Fraction 
Decreased, Left 
Ventricular 
Dysfunction, or 
Myocarditis 
3,4 
x 
Discontinue atezolizumab/placebo. 
x 
Hold trastuzumab and pertuzumab. 
x 
Admit to the hospital on telemetry. 
x 
Consult cardiologist to conduct cardiac evaluation including 
LVEF assessment, troponin, and EKG.   
x Initiate treatment with 1-2 mg/kg/day IV methylprednisolone 
or equivalent. 
x If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent. 
x Request urgent unblinding to guide subsequent medical 
management. 
x If receiving atezolizumab, resume trastuzumab and 
pertuzumab per investigator discretion when steroid taper 
completed and LVEF t 40%. 
x If receiving placebo, discontinue trastuzumab and pertuzumab. 
Other Cardiac 
Toxicities 
1 
x Continue trastuzumab and pertuzumab. 
x Continue atezolizumab/placebo at the discretion of the 
investigator. 
x Consult cardiologist to conduct cardiac evaluation including 
LVEF assessment, troponin, and EKG.   
x If intervention not indicated, continue trastuzumab and 
pertuzumab and resume atezolizumab/placebo if held by 
investigator. 
x If intervention indicated, manage per the appropriate toxicity 
grade. 
Grade 2 
requiring 
discontinuation 
of 
atezolizumab/ 
placebo (see 
list in Table 9) 
x Hold atezolizumab/placebo. 
x Hold trastuzumab and pertuzumab. 
x Consult cardiologist to conduct cardiac evaluation including 
LVEF assessment, troponin, and EKG. 
x If cardiac toxicity confirmed, request unblinding for medical 
management and consider hospitalization. 
- If receiving atezolizumab, initiate treatment with  
1-2 mg/kg/day IV methylprednisolone or equivalent if 
hospitalized.  If not hospitalized initiate 1-2 mg/kg/day oral 
prednisone with close outpatient follow-up. 
- When improved to d Grade 1, taper corticosteroids over  
4-6 weeks. 
x If receiving atezolizumab, resume trastuzumab and pertuzumab 
when steroid taper completed and toxicity has resolved to  
d Grade 1. 
x If receiving placebo, resume trastuzumab and pertuzumab when 
toxicity has resolved to d Grade 1. 
Use of this document is governed by the terms of use on the first page of this document.

 
NRG-BR004 
62 
NCI Version Date: August 15, 2022 
Table 8.  Treatment modifications and instructions for cardiac toxicities related to trastuzumab, 
pertuzumab, or atezolizumab/placebo (continued) 
 
 
CTCAE v5.0 
Adverse Event 
CTCAE 
Grade 
Instructions for Each Agent Patient is Receiving 
Other Cardiac 
Toxicities 
Other Cardiac 
Toxicities 
Grade 2 
NOT requiring 
discontinuatio
n of 
atezolizumab/ 
placebo 
x Hold atezolizumab/placebo. 
x Hold trastuzumab and pertuzumab. 
x Consult cardiologist to conduct cardiac evaluation including 
LVEF assessment, troponin, and EKG.   
x Resume trastuzumab and pertuzumab when improved to d 
Grade 1. 
x Resume atezolizumab/placebo per investigator discretion when 
improved to d Grade 1. 
3,4 
x Discontinue atezolizumab/placebo.  
x Hold trastuzumab and pertuzumab. 
x Admit to the hospital on telemetry. 
x Consult cardiologist to conduct cardiac evaluation including 
LVEF assessment, troponin, and EKG.   
x Request urgent unblinding for medical management. 
- 
If receiving atezolizumab, initiate treatment with  
1-2 mg/kg/day IV methylprednisolone or equivalent. 
- 
When event resolves to Grade 1 or better, taper 
corticosteroids over 4-6 weeks. 
x If receiving atezolizumab, resume trastuzumab and pertuzumab 
per investigator discretion when steroid taper completed and 
improved to d Grade 1. 
x If receiving placebo, permanently discontinue trastuzumab and 
pertuzumab. 
Use of this document is governed by the terms of use on the first page of this document.

 
NRG-BR004 
63 
NCI Version Date: August 15, 2022 
Table 9.  CTCAE Grade 2 Other Cardiac Disorders 
 
6.6.4 
Management of Trastuzumab, Pertuzumab, and Atezolizumab/Placebo During an Asymptomatic 
Decrease in LVEF 
The results of the LVEF assessments during trastuzumab, pertuzumab, and atezolizumab/placebo 
therapy will be used to determine if the antibodies can be continued (refer to Table 10). 
x 
If both trastuzumab and pertuzumab are discontinued for non-immune cardiac toxicity, 
atezolizumab/placebo should also be discontinued. 
x 
If atezolizumab/placebo must be discontinued due to immune-mediated cardiac toxicity, 
trastuzumab and pertuzumab may be resumed per investigator discretion when steroid taper is 
completed and cardiac toxicity has resolved to d Grade 1.  
x 
Echocardiogram is the preferred method for assessment of LVEF.  However, LVEF 
assessment by MUGA scan is permitted. 
x 
All LVEF assessments should be performed by the same method (either echocardiogram or 
MUGA scan) that was performed at baseline. 
x 
Investigators are strongly urged to schedule the LVEF assessment at the same cardiac 
imaging facility that performed the patient's baseline LVEF assessment. 
 
CTCAE Grade 2 Other Cardiac Disorders AEs That Require Referral to Cardiologist 
and Discontinuation of Atezolizumab/Placebo Therapy if Toxicity Confirmed 
CARDIAC DISORDERS – CTCAE v5.0 
Adverse Event 
Grade 2 Criteria 
Atrioventricular block complete 
Non-urgent intervention indicated 
Chest pain-cardiac 
Moderate pain; pain on exertion; limiting 
instrumental ADL; hemodynamically stable 
Mobitz (type) I atrioventricular block 
Symptomatic; medical intervention indicated 
Mobitz (type) II atrioventricular block 
Symptomatic; medical intervention indicated 
Pericarditis 
Symptomatic pericarditis (e.g., chest pain) 
Pericardial effusion 
Asymptomatic effusion size small to moderate 
Restrictive cardiomyopathy 
Symptomatic without signs of heart failure 
Right ventricular dysfunction 
Symptoms with moderate activity or exertion 
Sick sinus syndrome 
Symptomatic, intervention not indicated; change in 
medication initiated 
Ventricular arrhythmia 
Non-urgent medical intervention indicated 
Ventricular tachycardia 
Non-urgent medical intervention indicated 
Use of this document is governed by the terms of use on the first page of this document.

 
NRG-BR004 
64 
NCI Version Date: August 15, 2022 
6.6.5 
Management of Trastuzumab, Pertuzumab, and Atezolizumab/Placebo Based on LVEF 
Assessments in Asymptomatic Patients  
Table 10.  Trastuzumab, pertuzumab, and atezolizumab/placebo management based on LVEF 
assessments 
The following are instructions for patients who have an asymptomatic decrease in LVEF from 
baseline at the scheduled assessment time points during therapy. 
Note: A cardiology consultation is mandatory for any patient with an LVEF  50%. 
LVEF 
Asymptomatic decrease in LVEF percentage points (absolute drop) from baseline 
Decrease of < 10 percentage points 
Decrease of  10 percentage points 
t 50% 
Continue trastuzumab, pertuzumab, and atezolizumab/placebo 
40-49% 
Hold atezolizumab/placebo, continue 
trastuzumab and pertuzumab.  Repeat 
ECHO/MUGA in 3 weeks* 
Hold atezolizumab/placebo, 
trastuzumab, and pertuzumab.  Repeat 
ECHO/MUGA in 3 weeks* 
< 40% 
Manage as Grade 3 ejection fraction decreased in Table 8. 
* Treatment rules based on "repeat" LVEF results:  
x If the repeat LVEF is t 50%, continue/resume trastuzumab and pertuzumab, and resume 
atezolizumab/placebo. 
x If the repeat LVEF is 40-49%, manage as Grade 2 ejection fraction decreased in Table 8. 
x If the repeat LVEF is  40%, manage as Grade 3 ejection fraction decreased in Table 8. 
 
6.7 
Treatment Modifications for Other Toxicities Related to Trastuzumab and Pertuzumab 
Table 11.  Treatment modifications and instructions for other toxicities related to trastuzumab and 
pertuzumab  
CTCAE v5.0 
Adverse Event 
CTCAE 
Grade 
Management 
Injury, Poisoning and Procedural Complications 
Infusion-related reaction 
1, 2, 3, 4 
See instructions for allergic reaction 
Immune System Disorders 
Note: Follow instructions in Section 6.12 for management of atezolizumab/placebo. 
Table continued on next page. 
 
Use of this document is governed by the terms of use on the first page of this document.

 
NRG-BR004 
65 
NCI Version Date: August 15, 2022 
Table 11.  Treatment modifications and instructions for other toxicities related to trastuzumab and 
pertuzumab (continued) 
CTCAE v5.0 
Adverse Event 
CTCAE 
Grade 
Management 
Allergic reaction 
1 
Slow the infusion of and assess the patient; management is at 
the investigator's discretion. 
2 
Stop infusion and administer support medications per 
investigator's discretion.  When symptoms resolve to  
d Grade 1, infusion may be resumed later that day at a 
slower rate or on the next day at a slower rate with pre-meds.  
Pre-meds should be used for all subsequent treatments. 
3 
Administer IV interventions as indicated per investigator 
discretion.  Antibody causing the reaction may be 
discontinued at the investigator's discretion.  If continued, 
follow instructions for Grade 2. 
4 
Discontinue agent causing reaction. 
Anaphylaxis 
3 
At investigator's discretion, discontinue agent causing 
reaction.  If continued, follow instructions for Grade 3 
allergic reactions. 
4 
Discontinue agent causing reaction. 
Respiratory, Thoracic, and Mediastinal Disorders 
Note: Follow instructions in Section 6.8 for management of atezolizumab/placebo. 
Adult Respiratory 
Distress Syndrome 
3,4 
Discontinue trastuzumab and pertuzumab. 
Cough 
2,3 
Follow instructions in footnote a. 
Dyspnea 
1, 2, 3 
Hold trastuzumab and pertuzumab; rule out heart failure 
and non-infectious lung disease; follow instructions in 
footnote a. 
4 
Discontinue trastuzumab and pertuzumab. 
Hypoxia 
2,3 
Follow instructions in footnote a. 
4 
Discontinue trastuzumab and pertuzumab. 
Pneumonitis 
2 
Follow instructions in footnote a. 
3,4 
Discontinue trastuzumab and pertuzumab. 
Table continued on next page. 
 
Use of this document is governed by the terms of use on the first page of this document.

Use of this document is governed by the terms of use on the first page of this document.

 
NRG-BR004 
67 
NCI Version Date: August 15, 2022 
Table 12.  Management guidelines for pulmonary events, including pneumonitis, related to 
atezolizumab/placebo 
CTCAE v5.0 
Adverse Event/Grade 
Management 
Pulmonary event, 
Grade 1  
x Continue atezolizumab/placebo and monitor closely. 
x Consider diagnostic imaging.  If pneumonitis documented, monitor on 
serial imaging until resolution or stable. 
x Consider patient referral to pulmonary specialist. 
Pulmonary event,  
Grade 2 
x Hold atezolizumab/placebo. 
x Refer patient to pulmonary and infectious disease specialists and consider 
bronchoscopy or bronchoscopic alveolar lavage. 
x If evaluation fails to define non-immune etiology OR defines an immune 
etiology, discontinue atezolizumab/placebo and request unblinding if 
required for medical management. 
- 
If receiving atezolizumab, initiate treatment with 12 mg/kg/day oral 
prednisone or equivalent. 
- 
When event resolves to Grade 1 or better, taper corticosteroids over  
 1 month. 
Pulmonary event, 
Grade 3 or 4 
x Refer patient to pulmonary and infectious disease specialists for 
bronchoscopy or bronchoscopic alveolar lavage. 
x Discontinue atezolizumab/placebo and request unblinding. 
- 
If receiving atezolizumab, initiate treatment with 1-2 mg/kg/day 
intravenous 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. 
- 
When event resolves to Grade 1 or better, taper corticosteroids over  
 1 month. 
 
6.9 
Hepatic Events 
Immune-mediated hepatitis has been associated with the administration of atezolizumab.  Eligible 
patients must have adequate liver function, as manifested by measurements of total bilirubin and 
hepatic transaminases, and liver function will be monitored throughout study treatment.  
Management guidelines for hepatic events are provided in Table 13. 
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. 
 
Use of this document is governed by the terms of use on the first page of this document.

 
NRG-BR004 
68 
NCI Version Date: August 15, 2022 
Table 13.  Management guidelines for hepatic events related to atezolizumab/placebo 
CTCAE v5.0 
Adverse 
Event/Grade 
Management 
(Refer to Section 6.21.3 for management of paclitaxel) 
Hepatic event,  
Grade 1 
x 
Continue atezolizumab/placebo. 
x 
If LFT values are above normal limits, monitor LFTs weekly until resolved to 
within normal limits or to baseline values. 
Hepatic event,  
Grade 2 
x Hold atezolizumab/placebo and recheck LFTs in 3-7 days. 
- 
If LFTs are improving or have increased by  25 IU and remain Grade 2, 
monitor LFTs weekly until LFTs return to d Grade 1. 
- 
If LFTs increase further by a minimum of 25 IU but remain Grade 2, 
discontinue atezolizumab/placebo and request unblinding if required for 
medical management. 
x If patient was unblinded and was receiving atezolizumab, initiate treatment with 
12 mg/kg/day oral prednisone or equivalent. 
x When event resolves to Grade 1 or better, taper corticosteroids over  1 month. 
Hepatic event,  
Grade 3 or 4 
x Refer to hepatic specialist for evaluation and liver biopsy to establish etiology of 
hepatic injury.  
x Discontinue atezolizumab/placebo and request unblinding. 
- If receiving atezolizumab, initiate treatment with 1-2 mg/kg/day intravenous 
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. 
- When event resolves to Grade 1 or better, taper corticosteroids over  1 month. 
 
6.10 
Endocrine Events 
Thyroid disorders, adrenal insufficiency, diabetes mellitus, and pituitary disorders have been 
associated with the administration of atezolizumab.  Management guidelines for endocrine events 
are provided in Table 14. 
Patients experiencing one or more unexplained AEs possibly indicative of endocrine dysfunction 
(including headache, fatigue, myalgias, impotence, mental status changes, and constipation) 
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 T3 and T4 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 MRI of the brain 
(with detailed pituitary sections) may help to differentiate primary pituitary insufficiency from 
primary adrenal insufficiency.  Table 14 describes dose management guidelines for 
hyperthyroidism, hypothyroidism, symptomatic adrenal insufficiency, and hyperglycemia. 
 
 
Use of this document is governed by the terms of use on the first page of this document.

 
NRG-BR004 
69 
NCI Version Date: August 15, 2022 
Table 14.  Management guidelines for endocrine events related to atezolizumab/placebo  
CTCAE v5.0 
Adverse Event/Grade 
Management 
Asymptomatic 
Hypothyroidism  
 
x Continue atezolizumab/placebo. 
x Initiate treatment with thyroid replacement hormone. 
x Monitor TSH weekly until improvement documented. 
Symptomatic 
Hypothyroidism 
 
x Hold atezolizumab/placebo. 
x Initiate treatment with thyroid replacement hormone. 
x Monitor TSH every 3-4 weeks. 
x Consider patient referral to endocrinologist. 
x Resume atezolizumab/placebo when symptoms are controlled and thyroid 
function is improving. 
Asymptomatic 
Hyperthyroidism 
 
TSH t 0.1 mU/L and  0.5 mU/L: 
x Continue atezolizumab/placebo. 
x Monitor TSH every 3-4 weeks. 
TSH  0.1 mU/L: 
x Follow guidelines for symptomatic hyperthyroidism. 
Symptomatic 
Hyperthyroidism 
 
x Hold atezolizumab/placebo. 
x Refer to endocrinologist. 
x Initiate treatment with anti-thyroid drug such as methimazole or 
carbimazole as needed. 
x Resume atezolizumab/placebo when symptoms are controlled and thyroid 
function is improving. 
x For life-threatening hyperthyroidism, discontinue atezolizumab/placebo and 
request unblinding. 
- If receiving atezolizumab, initiate treatment with 1-2 mg/kg/day 
intravenous methylprednisolone or equivalent and convert to  
1-2 mg/kg/day oral prednisone or equivalent upon improvement. 
- When event resolves to Grade 1 or better, taper corticosteroids over  
 1 month. 
Hypopituitarism 
Grade 1 
x Hold atezolizumab/placebo until evaluated by endocrinologist. 
x If diagnosis confirmed, follow guidelines for Grades 2, 3, 4 hypopituitarism. 
Hypopituitarism 
Grades 2, 3, 4  
x Refer patient to endocrinologist. 
x Discontinue atezolizumab/placebo and request unblinding if required for 
medical management. 
- If receiving atezolizumab initiate treatment with 1-2 mg/kg/day 
intravenous methylprednisolone or equivalent and convert to  
1-2 mg/kg/day oral prednisone or equivalent upon improvement. 
- 
When event resolves to Grade 1 or better, taper corticosteroids over  
 1 month. 
Table continued on next page. 
 
Use of this document is governed by the terms of use on the first page of this document.

 
NRG-BR004 
70 
NCI Version Date: August 15, 2022 
Table 14.  Management guidelines for endocrine events related to atezolizumab/placebo (continued) 
CTCAE v5.0 
Adverse Event/Grade 
Management 
Hypophysitis 
(panhypopituitarism), 
Grades 2, 3, 4 
 
x Perform brain MRI (pituitary protocol). 
x Refer patient to endocrinologist. 
x Discontinue atezolizumab/placebo and request unblinding if required for 
medical management. 
- If receiving atezolizumab initiate treatment with 1-2 mg/kg/day 
intravenous methylprednisolone or equivalent and convert to  
1-2 mg/kg/day oral prednisone or equivalent upon improvement. 
- When event resolves to Grade 1 or better, taper corticosteroids over  
 1 month. 
Adrenal insufficiency 
(primary) Grade 1 
x Hold atezolizumab/placebo until evaluated by endocrinologist. 
x If primary adrenal insufficiency confirmed treat as  symptomatic adrenal 
insufficiency. 
Symptomatic adrenal 
insufficiency A 
disorder 
characterized by the 
adrenal cortex not 
producing enough of 
the hormone cortisol 
and in some cases, 
the hormone 
aldosterone.  It may 
be due to a disorder 
of the adrenal cortex 
as in Addison's 
disease or primary 
adrenal insufficiency. 
x Refer patient to endocrinologist. 
x Perform appropriate imaging. 
x Hold atezolizumab/placebo and request unblinding if diagnosis confirmed. 
- If receiving atezolizumab initiate treatment with 1-2 mg/kg/day 
intravenous methylprednisolone or equivalent and convert to 1-2 
mg/kg/day oral prednisone or equivalent upon improvement. 
- 
When event resolves to Grade 1 or better, taper corticosteroids over  1 
month. 
Hyperglycemia,  
Grades 1, 2  
x Continue atezolizumab/placebo. 
x Investigate for diabetes.  If patient has developed Type 1 diabetes, treat as a 
Grade 4 event.  If patient has not developed Type 1 diabetes, treat as per 
institutional guidelines. 
x Monitor for glucose control. 
Hyperglycemia 
Grade 3 
x Withhold atezolizumab/placebo. 
x Initiate treatment with insulin. 
x If patient has developed Type 1 diabetes, treat as a Grade 4 event.  If patient 
has not developed Type 1 diabetes, treat as per institutional guidelines. 
x Monitor for glucose control. 
x Resume atezolizumab/placebo when glucose levels are stable. 
Table continued on next page. 
 
Use of this document is governed by the terms of use on the first page of this document.

 
NRG-BR004 
71 
NCI Version Date: August 15, 2022 
Table 14.  Management guidelines for endocrine events related to atezolizumab/placebo (continued) 
CTCAE v5.0 
Adverse Event/Grade 
Management 
Hyperglycemia,  
Grade 4 
x Hold atezolizumab/placebo. 
x Initiate treatment with insulin. 
x Monitor for glucose control. 
x Resume or discontinue atezolizumab/placebo at investigator discretion 
when symptoms resolve, and glucose levels are stable. 
 
6.11 
Ocular Events 
An ophthalmologist should evaluate visual complaints (e.g., uveitis, retinal events).  Management 
guidelines for ocular events are provided in Table 15. 
Table 15.  Management guidelines for ocular events related to atezolizumab/placebo 
CTCAE v5.0 
Adverse Event/Grade 
Management 
Ocular event, Grade 1  
x Continue atezolizumab/placebo. 
x Patient referral to ophthalmologist is strongly recommended. 
x Initiate treatment with topical corticosteroid eye drops and topical 
immunosuppressive therapy. 
x If symptoms persist, manage as a Grade 2 event. 
Ocular event, Grade 2 
x Hold atezolizumab/placebo. 
x Refer to ophthalmologist. 
x If immune-mediated toxicity is suspected, permanently discontinue 
atezolizumab/placebo and request unblinding if required for medical 
management. 
- 
If receiving atezolizumab, initiate treatment with topical 
corticosteroid eye drops and topical immunosuppressive therapy. 
Ocular event,  
Grade 3 or 4 
x Refer patient to ophthalmologist. 
x Permanently discontinue atezolizumab/placebo and request unblinding 
if required for medical management. 
- 
If receiving atezolizumab, initiate treatment with 1-2 mg/kg/day 
intravenous methylprednisolone or equivalent and convert to  
1-2 mg/kg/day oral prednisone or equivalent upon improvement. 
- 
When event resolves to Grade 1 or better, taper corticosteroids 
over  1 month. 
6.12 
Infusion-Related Reaction and Cytokine-Release Syndrome 
No premedication is indicated for the administration of the first dose of atezolizumab/placebo.  
However, patients who experience an infusion-related reaction (IRR) or cytokine-release 
syndrome (CRS) with the first dose of atezolizumab/placebo may receive premedication with 
antihistamines, antipyretics 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 
Use of this document is governed by the terms of use on the first page of this document.

 
NRG-BR004 
72 
NCI Version Date: August 15, 2022 
and/or other chemical mediators, occur within 24 hours of atezolizumab administration and are 
generally mild to moderate in severity. 
Severe IRRs may result in anaphylaxis, which requires discontinue of atezolizumab/placebo.  See 
Table 16 for management of grade 3 or 4 anaphylaxis. 
CRS is defined as a supraphysiologic response following administration of any immune therapy 
that results in activation or engagement of endogenous or infused T cells and/or other immune 
effector cells.  Symptoms can be progressive, always include fever at the onset, and may include 
hypotension, capillary leak (hypoxia), and end-organ dysfunction (Lee 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 2017, Adashek 2019) including atezolizumab. 
There may be significant overlap in signs and symptoms of IRRs and CRS, and in recognition of 
the challenges in clinically distinguishing between the two, consolidated guidelines for medical 
management of IRRs and CRS are provided in Table 16. 
Table 16.  Management guidelines for infusion-related reactions and cytokine-release syndrome related 
to atezolizumab/placebo 
Event 
Management 
(Refer to Table 26 for management of paclitaxel, Table 27 for management 
of docetaxel, and Table 11 for trastuzumab and pertuzumab) 
Grade 1a  
Feverb with or 
without 
constitutional 
symptoms  
 
x Immediately interrupt atezolizumab/placebo infusion and administer 
symptomatic treatment per institutional practice. 
x Upon symptom resolution, wait for 30 minutes and then restart infusion 
at half the rate being given at the time of event onset. 
x If the infusion is tolerated at the reduced rate for 30 minutes, the 
infusion rate may be increased to the original rate. 
x If symptoms recur, discontinue atezolizumab/placebo. 
x Administer symptomatic treatment,c including maintenance of IV fluids 
for hydration. 
x 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. 
x For subsequent infusions, consider administration of oral 
premedication with antihistamines, anti-pyretics, and/or analgesics, and 
monitor closely for IRRs and/or CRS. 
Table continued on next page. 
 
Use of this document is governed by the terms of use on the first page of this document.

 
NRG-BR004 
73 
NCI Version Date: August 15, 2022 
Table 16.  Management guidelines for infusion-related reactions and cytokine-release syndrome related 
to atezolizumab/placebo (continued) 
Event 
Management 
(Refer to Table 26 for management of paclitaxel, Table 27 for 
management of docetaxel, and Table 11 for trastuzumab and pertuzumab) 
Grade 2a  
Feverb with 
hypotension not 
requiring 
vasopressors and/or  
Hypoxia requiring 
low-flow oxygend by 
nasal cannula or 
blow-by 
x Immediately interrupt atezolizumab/placebo infusion if infusion not 
completed. 
x 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 do 
not resolve within 30 minutes, discontinue atezolizumab/placebo and 
unblind. 
x If symptoms recur after restart of the infusion discontinue 
atezolizumab/placebo. 
x Administer symptomatic treatment per institutional practice).c  
x For hypotension, administer IV fluid bolus as needed. 
x Monitor cardiopulmonary and other organ function closely (in the ICU, 
if appropriate).  Administer IV fluids as clinically indicated and manage 
constitutional symptoms and organ toxicities as per institutional 
practice. 
x 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.   
x Consider IV corticosteroids (e.g., methylprednisolone 2 mg/kg/day or 
dexamethasone 10 mg every 6 hours). 
x Consider anti-cytokine therapy.e 
x 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. 
x If symptoms resolve to Grade 1 or better for 3 consecutive days, the 
next dose of atezolizumab may be administered.  For subsequent 
infusions, consider administration of oral premedication with 
antihistamines, anti-pyretics, and/or analgesics and monitor closely for 
IRRs and/or CRS. 
x If symptoms do not resolve to Grade 1 or better for 3 consecutive days, 
contact the Clinical Coordinating Department.  
x If evaluation fails to define etiology, consider unblinding if required for 
medical management. 
Table continued on next page. 
 
Use of this document is governed by the terms of use on the first page of this document.

 
NRG-BR004 
74 
NCI Version Date: August 15, 2022 
Table 16.  Management guidelines for infusion-related reactions and cytokine-release syndrome related 
to atezolizumab/placebo (continued) 
Event 
Management 
(Refer to Table 26 for management of paclitaxel, Table 27 for management 
of docetaxel, and Table 11 for trastuzumab and pertuzumab) 
Grade 3a 
Feverb with 
hypotension 
requiring a 
vasopressor (with or 
without vasopressin)  
and/or 
Hypoxia requiring 
high-flow oxygend 
by nasal cannula, 
face mask, non-
rebreather mask, or 
venturi mask 
x Immediately stop atezolizumab/placebo infusion.f 
x Request unblinding to guide further management. 
x Administer aggressive symptomatic treatment as per institutional 
guidelinesc  
x For hypotension, administer IV fluid bolus and vasopressor as needed. 
x 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. 
x 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. 
x Administer IV corticosteroids (e.g., methylprednisolone 2 mg/kg/day or 
dexamethasone 10 mg every 6 hours) if receiving atezolizumab. 
x Consider anti-cytokine therapy.e 
x 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 treatmentsf 
may be considered at the discretion of the investigator. 
x Permanently discontinue atezolizumab/placebo. 
Grade 3 or 4 
anaphylactic reaction 
In the event of a suspected anaphylactic reaction during atezolizumab 
infusion, the following procedures should be performed: 
1. 
Stop the study drug infusion. 
2. 
Permanently discontinue atezolizumab/placebo. 
3. 
Call for additional medical assistance. 
4. 
Ensure that appropriate monitoring is in place, with continuous 
ECG and pulse oximetry monitoring, if possible. 
5. 
Administer antihistamines, epinephrine, or other medications as 
required by patient status and directed by the physician in 
charge. 
6. 
Continue to observe the patient and document observation. 
Table continued on next page. 
 
Use of this document is governed by the terms of use on the first page of this document.

 
NRG-BR004 
75 
NCI Version Date: August 15, 2022 
Table 16.  Management guidelines for infusion-related reactions and cytokine-release syndrome related 
to atezolizumab/placebo (continued) 
Event 
Management 
(Refer to Table 26 for management of paclitaxel, Table 27 for management 
of docetaxel, and Table 11 for trastuzumab and pertuzumab) 
Grade 4a 
Feverb with 
hypotension 
requiring multiple 
vasopressors 
(excluding 
vasopressin) 
and/or 
Hypoxia requiring 
oxygen by positive 
pressure (e.g., CPAP, 
BiPAP, intubation 
and mechanical 
ventilation) 
x Permanently stop atezolizumab/placebo. 
x Administer symptomatic treatment.c 
x Request unblinding to guide further management. 
x 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. 
x 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. 
x Administer IV corticosteroids if receiving atezolizumab (e.g., 
methylprednisolone 2 mg/kg/day or dexamethasone 10 mg every 6 
hours). 
x Consider anti-cytokine therapy.e  For patients who are refractory to 
anti-cytokine therapy, experimental treatmentsf may be considered at 
the discretion of the investigator. 
x Hospitalize patient until complete resolution of symptoms. 
 
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; HLH = hemophagocytic lymphohistiocytosis; IRR 
= infusion-related reaction; MAS = macrophage activation syndrome. 
Note: The management guidelines have been adapted from NCCN guidelines for management of CAR 
T-cell-related toxicities (Version 2.2019). 
a. Grading system for management guidelines is based on ASTCT consensus grading for CRS.  NCI 
CTCAE (version as specified in the protocol) should be used when reporting severity of IRRs, 
CRS, or organ toxicities associated with CRS on the Adverse Event eCRF.  Organ toxicities 
associated with CRS should not influence overall CRS grading.  
b. Fever is defined as temperature  38°C not attributable to any other cause.  In patients who develop 
CRS and then receive anti-pyretic, anti-cytokine, or corticosteroid therapy, fever is no longer 
required when subsequently determining event severity (grade).  In this case, the grade is driven by 
the presence of hypotension and/or hypoxia. 
c. Symptomatic treatment may include oral or IV antihistamines, anti-pyretics, analgesics, 
bronchodilators, and/or oxygen.  For bronchospasm, urticaria, or dyspnea, additional treatment may 
be administered as per institutional practice. 
d. Low flow is defined as oxygen delivered at  6 L/min, and high flow is defined as oxygen delivered 
at > 6 L/min. 
e. There are case reports where anti-cytokine therapy has been used for treatment of CRS with 
immune checkpoint inhibitors (Rotz 2017, Adashek and Feldman 2019), but data are limited, and 
the role of such treatment in the setting of antibody-associated CRS has not been established.  
f. 
Refer to Riegler 2019 for information on experimental treatments for CRS. 
 
Use of this document is governed by the terms of use on the first page of this document.

 
NRG-BR004 
76 
NCI Version Date: August 15, 2022 
6.13 
Management of Pancreatic Events 
Symptoms of abdominal pain associated with elevations of amylase and lipase, suggestive of 
pancreatitis, have been associated with the administration of atezolizumab.  The differential 
diagnosis of acute abdominal pain should include pancreatitis.  Appropriate work-up should 
include an evaluation for ductal obstruction, as well as serum amylase and lipase tests.  
Management guidelines for pancreatic events, including pancreatitis, are provided in Table 17. 
Table 17.  Management guidelines for pancreatic events, including pancreatitis, related to 
atezolizumab/placebo 
CTCAE v5.0 
Adverse Event/Grade 
Management 
Amylase and/or lipase 
elevation, Grade 1 
x 
Continue atezolizumab/placebo. 
x 
Monitor amylase and lipase prior to dosing. 
Amylase and/or lipase 
elevation, Grade 2 
Amylase and/or lipase > 1.5-2.0 x ULN: 
x 
Continue atezolizumab/placebo. 
x 
Monitor amylase and lipase weekly. 
x 
For prolonged elevation (e.g., ! 3 weeks), hold atezolizumab/placebo. 
x 
If non-immune etiology not identified, discontinue atezolizumab/placebo 
and request unblinding if required for medical management. 
- 
If receiving atezolizumab, begin treatment with 1-2 mg/kg/day oral 
prednisone or equivalent. 
- 
When event resolves to Grade 1 or better, taper corticosteroids over  
 1 month. 
Asymptomatic with amylase and/or lipase > 2.0-5.0 x ULN: 
x Treat as a Grade 3 or 4 event. 
Table continued on next page. 
 
Use of this document is governed by the terms of use on the first page of this document.

 
NRG-BR004 
77 
NCI Version Date: August 15, 2022 
Table 17.  Management guidelines for pancreatic events, including pancreatitis, related to 
atezolizumab/placebo (continued) 
CTCAE v5.0 
Adverse Event/Grade 
Management 
Amylase and/or lipase 
elevation,  
Grade 3 or 4 
x Hold atezolizumab/placebo. 
x Refer patient to gastrointestinal specialist. 
x Monitor amylase and lipase every 2 to 3 days until improved. 
x May resume atezolizumab/placebo with next cycle if amylase and lipase 
are d Grade 1. 
x For prolonged elevation (e.g., > 3 weeks), continue to hold 
atezolizumab/placebo. 
x If non-immune etiology not identified, discontinue atezolizumab/placebo 
and request unblinding if required for medical management. 
- 
If receiving atezolizumab, begin treatment with 1-2 mg/kg/day oral 
prednisone or equivalent. 
- When event resolves to Grade 1 or better, taper corticosteroids over  
 1 month. 
Immune-mediated 
pancreatitis,  
Grade 2 or 3 
x 
Hold atezolizumab/placebo. 
x 
Monitor amylase and lipase every 2 to 3 days until improved. 
x 
For prolonged elevation (e.g., ! 3 weeks), hold atezolizumab/placebo. 
x 
Refer patient to gastrointestinal specialist. 
x 
May resume atezolizumab/placebo with next cycle if amylase and lipase 
are d Grade 1. 
x 
If non-immune etiology not identified, discontinue atezolizumab/placebo 
and request unblinding if required for medical management. 
- 
If receiving atezolizumab, begin treatment with 1-2 mg/kg/day oral 
prednisone or equivalent. 
- 
When amylase and lipase levels resolve to Grade 1, taper 
corticosteroids over  1 month. 
Immune-mediated 
pancreatitis,  
Grade 4 
x 
Refer patient to gastrointestinal specialist. 
x 
Discontinue atezolizumab/placebo and request unblinding. 
- If receiving atezolizumab, initiate treatment with 1-2 mg/kg/day 
intravenous 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. 
- When event resolves to Grade 1 or better, taper corticosteroids over  
 1 month. 
 
 
Use of this document is governed by the terms of use on the first page of this document.

 
NRG-BR004 
78 
NCI Version Date: August 15, 2022 
6.14 
Dermatologic Events 
Treatment-emergent rash has been associated with atezolizumab.  The majority of cases of rash 
were mild in severity and self-limited, with or without pruritus.  A dermatologist should evaluate 
persistent and/or severe rash or pruritus.  Although uncommon, cases of severe cutaneous adverse 
reactions such as Stevens-Johnson syndrome and toxic epidermal necrolysis have been reported 
with atezolizumab.  A biopsy should be considered unless contraindicated.  Management 
guidelines for dermatologic events are provided in Table 18. 
Table 18.  Management for dermatologic events related to atezolizumab/placebo 
CTCAE v5.0 
Adverse Event/Grade 
Management 
Dermatologic event,  
Grade 1  
x Continue atezolizumab/placebo. 
x Consider treatment with topical corticosteroids and/or other 
symptomatic therapy (e.g., antihistamines). 
Dermatologic event,  
Grade 2  
x Continue atezolizumab/placebo. 
x Refer to dermatologist and consider skin biopsy. 
x Initiate treatment with topical corticosteroids. 
x If rash does not improve, discontinue atezolizumab/placebo and 
consider unblinding if required for medical management. 
- If receiving atezolizumab, 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. 
- When event resolves to Grade 1 or better, taper corticosteroids 
over  1 month. 
Bullous dermatitis, 
Grade 2 
Treat as Grade 3 or 4 Dermatologic event. 
Dermatologic event,  
Grade 3 or 4 
x Refer patient to dermatologist. 
x Discontinue atezolizumab/placebo and request unblinding. 
- If receiving atezolizumab, initiate treatment with 1-2 mg/kg/day of 
methylprednisolone or equivalent. 
- When event resolves to Grade 1 or better, taper corticosteroids 
over  1 month. 
Stevens-Johnson 
syndrome or toxic 
epidermal necrolysis (any 
grade) 
Additional guidance for Stevens-Johnson syndrome or toxic 
epidermal necrolysis: 
x Withhold atezolizumab/placebo for suspected Stevens-Johnson 
syndrome or toxic epidermal necrolysis. 
x Confirm diagnosis by referring patient to a specialist (dermatologist, 
ophthalmologist, or urologist as relevant) for evaluation and, if 
indicated, biopsy. 
x Follow the applicable treatment and management guidelines as above 
for dermatologic event Grade 3 or 4. 
x If Stevens-Johnson syndrome or toxic epidermal necrolysis is 
confirmed, permanently discontinue atezolizumab/placebo. 
6.15 
Neurological Disorders 
Myasthenia gravis and Guillain-Barré syndrome have been observed with single-agent 
atezolizumab.  Patients may present with signs and symptoms of sensory and/or motor 
Use of this document is governed by the terms of use on the first page of this document.

 
NRG-BR004 
79 
NCI Version Date: August 15, 2022 
neuropathy.  Diagnostic work-up is essential for an accurate characterization to differentiate 
between alternative etiologies.  Management guidelines for neurologic disorders are provided in 
Table 19. 
Table 19.  Treatment management guidelines for neurological disorders related to atezolizumab/placebo 
CTCAE v5.0  
Adverse Event/Grade 
Management 
Immune-mediated 
neuropathy,  
Grade 1 
x Continue atezolizumab/placebo. 
x Investigate etiology. 
Immune-mediated 
sensory neuropathy  
Grade 2  
Grade 2 while receiving 
paclitaxel*: 
x Withhold atezolizumab/placebo. 
x Oral steroids should not be 
initiated for first or second 
episodes. 
x Resume atezolizumab/placebo if 
event resolves to Grade 1 or better 
within 3 weeks. 
x If event does not resolve to Grade 
1 or better within 3 weeks: 
 Refer patient to neurologist 
 Consider unblinding if required 
for medical management. 
 If receiving atezolizumab, 
begin treatment with 1-2 
mg/kg/day oral prednisone or 
equivalent. 
 When event resolves to Grade 
1 or better, taper 
corticosteroids over  1 month. 
Grade 2 if not receiving 
paclitaxel*: 
x Refer patient to neurologist. 
x Discontinue 
atezolizumab/placebo. 
x Request unblinding if required for 
medical management. 
- If receiving atezolizumab, 
begin treatment with 1-2 
mg/kg/day oral prednisone or 
equivalent. 
- When event resolves to Grade 
1 or better, taper 
corticosteroids over  1 month. 
Immune-mediated 
motor neuropathy 
Grade 2 
x Refer patient to neurologist. 
x Discontinue atezolizumab/placebo and request unblinding. 
- If receiving atezolizumab, begin treatment with 1-2 mg/kg/day oral 
prednisone or equivalent. 
- When event resolves to Grade 1 or better, taper corticosteroids over  
 1 month. 
Table continued on next page. 
 
Use of this document is governed by the terms of use on the first page of this document.

 
NRG-BR004 
80 
NCI Version Date: August 15, 2022 
Table 19.  Treatment management guidelines for neurological disorders related to atezolizumab/placebo 
(continued) 
CTCAE v5.0  
Adverse Event/Grade 
Management 
Immune-mediated 
neuropathy,  
Grade 3 or 4 
x 
Refer patient to neurologist. 
x 
Discontinue atezolizumab/placebo and consider unblinding if required 
for medical management. 
- If receiving atezolizumab, begin treatment with 1-2 mg/kg/day 
intravenous methylprednisolone or equivalent and convert to  
1-2 mg/kg/day oral prednisone or equivalent upon improvement. 
- When event resolves to Grade 1 or better, taper corticosteroids over  
 1 month. 
Myasthenia gravis and 
Guillain-Barré 
syndrome (any grade) 
x 
Refer patient to neurologist and initiate treatment as per institutional 
guidelines. 
x 
Discontinue atezolizumab/placebo and request unblinding. 
- 
If receiving atezolizumab, begin treatment with 1-2 mg/kg/day 
intravenous methylprednisolone or equivalent and convert to  
1-2 mg/kg/day oral prednisone or equivalent upon improvement. 
- 
When event resolves to Grade 1 or better, taper corticosteroids over  
 1 month. 
* 
Refer to Section 6.21.3 for concurrent dose modifications for chemotherapy. 
 
6.16 
Immune-mediated meningoencephalitis 
Immune-mediated meningoencephalitis is an identified risk associated with the administration of 
atezolizumab.  Immune-related 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 20. 
Table 20.  Management guidelines for immune-mediated meningoencephalitis related to 
atezolizumab/placebo 
CTCAE v5.0 
Adverse Event/Grade 
Management 
Immune-mediated 
meningoencephalitis,  
all grades 
x 
Refer patient to neurologist. 
x 
Permanently discontinue atezolizumab/placebo and request unblinding. 
- If receiving atezolizumab, 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. 
- When event resolves to Grade 1 or better, taper corticosteroids over  
 1 month. 
Use of this document is governed by the terms of use on the first page of this document.

 
NRG-BR004 
81 
NCI Version Date: August 15, 2022 
6.17 
Immune-Mediated Renal Events 
Immune-mediated nephritis has been associated with the administration of atezolizumab.  Eligible 
patients must have adequate renal function.  Renal function, including serum creatinine, should be 
monitored throughout study treatment.  Patients with abnormal renal function should be evaluated 
and treated for other more common 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 21. 
Table 21.  Management and evaluation of immune-mediated renal events (potential immune-mediated 
nephritis) 
CTCAE v5.0 
Adverse Event/Grade 
Management 
Renal event,  
Grade 1  
x 
Continue atezolizumab/placebo. 
x 
If creatinine value is above normal limits, monitor weekly. 
Renal event, 
Grade 2  
x 
Hold atezolizumab/placebo and recheck creatinine in 3-7 days. 
- 
If creatinine is improving but remains Grade 2, continue to 
hold atezolizumab/placebo and monitoring creatinine weekly 
until d Grade 1. 
- 
If repeat creatinine value does not improve but remains  
Grade 2, refer to nephrologist for evaluation and continue to 
hold atezolizumab/placebo. 
- If evaluation fails to define non-immune etiology OR defines 
an immune etiology, discontinue atezolizumab/placebo and 
request unblinding for medical management. 
x 
If patient was unblinded and was receiving atezolizumab, 
initiate treatment with 12 mg/kg/day oral prednisone or 
equivalent. 
x 
When event resolves to Grade 1 or better, taper corticosteroids 
over t 1 month. 
Renal event, 
Grade 3 or 4  
x 
Refer to nephrologist for evaluation and consideration of renal 
biopsy to establish etiology of renal injury.  
x 
Discontinue atezolizumab/placebo and request unblinding. 
- If receiving atezolizumab, 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. 
- When event resolves to Grade 1 or better, taper 
corticosteroids over t 1 month. 
 
6.18 
Immune-mediated myositis 
Immune-mediated myositis has been associated with the administration of atezolizumab.  
Myositis or inflammatory myopathies are a group of disorders sharing the common feature of 
inflammatory muscle injury; dermatomyositis and polymyositis are amongst the most common 
disorders.  Initial diagnosis is based on clinical (muscle weakness, muscle pain, skin rash in 
Use of this document is governed by the terms of use on the first page of this document.

 
NRG-BR004 
82 
NCI Version Date: August 15, 2022 
dermatomyositis), biochemical (serum creatine-kinase increase), and imaging 
(electromyography/MRI) features and is confirmed with a muscle-biopsy.   
Patients with signs and symptoms of myositis, in the absence of an identified alternate etiology, 
should be treated according to the guidelines in Table 22. 
Table 22.  Management and evaluation of immune-mediated myositis 
CTCAE v5.0 
Adverse Event/Grade 
Management 
Myositis, 
Grade 1 (mild pain 
with elevated CK) 
x Hold atezolizumab/placebo. 
x Refer patient to rheumatologist or neurologist. 
x If evaluation fails to define non-immune etiology OR defines an 
immune etiology, discontinue atezolizumab/placebo and request 
unblinding if required for medical management. 
- If receiving atezolizumab, 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. 
- When CK elevation resolves and pain improved, taper 
corticosteroids over t 1 month. 
x If non-immune etiology identified, may resume or discontinue 
atezolizumab/placebo per investigator discretion. 
Myositis, 
Grade 2 (moderate pain 
with weakness) 
x Hold atezolizumab/placebo. 
x Refer patient to rheumatologist or neurologist. 
x If evaluation fails to define non-immune etiology OR defines an 
immune etiology, discontinue atezolizumab/placebo and request 
unblinding if required for medical management. 
- If receiving atezolizumab, 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 
t 1 month. 
x If non-immune etiology identified, may resume or discontinue 
atezolizumab/placebo per investigator discretion. 
Table continued on next page. 
 
Use of this document is governed by the terms of use on the first page of this document.

 
NRG-BR004 
83 
NCI Version Date: August 15, 2022 
Table 22.  Management and evaluation of immune-mediated myositis (continued) 
CTCAE v5.0 
Adverse Event/Grade 
Management 
Myositis, 
Grade 3 or 4 (pain with 
severe weakness) 
x Hold atezolizumab/placebo. 
x Refer patient to neurologist or rheumatologist. 
x Evaluate for associated myocarditis and consider consulting 
cardiologist. 
x Respiratory support may be required in more severe cases. 
x Discontinue atezolizumab/placebo and request unblinding. 
- If receiving atezolizumab, initiate treatment with 1-2 mg/kg/day 
IV methylprednisolone or equivalent or higher-dose bolus if 
patient is severely compromised (e.g., cardiac or respiratory 
symptoms, dysphagia, or weakness that severely limits 
mobility) 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 
t 1 month. 
 
6.19 
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). 
Patients with suspected HLH should be diagnosed according to published criteria by McClain and 
Eckstein (2017).  A patient should be classified as having HLH if five of the following eight 
criteria are met: 
x 
Fever  38.5°C 
x 
Splenomegaly 
x 
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/mcL) 
 
ANC < 1.0 × 109/L (1000/mcL) 
x 
Fasting triglycerides > 2.992 mmol/L (265 mg/dL) and/or fibrinogen < 1.5 g/L (150 
mg/dL) 
x 
Hemophagocytosis in bone marrow, spleen, lymph node, or liver 
x 
Low or absent natural killer cell activity 
x 
Ferritin > 500 mg/L (500 ng/mL) 
x 
Soluble interleukin 2 (IL-2) receptor (soluble CD25) elevated  2 standard deviations
above age-adjusted laboratory-specific norms 
Patients with suspected MAS should be diagnosed according to published criteria for systemic 
juvenile idiopathic arthritis by Ravelli et al. (2016).  A febrile patient should be classified as 
having MAS if the following criteria are met: 
x 
Ferritin > 684 mg/L (684 ng/mL) 
x 
At least two of the following: 
 
Platelet count  181 × 109/L (181,000/mcL) 
 
AST  48 U/L 
Use of this document is governed by the terms of use on the first page of this document.

 
NRG-BR004 
84 
NCI Version Date: August 15, 2022 
 
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 23. 
Table 23.  Management and evaluation of hemophagocytic lymphohistiocytosis and macrophage 
activation syndrome 
Event 
Management 
Suspected HLH 
or MAS 
Ɣ Permanently discontinue atezolizumab/placebo and contact Protocol 
Officer. 
Ɣ Consider patient referral to hematologist. 
Ɣ Initiate supportive care, including intensive care monitoring if 
indicated per institutional guidelines. 
Ɣ Consider initiation of IV corticosteroids and/or an immunosuppressive 
agent. 
Ɣ If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent. 
Ɣ If event resolves to Grade 1 or better, taper corticosteroids over  
1 month. 
HLH=hemophagocytic lymphohistiocytosis; MAS=macrophage activation syndrome. 
6.20 
Management Guidelines for Other Immune-Mediated Toxicities Potentially Related to 
Atezolizumab/Placebo 
Table 24.  Management guidelines for other immune-mediated toxicities potentially related to 
atezolizumab/placebo not covered on other tables 
CTCAE v5.0 
Grade 
Management 
Grade 2 
x Hold atezolizumab/placebo. 
x Refer to appropriate specialists for evaluation and consideration of 
biopsy to evaluate for immune infiltrate if appropriate. 
x If immune-mediated toxicity is confirmed, permanently discontinue 
atezolizumab/placebo and request unblinding if required for medical 
management. 
- If receiving atezolizumab, initiate treatment with 1-2 mg/kg/day 
oral prednisone or equivalent. 
Grade 3 or 4 
x Hold atezolizumab/placebo. 
x Refer to appropriate specialist and consideration of biopsy to evaluate 
for immune infiltrate if appropriate. 
x Consider hospitalization. 
x Contact Protocol Officer. 
x If immune–mediated toxicity is confirmed or suspected request 
unblinding to guide medical management. 
- If receiving atezolizumab, initiate treatment with 1-2 mg/kg/day 
oral prednisone or 1 mg/kg/day intravenous methylprednisolone per 
investigator discretion. 
- Convert to 1-2 mg/kg/day oral prednisone or equivalent upon 
improvement. 
- When event resolves to Grade 1 or better, taper corticosteroids over 
4-6 weeks. 
Use of this document is governed by the terms of use on the first page of this document.

 
NRG-BR004 
85 
NCI Version Date: August 15, 2022 
6.21 
Liver dysfunction (Hy's Law) 
Hy’s Law is based on the observation that pure hepatocellular injury sufficient to cause 
hyperbilirubinemia is an ominous indicator of the potential for a drug to cause serious liver 
injury.  A diagnosis of potential drug-induced liver injury caused by a study drug can only be 
determined/inferred by excluding other potential causes of liver injury (e.g., other drugs or viral 
hepatitis) and by ruling out an obstructive cause for the elevated bilirubin (e.g., alkaline 
phosphatase should not be substantially elevated) (FDA-Guidance 2009, Temple 2006). 
6.21.1 Definition of Cases Potentially Meeting Hy's Law Criteria 
Patients who present with the following laboratory abnormalities should be evaluated further to 
definitively determine the etiology of the abnormal laboratory values: 
x 
Patients with AST or ALT baseline values within the normal range who subsequently present 
with AST or ALT ! 3 times the ULN concurrent with a total bilirubin ! 2 times the ULN 
with no evidence of hemolysis and an alkaline phosphatase  2 times the ULN or not 
available. 
x 
Patients with pre-existing AST or ALT baseline values above the normal range who 
subsequently present with AST or ALT ! 2 times the baseline values and ! 3 times the ULN, 
or t 8 times the ULN (whichever is smaller) concurrent with a total bilirubin of ! 2 times the 
ULN and increased by one ULN over baseline or > 3 times the ULN (whichever is smaller) 
with no evidence of hemolysis and an alkaline phosphatase  2 times the ULN or not 
available. 
6.21.2 Evaluation of Potential Hy's Law Cases 
The patient should return to the investigational site to be evaluated as soon as possible, preferably 
within 48 hours from awareness of the abnormal results and managed as Grade 3/4 
hepatotoxicity per Table 13.  This evaluation should include laboratory tests, detailed history, 
and physical assessment.  In addition to repeating AST and ALT, laboratory tests should include 
albumin, creatine kinase, total bilirubin, direct and indirect bilirubin, gamma-glutamyl transferase 
(GGT), international normalized ratio (INR) and alkaline phosphatase.  A detailed history, 
including relevant information, such as review of ethanol, recreational drug and supplement 
consumption, family history, sexual history, travel history, history of contact with a jaundiced 
patient, surgery, blood transfusion, history of liver or allergic disease, and work exposure, should 
be collected.  Further testing for acute hepatitis A, B, or C infection and liver imaging (e.g., 
biliary tract) may be warranted.  The possibility of recurrent disease should be considered. 
Potential Hy's Law cases should be reported as serious adverse events (see Section 7.5.4). 
6.22 
Treatment Management for Paclitaxel and Docetaxel for Arms 1 and 2 
If necessary, the timing of a treatment may be adjusted to 2 days earlier or 2 days later than the 
scheduled date of treatment.  For general chemotherapy instructions, see Section 6.1 and Section 
6.3. 
x 
Dose modifications for paclitaxel are based on the dose level changes outlined in Table 25. 
x 
See Table 28 for management of taxane-related neuropathy and Table 29 for taxane-related 
musculoskeletal pain.  Instructions for management of all other toxicities related to paclitaxel 
are listed on Table 26 and related to docetaxel are on Table 27.  See Section 6.5.1 for 
management of diarrhea. 
Use of this document is governed by the terms of use on the first page of this document.

 
NRG-BR004 
86 
NCI Version Date: August 15, 2022 
Table 25.  Dose levels for paclitaxel and docetaxel (Arm 1 and Arm 2) 
 
Dose Level 0 
Starting Dose 
(mg/m2) 
Dose Level -1 
(mg/m2) 
Dose Level -2 
(mg/m2) 
Dose Level -3 
Paclitaxel 
80 
60 
45 
Discontinue 
Docetaxel 
75 
60 
50 
Discontinue 
6.22.1 Management of Anemia 
Chemotherapy should not proceed with t grade 3 anemia.  Transfusion is acceptable for 
improving the hemoglobin value to allow therapy to continue without delay.  The patient should 
be assessed to rule out other causes of anemia.  Use of erythropoiesis-stimulating agents is 
prohibited. 
6.22.2 Management of Infusion-Related Reaction 
If a hypersensitivity and/or infusion reaction occurs during paclitaxel or docetaxel administration, 
nab-paclitaxel may be substituted per investigator and local guidelines for subsequent nab-
paclitaxel doses with starting dose and dose modifications if necessary per investigator discretion.  
Alternatively, patients may convert to the alternative taxane per investigator discretion.  Patients 
continue on study and continue to follow protocol requirements outlined on Table 2. 
 
 
Use of this document is governed by the terms of use on the first page of this document.

 
NRG-BR004 
87 
NCI Version Date: August 15, 2022 
6.22.3 Dose Modifications for Taxane Chemotherapy (Paclitaxel or Docetaxel) 
Table 26.  Dose modifications and instructions for paclitaxel (Arm 1 and Arm 2) 
Important table instructions: 
x Dose modifications must be based on AEs that occurred between treatments (column 2) and AEs present 
on the scheduled treatment day (column 3).  Refer to other applicable instructions in Section 6.1 and 
Section 6.3.  Dose modifications must be based on the AE requiring the greatest modification. 
x Refer to Section 6. 22.1 for management of anemia. 
CTCAE v5.0 
Adverse Event/Grade 
Modifications for AEs that 
occurred between treatments but 
DID NOT REQUIRE A DELAY OR 
AN OMISSION OF A TREATMENT 
(See footnote a) 
Modifications for AEs that 
REQUIRE A DELAY OR AN 
OMISSION OF A TREATMENT 
(See footnote b) 
Neutrophil count 
decreased: 
Grade 2  
 
 
Maintain dose 
 
 
Maintain dose 
Grades 3, 4 
Maintain dose 
ANC: Hold until t  1000/mm3;  
First occurrence: p one dose level. 
Second occurrence: add G-CSFc 
prophylaxis for subsequent doses.  
Third occurrence: p one dose level. 
Platelet count decreased: 
Grades 2, 3 
 
Maintain dose 
Hold until t  75,000/mm3.  If 
recovery takes: 
1 wk – maintain dose;  
2-3 wks – p one dose level 
 
Grade 4 
 
Ļ one dose level 
Hold until t  75,000/mm3 
Ļ one dose level 
Diarrhea (if related to chemotherapy): Refer to Section 6.5 
Immune System 
Disorders 
Allergic 
reaction/Anaphylaxis 
(despite premedication) 
Grades 1, 2, 3 
(Refer to Section 6.22.2) 
 
 
 
Treat as per institutional policy; may 
re-challenge (maintain dose) or 
convert to alternative taxane. 
 
 
 
Treat as per institutional policy; may 
re-challenge (maintain dose) or 
convert to alternative taxane. 
Grade 4 
Discontinue 
Discontinue 
Infection or febrile 
neutropenia: 
Grade 2 
(N/A for febrile 
neutropenia) 
 
 
If infection was present but not neutropenic: 
Maintain dose  
If infection and neutropenia were present: 
Maintain dose or modify dose per grade 3. 
Grade 3 
For initial episode, p one dose level for subsequent doses. 
For second episode, p one dose level for subsequent doses, or maintain 
dose and add G-CSFc prophylaxis for subsequent doses per investigator 
discretion. 
For third episode, p one dose level for subsequent doses or discontinue. 
For fourth episode, discontinue. 
Grade 4 
For initial episode, p one dose level for subsequent doses. 
For second episode, discontinue. 
Table continued on next page. 
 
Use of this document is governed by the terms of use on the first page of this document.

 
NRG-BR004 
88 
NCI Version Date: August 15, 2022 
Table 26.  Dose modifications and instructions for paclitaxel (Arm 1 and Arm 2) (continued) 
CTCAE v5.0 
Adverse Event/Grade 
Modifications for AEs that 
occurred between treatments but 
DID NOT REQUIRE A DELAY 
OR AN OMISSION OF A 
TREATMENT 
(See footnote a) 
Modifications for AEs that 
REQUIRE A DELAY OR AN 
OMISSION OF A TREATMENT 
(See footnote b) 
Other clinically 
significant AEs probably 
related to paclitaxel:d 
 
Grade 2 
 
 
 
 
Maintain dose or p one dose level 
 
 
 
 
Maintain dose or p one dose level 
Grade 3 
Maintain dose or Ļ one dose level 
Ļ one dose level 
Grade 4 
Ļ one dose level or discontinue 
Ļ one dose level or discontinue 
a Treatment may not proceed until clinically significant AEs are d Grade 1 (except neutrophils, 
which must be t 1000/mm3.  
b Hold and check weekly.  With exception of neutrophils, resume treatment when toxicity is  
≤Grade 1.  If toxicity has not resolved to d Grade 1 after 3 weeks of delay, discontinue paclitaxel. 
c 
Only filgrastim is to be given after each dose of paclitaxel.  At the investigator's discretion, 
filgrastim may be given for 3-5 days after each dose of paclitaxel.  Pegfilgrastim is prohibited 
during paclitaxel.   
x 
Do not administer G-CSF within 24 hours of chemotherapy. 
x 
Use of (prophylactic) filgrastim is required for all remaining doses in regimen. 
x 
If required by institutional standards, GM-CSF may be administered as an alternative. 
d Determination of "clinically significant" of paclitaxel AEs is at the discretion of the investigator. 
 
 
Use of this document is governed by the terms of use on the first page of this document.

 
NRG-BR004 
89 
NCI Version Date: August 15, 2022 
Table 27.  Dose modifications and instructions for docetaxel (Arm 1 and Arm 2) 
Important table instructions: 
x Dose modifications must be based on AEs that occurred between treatments (column 2) and AEs present 
on the scheduled treatment day (column 3).  Refer to other applicable instructions in Section 6.1 and 
Section 6.3.  Dose modifications must be based on the AE requiring the greatest modification. 
x Refer to Section 6. 22.1 for management of anemia. 
CTCAE v5.0 
Adverse Event/Grade 
Modifications for AEs that 
occurred between treatments but 
DID NOT REQUIRE A DELAY OR 
AN OMISSION OF A TREATMENT 
(See footnote a) 
Modifications for AEs that 
REQUIRE A DELAY OR AN 
OMISSION OF A TREATMENT 
(See footnote b) 
Neutrophil count 
decreased: 
Grade 2  
 
 
Maintain dose 
 
 
Maintain dose 
Grades 3, 4 
Maintain dose 
ANC: Hold until t  1000/mm3;  
First occurrence: add G-CSFc 
prophylaxis for subsequent doses.  
Second occurrence: p one dose 
level. 
Third occurrence: p one dose level. 
Platelet count decreased: 
Grades 2, 3 
 
Maintain dose 
Hold until t  75,000/mm3.  If 
recovery takes: 
1 wk – maintain dose;  
2-3 wks – p one dose level 
 
Grade 4 
 
Ļ one dose level 
Hold until t  75,000/mm3 
Ļ one dose level 
Diarrhea (if related to chemotherapy): Refer to Section 6.5 
Immune System 
Disorders 
Allergic 
reaction/Anaphylaxis 
(despite premedication) 
Grades 1, 2, 3 
(Refer to Section 6.22.2) 
 
 
 
 
Treat as per institutional policy; may 
re-challenge (maintain dose) or 
convert to alternative taxane 
 
 
 
 
Treat as per institutional policy; may 
re-challenge (maintain dose) or 
convert to alternative taxane 
Grade 4 
Discontinue 
Discontinue 
Infection or febrile 
neutropenia: 
Grade 2 
(N/A for febrile 
neutropenia) 
 
 
If infection was present but not neutropenic: 
Maintain dose  
If infection and neutropenia were present: 
Add G-CSFc prophylaxis for subsequent doses. 
Grade 3 
For initial episode, add G-CSFc prophylaxis for subsequent doses. 
For second episode, p one dose level for subsequent doses. 
For third episode, p one dose level for subsequent doses or discontinue. 
For fourth episode, discontinue. 
Grade 4 
For initial episode, add G-CSF prophylaxis and p one dose level for 
subsequent doses. 
For second episode, discontinue. 
Table continued on next page. 
 
Use of this document is governed by the terms of use on the first page of this document.

 
NRG-BR004 
90 
NCI Version Date: August 15, 2022 
Table 27.  Dose modifications and instructions for docetaxel (Arm 1 and Arm 2) (continued) 
CTCAE v5.0 
Adverse Event/Grade 
Modifications for AEs that 
occurred between treatments but 
DID NOT REQUIRE A DELAY 
OR AN OMISSION OF A 
TREATMENT 
(See footnote a) 
Modifications for AEs that 
REQUIRE A DELAY OR AN 
OMISSION OF A TREATMENT 
(See footnote b) 
Other clinically 
significant AEs probably 
related to docetaxel:d 
 
Grade 2 
 
 
 
 
Maintain dose or p one dose level 
 
 
 
 
Maintain dose or p one dose level 
Grade 3 
Maintain dose or Ļ one dose level 
Ļ one dose level 
Grade 4 
Ļ one dose level or discontinue 
Ļ one dose level or discontinue 
a Treatment may not proceed until clinically significant AEs are d Grade 1 (except neutrophils, 
which must be t 1000/mm3.  
b Hold and check weekly.  With exception of neutrophils, resume treatment when toxicity is  
≤Grade 1.  If toxicity has not resolved to d Grade 1 after 3 weeks of delay, discontinue docetaxel. 
c 
Pegfilgrastim or similar long-acting formulation is preferred to G-CSF but investigators should 
follow institutional standards.   
x 
Do not administer G-CSF within 24 hours of chemotherapy. 
x 
Use of (prophylactic) filgrastim is required for all remaining doses in regimen. 
x 
If required by institutional standards, GM-CSF may be administered as an alternative. 
d Determination of "clinically significant" of docetaxel AEs is at the discretion of the investigator. 
 
 
Table 28.  Treatment management for taxane-related neuropathy (Arm 1 and Arm 2) 
Nervous System Disorders 
x 
Paresthesias 
x 
Peripheral sensory neuropathy 
1–6 Days Duration 
Between Doses of Taxane 
Persistent for t 7 Days or 
Caused Treatment 
to be Delayed or Omitted 
Grade 1 
Maintain dose 
Grade 2 
Maintain taxane dosea 
Decrease taxane one dose levelb 
Grade 3 
First episode: 
Decrease taxane one dose 
levela 
Second episode: 
Discontinue taxane 
Discontinue taxane 
Grade 4 
Discontinue taxane 
a 
Hold until improved to less than moderate symptom intensity on the next treatment day. 
b 
Hold taxane (Arm 1 and Arm 2) for persistent moderate intensity Grade 2 neuropathy.  When 
improved to less than moderate symptom intensity, resume treatment with dose modification for 
taxane.  If moderate intensity Grade 2 toxicity persists after 3 weeks of delay, discontinue taxane. 
 
 
Use of this document is governed by the terms of use on the first page of this document.

 
NRG-BR004 
91 
NCI Version Date: August 15, 2022 
Table 29.  Treatment management for taxane-related musculoskeletal pain (Arm 1 and  
Arm 2) 
Note: The treatment management instructions in Table 29 apply to patients with musculoskeletal pain 
not controlled by analgesics.  Use of narcotics and NSAIDs is encouraged to maintain the taxane dose if 
possible. 
Musculoskeletal and 
Connective Tissue Disorders 
x 
Arthralgia 
x 
Myalgia 
1–6 Days Duration Between 
Doses of Taxane 
Persistent for t 7 Days or 
Caused Treatment to be 
Delayed or Omitted 
Grade 1 
(despite analgesics) 
Maintain taxane dose 
Grade 2 
(despite analgesics) 
Maintain taxane dose 
Maintain taxane dose 
or 
Decrease taxane one dose level* 
Grade 3 
(despite analgesics) 
First episode: 
Decrease taxane one dose level 
 
Second episode:  
Discontinue taxane 
First episode: 
Decrease taxane one dose level* 
or 
Discontinue taxane 
 
Second episode:  
Discontinue taxane 
* 
Hold taxane (Arm 1 and Arm 2) for persistent Grade 2 or 3 musculoskeletal pain.  When  
d Grade 1, resume treatment with dose modification for taxane.  If Grade 2 or Grade 3 toxicity 
persists after 3 weeks of delay, discontinue taxane. 
 
 
Use of this document is governed by the terms of use on the first page of this document.

 
NRG-BR004 
92 
NCI Version Date: August 15, 2022 
7.0 
ADVERSE EVENTS REPORTING REQUIREMENTS 
The NRG-BR004 study was permanently closed to accrual on May 20, 2022.  Please see Table 2A 
for immune-related adverse event reporting requirements for patients enrolled prior to study 
accrual closure. 
7.1 
Study Agents 
7.1.1 
U.S. and Canadian Institutions 
x 
Investigational Agent 
The investigational agent is atezolizumab/placebo. 
x 
Commercial Agents 
The commercial agents are paclitaxel, docetaxel, pertuzumab, and trastuzumab. 
7.2 
Adverse Events and Serious Adverse Events 
7.2.1 
Adverse Event Characteristics 
CTCAE term (AE description) and grade: The descriptions and grading scales found in the 
revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 will be 
utilized for AE reporting.  All appropriate treatment areas should have access to a copy of the 
CTCAE version 5.0.  A copy of the CTCAE version 5.0 can be downloaded from the CTEP 
website (http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm).   
PRO-CTCAE is not intended for expedited reporting, real time review, or safety reporting. 
7.2.2 
Definition of an Adverse Event (AE) 
Any untoward medical occurrence associated with the use of a drug in humans, whether or not 
considered drug related.  Therefore, an AE can be any unfavorable and unintended sign 
(including an abnormal laboratory finding), symptom, or disease temporally associated with the 
use of a medicinal (investigational) product, whether or not considered related to the medicinal 
(investigational) product (attribution of unrelated, unlikely, possible, probable, or definite).  
(International Conference on Harmonisation [ICH], E2A, E6). 
7.2.3 
Definition of a Serious Adverse Event 
Any adverse drug event (experience) occurring at any dose that results in ANY of the following 
outcomes: 
x 
Death 
x 
A life-threatening adverse drug experience 
x 
Inpatient hospitalization or prolongation of existing hospitalization (for t 24 hours) 
x 
A persistent or significant incapacity or substantial disruption of the ability to conduct normal 
life functions 
x 
A congenital anomaly/birth defect 
x 
Important Medical Events (IME) that may not result in death, be life-threatening, or require 
hospitalization may be considered a serious adverse drug experience when, based upon 
medical judgment, they may jeopardize the patient and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition (FDA, 21 CFR 312.32; 
ICH E2A and ICH E6). 
 
Use of this document is governed by the terms of use on the first page of this document.

 
NRG-BR004 
93 
NCI Version Date: August 15, 2022 
7.3 
Adverse Events for Study Agents 
7.3.1 
Commercial Agents  
Refer to the current FDA-approved package insert or current Health Canada-approved product 
monograph for detailed pharmacologic and safety information for paclitaxel. 
Paclitaxel 
Common adverse events (> 20%) include: anemia, neutropenia; infection; diarrhea; nausea; 
vomiting; mucositis; allergic reaction; thrombocytopenia; pain; myalgia/arthralgia; peripheral 
motor and sensory neuropathies; and alopecia. 
Less common events (d 20%) include: sinus bradycardia; pneumonitis; pleural effusion; 
pulmonary fibrosis; and thromboembolic event. 
Rare but serious events (< 3%) include: myocardial infarction; heart failure; and colonic 
perforation. 
Docetaxel 
Common adverse events (> 20%) include: thrombocytopenia; neutropenia; infection; anemia; 
diarrhea; nausea; vomiting; constipation; mucositis; irregular menstruation or amenorrhea; 
fatigue; fever; erythema multiforme; edema; pain; peripheral motor and sensory neuropathies; 
watering eyes; nail changes; rash; pruritus; and alopecia. 
Less common events (d 20%) include: irregular heart rate; chest pain; dyspnea; wheezing; 
thromboembolic event; acute kidney injury; abdominal pain; Stevens-Johnson syndrome. 
Rare but serious events (< 3%) include: Leukemia secondary to oncology chemotherapy; allergic 
reaction. 
Pertuzumab 
The Comprehensive Adverse Events and Potential Risks list (CAEPR) provides a single list of 
reported and/or potential adverse events (AE) associated with an agent using a uniform 
presentation of events by body system.  In addition to the comprehensive list, a subset, the 
Specific Protocol Exceptions to Expedited Reporting (SPEER), appears in a separate column and 
is identified with bold and italicized text.  This subset of AEs (SPEER) is a list of events that are 
protocol specific exceptions to expedited reporting to NCI (except as noted in Table 30).  Refer to 
the 'CTEP, NCI Guidelines: Adverse Event Reporting Requirements' 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguidelines.pdf for 
further clarification.  Frequency is provided based on 9575 patients.  Below is the CAEPR for 
Pertuzumab.  
NOTE: Report AEs on the SPEER ONLY IF they exceed the grade noted in parentheses 
next to the AE in the SPEER.  If this CAEPR is part of a combination protocol using 
multiple investigational agents and has an AE listed on different SPEERs, use the lower of 
the grades to determine if expedited reporting is required. 
NOTE: Frequencies of AEs on this CAEPR are based on pooled clinical data from treatment 
arms, pivotal clinical trials using pertuzumab in combination with trastuzumab and 
docetaxel in patients with MBC (metastatic breast cancer), and pertuzumab in combination 
with trastuzumab and chemotherapy in patients with EBC (early stage breast cancer).   
 
 
Use of this document is governed by the terms of use on the first page of this document.

Use of this document is governed by the terms of use on the first page of this document.

Use of this document is governed by the terms of use on the first page of this document.

 
NRG-BR004 
96 
NCI Version Date: August 15, 2022 
Adverse events reported on pertuzumab trials, but for which there is insufficient evidence to 
suggest that there was a reasonable possibility that pertuzumab caused the adverse event: 
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Bone marrow hypocellular; Leukocytosis 
CARDIAC DISORDERS - Atrial fibrillation; Chest pain - cardiac; Left ventricular systolic dysfunction; 
Pericardial effusion 
EYE DISORDERS - Blurred vision; Dry eye; Eye disorders – Other (diplopia) 
GASTROINTESTINAL DISORDERS - Abdominal distension; Ascites; Dry mouth; Esophagitis; 
Gastroesophageal reflux disease; Hemorrhoids 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Chills; Death NOS; Flu 
like symptoms; Generalized edema; Non-cardiac chest pain; Pain 
HEPATOBILIARY DISORDERS - Cholecystitis; Hepatobiliary disorders - Other (hepatitis fulminant); 
Hepatobiliary disorders - Other (hepatocellular injury) 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS - Fracture; Injury, poisoning and 
procedural complications - Other (post-procedural inflammation); Injury, poisoning and procedural 
complications - Other (procedural pain); Injury, poisoning and procedural complications - Other (skin 
toxicity); Wound complication; Wound dehiscence 
INVESTIGATIONS - Alkaline phosphatase increased; Blood bilirubin increased; Creatinine increased; 
GGT increased; Investigations - Other (granulocytopenia); Lymphocyte count decreased; Platelet count 
decreased; Weight gain; Weight loss 
METABOLISM AND NUTRITION DISORDERS - Dehydration; Hyperglycemia; Hypoglycemia; 
Hypokalemia; Hypomagnesemia 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Bone pain; Muscle cramp; 
Musculoskeletal and connective tissue disorder - Other (dermatomyositis syndrome); Musculoskeletal and 
connective tissue disorder - Other (spinal pain) 
NERVOUS SYSTEM DISORDERS - Amnesia; Dysarthria; Lethargy; Nervous system disorders - 
Other (osmotic demyelination syndrome); Somnolence; Syncope 
PSYCHIATRIC DISORDERS - Anxiety; Depression 
RENAL AND URINARY DISORDERS - Acute kidney injury; Dysuria; Urinary frequency 
REPRODUCTIVE SYSTEM AND BREAST DISORDERS - Amenorrhea; Breast pain; Irregular 
menstruation; Reproductive system and breast disorders - Other (metrorrhagia); Vaginal dryness 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS – Bronchospasm4; Nasal 
congestion; Oropharyngeal pain; Pleural effusion; Pneumonitis; Postnasal drip; Respiratory failure; 
Respiratory, thoracic and mediastinal disorders - Other (painful respiration); Rhinorrhea 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Erythema multiforme; Erythroderma; 
Hyperhidrosis; Nail discoloration; Pain of skin; Rash acneiform; Skin and subcutaneous tissue disorders - 
Other (onycholysis); Skin and subcutaneous tissue disorders - Other (onychomadesis); Skin 
hyperpigmentation; Urticaria 
VASCULAR DISORDERS - Flushing; Hypertension; Hypotension; Lymphedema; Thromboembolic 
event; Vascular disorders - Other (hyperemia) 
Note: Pertuzumab in combination with other agents could cause an exacerbation of any adverse event 
currently known to be caused by the other agent, or the combination may result in events never previously 
associated with either agent. 
Trastuzumab  
The Comprehensive Adverse Event and Potential Risks list (CAEPR) provides a single list of 
reported and/or potential adverse events (AE) associated with an agent using a uniform 
presentation of events by body system.  In addition to the comprehensive list, a subset, the Specific 
Protocol Exceptions to Expedited Reporting (SPEER), appears in a separate column and is 
identified with bold and italicized text.  This subset of AEs (SPEER) is a list of events that are 
Use of this document is governed by the terms of use on the first page of this document.

Use of this document is governed by the terms of use on the first page of this document.

Use of this document is governed by the terms of use on the first page of this document.

Use of this document is governed by the terms of use on the first page of this document.

 
NRG-BR004 
100 
NCI Version Date: August 15, 2022 
4Injection site reaction was observed primarily in subjects treated with Herceptin Hylecta™ SC 
formulation. 
5Severe hypersensitivity reactions including angioedema and pulmonary adverse events (e.g., hypoxia, 
dyspnea, pulmonary infiltrates, pleural effusion, interstitial lung disease, wheezing, and acute respiratory 
distress syndrome) have been reported. 
6Infection may include any of the 75 sites of infection under the INFECTIONS AND INFESTATIONS 
SOC. 
7Infusion related reaction was observed primarily in subjects treated with the trastuzumab IV formulation. 
Adverse events reported on trastuzumab (Herceptin) and/or Herceptin Hylecta™ (SQ 
trastuzumab) trials, but for which there is insufficient evidence to suggest that there was a 
reasonable possibility that trastuzumab (Herceptin) and/or Herceptin Hylecta™ (SQ trastuzumab) 
caused the adverse event: 
CARDIAC DISORDERS - Asystole; Atrial fibrillation; Atrial flutter; Chest pain - cardiac; Myocardial 
infarction; Myocarditis; Sinus bradycardia; Ventricular arrhythmia; Ventricular tachycardia 
EAR AND LABYRINTH DISORDERS - Hearing impaired; Vertigo 
EYE DISORDERS - Dry eye; Extraocular muscle paresis 
GASTROINTESTINAL DISORDERS - Ascites; Colitis; Constipation; Duodenal ulcer; Dyspepsia; 
Enterocolitis; Esophagitis; Gastric hemorrhage; Gastritis; Gastrointestinal pain; Small intestinal 
perforation; Typhlitis 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Generalized edema; 
Sudden death NOS 
HEPATOBILIARY DISORDERS: - Cholecystitis 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS - Dermatitis radiation; Fracture; 
Injury, poisoning and procedural complications – Other (incision site pain); Injury, poisoning and 
procedural complications – Other (procedural pain) 
INVESTIGATIONS - Alanine aminotransferase increased; Creatinine increased; Weight gain; White 
blood cell decreased 
METABOLISM AND NUTRITION DISORDERS - Dehydration; Hyperkalemia; Hypoalbuminemia; 
Hypokalemia; Hyponatremia; Hypophosphatemia 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Arthritis; Chest wall pain; 
Flank pain; Generalized muscle weakness; Neck pain 
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND POLYPS) – 
Leukemia secondary to oncology chemotherapy; Treatment related secondary malignancy 
NERVOUS SYSTEM DISORDERS - Amnesia; Depressed level of consciousness; Encephalopathy; 
Leukoencephalopathy; Muscle weakness left-sided; Paresthesia; Seizure; Syncope 
PSYCHIATRIC DISORDERS - Anxiety; Confusion 
RENAL AND URINARY DISORDERS - Acute kidney injury; Proteinuria 
REPRODUCTIVE SYSTEM AND BREAST DISORDERS - Amenorrhea 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Epistaxis; Nasal congestion; 
Oropharyngeal pain; Pharyngolaryngeal pain; Pleural effusion5; Pulmonary hypertension; Respiratory 
failure; Wheezing5 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Eczema; Erythema multiforme; 
Hyperhidrosis; Palmar-plantar erythrodysesthesia syndrome; Pruritus; Skin hyperpigmentation; Stevens-
Johnson syndrome 
VASCULAR DISORDERS - Hematoma; Thromboembolic event 
Note: Trastuzumab (Herceptin) and/or Herceptin Hylecta™ (SQ trastuzumab) in combination with other 
agents could cause an exacerbation of any adverse event currently known to be caused by the other agent, 
or the combination may result in events never previously associated with either agent. 
Use of this document is governed by the terms of use on the first page of this document.

Use of this document is governed by the terms of use on the first page of this document.

Use of this document is governed by the terms of use on the first page of this document.

Use of this document is governed by the terms of use on the first page of this document.

Use of this document is governed by the terms of use on the first page of this document.

 
NRG-BR004 
105 
NCI Version Date: August 15, 2022 
CARDIAC DISORDERS - Cardiac arrest; Ventricular tachycardia 
GASTROINTESTINAL DISORDERS - Constipation; Dry mouth; Ileus 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Chills; Edema limbs; 
Malaise; Multi-organ failure 
HEPATOBILIARY DISORDERS – Portal vein thrombosis 
INVESTIGATIONS – Lymphocyte count decreased; Neutrophil count decreased; Weight loss; White 
blood cell decreased 
METABOLISM AND NUTRITION DISORDERS - Hypophosphatemia; Tumor lysis syndrome 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Bone pain; Muscle cramp: 
Pain in extremity 
NERVOUS SYSTEM DISORDERS - Headache 
PSYCHIATRIC DISORDERS - Confusion; Insomnia; Suicide attempt 
REPRODUCTIVE SYSTEM AND BREAST DISORDERS - Breast pain 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Bronchopulmonary 
hemorrhage; Pulmonary hypertension; Respiratory failure 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Alopecia; Dry skin2; Hyperhidrosis 
VASCULAR DISORDERS - Hypertension; Hypotension; Thromboembolic event 
Note: Atezolizumab (MPDL3280A) in combination with other agents could cause an exacerbation of 
any adverse event currently known to be caused by the other agent, or the combination may result in 
events never previously associated with either agent. 
7.4 
PRO-CTCAE Assessment Items 
The NRG-BR004 study was permanently closed to accrual on May 20, 2022.  Modified scheduled 
status updates, as outlined on Table 2A, will be completed for patients enrolled prior to study 
accrual closure.  Patients will not be required to complete the PRO-CTCAE assessments. 
With Amendment #3, accrual to the PRO-CTCAE substudy is closed.  Patients enrolled on the 
PRO-CTCAE substudy prior to Amendment #3 will continue to complete the scheduled 
assessments as outlined on Table 2.  Accrual to the QOL substudy will continue. 
Clinician-graded CTCAE is the AE safety standard.  PRO-CTCAE items are to complement 
CTCAE reporting.  Patients will respond to PRO-CTCAE items but no protocol directed action 
will be taken.   
PRO-CTCAE is intended to enhance the quality of adverse event data reporting in clinical trials, 
provide data that complements and extends the information provided by clinician reporting using 
CTCAE, represent the patient perspective of the experience of symptomatic adverse events, and 
improve detection of potentially serious adverse events.  The selection of PRO-CTCAE should be 
complimentary to the clinician-identified AEs for ongoing monitoring.  To enhance the toxicity 
monitoring in this study, and in line with the goals of the FDA and NCI in examining the added 
value of patient reported outcomes to standard toxicity evaluations (Kleutz 2016), we are 
planning to monitor toxicity with PRO-CTCAE items along with their standard assessments as 
described in the AE reporting section of this protocol (see Section 7.0).  This has been found 
acceptable in clinical trials as recently reported by Basch (Basch 2017).  We have selected key 
symptoms for monitoring that reflect the standard drug exposures in the trial, including those 
associated with atezolizumab.  A key question is whether or not atezolizumab will exacerbate any 
of the common symptoms associated with the standard treatments that are being given to both 
treatment arms.  As has been recommended by the NCI (Basch 2016), symptoms will be assessed 
prior to initiation of treatment (baseline), and then weekly during the first 12 weeks (Cycles 1-2) 
after the initiation of therapy.  Subsequent assessments will occur at less frequent intervals and 
coincide with the timing of the investigator-evaluated AEs (i.e., on the same schedule).  The 
Use of this document is governed by the terms of use on the first page of this document.

 
NRG-BR004 
106 
NCI Version Date: August 15, 2022 
frequent monitoring, especially during the first 12 weeks, is designed to evaluate whether or not 
interim monitoring of symptoms (more frequent than at the time of usual visits), captures toxicity 
more accurately than when done intermittently.  While missing data is a threat with such frequent 
assessments, use of an electronic monitoring approach (ePRO), where patients are sent an 
electronic link that allows them to easily respond to the survey items, should facilitate regular 
reporting.  We list below the particular symptoms that will be assessed.  In addition, patients will 
be offered a free text space to report on additional symptoms they may be having. 
The PRO-CTCAE items used for the BR004 listed study are listed below.  Refer to Section 11.6 
for additional information.   
CTCAE Term 
PRO-CTCAE Terms with Attributes 
Anorexia 
Decreased appetite (Severity and Interference) 
Nausea 
Nausea (Frequency and Severity) 
Dyspnea 
Shortness of breath (Severity and Interference) 
Peripheral sensory neuropathy 
Numbness and tingling in hands or feet (Severity and 
Interference) 
Abdominal pain 
Pain in the abdomen (Frequency, Severity, and Interference) 
Arthralgia 
Joint pain (Frequency, Severity, and Interference) 
Fatigue 
Fatigue (Severity and Interference) 
Diarrhea 
Loose or watery stools (Frequency) 
Rash maculo-papular 
Rash (Present/Absent) 
Pruritus 
Itchy skin (Severity) 
Cough 
Cough (Severity and Interference) 
Mucositis oral 
Mouth or throat sores (Severity and Interference) 
7.5 
Expedited Reporting of Adverse Events 
NRG Oncology will follow procedures for the centralized reporting of adverse events for 
BR004, which requires that adverse events/serious adverse events be reported to the NRG 
Oncology SDMC.  NRG Oncology forwards reports to CTEP and, when necessary, the 
appropriate regulatory agencies.  All serious adverse events that meet expedited reporting criteria 
defined in Table 33 will be reported via the CTEP Adverse Event Reporting System, CTEP-
AERS, accessed via Rave-CTEP-AERS Integration. 
Refer to Section 13.5 for important operational details/information about Rave-CTEP-AERS 
Integration and how to obtain the Expedited Safety Reporting Rules Evaluation User Guide. 
NRG Oncology is identified in CTEP-AERS as the Lead Group for CTEP-AERS reporting. 
Submitting a report via CTEP-AERS serves as notification to the NRG Oncology Statistics and 
Data Management Center (SDMC) and satisfies NRG Oncology requirements for expedited 
adverse event reporting. 
In the rare event when Internet connectivity is disrupted, a 24-hour notification must be made to 
CTEP as the IND sponsor for this study by telephone at 301-897-7497 and to the NRG Oncology 
SDMC by phone at 412-624-2666.  An electronic report must be submitted into CTEP-AERS 
upon re-establishment of the Internet connection.   
Use of this document is governed by the terms of use on the first page of this document.

 
NRG-BR004 
107 
NCI Version Date: August 15, 2022 
7.5.1 
Expedited Reporting Methods 
x 
Per CTEP NCI Guidelines for Adverse Events Reporting Requirements, a CTEP-AERS 
24-Hour Notification must be submitted to the NCI within 24 hours of learning of the 
adverse event.  Each CTEP-AERS 24-hour notification must be followed by a CTEP-AERS  
3 Calendar Day Report (see Table 33). 
x 
CTEP-AERS 3 Calendar Day Report requires that a complete report is electronically 
submitted to the NRG Oncology Lead Group within 3 calendar days of submission of the 
CTEP-AERS 24-hour notification (see Table 33). 
x 
CTEP-AERS 5 Calendar Day Report requires that a complete report is electronically 
submitted to the NRG Oncology Lead Group within 5 calendar days of learning of the AE 
(see Table 33). 
x 
Reports submitted via CTEP-AERS 24-hour notification are available for review by both the 
NCI and NRG Oncology after submission.  All other CTEP-AERS reports are first sent to 
the NRG Oncology Lead Group and then are forwarded to the NCI.  The timelines in 
Table 33 have been set so that the information can be forwarded to the NCI in a timely 
manner per the NCI's/CTEP's guidelines. 
x 
Supporting documentation is requested by the IND sponsor for this study (CTEP/DCTD) 
and NRG Oncology as needed to complete adverse event review.  All CTEP-AERS 
documentation is faxed to CTEP at 301-897-7404.  When submitting supporting source 
documentation, remove all identifiers and include the protocol number, patient ID number, 
and CTEP-AERS ticket number on each page. 
x 
A serious adverse event that meets expedited reporting criteria as outlined in the AE 
Reporting Table but is assessed by the CTEP-AERS as “An action is NOT recommended”, 
must still be reported to fulfill NRG Oncology safety reporting obligations.  Therefore, sites 
must override the “NOT recommended” assessment.  CTEP-AERS allows submission of all 
reports regardless of the results of the assessment. 
7.5.2 
Expedited Reporting Requirements 
Expedited reporting requirements begin with the administration of the first study therapy dose.  
Expedited reporting requirements for all patients are provided in Table 33. 
 
 
Use of this document is governed by the terms of use on the first page of this document.

Use of this document is governed by the terms of use on the first page of this document.

 
NRG-BR004 
109 
NCI Version Date: August 15, 2022 
7.5.4 
Adverse Events of Special Interest 
Adverse Events of Special Interest: Adverse events of special interest (AESI) require expedited 
reporting via CTEP-AERS regardless of attribution from the first dose of study therapy through 
April 2024.  Adverse events of special interest for this study include the following: 
Atezolizumab AESIs 
x 
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 6.21) and based on the following observations: 
 
Treatment-emergent ALT or AST ! 3 x ULN (or > 3 x baseline value in disease states 
where LFTs may be elevated at baseline) in combination with total bilirubin ! 2 x ULN 
(of which t 35% is direct bilirubin).  Report as Hepatobiliary disorders - Other, potential 
drug-induced liver injury. 
 
Treatment-emergent ALT or AST ! 3 x ULN (or 3 x baseline value in disease states 
where LFTs may be elevated at baseline) combination with clinical jaundice.  Report as 
Hepatobiliary disorders - Other, potential drug-induced liver injury. 
x 
Suspected transmission of an infectious agent by the study treatment (STIAMP), defined as – 
Any organism, virus, or infectious particle (e.g., prion protein transmitting transmissible 
spongiform encephalopathy), pathogenic or non-pathogenic, is considered an infectious 
agent.  A transmission of an infectious agent may be suspected from clinical symptoms or 
laboratory 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.  Report as  
t Grade 2 Infections and infestations – Other and specify the infectious agent identified. 
x 
Pneumonitis  
x 
Colitis  
x 
Pancreatitis 
x 
Hypophysitis 
x 
Adrenal insufficiency 
x 
Hyperthyroidism  
x 
Diabetes mellitus (t Grade 2 Hyperglycemia) 
x 
Hepatitis including AST or ALT ! 5 x ULN (t Grade 3) 
x 
Systemic lupus erythematosus.  Report as Immune system disorders – Other, systemic lupus 
erythematosus. 
x 
Guillain-Barré syndrome 
x 
Myasthenic syndrome.  Report as Nervous system disorders-Other, myasthenic syndrome.  
x 
Myasthenia gravis.  Report as Myasthenia gravis. 
x 
Meningoencephalitis.  Report as Encephalitis infection. 
x 
Hypersensitivity.  Report as allergic reaction. 
x 
Infusion-related reactions.  Report as Infusion related reaction. 
x 
Cytokine release syndrome 
x 
Influenza-like illness.  Report as Flu like symptoms. 
x 
Systemic inflammatory response syndrome.  Report as Immune system disorders – Other, 
systemic inflammatory response syndrome. 
x 
Systemic immune activation.  Report as Immune system disorders – Other, systemic immune 
activation. 
x 
Nephritis.  Report as Renal and urinary disorders – Other, nephritis. 
x 
Optic neuritis.  Report as Eye disorders – Other, optic neuritis. 
x 
Retinitis.  Report as Eye disorders – Other, retinitis. 
x 
Uveitis 
Use of this document is governed by the terms of use on the first page of this document.

 
NRG-BR004 
110 
NCI Version Date: August 15, 2022 
x 
Myositis.  Report as myositis. 
x 
Myopathy.  Report as Musculoskeletal and connective tissue disorder – Other, myopathy. 
x 
Rhabdomyolysis 
x 
Serious Adverse Cutaneous Reactions (SCARs) – erythema multiforme, acute generalized 
exanthematous pustulosis, Stevens-Johnson syndrome (SJS), Toxic Epidermal Necrolysis 
(TEN), drug rash with eosinophilia and systemic symptoms (DRESS) 
x 
Vasculitis 
x 
Autoimmune hemolytic anemia.  Report as Blood and lymphatic system disorders – Other, 
autoimmune hemolytic anemia. 
x 
Cardiac disorders ! Grade 2 (e.g., atrial fibrillation, myocarditis, pericarditis) 
Trastuzumab AESI 
x 
Congestive heart failure.  Report as Cardiac disorders – Other, congestive heart failure. 
Pertuzumab AESI 
x 
Asymptomatic decline in LVEF requiring treatment or leading to discontinuation of 
monoclonal antibodies.  Report as Ejection fraction decreased. 
7.5.5 
Reporting to the Site IRB/REB 
Investigators will report serious adverse events to the local Institutional Review Board (IRB) or 
Research Ethics Board (REB) responsible for oversight of the patient according to institutional 
policy. 
7.5.6 
Secondary Malignancy 
A secondary malignancy is a cancer caused by treatment for a previous malignancy (e.g., 
treatment with investigational agent/intervention, radiation, or chemotherapy).  A secondary 
malignancy is not considered a metastasis of the initial neoplasm.  
All secondary malignancies that occur during or subsequent to treatment must be reported via 
CTEP-AERS within 10 days of learning of the secondary malignancy.  Three options are 
available to describe the event: 
x 
Leukemia secondary to oncology chemotherapy (e.g., acute myelocytic leukemia [AML])  
x 
Myelodysplastic syndrome (MDS) 
x 
Treatment-related secondary malignancy 
Any malignancy possibly related to cancer treatment (including AML/MDS) should also be 
reported via the BR004 Follow-up Folder in Medidata Rave.  Supporting documentation should 
be uploaded into the relevant form in the Follow-up folder in Medidata Rave using available 
upload fields within those forms.  Please upload each document into a different upload field, as 
any later uploads into a given field erases the document that exists there. 
7.5.7 
Second Malignancy 
A second malignancy is one unrelated to the treatment of a prior malignancy (and is NOT a 
metastasis from the initial malignancy).  Second malignancies require ONLY routine reporting 
within the BR004 Follow-up Folder in Medidata Rave (see Section 7.7). 
 
Use of this document is governed by the terms of use on the first page of this document.

 
NRG-BR004 
111 
NCI Version Date: August 15, 2022 
7.5.8 
Expedited Reporting of Pregnancy, Pregnancy Loss, and Death Neonatal  
Any pregnancy, pregnancy loss, or death neonatal occurring in a female patient or a male patient's 
partner from the time of consent to 5 months (150 days) after the last dose of 
atezolizumab/placebo or 7 months after the last dose of trastuzumab and pertuzumab must be 
reported via CTEP-AERS as a medically significant event.  Definitions and reporting instruction 
for these events are provided in the Cancer Therapy Evaluation Program's (CTEP) revised NCI 
guidelines for Investigators: Adverse Event Reporting Requirements (Section 5.5.6) located at the 
following CTEP website: 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguidelines.pdf).  
Upon learning of a pregnancy, pregnancy loss, or death neonatal that occurs during study or 
within 5 months (150 days) after the last dose of atezolizumab/placebo or 7 months after the 
last dose of trastuzumab and pertuzumab the investigator is required to: 
x 
Immediately discontinue study therapy. 
x 
Call the NRG Oncology Clinical Coordinating Department. 
x 
Within 5 working days of learning of the event, and as required by the NCI Guidelines for 
Investigators: Adverse Event Reporting Requirements (Section 5.5.6.): 
 
Create and submit a CTEP-AERS report; 
 
Complete the Pregnancy Information Form (located on the CTEP website at 
http://ctep.cancer.gov/protocolDevelopment/adverse_effects.htm); and 
 
Fax the completed Pregnancy Information Form with all available supporting 
documentation to CTEP at 301-897-7404. 
x 
The pregnancy outcome for patients on study should be reported via CTEP-AERS at the time 
the outcome becomes known, accompanied by the same Pregnancy Information Form used 
for the initial report. 
x 
Additional information on any pertuzumab and trastuzumab exposed pregnancy and infant 
will be requested by Genentech/Roche Drug Safety at specific time points (i.e., after having 
received the initial report, at the end of the second trimester, 2 weeks after the expected date 
of delivery, and at 3, 6, and 12 months of the infant’s life). 
x 
Pregnancy loss is defined in CTCAE v5.0 as "Death in utero."  Report pregnancy loss 
expeditiously as Grade 4 "pregnancy loss" under the Pregnancy, puerperium and perinatal 
conditions system organ class (SOC).  A pregnancy loss is not reported as a Grade 5 event. 
x 
For questions concerning pregnancy, contact the AE Reporting Nurse. 
7.6 
Routine Reporting of Adverse Events 
7.6.1 
Reporting Routine Adverse Events Through Medidata Rave 
x 
Reporting of routine adverse events is done through Medidata Rave (see Section 13.2). 
x 
All t grade 1 adverse events not reported via CTEP-AERS that occurred during study 
therapy must be reported on the BR004 Adverse Event forms through Medidata Rave. 
x 
Reporting of AEs is not required following documented disease progression or diagnosis of a 
second primary malignancy. 
x 
Supporting documentation for each AE reported on the BR004 Adverse Event forms through 
Medidata Rave must be maintained in the patient's research record.  When submission of 
supporting documentation to the NRG Oncology Statistics and Data Management Center is 
required, remove patient names and identifiers such as social security number, address, 
telephone number, etc., from reports and supporting documentation. 
 
Use of this document is governed by the terms of use on the first page of this document.

 
NRG-BR004 
112 
NCI Version Date: August 15, 2022 
7.6.2 
Schedule for Reporting Routine Adverse Events 
Adverse event reports are to be submitted through Medidata Rave, even if no AEs were 
experienced by the patient.   
x 
Submit the BR004 Adverse Event Report Form every 6 weeks after the start of study therapy 
through 2 years and 30 to 45 days after last dose of atezolizumab/placebo. 
x 
Submit the BR004 Adverse Event Report Form every 3 months in Years 3 through 5 and 
every 6 months in Years 6 through 10. 
7.6.3 
Reporting PRO-CTCAE 
Symptomatic Adverse Events reported by patients through PRO-CTCAE are not safety reporting 
and may be presented with other routine AE data. 
7.7 
Reporting Breast Cancer Progression and Second Primary Cancer 
Report disease progression and second primary cancer (a malignancy which is unrelated to the 
treatment of a prior malignancy and which is not a metastasis from the initial malignancy) within 
the BR004 Follow-up folder in Medidata Rave.  Supporting documentation should be uploaded 
into the relevant form in the Follow-up folder in Medidata Rave using available upload fields 
within those forms.  Please upload each document into a different upload field, as any later 
uploads into a given field erases the document that exists here.  (See Section 7.5.6 for reporting 
instructions for secondary malignancies.) 
 
Use of this document is governed by the terms of use on the first page of this document.

Use of this document is governed by the terms of use on the first page of this document.

 
NRG-BR004 
114 
NCI Version Date: August 15, 2022 
In addition, all investigators act as the Site-Protocol PI (investigator listed on the IRB approval), 
consenting/treating/drug shipment investigator in OPEN, or as the CI on the DTL must be 
rostered at the enrolling site with a participating organization.   
Additional information can is located on the CTEP website at 
https://ctep.cancer.gov/investigatorResources/default.htm.  mailto:For questions, please contact 
the RCR Help Desk by email at RCRHelpDesk@nih.gov. 
8.2 
Cancer Trials Support Unit Registration Procedures 
This study is supported by the NCI Cancer Trials Support Unit (CTSU). 
8.2.1 
IRB Approval 
For CTEP and Division of Cancer Prevention (DCP) studies open to the National Clinical Trials 
Network (NCTN) and NCI Community Oncology Research Program (NCORP) Research Bases 
after March 1, 2019, all U.S.-based sites must be members of the NCI Central Institutional 
Review Board (NCI CIRB).  In addition, U.S.-based sites must accept the NCI CIRB review to 
activate new studies at the site after March 1, 2019.  International sites should continue to submit 
Research Ethics Board (REB) approval to the CTSU Regulatory Office following country-
specific regulations.  
Sites participating with the NCI CIRB must submit the Study Specific Worksheet (SSW) for 
Local Context to the CIRB using IRBManager to indicate their intent to open the study locally.  
The NCI CIRB’s approval of the SSW is automatically communicated to the CTSU Regulatory 
Office, but sites are required to contact the CTSU Regulatory Office at 
CTSURegPref@ctsu.coccg.org to establish site preferences for applying NCI CIRB approvals 
across their Signatory Network.  Site preferences can be set at the network or protocol level.  
Questions about establishing site preferences can be addressed to the CTSU Regulatory Office by 
email or calling 1-888-651-CTSU (2878). 
Sites using their local IRB or REB, must submit their approval to the CTSU Regulatory Office 
using the Regulatory Submission Portal located in the Regulatory section of the CTSU website.  
Acceptable documentation of local IRB/REB approval includes: 
x 
Local IRB documentation; 
x 
IRB-signed CTSU IRB Certification Form; and/or 
x 
Protocol of Human Subjects Assurance Identification/IRB Certification/Declaration 
of Exemption Form. 
In addition, the Site-Protocol Principal Investigator (PI) (i.e., the investigator on the IRB/REB 
approval) must meet the following criteria in order for the processing of the IRB/REB approval 
record to be completed:  
x 
Holds an active CTEP status; 
x 
Active status at the site(s) on the IRB/REB approval (applies to US and Canadian sites only) 
on at least one participating organization’s roster; 
x 
If using NCI CIRB, active on the NCI CIRB roster under the applicable CIRB Signatory 
institution(s) record; 
x 
Includes the IRB number of the IRB providing approval in the Form FDA 1572 in the RCR 
profile;  
x 
Lists all sites on the IRB/REB approval as Practice Sites in the Form FDA 1572 in the RCR 
profile; and 
x 
Holds the appropriate CTEP registration type for the protocol. 
Use of this document is governed by the terms of use on the first page of this document.

 
NRG-BR004 
115 
NCI Version Date: August 15, 2022 
8.2.2 
Additional Requirements 
Additional site requirements to obtain an approved site registration status include: 
x 
An active Federal Wide Assurance (FWA) number; 
x 
An active roster affiliation with the Lead Protocol Organization (LPO) or a Participating 
Organization (PO);  
x 
An active roster affiliation with the NCI CIRB roster under at least one CIRB Signatory 
Institution (US sites only); and 
x 
Compliance with all protocol-specific requirements (PSRs). 
8.2.3 
Protocol Specific Requirements for NRG-BR004 Site Registration 
x 
Site Initiation Visit 
8.2.4 
Downloading Site Registration Documents 
Download the site registration forms from the protocol-specific page located on the CTSU 
members’ website.  Permission to view and download this protocol and its supporting documents 
is restricted to institutions and its associated investigators and staff on a participating roster.  To 
view/download stie registration forms: 
x 
Log in to the CTSU members' website (https://www.ctsu.org) using your CTEP-IAM 
username and password; 
x 
Click on Protocols in the upper left of the screen 
o Enter the protocol number in the search field at the top of the protocol tree, or 
o Click on the By Lead Organization folder to expand, then select NRG, and protocol 
number (NRG-BR004); 
x 
Click on Documents, Protocol Related Documents, and use the Document Type filter and 
select Site Registration and download and complete the forms provided.  (Note: For sites 
under the CIRB, IRB data will load automatically to the CTSU.) 
8.2.5 
Submitting Regulatory Documents 
Submit required forms and documents to the CTSU Regulatory Office using the Regulatory 
Submission Portal on the CTSU members’ website. 
To access the Regulatory Submission Portal log in to the CTSU members' website, go to the 
Regulatory section and select Regulatory Submission. 
Institutions with patients waiting that are unable to use the Regulatory Submission Portal should 
alert the CTSU Regulatory Office immediately by phone or email:  1-866-651-CTSU (2878), or 
CTSURegHelp@coccg.org in order to receive further instruction and support. 
8.2.6 
Delegation of Tasks Log (DTL) 
Each site must complete a protocol-specific Delegation of Tasks Log (DTL) using the DTL 
application in the Delegation Log section on the CTSU members’ website.  The Clinical 
Investigator (CI) is required to review and electronically sign the DTL prior to the site receiving 
an approved site registration status and enrolling patients to the study.  To maintain an approved 
site registration status, the CI must re-sign the DTL at least annually and when a new version of 
the DTL is released; and to activate new task assignments requiring CI sign-off.  Any individual 
at the enrolling site on a participating roster may initiate the site DTL.  Once the DTL is 
submitted for CI approval, only the designated DTL Administrators or the CI may update the 
DTL.  Instructions on completing the DTL are available in the Help Topics button in the DTL 
Use of this document is governed by the terms of use on the first page of this document.

 
NRG-BR004 
116 
NCI Version Date: August 15, 2022 
application and include a Master Task List, which describes DTL task assignments, CI signature, 
and CTEP registration requirements. 
In addition, the following task assignment restrictions apply to this protocol: 
The individual initiating the DTL for the site should upload the above listed training 
documentation when making the task assignment.  The designated reviewer will accept or reject 
the documentation.  A note regarding rejection of any training documents will display on the Site 
DTL Browser next to the task assignment.  The DTL cannot be submitted for CI sign-off until the 
minimum number of persons are assigned to the task and have met the training requirements.   
Canadian sites participating under Canadian Cancer Trials Group (CCTG), should complete the 
DTL in CCTG’s Ripple application when CCTG holds the Clinical Trials Agreement with Health 
Canada.  Ripple is integrated with the CTSU DTL application for this trial.  
8.2.7 
Checking Site's Registration Status 
Site registration status may be verified on the CTSU members' website.  
x 
Click on Regulatory at the top of the screen;  
x 
Click on Site Registration; and 
x 
Enter the site’s 5-character CTEP Institution Code and click on Go. 
o Additional filters are available to sort by Protocol, Registration Status, Protocol 
Status, and/or IRB Type. 
Note: The status shown only reflects institutional compliance with site registration requirements 
as outlined within the protocol.  It does not reflect compliance with protocol requirements for 
individuals participating on the protocol or the enrolling investigator's status with NCI or their 
affiliated networks. 
8.3 
Patient Enrollment 
Patient registration can occur only after evaluation for eligibility is complete, eligibility criteria 
have been met, and the study site is listed as ‘approved’ in the CTSU RSS.  Patients must have 
signed and dated all applicable consents and authorization forms. 
8.4 
Oncology Patient Enrollment Network (OPEN) 
The Oncology Patient Enrollment Network (OPEN) is a web-based registration system available 
on a 24/7 basis.  OPEN is integrated with CTSU Regulatory and roster data and with the LPOs 
registration/randomization systems or Theradex Interactive Web Response System (IWRS) for 
retrieval of patient registration/randomization assignment.  OPEN will populate the patient 
enrollment data in NCI's clinical data management system, Medidata Rave.   
Requirements for OPEN access: 
x 
A valid CTEP-IAM account; 
x 
To perform enrollments or to request slot reservations: Must be on an LPO roster, ETCTN 
corresponding roster, or participating organization roster with the role of Registrar.  
Registrars must hold a minimum of an Associate Plus (AP) registration type;  
x 
If a Delegation of Tasks Log (DTL) is required for the study, the registrars must hold the 
OPEN Registrar task on the DTL for the site; and 
x 
Have an approved site registration for the protocol prior to patient enrollment. 
Use of this document is governed by the terms of use on the first page of this document.

 
NRG-BR004 
117 
NCI Version Date: August 15, 2022 
To assign an Investigator (IVR) or Non-Physician Investigator (NPIVR) as the treating, crediting, 
consenting, drug shipment (IVR only), or receiving investigator for a patient transfer in OPEN, 
the IVR or NPIVR must list the IRB number used on the site’s IRB approval on their Form FDA 
1572 in RCR.  If a DTL is required for the study, the IVR or NPIVR must be assigned the 
appropriate OPEN-related tasks on the DTL. 
Prior to accessing OPEN, site staff should verify the following: 
x 
Patient has met all eligibility criteria within the protocol stated timeframes; and 
x 
All patients have signed an appropriate consent form and Health Insurance Portability and 
Accountability (HIPAA) authorization form (if applicable). 
Note: The OPEN system will provide the site with a printable confirmation of registration and 
treatment information.  You may print this confirmation for your records. 
Access OPEN at https://open.ctsu.org or from the OPEN link on the CTSU members' website.  
Further instructional information is in the OPEN section of the CTSU website at 
https://www.ctsu.org or https://open.ctsu.org.  For any additional questions, contact the CTSU 
Help Desk at 1-888-823-5923 or ctsucontact@westat.com. 
8.5 
ePRO Registration Process 
8.5.1 
Medidata Patient Cloud ePRO 
This study includes the use of Medidata Patient Cloud ePRO (electronic patient-reported 
outcomes).  The ePRO application allows patients to report clinical trial information (patient 
reported outcomes (PROs)) directly from their mobile devices into the Medidata Clinical Cloud.  
In this document ePRO application refers to the application accessed by the site via iMedidata 
and Rave, and ePRO mobile app refers to the app accessed by the patient on a mobile device.  
After the patient is registered to the trial via OPEN, and the patient is willing to participate in 
electronic data collection, the site staff will complete a registration for the patient to the ePRO 
application through iMedidata.  Sites are not permitted to delete the ePRO component from the 
protocol or from the informed consent form.  Site staff must complete the required eLearning 
(assigned in iMedidata) for the ePRO application before registering a patient.  Information about 
the training is in Appendix B.  The registration to the ePRO application will create a unique 
patient registration code that the site staff will provide to the patient.  The patient (with assistance 
from the site staff) should be instructed to download the appropriate ePRO mobile app onto 
his/her own device (IOS, Android, phone, or tablet) and use the unique patient registration code 
to create an account.  Once the patient's account is set up, the patient will be able to complete the 
submission of patient-reported outcomes electronically for the trial.  
There are multiple versions of the ePRO mobile app available.  Ensure that the correct version of 
the ePRO mobile app is downloaded by the patient by verifying the correct version per the 
protocol requirements.  Note only one version of the app is active per protocol and this protocol is 
using Patient Cloud.   
 
For sites providing a shared institutional device for use by multiple patients on site:  
x 
The site staff should assist the patient with access and registration to the ePRO 
application and access to the ePRO mobile app, and the patient can then complete the 
Use of this document is governed by the terms of use on the first page of this document.

 
NRG-BR004 
118 
NCI Version Date: August 15, 2022 
electronic data submission independently.  Site staff may need to assist patients with 
logging on to the device at each visit. 
8.5.2 
CRA Patient Registration Instructions for ePRO 
Site staff must complete the required ePRO online training (assigned in iMedidata) for studies 
using the ePRO application before registering a patient.  Reference materials for the Patient 
Cloud (current) app can be found at the links below; the landing page contains patient registration 
information as well as links to additional resources on the left side of the screen:  Patient Cloud 
Patient Registration Instructions.   
The subject registration process starts in iMedidata.  To register a patient: 
i. 
 Select the Patient Cloud Registration link for your study. 
ii. 
From the patient management app, select your STUDY and SITE from the drop down 
menus and click Launch. 
iii. 
Register your first patient.  Create a subject ID and select a Country / Language from 
the drop down (required data fields).  The subject initials are optional but are helpful in 
identifying which subject ID maps with which activation code.  When finished, click 
Add. 
iv. 
The subject will be added and will include the date the patient was added, the subject ID, 
subject initials (if included), and a unique auto-generated activation code.  The activation 
code is unique for each patient and linked to the subject ID, it is not interchangeable.  In 
addition, there is a status section, which indicates if the patient has registered.  When the 
patient has registered, the status will change from "invited" to "registered". 
8.6 
Reimbursement 
To receive site reimbursement for biospecimen submissions, completion dates must be entered in 
the OPEN Funding screen post registration.  Please refer to the NRG-BR004 specific funding 
page on the CTSU members' website for additional information.  Timely entry of completion 
dates is recommended as this will trigger site reimbursement.  The collection of specimens for 
exploratory endpoints is not funded by CTEP and will be reimbursed by the sponsor with  
non-CTEP funding. 
8.7 
Investigator-Initiated Discontinuation of Study Therapy 
In addition to the conditions outlined in the protocol, the investigator may require a patient to 
discontinue study therapy if one of the following occurs: 
x 
the patient develops a serious side effect that cannot be tolerated or that cannot be controlled 
with other medications, 
x 
the patient's health gets worse, 
x 
the patient is unable to meet the study requirements, or 
x 
new information about the study therapy or other treatments for breast cancer becomes 
available. 
If study therapy is stopped, study data, other materials, and the tumor samples (at the time of 
disease progression) should be submitted according to the study schedule unless the patient 
withdraws from the study (see Section 8.9). 
Use of this document is governed by the terms of use on the first page of this document.

 
NRG-BR004 
119 
NCI Version Date: August 15, 2022 
8.8 
Patient-Initiated Discontinuation of Study Therapy 
Even after a patient agrees to take part in this study, the patient may stop study therapy or 
withdraw from the study at any time.  If study therapy is stopped but the patient still allows the 
investigator to submit information, study data, other materials, and the tumor samples (at the time 
of disease progression) should be submitted according to the study schedule. 
8.9 
Patient-Initiated Consent Withdrawal from the Study 
If a patient chooses to have no further interaction regarding the study (i.e., allow no future follow-
up data to be submitted to NRG Oncology), the consent withdrawal form is to be completed via 
the Add-Event function in Medidata Rave. 
 
Use of this document is governed by the terms of use on the first page of this document.

 
NRG-BR004 
120 
NCI Version Date: August 15, 2022 
9.0 
DRUG INFORMATION 
9.1 
Atezolizumab (IND #
 NSC #783608) 
The current version of the Investigator Brochure (IB) will be accessible to site investigators and 
research staff through the PMB Online Agent Order Processing (OAOP) application.  Access to 
OAOP requires the establishment of a CTEP Identity and Access Management (IAM) account 
and the maintenance of an "active" account status and a "current" password.  Questions about IB 
access may be directed to the PMB IB Coordinator. 
9.1.1 
Atezolizumab/Placebo 
Atezolizumab/placebo used for this study is considered investigational in the U.S. and by Health 
Canada to be investigational/used outside the authorized indication in Canada. 
x 
Other Names: Tecentriq, MPDL3280A 
x 
Classification: monoclonal antibody 
x 
Molecular Weight: 150 KD 
x 
Mode of Action: anti-PD-L1 
x 
Description: Atezolizumab is a humanized IgG1 monoclonal antibody consisting of two 
heavy chains (448 amino acids) and two light chains (214 amino acids).  Atezolizumab 
targets human PD-L1 and inhibits its interaction with its receptor PD-1.  Atezolizumab also 
blocks the binding of PD-L1 to B7.1, an interaction that is reported to provide additional 
inhibitory signals to T cells (Butte 2007).  (Note: The placebo will be identical in 
appearance to atezolizumab and comprise the same excipients but without atezolizumab 
drug product.) 
x 
How Supplied: Atezolizumab/placebo is provided by Genentech/F.Hoffmann-La Roche LTD 
and distributed by the Pharmaceutical Management Branch, CTEP, NCI.  The agent is 
supplied in a single-use, 20-mL glass vial as a colorless-to-slightly-yellow, sterile, 
preservative-free clear liquid solution intended for IV administration.  Atezolizumab is 
formulated as 60 mg/mL atezolizumab in 20 mM histidine acetate, 120 mM sucrose, 0.04% 
polysorbate 20, at a pH of 5.8.  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. 
x 
Preparation: The prescribed dose of atezolizumab/placebo should be diluted in 250 mL 0.9% 
NaCl and infused through a 0.2 micrometer in-line filter.  The IV bag may be constructed of 
PVC or PO; the IV infusion line may be constructed of PVC or PE; and the 0.2 micrometer 
in-line filter may be constructed of PES.  The prepared solution may be stored at 2°C-25°C 
for up to 8 hours. 
x 
Storage: 2°C-8°C (36°F-46°F) Vial contents should not be frozen or shaken and should be 
protected from direct sunlight. 
If a storage temperature excursion is identified, promptly return atezolizumab/placebo to 2°C-
8°C (36°F-46°F) and quarantine the supplies.  Provide a detailed report of the excursion 
(including documentation of temperature monitoring and duration of the excursion) to 
PMBAfterHours@mail.nih.gov for determination of suitability. 
 
Use of this document is governed by the terms of use on the first page of this document.

 
NRG-BR004 
121 
NCI Version Date: August 15, 2022 
x 
Stability: Stability studies are ongoing. 
CAUTION: No preservative is used in atezolizumab/placebo; therefore, the vial is intended 
for single use only.  Discard any unused portion of drug remaining in a vial. 
x 
Route of Administration: IV infusion  
x 
Method of Administration: Atezolizumab/placebo is administered as an intravenous infusion 
over 60 minutes.  If the first infusion is tolerated, all subsequent infusions may be delivered 
over 30 minutes.  Do not administer atezolizumab/placebo as an intravenous push or bolus.  
No premedication is indicated for administration of Cycle 1 of atezolizumab/placebo.  
Patients who experience an infusion related reaction with Cycle 1 of atezolizumab/placebo 
may receive premedication with antihistamines or antipyretics/analgesics (e.g. 
acetaminophen) for subsequent infusions. 
x 
Potential Drug Interactions: Cytochrome P450 enzymes as well as 
conjugation/glucuronidation reactions are not involved in the metabolism of atezolizumab.  
No drug interaction studies for atezolizumab have been conducted or are planned.  There are 
no known interactions with other medicinal products or other form of interactions. 
x 
Patient Care Implications: Male patients and female patients of childbearing potential should 
utilize contraception and take active measures to avoid pregnancy while undergoing 
atezolizumab/placebo treatment and for at least 5 months (150 days) after the last dose of 
atezolizumab/placebo.  
Refer to Section 6.4 for information on evaluation and management of potential immune-
mediated adverse events. 
9.1.2 
Procurement of Atezolizumab/Placebo and Trastuzumab 
x 
Atezolizumab/placebo and open-label trastuzumab will be supplied free of charge by 
Genentech, a Member of the Roche Group/F.Hoffmann-La Roche LTD, and will be 
distributed by the Pharmaceutical Management Branch (PMB), Cancer Therapy Evaluation 
Program (CTEP), Division of Cancer Treatment and Diagnosis (DCTD), National Cancer 
Institute (NCI).  (NOTE: Canadian supplies of trastuzumab will be obtained from 
commercial sources.) 
x 
The placebo will be centrally supplied and distributed by Genentech, a Member of the Roche 
Group/F.Hoffmann-La Roche LTD and will be identical in appearance to atezolizumab and 
comprise the same excipients but without atezolizumab drug product. 
x 
NCI-supplied agents may be requested by eligible participating Investigators (or their 
authorized designee) at each participating institution.  The CTEP-assigned protocol number 
must be used for ordering all CTEP-supplied investigational agents.  The eligible 
participating investigator at each participating institution must be registered with CTEP, 
DCTD through an annual submission of FDA Form 1572 (Statement of Investigator), NCI 
Biosketch, Agent Shipment Form, and Financial Disclosure Form (FDF).  If there are several 
participating investigators at one institution, CTEP-supplied investigational agents for the 
study should be ordered under the name of one lead investigator at that institution. 
x 
No starter supplies will be available for this study.  Patient-specific clinical supplies will be 
sent to the registering investigator at the time of randomization and should arrive within 
approximately 5 to 7 days.  This randomization will be performed by the NRG Statistics and 
Data Management Center (SDMC).  The assigned NRG patient ID number must be recorded 
by the registering institution for proper agent dispersion.  Once a patient has been registered, 
Use of this document is governed by the terms of use on the first page of this document.

 
NRG-BR004 
122 
NCI Version Date: August 15, 2022 
the NRG SDMC will electronically transmit a clinical drug request for that patient to the 
PMB.  This request will be entered and transmitted by the NRG SDMC the day the patient is 
registered and will be processed by the PMB the next business day and shipped the following 
business day.  Shipments within the United States will be sent by FedEx and shipments to 
Canada will be sent by FedEx International (generally one to two-day delivery).  Thus, if a 
patient is registered on Monday, NRG would enter a clinical drug request for that patient on 
Monday and PMB would process that request on Tuesday and ship the drug on Wednesday.  
Sites could expect to receive their order approximately Thursday or Friday.  Shipments to 
United States sites can be expedited (i.e., receipt on Thursday in example above) by the 
provision of an express courier account name and number to the NRG SDMC at the time the 
patient is randomized. 
The initial request will be for 3 vials (a 9 week supply at a dose of 1200 mg or placebo) of 
atezolizumab 1200 mg or matching Placebo and 13 vials of trastuzumab (sufficient for the 
loading dose and two additional doses).  After 6 weeks (three weeks before needed), sites 
may reorder an additional 3 vials (a 9 week supply at a dose of 1200 mg or placebo) of 
atezolizumab 1200 mg or matching Placebo and 12 vials of trastuzumab (a 9 week supply) 
using the PMB Online Agent Order Processing (OAOP) application 
(https://ctepcore.nci.nih.gov/OAOP/).  Active CTEP -registered investigators and 
investigator-designated shipping designees and ordering designees can submit agent requests 
through the PMB Online Agent Order Processing (OAOP) application.  Access to OAOP 
requires the establishment of a CTEP Identity and Access Management (IAM) account 
(https://ctepcore.nci.nih.gov/iam/index.jsp) and the maintenance of an “active” account status 
and a “current” password.  The assigned patient ID number (e.g., "999999") and the patient 
initials (e.g., "L, FM") must be entered in the "Patient or Special Code" field.  A separate 
order is required for each patient ID number (e.g., "999999") being ordered.  All drug orders 
will be shipped directly to the physician responsible for treating the patient. 
Each blinded or open-label, patient-specific box will be labeled with:  
x 
The protocol number (i.e., NRG-BR004) 
x 
The box number (i.e., “Box 1 of 2”, “Box 2 of 2”, etc.) 
x 
The number of vials (i.e., ”4 vials”) 
x 
The patient ID number (e.g., "999999") 
x 
The patient initials (i.e., Last initial, First initial, Middle initial [e.g., “L, FM”]) 
x 
The agent identification (i.e., “Atezolizumab 1200 mg or Placebo” or "Trastuzumab 
150 mg") 
x 
A blank line for the pharmacist to enter the patient’s name 
x 
Storage instructions (i.e., “Store in refrigerator [2 – 8°C].  Do not freeze.  Do not 
shake.”) 
x 
Emergency contact instructions 
x 
A Julian date 
The Julian date indicates the day the vials were labeled and shipped and is composed of the 
last two digits of the calendar year (e.g., 2017 = 17, 2018 = 18) and a day count (e.g., January 
1 = 001, December 31 = 365).  For example, a box labeled and shipped on January 1, 2018 
would have a Julian date of ‘18001’ and a box labeled and shipped on December 31, 2018 
would have a Julian date of ‘18365’.  The Julian date will be used by PMB for recalls.  When 
a lot expires, PMB will determine the last date the expired lot was shipped and will recall all 
vials (i.e., both atezolizumab and Placebo) shipped on or before that date thus eliminating any 
Use of this document is governed by the terms of use on the first page of this document.

 
NRG-BR004 
123 
NCI Version Date: August 15, 2022 
chance of breaking the blind.  The Julian Date – Order number (e.g., 2017352-0003) from the 
patient-specific label must be used as the Lot number on the NCI DARF. 
Questions about drug orders, transfers, returns, or accountability should be addressed to the 
PMB by calling (240) 276-6575 Monday through Friday between 8:30am and 4:30pm 
Eastern Time.  You may also contact the PMB via e-mail at PMBAfterHours@mail.nih.gov. 
9.1.3 
Useful Links and Contacts 
x 
CTEP Forms, Templates, Documents: http://ctep.cancer.gov/forms/ 
x 
NCI CTEP Registration (RCR): RCRHelpDesk@nih.gov 
x 
PMB policies and guidelines: http://ctep.cancer.gov/branches/pmb/agent_management.htm  
 
Refer to the Policy and Guidelines for Investigational Agent Ordering for order 
processing time and conditions.  Normal order processing time is two business days.  An 
express courier account number must be provided for next-day delivery.  International 
orders require additional processing and shipment transit time and are not available for 
next day delivery. 
x 
PMB Online Agent Order Processing (OAOP) application: 
https://ctepcore.nci.nih.gov/OAOP/  
x 
CTEP Identity and Access Management (IAM) account: https://ctepcore.nci.nih.gov/iam 
x 
CTEP Associate Registration and IAM account help: ctepreghelp@ctep.nci.nih.gov  
x 
IB Coordinator: IBCoordinator@mail.nih.gov 
x 
PMB email: PMBAfterHours@mail.nih.gov 
PMB phone and hours of service: (240) 276-6575 Monday through Friday between 8:30 am 
and 4:30 pm (ET). 
9.1.4 
Transfer of Atezolizumab/Placebo or Trastuzumab 
Patient-specific agent supplies MAY NOT be transferred from one patient to another patient or 
from one protocol to another protocol.  All other transfers (e.g., a patient moves from one 
participating clinical site to another participating clinical site, the principal investigator at a given 
clinical site changes) must be approved in advance by the PMB.  To obtain an approval for 
transfer, investigators should complete and submit to PMBAfterhours@mail.nih.gov a Transfer 
Investigational Agent Form available on the CTEP home page (http://ctep.cancer.gov).  The 
patient ID number (e.g., "99999"') and the patient initials (e.g., "L, FM") should be entered in the 
"Received on NCI Protocol No." and the "Transferred to NCI Protocol No." fields in addition to 
the protocol number (i.e., "NRG-BR004"). 
9.1.5 
Return of Atezolizumab/Placebo or Trastuzumab 
When it is necessary to return unused study drug (e.g., sealed vials remaining when a patient 
permanently discontinues protocol treatment, expired vials recalled by the PMB), investigators 
should return the study drug to the PMB using the NCI Return Drug List available on the CTEP 
home page (http://ctep.cancer.gov).  The patient ID number (e.g., "99999") and the patient initials 
(e.g., "L, FM") should be entered in the "Lot Number" field. 
 
Use of this document is governed by the terms of use on the first page of this document.

 
NRG-BR004 
124 
NCI Version Date: August 15, 2022 
9.1.6 
Drug Accountability 
The investigator, or a responsible party designated by the investigator, must maintain a careful 
record of the receipt, disposition, and return of all drugs received from the PMB using the NCI 
Investigational Agent Accountability Record available on the CTEP home page 
(http://ctep.cancer.gov).  A separate NCI Investigational Agent Accountability Record must be 
maintained for each patient ID number (e.g., "99999") on this protocol.  NOTE: The Julian Date – 
Order number combination found in the upper right-hand portion of the patient-specific label 
must be used as the Lot Number.  This number will be used in the event of a stock recovery or 
recall of the investigational agent.  (NOTE: U.S. sites must maintain a Drug Accountability 
Form (DARF) for the patient specific atezolizumab/placebo and trastuzumab.  Canadian 
sites must maintain a DARF for the patient specific atezolizumab/placebo but are not 
required to maintain a DARF for trastuzumab, which is obtained from commercial 
sources.) 
9.2 
Paclitaxel (NSC #673089) 
9.2.1 
Availability/Supply 
Paclitaxel is obtained by the investigator from commercial supply. 
9.2.2 
Product Description 
Refer to the paclitaxel package insert or monograph. 
9.2.3 
Preparation 
Refer to the current FDA-approved package inserts or current Health Canada-approved product 
monographs provided with paclitaxel and the site-specific pharmacy for standard drug 
preparation instructions, handling, and storage.  Canadian-specific instructions for labeling, 
storage, and documentation of receipt, disposition, and return or destruction will be provided 
separately to Canadian investigators. 
9.2.4 
Route of Administration 
Please see Section 5.1 (Table 3) for administration instructions.   
9.2.5 
Adverse Events 
Please refer to the current FDA-approved package inserts and current Health Canada-approved 
product monographs provided with paclitaxel and the site-specific pharmacy for toxicity 
information and Section 7.3. 
9.3 
Docetaxel (NSC #628503) 
9.3.1 
Availability/Supply 
Docetaxel is obtained by the investigator from commercial supply. 
9.3.2 Product Description 
Refer to the docetaxel package insert or monograph. 
 
Use of this document is governed by the terms of use on the first page of this document.

 
NRG-BR004 
125 
NCI Version Date: August 15, 2022 
9.3.3 Preparation 
Refer to the current FDA-approved package inserts or current Health Canada-approved product 
monographs provided with docetaxel and the site-specific pharmacy for standard drug preparation 
instructions, handling, and storage.  Canadian-specific instructions for labeling, storage, and 
documentation of receipt, disposition, and return or destruction will be provided separately to 
Canadian investigators. 
9.3.4 Route of Administration 
Please see Section 5.1 (Table 3) for administration instructions. 
9.3.5 Adverse Events 
Please refer to the current FDA-approved package inserts and current Health Canada-approved 
product monographs provided with docetaxel and the site-specific pharmacy for toxicity 
information and Section 7.3. 
9.4 
Pertuzumab (NSC #740102) 
9.4.1 
Availability/Supply 
Pertuzumab is obtained by the investigator from commercial supply. 
9.4.2 
Product Description 
Refer to the pertuzumab package insert or monograph. 
9.4.3 
Preparation 
Refer to the current FDA-approved package inserts or current Health Canada-approved product 
monographs provided with pertuzumab and the site-specific pharmacy for standard drug 
preparation instructions, handling, and storage.  Canadian-specific instructions for labeling, 
storage, and documentation of receipt, disposition, and return or destruction will be provided 
separately to Canadian investigators. 
9.4.4 
Route of Administration 
Please see Section 5.1 (Table 3) for administration instructions.   
9.4.5 
Adverse Events 
Please refer to the current FDA-approved package inserts and current Health Canada-approved 
product monographs provided with pertuzumab and the site-specific pharmacy for toxicity 
information and Section 7.3. 
9.5 
Trastuzumab (NSC #688097) 
9.5.1 
Availability/Supply 
US supply (Please see Section 9.1.2 for procurement information.): 
Genentech supplies and the Pharmaceutical Management Branch, CTEP, NCI, distributes 
trastuzumab as a lyophilized sterile powder, under vacuum.  Each carton contains one vial of 150 
mg trastuzumab as a lyophilized preparation for parenteral administration.  The commercially-
Use of this document is governed by the terms of use on the first page of this document.

 
NRG-BR004 
126 
NCI Version Date: August 15, 2022 
labeled 150 mg vials are formulated in histidine/histidine-HCl monohydrate, Į,Į-trehalose 
dihydrate, and polysorbate 20.  NOTE: The 150 mg vials are not multi-use vials.   
Canadian Supply: 
Canadian institutions will obtain trastuzumab from commercial sources.  Commercial 
labeling, preparation and administration guidelines should be followed. 
9.5.2 
Product Description 
Trastuzumab is a humanized IgG1 kappa monoclonal antibody that selectively binds with high 
affinity to the extracellular domain of the human epidermal growth factor receptor 2 protein, 
HER2.  Trastuzumab is produced by recombinant DNA technology in a mammalian cell (Chinese 
Hamster Ovary) culture containing the antibiotic gentamicin.  Gentamicin is not detectable in the 
final product. 
9.5.3 
Preparation 
Reconstitute each 150 mg vial of trastuzumab with 7.4 mL of Sterile Water for Injection (SWFI), 
USP to yield a solution containing approximately 21 mg/mL trastuzumab at a pH of 
approximately 6.0.  Use of other reconstitution solvents should be avoided.  A volume overfill 
ensures that the labeled dose of 150 mg can be withdrawn from each vial. 
x 
150 mg vials 
 
 Using a sterile syringe, slowly inject the 7.4 mL of Sterile Water for Injection (SWFI), 
USP into the vial containing the lyophilized cake of trastuzumab.  The stream of diluent 
should be directed into the lyophilized cake. 
 
Swirl the vial gently to aid reconstitution.  DO NOT SHAKE. 
 
Slight foaming of the product may be present upon reconstitution.  Allow the vial to stand 
undisturbed for approximately 5 minutes. 
 
Parenteral drug products should be inspected visually for particulate matter and 
discoloration prior to administration, whenever solution and container permit.  Inspect 
visually for particulates and discoloration.  The solution should be free of visible 
particulates, clear to slightly opalescent and colorless to pale yellow. 
 
Single-use vial should be used immediately after reconstitution. 
Dilution 
x 
Determine the dose (mg) of trastuzumab.  Calculate the volume of the 21 mg/mL 
reconstituted trastuzumab solution needed, withdraw this amount from the vial and add it to 
an infusion bag containing 250 mL of 0.9% Sodium Chloride Injection, USP.  DO NOT USE 
DEXTROSE (5%) SOLUTION. 
x 
Gently invert the bag to mix the solution. 
9.5.4 
Route of Administration 
Trastuzumab is given by slow intravenous infusion only.  The initial dose is 8 mg/kg as a loading 
dose, followed by every three-week doses at 6 mg/kg.  The loading dose is infused over  
90 minutes (+/- 10 minutes).  If this is well tolerated, subsequent infusions may be given over 30-
60 minutes.  Please see Section 5.1 (Table 3) for detailed administration instructions. 
 
 
Use of this document is governed by the terms of use on the first page of this document.

 
NRG-BR004 
127 
NCI Version Date: August 15, 2022 
9.5.5 
Storage 
Store at 2í8°C (36í46°F) prior to reconstitution.  
9.5.6 
Stability 
Do not use beyond the expiration date stamped on the product label. 
9.5.7 
Adverse Events 
Please refer to the current FDA-approved package inserts and current Health Canada-approved 
product monographs provided with trastuzumab and the site-specific pharmacy for toxicity 
information and Section 7.3. 
9.6 
Unblinding 
When unblinding is required, local investigators must contact the NRG Oncology SDMC at  
412-624-2666 and state that they wish to unblind a patient's study drug assignment.  The same 
procedure applies to 24-hour emergency unblinding.  A data file is maintained for the study and 
can be accessed by a limited number of designees within the NRG Oncology SDMC who serve 
the study in an administrative, nonclinical capacity.  The NRG Oncology SDMC personnel will 
require the protocol number, the patient ID number, the patient's initials (e.g., "LFM"), and the 
reason for the unblinding request in order to unblind the study drug assignment.  After the 
confirmation of the indication for unblinding is obtained, the investigator will be notified 
immediately of the patient's treatment assignment.  A computer record will be created to identify 
the patient as having been unblinded.  The institution is responsible for providing continued 
follow-up (for patients whose treatment assignment has been unblinded) on the same schedule as 
indicated in the study protocol for patients who have not been unblinded, unless otherwise 
specified (see Table 2). 
 
 
Use of this document is governed by the terms of use on the first page of this document.

 
NRG-BR004 
128 
NCI Version Date: August 15, 2022 
10.0 
BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES 
The NRG-BR004 study was permanently closed to accrual on May 20, 2022.  Modified scheduled 
status updates, as outlined on Table 2A, will be completed for patients enrolled prior to study 
accrual closure.  Biospecimen submissions are no longer required. 
10.1 
Overview of Tumor Specimen Submissions 
Tumor sample submission at study entry is a protocol requirement and, therefore, mandatory for 
participation in the study (see Table 34 for specific requirements).  NOTE: A "Notice of HER2 
Eligibility" must appear in Medidata Rave to confirm testing for HER2, ER/PgR, and PD-L1 has 
been completed before a patient can be randomized. 
By signing the BR004 consent form, the patient agrees to a tumor sample submission.  
Submission of optional tumor tissue and blood specimens is only required for patients who 
agree to submission of optional tumor tissue and blood in the BR004 consent form. 
Table 34.  Mandatory and optional sample requirements 
Specimen Type 
Collection 
Time Points 
Submission 
Information  
Shipping 
Mandatory 
x 
De novo (newly diagnosed)a,b,c 
 
3-5 unstained positively charged 
slides (4 microns) from the 
metastatic disease, breast primary, 
or involved regional lymph nodes 
submitted for central PD-L1 
testing 
 
8 unstained positively charged 
slides (3-5 microns) from the 
metastatic disease, breast primary, 
or involved regional lymph nodes 
for central confirmation of HER2 
and ER/PgR status 
x 
Recurrentb,c  
 
3-5 unstained positively charged 
slides (4 microns) from biopsy 
done to confirm 
recurrent/metastatic cancer 
submitted for central  
PD-L1 testing 
 
8 unstained positively charged 
slides (3-5 microns) from biopsy 
done to confirm 
recurrent/metastatic cancer 
submitted for central confirmation 
of HER2 and ER/PgR status 
Baseline 
(at study entry) 
Refer to the 
CTSU Member 
website 
(www.ctsu.org) 
for the BR004 
Pathology, 
Correlative 
Science, and 
Imaging 
Submission 
Instructions for 
detailed 
submission 
instructions. 
Shipment of 3-5 unstained 
positively charged slides: 
HistoGeneX  
Attn. Sample Reception 
Team - P1064 
1331 W 75th Street 
Suite 401  
Naperville, IL 60540  
USA 
 
 
Shipment of 8 unstained 
positively charged slides 
for central confirmation of 
HER2 and ER/PgR status: 
Magee-Womens Hospital of 
UPMC, Department of 
Pathology 
300 Halket Street  
4th Floor, Room 4139 
Pittsburgh, PA 15213 
Attn: NRG-BR004 
Table continued on next page. 
 
Use of this document is governed by the terms of use on the first page of this document.

 
NRG-BR004 
129 
NCI Version Date: August 15, 2022 
Table 34.  Mandatory and optional sample requirements (continued) 
Specimen Type 
Collection Time 
Points 
Submission 
Information  
Shipping 
Optional 
x 
De novo (newly diagnosed)a 
 
10-15 unstained positively 
charged slides (3-5 microns) 
from the metastatic disease, 
breast primary, or involved 
regional lymph nodes  
x 
Recurrent  
 
10-15 unstained positively 
charged slides (3-5 microns) 
from biopsy done to confirm 
recurrent/metastatic cancer 
Baseline 
(Submission of 
unstained slides 
within 45 days 
following 
randomization) 
Refer to the 
CTSU Member 
website 
(www.ctsu.org) 
for the BR004 
Pathology, 
Correlative 
Science, and 
Imaging 
Submission 
Instructions for 
detailed 
submission 
instructions. 
NSABP Division of 
Pathology 
NRG Oncology 
Biospecimen Bank-Pittsburgh 
1307 Federal Street 
Suite 303 
Pittsburgh, PA 15212 
10-15 unstained positively charged 
slides (3-5 microns)d 
Tumor 
Progression 
Optional 
Plasma collected in Streck Cell-Free 
DNA BCT tube (2 tubes) 
x Baseline 
x Prior to Weeks 
10, 19, and 28 
x At 9, 12, 18, 
and 24 months 
x Every 6 
months Year 3 
through Year 5 
(in absence of 
progression) 
x Tumor 
progression 
Baylor College of Medicine  
NRG Oncology Serum Bank 
Room 330C 
One Baylor Plaza 
Houston, TX 77030 
a 
Slides from the diagnostic biopsy performed to determine metastatic disease must be submitted; 
however, if a biopsy of the metastatic disease may have excessive risk to the patient as determined 
by the investigator, slides from the breast primary or involved regional lymph nodes may be 
submitted. 
b If there is insufficient material for central confirmation of HER2 and for PD-L1 testing, a research 
biopsy may be done to obtain tumor tissue.  It is strongly recommended that the research biopsy be 
done before therapy is started at study entry. 
c 
The priority for testing if there is limited tumor tissue available: 
1.) Four unstained positively charged slides for central confirmation of HER2.  Note: Central 
confirmation of HER2 is mandatory for eligibility. 
2.) Three to five unstained positively charged slides for central testing of PD-L1 
3.) Two unstained positively charged slides for central confirmation of ER and PgR.   
d If a biopsy was done at the time of tumor progression, submission of slides is required for patients 
who have agreed to the optional tumor sample submission in the BR004 consent form. 
Use of this document is governed by the terms of use on the first page of this document.

 
NRG-BR004 
130 
NCI Version Date: August 15, 2022 
10.2 
Specimen Submission Information 
Refer to the BR004 Pathology, Correlative Science, and Imaging Submission Instructions in the 
Members' Area of the CTSU website for details regarding submission of specimens. 
x 
If there is insufficient material available for the mandatory specimen submissions as outlined 
on Table 34, the prioritization for specimen submissions is: 
 
Four unstained positively charged slides (3-5 microns) from the locally recurrent or 
metastatic disease are to be submitted to Magee-Womens Hospital of UPMC, Department 
of Pathology for central confirmation of HER2. 
 
Three to five unstained positively charged slides (4 microns) from the locally recurrent or 
metastatic disease are to be submitted to HistoGeneX for central PD-L1 testing. 
 
Two unstained positively charged slides (3-5 microns) from the locally recurrent or 
metastatic disease are to be submitted to Magee-Womens Hospital of UPMC, Department 
of Pathology for central confirmation of ER/PgR.  If sufficient material for central 
confirmation of ER and PgR is unavailable, local testing results for ER and PgR may be 
used for eligibility. 
x 
For patients who agree to the optional submissions of tissue and blood:  
 
Unused slides that were sent for central confirmation of HER2 and ER/PgR at Magee-
Womens Hospital of UPMC, Department of Pathology will be sent to the NRG Oncology 
Biospecimen Bank – Pittsburgh upon notification from the NRG Oncology SDMC that a 
patient has agreed to the optional submission of tumor tissue.  For patients who did not 
agree to the optional submission of tissue, the unused slides will be retained and stored by 
the Magee-Womens Hospital of UPMC, Department of Pathology. 
 
Two Streck Cell-Free DNA BCT tubes drawn at the time points listed on Table 34. 
 
Ten to fifteen unstained positively charged slides (3-5 microns) from the locally recurrent 
or metastatic disease and from tumor progression (if biopsy was performed) are to be 
submitted to the NRG Oncology Biospecimen Bank – Pittsburgh. 
10.3 
Integral Marker Testing  
10.3.1 HER2 Testing 
The HER2 IHC testing will be performed using the FDA cleared assay Ventana anti-HER-2/neu 
(4B5) Rabbit Monoclonal Primary Antibody according to the package insert without 
modification. 
The reflex HER2 FISH testing, when required, will be performed using the FDA cleared DAKO 
assay according to the package insert without modification. 
10.3.2 ER/PgR Testing 
Estrogen receptor antibody SP1 is performed using the FDA cleared /VIEW detection on the 
Benchmark ULTRA (Ventana, Tucson, AZ) according to the package insert without 
modification.  Progesterone receptor antibody 1E2 is performed using the FDA cleared /VIEW 
detection on the Benchmark ULTRA (Ventana, Tucson, AZ) according to the package insert 
without modification. 
 
Use of this document is governed by the terms of use on the first page of this document.

 
NRG-BR004 
131 
NCI Version Date: August 15, 2022 
10.3.3 Reporting and Location of Testing 
Results will be provided to the investigator. 
Magee-Womens Hospital of UPMC, Department of Pathology 
300 Halket Street, 4th Floor, Room 4139 
Pittsburgh, PA 15213 
Atten: NRG-BR004 
10.3.4 PD-L1 Testing 
PD-L1 expression within biopsied tumor will be assessed as an integral marker.  The association 
between PD-L1 expression and prognosis has been extensively investigated for a range of solid 
tumors, suggesting that its expression is a negative prognostic indicator.  For study entry, tumor 
PD-L1 status determination must be documented through central testing of a representative tumor 
tissue specimen.  
10.3.5 
Method of Testing  
Central testing of PD-L1 will be performed at Histogenex, a CAP-accredited, CLIA-certified 
reference laboratory.  PD-L1 testing will be performed with the FDA cleared assay Ventana PD-
L1 (SP142) assay kit which uses the OptiView DAB IHC detection kit and OptiView 
Amplification kit on a Ventana BenchMark Ultra Instrument along with the specified antibody.   
10.3.6 Reporting and Location of Testing 
For the purposes of stratification, the results will be provided to the NRG Oncology SDMC.  
Results will not be provided to the investigator or the patient. 
HistoGeneX  
Attn. Sample Reception Team – P1064 
1331 W 75th Street 
Suite 401  
Naperville, IL 60540  
USA 
10.4 
Exploratory Analyses 
We will further explore the prognostic and predictive utility (of the efficacy of atezolizumab) of 
potential immune biomarkers such as the immune-mediated gene expression signatures, 
antibodies status from multiplex immunofluorescence, stromal tumor infiltrating lymphocytes 
(sTIL), intrinsic subtype of the tumor, and cell-free circulating tumor DNA (ctDNA).  An 
amendment or proposal for any correlative science studies to be performed on biological samples 
will be submitted to CTEP, NCI for review and approval according to NCTN guidelines.  
Amendments to the protocol and/or proposals for use of biological samples will include the 
appropriate background, experimental plans with assay details, and a detailed statistical section.  
Samples for testing will not be released for testing until the appropriate NCI approvals have been 
obtained. 
 
 
Use of this document is governed by the terms of use on the first page of this document.

 
NRG-BR004 
132 
NCI Version Date: August 15, 2022 
11.0 
SPECIAL STUDIES (NON-TISSUE) 
The NRG-BR004 study was permanently closed to accrual on May 20, 2022.  Modified scheduled 
status updates, as outlined on Table 2A, will be completed for patients enrolled prior to study 
accrual closure.  Patients will not be required to complete the QOL and PRO-CTCAE 
assessments. 
With Amendment #3, accrual to the PRO-CTCAE substudy is closed.  Patients enrolled on the 
PRO-CTCAE substudy prior to Amendment #3 will continue to complete the scheduled 
assessments as outlined on Table 2.  Accrual to the QOL substudy will continue. 
11.1 
Quality of Life (QOL) Background 
11.1.1 General Considerations 
The therapeutic goal of this study is to prolong survival among patients with newly diagnosed 
metastatic breast cancer through the focused use of agents that target HER2-neu overexpression 
in their tumors.  A taxane of investigator choice (paclitaxel or docetaxel) will be the 
chemotherapy backbone for the trial and will be received by patients in both arms of the study, 
along with trastuzumab and pertuzumab.  The primary QOL question for this trial is whether or 
not the addition of an immune modulatory agent contributes to the established toxicity of 
chemotherapy with the two HER2-targeted therapies that all patients will be receiving.  In the 
CLEOPATRA Trial (Baselga 2012), the most frequent toxicities recorded by standard CTCAE 
were diarrhea in 66.8%, fatigue in 37.6% and mucositis in 27.8% of patients.  These toxicity 
reports are likely an underestimate of what patients might report.   
However, the CLEOPATRA trial also included a companion QOL study that used the FACT-B as 
its study questionnaire with a primary analysis that focused on the FACT-B-Trial Outcome Index 
(TOI) (Cortes 2013), and a post-hoc analysis that looked at the symptom scale of the FACT-B.  
The CLEOPATRA QOL study did not detect a significant contribution to deterioration in 
functioning with the addition of pertuzumab to the treatment regimen, although both treatment 
groups had a decline in the TOI during the first 18 weeks on therapy that improved back to 
baseline by 12 months (Cortes 2013).  An exploratory post-hoc symptom deterioration analysis 
suggested that the pertuzumab arm might have been better with symptoms worsening earlier in 
the control group, possible due to greater efficacy in the pertuzumab arm.  However, the symptom 
items in FACT-B symptom scale are broad and were not targeted to the key items identified by 
the CTCAE toxicity noted earlier.  Specific toxicities of paclitaxel and the antibody therapies are 
described earlier in the CAEPR tables, and specific toxicities of concern are neuropathy, diarrhea, 
musculoskeletal pain, mucositis, and fatigue.  To a large extent, these overlap with the 
independent toxicities of atezolizumab, so measurement of these symptoms will be essential as 
they could be exacerbated by the anti-PD-L1 therapy. 
In considering the addition of an anti-PD-L1 monoclonal antibody to the proposed standard 
therapy, we must take into consideration what is known about this class of agents, and the 
symptom profile expected.  As described earlier in Sections 2.4 and 2.5, the most common 
adverse events reported in t10% of treated patients were fatigue, decreased appetite, nausea, 
pyrexia, constipation, cough, dyspnea, diarrhea, anemia, vomiting, asthenia, back pain, headache, 
arthralgia, pruritus, rash, abdominal pain, insomnia, peripheral edema and dizziness.  Only a 
limited amount of data is available specifically in breast cancer patients, as noted in Section 2.5.  
Thus, we need to ensure that the QOL study for this trial addresses the symptoms that are 
prominent in association with this class of agents, in particular fatigue.  
Use of this document is governed by the terms of use on the first page of this document.

 
NRG-BR004 
133 
NCI Version Date: August 15, 2022 
11.1.2 Fatigue as the Primary QOL Endpoint 
For more than two decades, fatigue in cancer patients has been recognized as one of the most 
prevalent and troublesome side effects of cancer and its treatment, having adverse effects on 
quality of life (Jacobsen 2004, Bower 2014).  Fatigue is often a direct consequence of the cancer, 
especially when associated with uncontrolled metastatic disease.  However, fatigue may also be a 
specific consequence of cancer-directed treatments (e.g., radiation, chemotherapy, 
immunotherapy) (Bower 2014).  It is generally agreed that fatigue is subjective, and must be 
assessed by self-report, rather than by an observer, and there are currently many reliable and valid 
questionnaires to assess fatigue (Jacobsen 2004, Lai 2014).  Fatigue impacts the physical, 
emotional, social and cognitive functioning of cancer patients (Donovan 2015), and as such 
serves as an effective composite measure of well-being during and after cancer therapy.  In this 
trial, we expect that fatigue will be an important side effect of both treatments and that some 
patients will have fatigue even before treatment starts.  Fatigue was not specifically assessed in 
the CLEOPATRA QOL study, nor do we have any self-reported data on fatigue from recent 
immunotherapy trials.  However, given the hypothesized efficacy of the experimental treatment 
arm, with increased disease response and prolonged progression-free survival, we expect that any 
additional fatigue associated with the immunotherapy will be balanced by reduced fatigue from 
better disease control, and propose to examine the trajectory of fatigue during the first 12 months 
on treatment.  We believe that this will be the most important QOL outcome for future patients 
once the trial results are available. 
11.1.3 Assessment Approach, Considerations, and Questionnaires 
In addition to the assessment of fatigue as the primary QOL outcome, we will also assess the 
impact of the study treatments on physical functioning and symptoms (Kluetz 2016).  To this end, 
examination of the longitudinal pattern of physical functioning, disease and treatment associated 
symptoms among the secondary outcomes assessed in the QOL study.  The CLEOPATRA QOL 
study gives some suggestion that there is a decline in functioning during the first 18 weeks of 
treatment; however, the FACT-B-TOI items are a mixture of diverse symptoms and functions, 
and thus it is difficult to predict how physical functioning and symptoms will be affected by the 
planned treatments in this trial. 
Specifically, this trial will have a heterogeneous sample of patients with metastatic disease who 
are likely to have more limited metastatic burden (i.e., scan detected only metastases without 
clinical symptoms; de novo stage IV disease), although some patients may have had extensive 
prior neoadjuvant and adjuvant therapies. 
This heterogeneity will likely affect the baseline physical functioning and symptoms of the 
enrolled patients.  Thus, we will take this into account in the QOL analysis.  For example, newly-
diagnosed stage IV disease patients may be a special subgroup who may have better baseline 
physical functioning and symptoms and may better tolerate the study therapy.  In addition, these 
patients may represent a potential group of long-term survivors.  We will also examine patients 
who did and did not have previous HER2-directed therapy.   
Other considerations in a trial of patients with metastatic disease include potential for QOL study 
attrition as disease progression is expected to be significantly greater in the standard arm.  Thus, 
we plan to do more frequent assessments early in the study where less asymmetry is likely in 
comparison of the two arms based on progression.  However, we plan to continue assessment 
through the 24 months of planned immunotherapy, with a final assessment at 30 months to 
determine whether or not there are any residual effects once this treatment has been discontinued, 
Use of this document is governed by the terms of use on the first page of this document.

 
NRG-BR004 
134 
NCI Version Date: August 15, 2022 
allowing us to descriptively capture the patient experience during the full course of experimental 
treatment.  Of note, the CLEOPATRA QOL study had relatively high compliance with data 
collection (>75%) out to 99 weeks, especially in the treatment arm with pertuzumab (Cortes 
2013). 
We plan to use the following questionnaires for this QOL study: The Patient-Reported Outcomes 
Measurement Information System (PROMIS) Fatigue scale, which is a 7-item self-report 
measure, will be used to assess severity, frequency, and daily pattern of fatigue as the primary 
outcome.  The impact of treatment on physical functioning will be assessed with the PROMIS 
Physical Function (PF) domain using the 6-item short form scale (Jensen 2015).  Using PRO-
CTCAE, we will assess the following treatment related symptoms, which have been commonly 
reported in therapeutic trials of PD-L1 inhibitors: fatigue, diarrhea, mucositis, neuropathy, rash, 
itching, cough, and musculoskeletal pain.  Finally, core disease-related symptoms that are 
common across cancers will be measured as suggested by Reeve et al. (Reeve 2014) and will 
supplement those already being measured as part of treatment-related symptoms (i.e., insomnia, 
pain, anorexia, dyspnea, cognitive problems, anxiety, nausea, depression, constipation) and will 
also be taken from the PRO-CTCAE.  We will also include the FACT-B-TOI as an overall 
measure of QOL, and as means of comparing this study population to the patients included in the 
CLEOPATRA trial (Baselga 2012, Cortes 2013). 
11.2 
Aims and Hypotheses 
11.2.1 Primary QOL Aim 
To compare the severity of fatigue experienced by patients receiving atezolizumab to patients 
without this therapy during the first year after randomization, as measured by the PROMIS 
Fatigue questionnaire. 
11.2.2 Secondary QOL Aims 
x 
To compare the physical functioning of patients receiving atezolizumab to patients receiving 
placebo over all of the data collection time points. 
x 
To compare the severity and frequency of treatment- and disease-related symptoms over all 
of the data collection time points experienced by patients receiving atezolizumab to patients 
receiving placebo. 
x 
To compare the severity of fatigue experienced by patients receiving atezolizumab to patients 
receiving placebo over all of the data collection time points. 
x 
To examine the impact of treatment and treatment-related symptoms on physical functioning 
at 12 months in patients receiving atezolizumab compared to patients receiving placebo. 
x 
To examine overall QOL experienced at 12 and 24 months by patients assigned to 
atezolizumab compared to patients assigned to placebo. 
11.2.3 Primary QOL Hypothesis 
During the first year after randomization, the average level of fatigue experienced by patients 
assigned to atezolizumab will not be worse than that experienced by patients assigned to placebo 
as it is defined in Section 14.6.2. 
 
Use of this document is governed by the terms of use on the first page of this document.

 
NRG-BR004 
135 
NCI Version Date: August 15, 2022 
11.2.4 Secondary QOL Hypotheses 
x 
There will be no difference in physical functioning between patients assigned to atezolizumab 
and patients receiving placebo at 12 weeks after randomization.  Patients assigned to 
atezolizumab will experience better physical functioning at 24 and 30 months than patients 
who receive placebo. 
x 
Patients assigned to atezolizumab will experience greater severity and frequency of 
treatment-related symptoms during the 12 months on therapy, but these will resolve by  
30 months.  In contrast, patients on atezolizumab will have improved disease-related 
symptoms during treatment and at the first follow-up assessment after the end of this 
treatment (30 months after randomization) than patients assigned to receive placebo. 
x 
Patients assigned to atezolizumab will experience greater level of fatigue at 12 weeks after 
randomization than patients assigned to placebo but there will be no difference in fatigue 
between the two treatment groups at 30 months after randomization. 
x 
Patients who have greater treatment-related symptoms will have poorer physical functioning 
at 12 months. 
x 
There will be no difference in QOL between patients assigned to atezolizumab and patients 
assigned to placebo at the 12- and 24-month time points. 
11.3 
Administration of BR004 Patient-Completed Questionnaires 
11.3.1 Time points for Administration 
The BR004 QOL questionnaire (Form QOL) will be administered via the Medidata Patient Cloud 
app at the following time points: 
x 
Prior to study entry after the BR004 consent form has been signed. 
x 
Following study entry: 
 
12 weeks  
 
24 weeks  
 
12 months  
 
18 months 
 
24 months 
 
30 months 
11.4 
Administration Instructions 
Questionnaires are to be administered per Section 11.3.1.  For patients who complete the 
questionnaires on-site using devices supplied by the institution or for patients opting out of 
Medidata Patient Cloud (ePRO), after the baseline assessment, questionnaires should be 
administered during an office visit if at all possible, preferably while the patient is waiting to be 
seen.  When a follow-up visit is delayed, completion of the QOL questionnaire may also be 
delayed.  The QOL questionnaire may be completed via paper.  Once the questionnaire is 
completed by the patient, the site staff should review it to ensure that no items were 
unintentionally left blank.  When absolutely necessary, the questionnaire may be administered by 
mail or phone.  The completed questionnaire will be data that is manually entered in Rave by site 
staff.  The paper forms should not be submitted to NRG Oncology but should be retained in the 
patient's chart for audit purposes. 
Use of this document is governed by the terms of use on the first page of this document.

 
NRG-BR004 
136 
NCI Version Date: August 15, 2022 
If a patient who opted out of Medidata Patient Cloud does not come into clinic, the questionnaire 
will either be mailed to the patient or the site staff will call the patient to complete the 
questionnaire.  If the patient does not return the questionnaire within two weeks, the patient will 
be called and either another questionnaire will be sent, or the patient will complete the 
questionnaire over the phone with the site staff.  
Patients who never initiate BR004 study therapy or who experience disease progression should 
not continue participating in the QOL study. 
The relevant QOL Coversheet should also be completed when the patient completes the matching 
form, whether via Medidata Patient Cloud, paper, phone, or mail.  This notifies NRG Oncology 
that the assessment was completed and provides information about how the assessment was 
completed.  If a patient declines to complete a scheduled QOL assessment or if the assessment is 
not completed for any other reason (and cannot be completed by phone or mail), the reason the 
assessment was missed must be reported on the QOL Coversheet in Medidata Rave.  For patients 
who agree to use ePRO for OQL collection, please refer to Appendix B. 
11.5 
QOL Patient Population 
All patients enrolled in BR004 who read or understand English, Spanish, or French must be 
offered participation in the QOL study.  QOL will be evaluated in 526 consecutively enrolled 
BR004 patients who have completed the baseline questionnaire.  If a patient chooses to not 
complete the baseline QOL questionnaire or if completion of the baseline questionnaire is missed, 
the patient will not be included in the QOL patient sample but will still be eligible for BR004.  
Please complete the QOL Coversheet in Rave to report patient refusal or missed assessments. 
11.6 
Additional Toxicity Monitoring with PRO-CTCAE 
With Amendment #3, accrual to the PRO-CTCAE substudy is closed.  Patients enrolled on the 
PRO-CTCAE substudy prior to Amendment #3 will continue to complete the scheduled 
assessments as outlined on Table 2.  Accrual to the QOL substudy will continue. 
Additional toxicity monitoring with PRO-CTCAE will be conducted.  The following 23 items, 
covering 12 symptoms, will be assessed: fatigue (2), mucositis (2), diarrhea (1), numbness and 
tingling (2), rash (1), itching (1), cough (2), shortness of breath (2), abdominal pain (3), joint pain 
(3), nausea (2), and decreased appetite (2).  Also, a free-text item will be included.  Refer to 
Section 7.4 for additional information regarding toxicity monitoring with PRO-CTCAE. 
11.6.1 Primary Objective (Feasibility Stage) 
To assess the feasibility of frequent assessment of toxicity with ePRO reporting and to assess the 
degree of data missingness in the first 100 patients who read or understand English, Spanish, or 
French accrued to the study. 
11.6.2 Secondary Objectives 
x 
To monitor the patient experience of common expected toxicities from the agents being 
evaluated in this study. 
x 
To monitor toxicities more frequently than standard AE reporting to determine if there are 
interval toxicities not captured by the every 3- to 6 week assessments. 
x 
To capture baseline toxicities (pre-treatment) that may influence the subsequent treatment 
toxicity experience. 
x 
To compare the PRO–CTCAE data with the Investigator report of AE for the same items. 
Use of this document is governed by the terms of use on the first page of this document.

 
NRG-BR004 
137 
NCI Version Date: August 15, 2022 
x 
To examine the pattern of treatment toxicity over time during the first 12 weeks of PRO-
CTCAE monitoring. 
11.7 
Administration of PRO-CTCAE 
11.7.1 Time Points for Administration 
The BR004 PRO-CTCAE assessment will be administered via Medidata Patient Cloud at the 
following time points: 
x 
Prior to study entry after the BR004 consent form has been signed. 
x 
Following study entry: 
 
Weekly during the first 12 weeks (Cycles 1-2) 
 
Every three weeks (Cycles 3-4) 
 
Every six weeks (through 2 years) 
 
At 30 months 
11.7.2 Recall Period 
A 1-week recall period will be used for the PRO-CTCAE data collected during Cycles 1-2, and a 
3-week recall period will be used for all other assessments. 
11.8 
Administration Instructions 
For patients who complete the assessments on-site using devices supplied by the institution, 
please use the following guidelines: 
 
For the weekly assessments (Cycles 1-2), a patient should complete the assessment 
during the weekly treatment visit.  An assessment that is not obtained at a weekly visit 
will be considered a missed assessment.  Assessments should resume with the next visit. 
 
After the first 12 weeks, assessments are to be administered at the subsequent time points, 
so that when a visit is delayed, the PRO-CTCAE assessment may also be delayed. 
 
PRO-CTCAE assessments should be discontinued at the time of progression. 
Questionnaires are to be administered per Section 11.7.1.  For patients who complete the 
questionnaires on-site using devices supplied by the institution or for patients opting out of 
Medidata Patient Cloud (ePRO), after the baseline assessment, questionnaires should be 
administered during an office visit if at all possible, preferably while the patient is waiting to be 
seen.  When a follow-up visit is delayed, completion of the PRO-CTCAE assessment may also be 
delayed.  If unable to complete the PRO-CTCAE assessment via Medidata Patient Cloud, the 
PRO-CTCAE assessment may be completed via paper.  Once the assessment is completed by the 
patient, the site staff should review it to ensure that no items were unintentionally left blank.  
When absolutely necessary, the assessment may be administered by mail or phone.  The 
completed assessment will be data that is manually entered in Rave by site staff.  The paper forms 
should not be submitted to NRG Oncology but should be retained in the patient's chart for audit 
purposes. 
If a patient who opted out of Medidata Patient Cloud does not come into clinic, the assessment 
will either be mailed to the patient or the site staff will call the patient to complete the assessment.  
If the patient does not return the assessment within two weeks, the patient will be called and 
Use of this document is governed by the terms of use on the first page of this document.

 
NRG-BR004 
138 
NCI Version Date: August 15, 2022 
either another assessment will be sent, or the patient will complete the assessment over the phone 
with the site staff.  
Patients who never initiate BR004 study therapy or who experience disease progression should 
not continue participating in the PRO-CTCAE study. 
The relevant PRO-CTCAE Coversheet should also be completed when the patient completes the 
matching form, whether via Medidata Patient Cloud, paper, phone, or mail.  This notifies NRG 
Oncology that the assessment was completed and provides information about how the assessment 
was completed.  If a patient declines to complete a scheduled PRO-CTCAE assessment or if the 
assessment is not completed for any other reason (and cannot be completed by phone or mail), the 
reason the assessment was missed must be reported on the PRO-CTCAE Coversheet in Medidata 
Rave.  For patients who agree to use ePRO for PRO-CTCAE collection, please refer to  
Appendix B. 
11.9 
PRO-CTCAE Patient Population 
With Amendment #3, accrual to the PRO-CTCAE substudy is closed.  Patients enrolled on the 
PRO-CTCAE substudy prior to Amendment #3 will continue to complete the scheduled 
assessments as outlined on Table 2.  Accrual to the QOL substudy will continue. 
The first 100 patients enrolled in NRG-BR004 who read or understand English, Spanish, or 
French, have the ability to use Medidata Patient Cloud reporting, and who have completed the 
baseline PRO-CTCAE assessment will be required to participate in the PRO-CTCAE feasibility 
study.  If a patient chooses to not complete the baseline PRO-CTCAE assessment or if 
completion of the baseline assessment is missed, the patient will not be included in the PRO-
CTCAE patient sample but will still be eligible for BR004.  Please complete the PRO-CTCAE 
Coversheet in Rave to report patient refusal or missed assessments. 
 
 
Use of this document is governed by the terms of use on the first page of this document.

 
NRG-BR004 
139 
NCI Version Date: August 15, 2022 
12.0 
MEASUREMENT OF EFFECT 
Tumor response and progression will be evaluated in this study using the Response Evaluation 
Criteria in Solid Tumors (RECIST) 1.1 (Eisenhauer 2009) except in the documentation of 
progressive disease (PD).   
12.1 
Definitions 
12.1.1 Evaluable Toxicity 
All patients will be evaluable for toxicity from the time of their first administration of protocol 
therapy. 
12.1.2 Evaluable for Objective Response 
Patients who have measurable disease present at baseline and have had their disease re-evaluated 
will be considered evaluable for response.  These patients will have their response classified 
according to the definitions stated below.  (Note: Patients who exhibit objective disease 
progression prior to the end of the first 3 weeks of treatment will also be considered evaluable.) 
12.2 
Disease Parameters 
12.2.1 Measurable Disease 
Measurable lesions are defined as those that can be accurately measured in at least one dimension 
(longest diameter to be recorded) t 10 mm by CT scan with slice thickness no greater than 5 mm, 
MRI, or calipers in clinical exam.  All tumor measurements must be recorded in millimeters (or 
decimal fractions of centimeters).  The same method (CT or MRI) used at baseline should be used 
at all other tumor measurement time points. 
In rare instances in which none of the metastatic sites can be used as a measurable lesion, the 
breast primary, if intact, can be used as a measurable lesion.  If it meets the criterion of t 10 mm, 
it can be monitored on serial chest CT or on breast imaging techniques (e.g., mammography, 
ultrasound).  The breast primary should not be used as a site of measurable disease if other sites 
of measurable disease have been identified.  This should only be done when resection of the 
breast primary is not anticipated. 
12.2.2 Malignant Lymph Nodes 
To be considered pathologically enlarged and measurable, a lymph node must be t 15 mm in 
short axis when assessed by CT scan (CT scan thickness recommended to be no greater than  
5 mm).  At baseline and in follow-up, only the short axis will be measured and followed. 
12.2.3 Non-Measurable Disease 
All other lesions (or sites of disease), including small lesions (longest diameter  10 mm or 
pathological lymph nodes with t 10 to  15 mm short axis), are considered non-measurable 
disease.  Bone lesions, leptomeningeal disease, ascites, pleural/pericardial effusions, lymphangitis 
cutis/pneumonitis, inflammatory breast disease, and abdominal masses (not followed by CT or 
MRI), are considered as non-measurable. 
 
Use of this document is governed by the terms of use on the first page of this document.

 
NRG-BR004 
140 
NCI Version Date: August 15, 2022 
12.2.4 Special Considerations Regarding Tumor Measurability 
x 
Bone lesion measurability 
When evaluating bone lesions, the following should be considered: 
 
Bone scan or plain films are not considered adequate imaging techniques to measure 
bone lesions.  However, these techniques can be used to confirm the presence or 
disappearance of bone lesions. 
 
Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue components, 
that can be evaluated by cross sectional imaging techniques such as CT or MRI can be 
considered as measurable lesions if the soft tissue component meets the definition of 
measurability described above. 
 
Blastic bone lesions are non-measurable. 
x 
Cystic lesions 
 
Lesions that meet the criteria for radiographically defined simple cysts should not be 
considered as malignant lesions (neither measurable nor non-measurable) since they are, 
by definition, simple cysts. 
 
'Cystic lesions' thought to represent cystic metastases can be considered as measurable 
lesions, if they meet the definition of measurability described above.  However, if non-
cystic lesions are presented in the same patient, these are preferred for selection as target 
lesions.  
x 
Tumors with prior local treatment 
 
Tumor lesions situated in a previously irradiated area, or in an area subjected to other 
loco-regional therapy, are usually not considered measurable unless there has been 
demonstrated progression in the lesion. 
12.2.5 Target Lesions 
Up to a maximum of five measurable lesions (maximum 2 lesions per organ), should be identified 
as target lesions and recorded and measured at baseline.  Target lesions should be selected on the 
basis of their size (lesions with the longest diameter), be representative of all involved organs, 
and lend themselves reproducible repeated measurements by CT scan or MRI.  It may be the case 
that, on occasion, the largest lesion does not lend itself to reproducible measurement in which 
circumstance the next largest lesion which can be measured reproducibly should be selected.  A 
sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target 
lesions will be calculated and reported as the baseline sum diameters.  If lymph nodes are to be 
included in the sum, then only the short axis is added into the sum.  The baseline sum diameters 
will be used as reference by to further characterize any objective tumor regression in the 
measurable dimension of the disease. 
12.2.6 Non-Target Lesions 
All other lesions (or sites of disease) including pathological lymph nodes which are not used as 
target lesions should be identified as non-target lesions and should also be recorded at baseline.  
All sites of non-target lesions must be assessed along with the target lesions.  Measurements of 
Use of this document is governed by the terms of use on the first page of this document.

 
NRG-BR004 
141 
NCI Version Date: August 15, 2022 
these lesions are not required, but the presence, absence, or in rare cases unequivocal progression 
of each should be noted throughout follow-up. 
12.2.7 Lesions 
If new lesions appear and there is clinical doubt as to whether a lesion is new or an inflammatory 
change, follow-up scans are required in no less than 6 weeks.  If the new lesion is confirmed as 
unequivocal (i.e., not attributable to differences in scanning technique, change in imaging 
modality or findings thought to be something other than the tumor by a scan obtained at least  
6 weeks after the initial scan), the date of progression is taken to be the date on which the new 
lesion was first detected.  If a lesion reappears after disappearing in a patient previously declared 
to have a CR, PD is declared.  However, if such a lesion behaves in this manner in a patient with 
SD or PR, confirmation as stated above defines the response or progression. 
12.2.8 Pseudoprogression 
Delayed responses after a tumor flare have been reported in patients who have received immune-
based therapy.  Caution must be exercised not to confuse a possible tumor flare with PD.  In 
scenarios where pseudoprogression of previously targeted or not-targeted lesions is suspected, 
follow-up scans are required in 4 to 6 weeks.  Based on that repeating imaging, if there is 
confirmatory evidence of tumor progression, the date of PD will be documented as the initial 
evaluation.  However, if subsequent response is confirmed, no progression is documented and the 
imaging schedule reverts to that otherwise stated in the protocol. 
12.3 
Response Criteria 
12.3.1 Evaluation of Target Lesions 
x 
Complete response (CR) 
Disappearance of all target lesions.  Any pathological lymph nodes (whether target or non-
target) must have reduction in short axis to <10 mm). 
x 
Partial response (PR) 
At least a 30% decrease in the sum of diameters of target lesions, taking as reference the 
baseline sum diameters. 
x 
Progressive disease (PD) 
At least a 20% increase in the sum of diameters of target lesions, taking as reference the 
smallest sum on study (this includes the baseline sum if that is the smallest on study).  In 
addition to the relative increase of 20%, the sum must also demonstrate an absolute increase 
of at least 5 mm.  (Note: The appearance of one or more new lesions is also considered 
progression.) 
x 
Stable disease (SD) 
Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking 
as reference the smallest sum diameters while on study. 
12.3.2 Evaluation of Non-Measurable/Non-Target Lesions 
x 
Complete response (CR): Disappearance of all non-target lesions.  All lymph nodes must be 
non-pathological in size ( 10 mm short axis). 
Use of this document is governed by the terms of use on the first page of this document.

 
NRG-BR004 
142 
NCI Version Date: August 15, 2022 
x 
Non-CR/Non-PD: Persistence of one or more non-target lesion(s).   
x 
Progressive disease (PD): Appearance of one or more new lesions and/or unequivocal 
progression of existing non-target lesions.  Unequivocal progression should not normally 
trump target lesion status.  It must be representative of overall disease status change, not a 
single lesion increase. 
12.4 
Evaluation of Best Overall Response 
The best overall response is the best response recorded from the start of the treatment until 
disease progression/recurrence (taking as reference for progressive disease the smallest 
measurements recorded since the treatment started).  The patient's best response assignment will 
depend on the achievement of both measurement and confirmation criteria.   
In BR004, the next regularly scheduled scan will be used for confirmation.  Extra scans are 
not required. 
Refer to Table 35 and Table 36 for a summary of the criteria that contribute to the determination 
of response. 
Table 35.  Time point response: patients with target (r non-target) disease 
Target Lesions 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
CR 
No 
CR 
CR 
Non-CR/Non-PD 
No 
PR 
CR 
Not evaluated 
No 
PR 
PR 
Non-PD or not all 
evaluated 
No 
PR 
SD 
Non-CR/Non-PD or 
not all evaluated 
No 
SD 
Not all 
evaluated 
Non-PD 
No 
Inevaluable 
PD 
Any 
Yes or No 
PD 
Any 
PD** 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
* 
See RECIST 1.1 manuscript for further details on what is evidence of a new 
lesion (Eisenhauer 2009). 
** In exceptional circumstances, unequivocal progression in non-target lesions 
may be accepted as disease progression. 
 
Table 36.  Time point response: patients with non-target disease only 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/Non-PD 
No 
Non-CR/Non-PD* 
Not all evaluated 
No 
Inevaluable 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
* ‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease 
since SD is increasingly used as an endpoint for assessment of efficacy in 
some trials so to assign this category when no lesions can be measured is not 
advised 
 
 
Use of this document is governed by the terms of use on the first page of this document.

 
NRG-BR004 
143 
NCI Version Date: August 15, 2022 
12.5 
Symptomatic Deterioration 
Patients with a global deterioration of health status requiring discontinuation of treatment without 
objective evidence of disease progression at that time should be reported as "symptomatic 
deterioration."  Every effort should be made to document objective progression even after 
discontinuation of treatment.  Symptomatic deterioration is not a descriptor of an objective 
response: it is a reason for stopping protocol therapy. 
12.6 
Duration of Response 
12.6.1 Duration of Overall Response 
The duration of overall response is measured from the time measurement criteria are met for CR 
or PR (whichever is first recorded) until the first date that recurrent or progressive disease is 
objectively documented (taking as reference for progressive disease the smallest measurements 
recorded since the treatment started). 
The duration of overall CR is measured from the time measurement criteria are first met for CR 
until the first date that progressive disease is objectively documented. 
12.6.2 Duration of Stable Disease 
Stable disease is measured from the start of the treatment until the criteria for progression are 
met, taking as reference the smallest measurements recorded since the treatment started, including 
the baseline measurements. 
12.7 
Progression-Free Survival 
Progression-free survival is defined as the time from randomization to the first documented 
progressive disease, as determined using the current RECIST 1.1 criteria, or death from any 
causes, whichever occurs first. 
 
 
Use of this document is governed by the terms of use on the first page of this document.

 
NRG-BR004 
144 
NCI Version Date: August 15, 2022 
13.0 
DATA AND RECORDS 
The NRG-BR004 study was permanently closed to accrual on May 20, 2022.  Modified scheduled 
status updates, as outlined on Table 2A, will be completed for patients enrolled prior to study 
accrual closure. 
13.1 
Data Management/Collection 
Medidata Rave is a clinical data management system being used for data collection for this 
trial/study.  Access to the trial in Rave is controlled through the CTEP-IAM system and role 
assignments.   
Requirements to access Rave via iMedidata: 
x 
A valid CTEP-IAM account; and  
x 
Assigned a Rave role on the LPO or PO roster at the enrolling site: Rave CRA, Rave 
Read Only, Rave CRA [LabAdmin], Rave SLA, or Rave Investigator.   
Rave role requirements: 
x 
Rave CRA or Rave CRA (Lab Admin) role must have a minimum of an Associate Plus 
(AP) registration type; 
x 
Rave Investigator role must be registered as a Non-Physician Investigator (NPIVR) or 
Investigator (IVR); and 
x 
Rave Read Only role must have at a minimum an Associates (A) registration type. 
Refer to https://ctep.cancer.gov/InvestigatorResources/default.htm for registration types and 
documentation required. 
This study has a Delegation of Tasks Log (DTL).  Therefore, those requiring write access to Rave 
must also be assigned the appropriate Rave tasks on the DTL. 
Upon initial site registration approval for the study in Regulatory Support System (RSS), all 
persons with Rave roles assigned on the appropriate roster will be sent a study invitation e-mail 
from iMedidata.  To accept the invitation, site staff must either click on the link in the email or 
log into iMedidata via the CTSU members’ website under Data Management > Rave Home and 
click to accept the invitation in the Tasks pane located in the upper right corner of the Medidata 
screen.  Site staff will not be able to access the study in Rave until all required Medidata and 
study specific trainings are completed.  Trainings will be in the form of electronic learnings 
(eLearnings) and can be accessed by clicking on the eLearning link in the Tasks pane located in 
the upper right corner of the iMedidata screen.  If an eLearning is required and has not yet been 
taken, the link to the eLearning will appear under the study name in the Studies pane located in 
the center of the iMedidata screen; once the successful completion of the eLearning has been 
recorded, access to the study in Rave will be granted, and a Rave EDC link will display under the 
study name. 
Site staff that have not previously activated their iMedidata/Rave account at the time of initial site 
registration approval for the study in RSS will receive a separate invitation from iMedidata to 
activate their account.  Account activation instructions are located on the CTSU website in the 
Data Management section under the Rave resource materials (Medidata Account Activation and 
Study Invitation Acceptance).  Additional information on iMedidata/Rave is available on the 
CTSU members' website in the Data Management > Rave section at www.ctsu.org/RAVE/ or by 
contacting the CTSU Help Desk at 1-888-823-5923 or by e-mail at ctsucontact@westat.com. 
QOL and PRO-CTCAE items will be collected using ePRO.  The patient will use personal hand-
held devices or tablets.  Once a patient submits the responses, the data goes directly from the 
Use of this document is governed by the terms of use on the first page of this document.

 
NRG-BR004 
145 
NCI Version Date: August 15, 2022 
device into the Rave database.  There are no documents to audit.  The electronic responses are the 
source documentation. 
All imaging tests performed during this study must be submitted to Bioclinica.  Refer to the 
NRG-BR004 Pathology, Correlative Science, and Imaging Instructions and the BR004 Bioclinica 
site manual for imaging submission procedures.  Submission of images to Bioclinica is not 
required following the discontinuation of study therapy and study closure to accrual on May 
20, 2022. 
13.2 
Summary of Data Submission 
Adverse event data collection and reporting, which are required as part of every clinical trial, are 
done to ensure the safety of patients enrolled in the studies as well as those who will enroll in 
future studies using similar agents.  Adverse events are reported in a routine manner at scheduled 
times during the trial using Medidata Rave.  Additionally, certain adverse events must be reported 
in an expedited manner for more timely monitoring of patient safety and care.  See Section 7.5 
and Section 7.6 for information about expedited and routine reporting.  PRO-CTCAE is not 
intended for expedited reporting, real time review, or safety reporting.  PRO-CTCAE data are 
exploratory and not currently intended for use in data safety monitoring or adverse event stopping 
rules. 
Summary of Data Submission: Refer to the CTSU Member website for the table of Required 
Forms and Materials. 
13.3 
Enhanced Centralized Data Monitoring  
13.3.1 Central Monitoring 
Central Monitoring (CM) Review is required for this protocol.  CM allows Lead Protocol 
Organizations (LPOs) to remotely compare data entered in Rave to source documentation to 
ensure that sites are adhering to the protocol and central monitoring plan as well as accurately 
transcribing data from patients’ charts (i.e., source data verification).  
Sites can upload source documents required for CM Review as documented in the central 
monitoring plan using the Source Document Portal (SDP).  This application is available on the 
CTSU members’ website under Auditing & Monitoring and may also be accessed using a direct 
link within Rave on the CM Alert form.  Site staff with the CRA or Investigator roles in Rave can 
view and upload source documents.  Prior to saving source documents on the SDP, each site is 
responsible for removing or redacting any Personally Identifiable Information (PII) (note that 
functionality to do this redaction exists within the SDP itself).  Designated LPO staff will review 
each document after it has been loaded on the SDP to ensure the appropriate documents have 
been uploaded and to ensure PII is redacted. 
Additional information on the SDP is available on the CTSU members’ website under Auditing & 
Monitoring > Source Document Portal in the Help Topics button or by contacting the CTSU Help 
Desk (1-888-823-5923 or ctsucontact@westat.com). 
13.3.2 Quality Assurance Enhancements 
Site Initiation Visit 
The study initiation will be conducted via video posted on a secure website and available for all 
NCTN Member Institutions.  It is mandatory that the Principal Investigator (PI) (the PI on the 
Use of this document is governed by the terms of use on the first page of this document.

 
NRG-BR004 
146 
NCI Version Date: August 15, 2022 
IRB documentation) and at least one research associate (RA) view the initiation video.  During 
the site initiation video, at a minimum, the following activities will be performed by NRG 
Oncology: 
x 
An in-depth review of the protocol using a lecture format. 
x 
Presentation of study requirements and procedures including, but not limited to: 
study objectives, study design, eligibility criteria, enrollment procedures, schedule of 
evaluations, criteria for patient discontinuation, adverse event reporting (definitions, 
SAE reporting procedures), study drug administration, study time frame, drug 
ordering, blood and tumor sample submission requirements (if applicable), and 
laboratory procedures; 
x 
Discussion of the structure of the auditing/monitoring process for the Study; 
x 
Discussion of the patient enrollment procedures; 
x 
Discussion of the importance of maintaining adequate source and regulatory 
documents; 
x 
Review of Electronic Case Report Forms and completion guidelines including visit-
specific pages, correction procedure, patient identification numbers, and the data 
query resolution process; 
x 
Review of the NRG Oncology contact list; 
x 
Discussion of the Drug Accountability Log requirements; 
x 
Documentation of all attendees by obtaining a signed confirmation of completion 
from the attendees 
13.3.3 Eligibility 
The source records which document the eligibility for the first one to three individuals enrolled 
from each site (as identified by a unique NCI identifier) will be reviewed for completeness and 
consistency with the eligibility criteria, the data reported during the enrollment process and the 
data reported on the case report forms (CRFs).  (Sites enrolling rapidly to the trial will undergo 
monitoring for up to three patients.)  Documents are to be submitted within two weeks of patient 
enrollment. 
In the event that this monitoring identifies unacceptable enrollment procedures or significant 
deviations from eligibility criteria, then the site will need to submit a corrective action plan within 
two weeks of being notified of the findings of the centralized monitoring.  The source records for 
the eligibility of treatment for the next individual enrolled to the study from the site are again to 
be submitted and reviewed.  In the event of significant repeated deviations from the protocol, 
accrual at the site may be suspended per discretion of the overall Study Chair.  
The pretreatment documents to be reviewed include: 
x 
Pathology Report to document the diagnosis of locally recurrent or metastatic disease. 
x 
Medical history and physical examinations records and laboratory results, including all blood 
tests. 
x 
LVEF assessments 
x 
Consent forms will be submitted to the SDMC and reviewed upon receipt for signatures, date 
of consent, and patient consent to optional sample collection/use. 
 
Use of this document is governed by the terms of use on the first page of this document.

 
NRG-BR004 
147 
NCI Version Date: August 15, 2022 
13.3.4 Enhanced Consent Form Review 
Central review of the consent form for the essential elements of informed consent (as defined by 
the Department of Health and Human Services Office for Human Research Protection) for the 
first signed consent form and signed amended consent forms (when required by protocol 
amendment) submitted from each site (as identified by a unique NCI identifier) will be performed 
in real time after first patient entry. 
13.3.5 Drug Accountability, Drug-Dose Compliance, and Adverse Events 
The source records and adverse events (AEs) during the first cycle of treatment for the first one to 
three individuals enrolled from each site will be reviewed for compliance with the protocol, 
completeness and consistency with the data reported on the case report forms, and drug 
accountability records.  The documents listed below should be submitted at two time-points:  
(1) within two weeks of Cycle 1, Day 22 of treatment (for records and AEs during the first  
3 weeks of treatment), and (2) within two weeks of Day 1, Cycle 2 of treatment (for records and 
AEs during the second 3 weeks of treatment).  
In the event that this monitoring identifies unacceptable procedures or significant deviations from 
protocol procedures, then the site will need to submit a corrective action plan within two weeks.  
The source records for the first cycle of treatment for the next individual enrolled to the study 
from the site should then again be submitted and reviewed.  In the event of significant repeated 
deviations from the protocol, accrual at the site may be suspended per discretion of the overall 
Study Chair.   
The documents to be reviewed include: 
x 
Study drug orders treatment dose calculations and administration records. 
x 
Reports from protocol-directed laboratory studies. 
x 
Reports from any additional tests performed to document an adverse event. 
x 
All progress notes relating to pre-therapy history and physical and AE assessments 
x 
Pharmacy drug accountability records. 
x 
Summaries of hospital admissions and discharge for hospitalizations.  
x 
Summaries of surgical procedures performed. 
13.3.6 Endpoint Review 
Medical Review Nurse will perform ongoing centralized medical review of copies of source 
documents related to all endpoints as they are reported to verify the event. 
De-identified copies of disease imaging scan reports must be submitted at the following time 
points: 
x 
Baseline 
x 
Progression 
x 
At the time of PR or CR 
x 
At the time of confirmation of PR or CR 
13.3.7 Enhanced Record Review 
The enhanced record review will be conducted by the NRG SDMC at any NCTN institution 
which enrolled a patient on the Study. 
Use of this document is governed by the terms of use on the first page of this document.

 
NRG-BR004 
148 
NCI Version Date: August 15, 2022 
x 
Time of Site Visit Audits 
During the audit visits that occur under the CTEP audit procedures, additional cases will be 
reviewed to ensure that all sites that enrolled patients to the Study will be selected for review. 
13.4 
Data Quality Portal 
The Data Quality Portal (DQP) provides a central location for site staff to manage unanswered 
queries and form delinquencies, monitor data quality and timeliness, generate reports, and review 
metrics.  
The DQP is located on the CTSU members’ website under Data Management.  The Rave Home 
section displays a table providing summary counts of Total Delinquencies and Total Queries.  
DQP Queries, DQP Delinquent Forms, DQP Form Status and the DQP Reports modules are 
available to access details and reports of unanswered queries, delinquent forms, and forms with 
current status and timeliness reports.  Review the DQP modules on a regular basis to manage 
specified queries and delinquent forms. 
The DQP is accessible by site staff that are rostered to a site and have access to the CTSU 
website.  Staff that have Rave study access can access the Rave study data using a direct link on 
the DQP. 
To learn more about DQP use and access, click on the Help icon displayed on the Rave Home, 
DQP Queries, DQP Delinquent Forms, DQP Forms Status, and DQP Reports modules. 
Complications or unexpected outcomes reporting is required as part of this clinical trial, to ensure 
the safety of participants enrolled in the studies as well as those who will enroll in future studies.  
See Section 7.0 for information about reporting complications or unexpected outcomes.   
13.5 
Rave-CTEP-AERS Integration 
The Rave Cancer Therapy Evaluation Program Adverse Event Reporting System (CTEP-AERS) 
Integration enables evaluation of post-baseline Adverse Events (AE) entered in Rave to determine 
whether they require expedited reporting and facilitates entry in CTEP-AERS for those AEs 
requiring expedited reporting.  Sites must initiate all AEs for this study in Medidata Rave. 
All AEs that occur after baseline are collected in Medidata Rave using the Adverse Event form, 
which is available for entry at each treatment or reporting period and used to collect AEs that start 
during the period or persist from the previous reporting period.  CRA will enter AEs that occur 
prior to the start of treatment on a baseline form that is not included in the Rave-CTEP-AERS 
integration.  AEs that occur prior to enrollment must begin and end on the baseline Adverse 
Events form and should not be included on the standard Adverse Events form that is available at 
treatment unless there has been an increase in grade. 
Prior to sending AEs through the rules evaluation process, site staff should verify the following 
on the Adverse Event form in Rave: 
x 
The reporting period (course/cycle) is correct; and 
x 
AEs are recorded and complete (no missing fields) and the form is query free. 
The CRA reports AEs in Rave at the time the Investigator learns of the event.  If the CRA 
modifies an AE, it must be re-submitted for rules evaluation. 
Upon completion of AE entry in Medidata Rave, the CRA submits the AE for rules evaluation by 
completing the Expedited Reporting Evaluation form.  Both NCI and protocol-specific reporting 
rules evaluate the AEs submitted for expedited reporting.  A report is initiated in CTEP-AERS 
Use of this document is governed by the terms of use on the first page of this document.

 
NRG-BR004 
149 
NCI Version Date: August 15, 2022 
using information entered in Medidata Rave for AEs that meet reporting requirements.  The CRA 
completes the report by accessing CTEP-AERS via a direct link on the Medidata Rave Expedited 
Reporting Evaluation form.  Contact the CTSU Help Desk at 1-888-823-5923 or by email at 
ctsucontact@westat.com if you have any issues submitting an expedited report in CTEP-AERS. 
In the rare occurrence that internet connectivity is lost; a 24-hour notification is to be made to 
CTEP by telephone at 301-897-7497.  Once internet connectivity is restored, the 24-hour 
notification that was phoned in must be entered immediately into CTEP-AERS using the direct 
link from Medidata Rave. 
Additional information about the CTEP-AERS integration is available on the CTSU members’ 
website: 
x 
Study specific documents: Protocols > Documents> Protocol Related Documents > 
Adverse Event Reporting; and   
x 
Additional resources: Resources > CTSU Operations Information> User Guides & Help 
Topics. 
NCI requirements for SAE reporting are available on the CTEP website:  
x 
NCI Guidelines for Investigators: Adverse Event Reporting Requirements is available at 
https://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguidelines.p
df. 
13.6 
Global Reporting/Monitoring 
This study will be monitored by the Clinical Data Update System (CDUS) Version 3.0.  
Cumulative protocol- and patient-specific CDUS data will be submitted electronically to CTEP 
on a quarterly basis.  Reports are due January 31, April 30, July 31, and October 31. 
 
 
Use of this document is governed by the terms of use on the first page of this document.

 
NRG-BR004 
150 
NCI Version Date: August 15, 2022 
14.0 
STATISTICAL CONSIDERATIONS 
The NRG-BR004 study was permanently closed to accrual on May 20, 2022.  Refer to Section 
14.8 for the amended statistical considerations.  Due to the timing of the unblinding of study 
therapy and the termination of patient accrual to NRG-BR004, it will not be possible to achieve 
the study aims initially proposed for the study.  For historical reference, the text in this section 
remains as stated before the unblinding occurred.  Effective with Amendment #6 to this protocol, 
follow-up data collected through April 2024, will be used to monitor for late-immune adverse 
events and to assess PFS and OS outcomes. 
14.1 
Study Design 
NRG-BR004 is a Phase III, randomized, double-blind, clinical trial.  Patients will be randomized 
in a 1:1 ratio to receive a regimen of pertuzumab and trastuzumab with a taxane (paclitaxel or 
docetaxel) and either atezolizumab or placebo. 
Patients will be stratified by 1) prior neoadjuvant or adjuvant therapy with trastuzumab (no; yes), 
2) estrogen receptor status (positive; negative), 3) PD-L1 status (positive; negative or 
indeterminant), 4) disease sites (visceral without brain metastasis; non-visceral only without brain 
metastasis; brain metastasis), and 5) choice of taxane (paclitaxel; docetaxel).  A stratified random 
permuted blocks scheme will be followed for the treatment assignment. 
14.2 
Study Endpoints 
14.2.1 Primary Endpoint 
The primary endpoint is PFS, defined as the time from randomization to the first documented 
progressive disease, as determined by investigator using the current RECIST 1.1 criteria, or death 
from any causes, whichever occurs first. 
14.2.2 Secondary Endpoints 
Secondary endpoints of this study are: 
x 
Overall survival (OS), defined as time from randomization to death from any cause. 
x 
Overall objective response (OR), defined as complete response or partial response according 
to the current RECIST 1.1 criteria, on two consecutive occasions t 4 weeks apart.  
x 
Duration of objective response, defined as the period from the date of initial confirmed partial 
response (PR) or complete response (CR) until the date of progressive disease or death from 
any cause.  Tumor responses will be based on the current RECIST 1.1 criteria. 
x 
Progression-free survival, overall objective response, and the duration of objective response, 
as assessed by a blinded central review using the RECIST 1.1 criteria. 
x 
Cumulative incidence of brain metastases, with event time defined as time from 
randomization to documentation of brain metastases in patients who do not have brain 
metastases at entry. 
x 
Frequencies of adverse events, including cardiac events and late immune-mediated toxicities, 
categorized using the NCI Common Terminology Criteria for Adverse Events Version 5.0 
(CTCAE v5.0). 
Use of this document is governed by the terms of use on the first page of this document.

 
NRG-BR004 
151 
NCI Version Date: August 15, 2022 
14.3 
Primary Objective and Primary Hypothesis 
14.3.1 Primary Objective 
The primary objective is to determine whether the addition of atezolizumab to a regimen of 
taxane chemotherapy (paclitaxel or docetaxel), administered with pertuzumab and trastuzumab 
will improve PFS, assessed by investigator using RECIST 1.1 criteria, relative to the addition of a 
placebo to a regimen of taxane chemotherapy (paclitaxel or docetaxel) administered with 
pertuzumab and trastuzumab, and placebo in patients with newly documented HER2-positive 
measurable metastatic breast cancer. 
14.3.2 Primary Hypothesis 
The addition of atezolizumab to a regimen of taxane chemotherapy (paclitaxel or docetaxel), 
administered with pertuzumab and trastuzumab is superior to the addition of placebo to a regimen 
of taxane chemotherapy (paclitaxel or docetaxel) administered with pertuzumab and trastuzumab 
in patients with newly documented HER2-positive measurable metastatic breast cancer, as 
measured by PFS per RECIST 1.1 as assessed by investigators from the participating institutions. 
14.3.3 Power Justification 
In this trial, patients will be randomized to receive atezolizumab added to a regimen of taxane 
chemotherapy (paclitaxel or docetaxel) administered with pertuzumab and trastuzumab or a 
placebo added to a regimen of taxane chemotherapy (paclitaxel or docetaxel) administered with 
pertuzumab and trastuzumab.  In the CLEOPATRA study, the median PFS time was 16.5 months 
for patients with HER2-positive measurable MBC who were randomized to docetaxel, 
pertuzumab, and trastuzumab.  We assume that patients on the arm treated with a placebo added 
to a regimen of taxane chemotherapy (paclitaxel or docetaxel) administered with pertuzumab and 
trastuzumab will have a similar PFS.  In this trial, it is hypothesized that the addition of 
atezolizumab will improve the median PFS time by 6 months from 16.5 months to 22.5 months, 
which corresponds to a hazard ratio at 0.733.  With a type I error rate of 0.05, we would have 
80% power to detect such an improvement in median PFS from the addition of atezolizumab 
when 326 PFS events are observed at the definitive analysis in this study (Schoenfeld 1983). 
14.3.4 Expected Sample Size and Accrual Estimates 
Based on accrual data from the CLEOPATRA study and accrual pattern before protocol 
Amendment #3, it is expected that 20 patients with newly documented HER2-positive measurable 
MBC will be enrolled each month.  By March 22, 2021, a total of 99 patients were enrolled.  
After Amendment #3, we expect the monthly accrual rates will increase at about 5, 7, 10, 12, 15, 
and 20 during the first 6 months and reach 20 per month afterwards.  We expect to complete the 
target accrual of 600 patients after another 29 months.  Considering the event rates, a 5% annual 
loss-to-follow-up rate and time needed for clinical assessment and data collection, the definitive 
analyses will be carried out at about 59 months after the initiation of this study or 40 months after 
Amendment #3. 
14.4 
Statistical Analyses 
14.4.1 Analysis Populations 
The intent-to-treat population is defined as all patients who are randomized in the study.  
Analyses of PFS, OS, brain metastasis, overall objective response, and duration of objective 
Use of this document is governed by the terms of use on the first page of this document.

 
NRG-BR004 
152 
NCI Version Date: August 15, 2022 
response will be based on the ITT population.  For analysis on brain metastasis, patients with 
brain metastasis at study entry will be excluded.  For duration of response, only patients who have 
developed PR or CR during the study will be included in the analysis. 
The safety population includes all patients who have received study medication (atezolizumab or 
placebo) along with a taxane (paclitaxel or docetaxel) pertuzumab and trastuzumab have at least 
one safety assessment on treatment. 
14.4.2 Analyses of Data on the Primary Endpoint 
The intention-to-treat principle will be used for primary analyses of the endpoints.  Therefore, the 
analyses will be performed on all randomized patients. 
The event time for PFS is defined as time from randomization to the first occurrence of 
documented disease progression, as determined using the current RECIST 1.1 criteria, or death 
from any causes.  PFS is censored at the last adequate tumor assessment using the RECIST 1.1 
criteria for patients who have not had disease progression and are still alive by the data closure 
date.  For patients who never have any tumor assessment or survival follow-up, their PFS is 
censored at time of randomization.  As the primary analysis, the stratified log-rank test will be 
used to compare the PFS between the two treatment arms with the following stratification factors: 
prior neoadjuvant or adjuvant therapy with trastuzumab (no; yes), estrogen receptor status 
(positive; negative), PD-L1 status (positive; negative or indeterminant), disease sites (any visceral 
without brain metastasis; non-visceral only without brain metastasis; brain metastasis), and choice 
of taxane (paclitaxel; docetaxel).  In case sparse strata pose a problem for the stratified log-rank 
test, we plan to collapse on disease sites before performing the test because we do not expect 
many patients with brain metastasis.  However, if the enrollment data show a different pattern, we 
will consider alternative proposals to collapse the sparse strata and amend the protocol before the 
definitive analysis.  The Kaplan-Meier estimates will be calculated by treatment arms (Kaplan 
1958).  We will use stratified Cox proportional hazards models to estimate the hazard ratio 
associated with the addition of atezolizumab vs placebo after adjusting for the stratification 
factors, and the following potential confounders: nature of the distant metastasis (de novo vs. 
recurrent), age, and number of metastatic sites (<3, t3) (Cox 1975).  The Efron's method will be 
used to handle the ties in event times.  The underlying assumption of proportional hazards will be 
evaluated using Schoenfeld residuals and martingale residuals (Lin 1993).  If there is indication 
of assumption violation, time-dependent Cox models or Cox models with penalized smoothing 
spline will be explored (Kalbfleisch 2000).  Cox proportional hazards models will be further used 
to study the interactions between treatment and patient characteristics such as estrogen receptor 
status, disease site, nature of the distant metastasis (de novo vs. recurrent), age, number of 
metastatic sites (3, t3), and potential biomarkers for predicting the magnitude of superiority of 
atezolizumab to placebo in this study population. 
Disease progression will be formally assessed every three months during the first three years and 
every six months during Years 4 through 10.  However, some patients may miss follow-up visits 
and do not have adequate tumor assessment for a prolonged time period.  For patients who 
developed disease progression or died without an adequate tumor assessment within a lengthy 
period (five months during the first three years after study entry and eight months after three 
years) prior to the event, we will censor their PFS at their last radiological assessment 
determining a lack of progression and perform sensitivity analyses on the PFS data accordingly.  
Anticipating that some patients may take non-protocol anti-cancer therapies, in the sensitivity 
analyses we will also consider censoring their PFS at the last radiological assessment prior to the 
off-protocol therapies either only for those who do not develop a PFS event later on or for all 
Use of this document is governed by the terms of use on the first page of this document.

 
NRG-BR004 
153 
NCI Version Date: August 15, 2022 
these patients regardless whether or not they develop disease progression or die after the non-
protocol anti-cancer therapies.  Patients who discontinue all protocol therapy in the absence of 
progression should continue to be followed per study calendar until they have first progression 
event.  Non-protocol therapy must be reported in eCRF. 
14.4.3 Analyses of Data on Overall Survival 
Overall survival (OS) is defined as time from randomization to death due to any cause.  
Following the determination of the first disease progression, patients will be assessed every  
6 months for survival.  For patients who are alive at the last tumor assessment or survival follow-
up, their OS is censored at the corresponding occasion.  For patients who never have any tumor 
assessment or survival follow-up, their OS is censored at time of randomization.  The intent-to-
treat analyses will be performed for OS.  The stratified log-rank test will be used as the primary 
analysis to compare the OS between the two treatment arms, and a two-sided alpha level at 0.05 
will be used for claiming statistical significance.  The stratification factors are the same as what 
are used in the stratified log-rank test for the primary analysis on PFS.  The Kaplan-Meier 
estimates will be calculated by treatment arms.  We will use stratified Cox proportional hazards 
models to estimate the hazard ratio associated with the addition of atezolizumab vs placebo after 
adjusting for the stratification factors and other potential confounders such as nature of the distant 
metastasis (de novo vs. recurrent), age, and number of metastatic sites ( 3, t 3).  The Efron's 
method will be used to handle the ties in event times.  The underlying assumption of proportional 
hazards will be evaluated using Schoenfeld residuals and martingale residuals (Lin 1993).  Cox 
proportional hazards models will be further used to study the interactions between treatment and 
patient characteristics such as estrogen receptor status, disease site, nature of the distant 
metastasis (de novo vs. recurrent), age, number of metastatic sites ( 3, t 3), and potential 
biomarkers for predicting the magnitude of superiority of atezolizumab to placebo in OS in this 
study population. 
To control the type I error, the hypothesis testing in comparing PFS and OS between the two 
treatment arms will follow a hierarchical fixed sequence testing procedure with PFS as the 
primary endpoint and OS as the secondary endpoint.  If there is no statistical significant 
difference in PFS between the two treatment arms, analysis of OS data will be performed without 
a formal test or claim for statistical significance.  If the atezolizumab arm is shown to be 
statistically significantly superior to the placebo arm with a 2-sided alpha level at 0.05, a formal 
comparison in OS between the atezolizumab arm and the placebo arm will be performed with a  
2-sided alpha level at 0.05.  
The final analysis of OS will be performed when 326 deaths are observed.  If OS were the sole 
endpoint under consideration other than a secondary endpoint of the hierarchical fixed sequence 
testing procedure, we would have 80% power to detect a hazard ratio of 0.733 in OS as well as 
between the atezolizumab arm and the placebo arm with a two-sided alpha level at 0.05.  
Anticipating that the median OS of the placebo arm is about 56.5 months according to the 
CLEOPATRA study, the final analysis of OS is expected at about ten years after study initiation. 
14.4.4 Analyses of Data on Other Secondary Efficacy Endpoints 
Following the determination of the first disease progression, patients will be assessed every  
6 months for survival, late immune toxicities, and use of subsequent immuno-oncology (IO) 
therapy.  Late IO toxicities will be collected up to final analysis of OS, death, or receipt of 
alternative IO therapy.  If the study is shown negative at the definitive analysis of the PFS data, 
further follow-up will be limited to survival and late IO toxicities.  Similar to PFS, intent-to-treat 
analyses will be performed for brain metastases.  Patients with brain metastasis at study entry will 
Use of this document is governed by the terms of use on the first page of this document.

 
NRG-BR004 
154 
NCI Version Date: August 15, 2022 
be excluded from the analysis on brain metastasis.  The event time is time from randomization to 
the occurrence of brain metastasis.  Patients who are alive or die without brain metastasis at their 
last follow-up are censored at their last follow-up.  Patients who never have any tumor assessment 
or survival follow-up are censored at time of randomization.  The stratified log-rank test will be 
used to compare the risk of brain metastasis between the two treatment arms.  The stratification 
factors are the same as what are adopted for the analysis on PFS.  The Kaplan-Meier estimates 
will be calculated by treatment arms.  We will use stratified Cox proportional hazards models to 
estimate the hazard ratio associated with the addition of atezolizumab vs placebo after adjusting 
for the stratification factors and other potential confounders such as nature of the distant 
metastasis (de novo vs. recurrent), age, and number of metastatic sites ( 3, t 3). 
The duration of objective response is defined as the duration from the initial confirmed PR or CR 
until the date of disease progression or death from any cause.  Because patients who never 
developed PR or CR during the study will not be included in the analysis, the comparison in the 
duration of objective response between the two treatment arms will be performed similar to the 
analysis of quality-adjusted lifetime (Zhao 2001). 
The overall objective response is defined as CR or PR according to the current RECIST 1.1 
criteria, on two consecutive occasions, t 4 weeks apart.  Patients with disease localized only to 
the bone will not be included in the analysis of objective response.  Patients who never have 
subsequent tumor assessment during the study will be regarded as non-responders.  The stratified 
Cochran-Mantel-Haenszel test will be used to compare the object response between the treatment 
arms. 
The PFS, overall objective response, and duration of objective response, as assessed by a blinded 
central review using the RECIST 1.1 criteria, will be compared as secondary endpoints between 
the two treatment arms via similar aforementioned analytical methods as their counterparts as 
determined by investigators.  The blinded central review uses CT/MRI images to assess PFS.  
Patients with a breast primary as the only measurable lesion, which is being followed by 
mammogram or ultrasound rather than CT scan, will not be included in the secondary analyses of 
PFS, overall objective response, and duration of objective response based on blinded central 
review.  Submission of images for blinded review are no longer required for these patients. 
Exploratory analyses will be performed with PFS assessed under the iRECIST criteria to tease out 
pseudoprogression due to temporary tumor flare from progressive disease in patients under 
immunotherapy.  The statistical analysis of this exploratory endpoint will follow the same 
approach as that for the primary endpoint except that the iRECIST criteria will be used for 
assessing disease progression instead of the RECIST 1.1 criteria.  If pseudoprogression is very 
rare in this study, we will not pursue the analysis of this secondary endpoint.  
Analysis of objective response, duration of objective response, toxicity profiles, and PFS as 
assessed via iRECIST criteria will occur at the definitive analysis of PFS.  The analysis of brain 
metastasis will be performed at the same time as the final analysis of OS. 
14.4.5 Early Safety Run-in Analysis of Adverse Events 
In order to provide an early safety look, a formal analysis of the toxicity data will be performed at 
sixteen weeks after the hundredth patient is randomized and reviewed by the DMC.  All toxicity 
data collected from the first 100 patients up to that time point are included in this analysis. 
Use of this document is governed by the terms of use on the first page of this document.

 
NRG-BR004 
155 
NCI Version Date: August 15, 2022 
14.4.6 Monitoring and Analyses of Adverse Events Data and Drug Delivery 
All adverse events, including late immune-mediated events and cardiac toxicity, will be graded 
according to the CTCAE v5.0, and the endpoint for the safety analyses is the proportions of the 
highest grades in various adverse events categories.  Comparisons of the adverse events between 
the two treatment arms will be done by the Fisher’s exact test.  Immune-mediated adverse events 
will be tabulated.  The DMC will review safety data every 6 months after the study is activated. 
In addition to reporting the cumulative toxicity data for all study patients to the DMC, we will 
also report toxicity data by timing of occurrence during specific periods of treatment after study 
entry: first 6 months, between 6 months and 12 months, 12-24 months and after 24 months.  
During the first 6 months after study entry, most of the patients on study treatments would have 
paclitaxel or docetaxel and HER2-targeted therapies with or without atezolizumab.  Between  
6 months and 24 months after study entry, most of patients on study treatments would have 
HER2-targeted therapies with or without atezolizumab.  From 24 months on, most of patients on 
study treatments would only have HER2-targeted therapies.  Analysis of the adverse events data 
will be performed at the definitive analysis of PFS.  Final analysis of long term safety data, 
especially the late-immune mediated events data, will also be performed when the final analysis 
of OS occurs. 
We will monitor drug delivery and share with the DMC.  For paclitaxel or docetaxel, we will 
monitor the distribution of number of doses (mean, median, and standard deviation) for each  
6-week cycle overall and by treatment arm.  For trastuzumab and pertuzumab, we will monitor 
the distribution of administered doses every three months overall and by treatment arm during the 
first year of protocol therapy. 
In order to assess the potential cardiac side effects due to trastuzumab, pertuzumab, and 
atezolizumab, we will perform LVEF assessments every 3 months during the first 2 years and 
report to DMC the overall distribution of LVEF assessments and by treatment arm. 
PRO-CTCAE data will not be included in the formal analysis of the toxicity data and will not be 
shared with the DMC as it is being collected as part of a feasibility study.  See Section 14.6.2 for 
details. 
14.4.7 Evaluation of Potential Prognostic and Predictive Markers Retrieved from Tissue Samples 
14.4.7.1 PD-L1 Expression 
The PD-L1 expression is determined by the VENTANA anti-PD-L1 (SP142) Rabbit 
Monoclonal Primary Antibody assay and scored in two categories: IC0 and IC1/2/3.  
Tissue samples that are scored IC1/2/3 are called PD-L1 positive.  Clinical response to 
therapies targeting the PD1/PD-L1 axis has been shown to be associated with 
expression of PD-L1 in a number of cancers (Topalian 2012, Herbst 2014, Borghaei 
2015, Fehrenbacher 2016, Herbst 2016, Rosenberg 2016), including HER2-positive 
breast cancer (Loi 2017).  The expression of PD-L1 in at least one percent of tumoral 
immune cells using the SP142 PDL1 IHC assay has been associated with clinical 
response to atezolizumab in the OAK and POPLAR studies in metastatic NSCLC 
(Rittmeyer 2017, Fehrenbacher 2016), the IMvigor210 study in metastatic urethral 
carcinoma (Rosenberg 2016) and the IMmotion151 in metastatic renal cell carcinoma 
(Motzer 2018).  A retrospective analysis of the Phase 1 PDC4989g atezolizumab 
monotherapy clinical study suggests that PD-L1 expression in at least one percent of 
tumoral immune cells may be associated with improved overall response rate and 
overall survival in TNBC patients (Li 2018).  Based on these data, additional studies 
Use of this document is governed by the terms of use on the first page of this document.

 
NRG-BR004 
156 
NCI Version Date: August 15, 2022 
are testing the association of PD-L1 status (using this t 1 percent immune cell cutoff 
for the SP142 PDL1 IHC assay) with benefit of atezolizumab treatment in breast cancer 
(Mittendorf 2018, Miles 2018). 
The PD-L1 status (positive vs. negative will be the primary predictive marker under 
investigation in this correlative science sub-study.  Patients with indeterminant PD-L1 
status will be excluded in the following analysis.  At first, contingency table analyses 
will be used to explore the association between PD-L1 expression (positive vs negative, 
or in ordinal scale) and clinicopathological characteristics such as ER, tumor grade, 
disease sites.  Two-sample t-test or the nonparametric Wilcoxon rank-sum test will be 
used to study the association between PD-L1 status (positive vs negative) and 
continuous clinicopathological characteristics such as age.  The stratified Cox 
proportional hazard model that includes treatment, the PD-L1 status and their 
interaction will be used to test whether the PD-L1 status is a predictor for the benefit in 
PFS from atezolizumab (vs placebo), in patients with newly documented HER2-
positive measurable metastatic breast cancer treated with a regimen of paclitaxel or 
docetaxel, pertuzumab, and trastuzumab.  Potential confounders such as the nature of 
the distant metastasis (de novo vs. recurrent), age, and number of metastatic sites (< 3, 
t 3) will be adjusted.  The likelihood ratio test will be used for testing the interaction 
term in the model and the alpha level for claiming statistical significance is 0.05.  
Subsequently, interaction between treatment and PD-L1 expression in the ordinal scale 
or nominal scale will be explored in such Cox models to look for potential trend or cut-
off in PD-L1 expression.  In case there is no enough evidence to support PD-L1 as a 
predictive marker for benefit from atezolizumab, stratified Cox models will be used to 
determine whether PD-L1 status is a prognostic marker for PFS, after adjusting for 
other potential confounders and treatment, in the study population.  Similar analyses 
will be performed with OS as the endpoint.  Contingency table analyses and logistic 
regression models will be used to study the prognostic and predictive utility of PD-L1 
status on the overall objective response. 
We expect that 40% of the study patients will be PD-L1 positive.  With 326 PFS events 
at the definitive analysis, we will have about 86% power to detect a ratio of 0.5 
between the efficacy of atezolizumab (vs placebo), in terms of hazard ratio, among  
PD-L1 positive patients and the efficacy of atezolizumab among PD-L1 negative 
patients under a 2-sided type I error at 0.05. 
14.4.7.2 Other Potential Immune Markers 
We will further explore the prognostic and predictive utility (of the efficacy of 
atezolizumab) of potential immune biomarkers such as the immune-mediated gene 
expression signatures, antibodies status from multiplex immunofluorescence, cell-free 
circulating tumor DNA (ctDNA), stromal tumor infiltrating lymphocytes (sTIL), and 
intrinsic subtype of the tumor.  Formal proposals with detailed statistical analysis plan 
will be submitted to CTEP for approval according to NCTN guidelines. 
14.5 
Study Monitoring 
14.5.1 Interim Futility Monitoring of the Primary Objective 
One interim futility analysis will be performed when the number of PFS events reaches 218.  The 
protocol statistician will prepare necessary data with treatment blinded.  Another NRG Oncology 
statistician will have access to the treatment assignment and perform the comparison in PFS 
Use of this document is governed by the terms of use on the first page of this document.

 
NRG-BR004 
157 
NCI Version Date: August 15, 2022 
between the atezolizumab arm and the placebo arm via the stratified log-rank test with the 
following stratification factors: prior neoadjuvant or adjuvant therapy with trastuzumab (no; yes), 
estrogen receptor status (positive; negative), PD-L1 status (positive; negative or indeterminant), 
disease sites (any visceral without brain metastasis; non-visceral only without brain metastasis; 
brain metastasis), and choice of taxane (paclitaxel; docetaxel).  The futility bound is a one-sided 
p-value at 0.05 in favor of the placebo arm under this stratified log-rank test.  To cross this futility 
bound, the estimated hazard ratio between the atezolizumab arm and the placebo arm is at least 
1.25.  This NRG Oncology statistician will only present whether or not the futility bound has 
been crossed to the NRG Oncology Data Monitoring Committee (DMC).  The result from this 
interim futility analysis will be used by the DMC to decide together with all other information 
relevant to the trial if it is appropriate to make a recommendation regarding the continuation of 
the trial as planned.  The interim futility analysis is expected to occur at about 47 months after the 
initiation of the study. 
14.5.2 Interim Analyses of the Overall Survival 
If the atezolizumab arm is shown to be statistically significantly superior to the placebo arm in the 
primary analysis on PFS, two superiority interim analyses of OS will be performed.  The first 
interim analysis of OS will be performed at the time of the definitive analysis of PFS.  
Anticipating that the median OS of the control arm is about 56.5 months according to the 
CLEOPATRA study and assuming that the hazard ratio in OS between the two treatment arms 
remains at 0.733, about 133 deaths are expected at that occasion.  The second interim analysis of 
OS will be performed when 229 deaths occur in this study.  The decision boundaries of the two 
interim analyses will be two-sided with alpha levels fixed at 0.005 and 0.01, respectively.  Alpha 
spending will be used to determine the significance level of the final analysis (Fleming 1984).  
Anticipating that 133 and 229 deaths will occur at the first two interim analyses and 326 deaths 
occur at the final analysis of OS, we expect the two-sided significance level of the final analysis 
will be approximately 0.047 in order to control the type I error rate at 0.05.  Depending on the 
actual number of deaths observed at the first interim analysis, the two-sided alpha level for the 
final analysis may need to be adjusted slightly according to the alpha spending function approach 
for type I error control at 0.05.  The protocol will be amended after the first interim analysis of 
OS to reflect that change if the number of deaths then differ from 133, although the adjustment is 
expected to be minimal.  The second interim analysis of OS is anticipated at about six years and 9 
months after study initiation.   
If this trial fails to demonstrate the superiority of the atezolizumab arm in PFS, two analyses of 
OS will be performed without a formal test or claim for statistical significance.  The first analysis 
of OS will be performed at the time of the definitive analysis of PFS and the second analysis of 
OS will be performed when 326 deaths are observed or 10 years after the study initiation, 
whichever occurs first. 
14.5.3 Monitoring of Patient Accrual 
The NRG Oncology DMC will review the study twice a year with respect to patient accrual, 
including accrual rate and disease sites.   
14.5.4 Monitoring of Protocol Treatment 
Treatment adherence data will be summarized every 6 months and shared with the DMC. 
Use of this document is governed by the terms of use on the first page of this document.

 
NRG-BR004 
158 
NCI Version Date: August 15, 2022 
14.5.5 Further Monitoring 
The NRG Oncology DMC will review morbidity, serious adverse events, and loss to follow-up.  
We expect that the annual loss to follow-up is at most 5%.  If the annual follow-up is more than 
5% at 2 years after the initiation of this study, we will study the loss to follow-up data, identify 
possible causes, and take actions to reduce loss to follow-up. 
The NRG Oncology DMC also will review the study on an "as needed" basis. 
14.6 
Statistical Consideration for QOL Study 
14.6.1 QOL sample size 
A sample of 420 patients is sufficient to provide a statistical power of 86% to detect non-
inferiority of atezolizumab, compared to placebo, in terms of average level of fatigue during the 
first year after randomization.  The two-sided probability of type I error is 0.05 and the margin of 
non-inferiority is 30% of the standard deviation of the average fatigue score during the first year 
after randomization.  Adjusting upward dropout rate of 20%, we will require 526 patients to 
participate in the QOL study. 
14.6.2 QOL Analyses 
The timing of patient’s baseline assessment will be different beginning with Amendment #3 (at 
randomization prior Amendment #3 vs. at study entry after Amendment #3).  In addition, starting 
with Amendment #3, docetaxel will also be allowed as an option for the choice of standard 
chemotherapy.  To account for these differences, all analyses will be adjusted for the choice of a 
taxane and the timing of patient’s randomization to the study (prior Amendment #3, paclitaxel 
after Amendment #3, docetaxel after Amendment #3). 
For our primary hypothesis, the average PROMIS Fatigue score over three time points during the 
first year after study entry (12 weeks, 24 weeks, and 12 months) will be computed for each 
patient.  To address the primary hypothesis on QOL, we will compare the means of those scores 
between the two treatment groups.  The non-inferiority of atezolizumab in terms of fatigue will be 
claimed if the upper bound of the two-sided 95% confidence interval for the difference of these 
two means is below the defined margin of non-inferiority.  A linear mixed model for repeated 
measures with adjustment for the corresponding baseline score, time, and nature of distant 
metastasis (de novo vs. recurrent) will be used to impute the PROMIS Fatigue score for patients 
with missing assessments.  Presence of treatment-by-time interaction will be investigated in this 
linear mixed model.   
To assess the effect of atezolizumab on physical functioning, the PROMIS PF scale scores will be 
compared between the two treatment groups using a linear mixed model for repeated measures 
with adjustment for the baseline score, time, and nature of distant metastasis (de novo vs. 
recurrent).  Presence of treatment-by-time interaction will be investigated.  Similar analysis will 
be performed to evaluate the effect of atezolizumab on fatigue as measured by the PROMIS 
Fatigue scale over all of the data collection time points and on QOL as measured by FACT-B-
TOI over 12 and 24 months.   
To assess the effect of atezolizumab on treatment- and disease-related symptoms over time, the 
distributions of the corresponding PRO-CTCAE items will be compared between the two 
treatment groups using a mixed ordinal logistic regression model.  The model will also include 
the corresponding baseline measurement, time, and nature of distant metastasis (de novo vs. 
recurrent).  Presence of treatment-by-time interaction will be tested for each of these endpoints.  
Use of this document is governed by the terms of use on the first page of this document.

 
NRG-BR004 
159 
NCI Version Date: August 15, 2022 
The descriptive and graphical methods suggested in Basch et al. (Basch 2016) will be used to 
summarize the distributions of different symptoms by treatment group over time. 
To examine the impact of treatment and treatment-related symptoms on physical function at  
12 months after study entry, a multiple linear regression model will be performed with the 
PROMIS PF scale score as an outcome and treatment and treatment-related symptoms as 
covariates.  Presence of treatment by each individual symptom item interactions will be 
investigated. 
The clinical meaningfulness of all comparisons will be considered (Yost 2011). 
14.6.3 Missing QOL Data 
A certain amount of missing data is expected; however, we have extensive experience in the 
collection of patient-reported outcome data with excellent adherence to data collection across 
multiple studies as such data are considered as part of institutional performance metrics.  
Prospective calendars and reminder systems are in place to ensure collection of these data.  The 
information from patients with missing data will be reviewed in order to determine whether data 
analytic procedures are likely to be biased.  Patients with missing data will be reviewed for 
imbalances in factors such as trial arm, treatment adherence, institution, and reason for non-
adherence.  When QOL data are missing at a particular time point, data from prior time points 
will be reviewed in order to investigate whether missing status was preceded by a significant 
change in QOL scores.  In addition, we will investigate whether missing item status is related to 
other scores on the same questionnaire.  If no missing data mechanism can be detected following 
this review, the data will be analyzed assuming that the data are missing at random.  If, on the 
other hand, a non-random missing data mechanism appears to be present, we will undertake to 
develop an appropriate analytic strategy to control for the potential bias.  We will also present 
sensitivity analyses based on varying assumptions about the missing-data mechanism. 
14.6.4 Statistical Consideration for PRO-CTCAE Monitoring 
With Amendment #3, accrual to the PRO-CTCAE substudy is closed.  Patients enrolled on the 
PRO-CTCAE substudy prior to Amendment #3 will continue to complete the scheduled 
assessments as outlined on Table 2.  Accrual to the QOL substudy will continue. 
14.6.4.1 Primary Analysis (Feasibility Stage) 
The frequent PRO-CTCAE data collection will be conducted in the first 100 patients 
who read or understand English, Spanish, or French accrued to the study. 
An early feasibility look will be performed after 50 patients are randomized.  The 
descriptive and graphical methods will be used to summarize the available data 
(combined across treatment groups) and assess the amount of data missing.  If it 
appears that a substantial amount of data is missing, the appropriate activities will be 
initiated to boost the data collection. 
Twelve weeks after the hundredth patient is randomized (when the toxicity data on the 
first 2 cycles is available from the first 100 patients), the feasibility of weekly 
assessment (Cycles 1-2) of toxicity with ePRO reporting will be assessed.  A cutoff of 
25% of expected data missing will be used to determine feasibility.  A patient will be 
defined as compliant if he/she has submitted 75% or more of the scheduled assessments 
(at least 9 out of 12 weekly assessments), otherwise the patient will be considered to be 
non-compliant.  A formal test of ܪ଴ǣ݌൑ͲǤʹͷ vs. ܪ௔ǣ ݌൐ͲǤʹͷ, where ݌ is the 
Use of this document is governed by the terms of use on the first page of this document.

 
NRG-BR004 
160 
NCI Version Date: August 15, 2022 
proportion of compliant patients, will be conducted using an ߙ-level of 0.05.  After 
reviewing the compliance data, the study team will reassess the feasibility of the PRO-
CTCAE data collection from all patients in the trial. 
At the end of the study, a thorough analysis of the available PRO-CTCAE data  
(Cycles 1-2) will be performed.  Univariate and multivariate logistic regression will be 
used to assess the factors that are associated with patients’ compliance with the weekly 
assessments.  All tests will be based on an alpha level of 0.05. 
14.6.4.2 Secondary Analyses 
The descriptive and graphical methods suggested in Basch et al. (Basch 2016) will be 
used to summarize the distributions of different symptoms by treatment group over 
time.  The patterns of differences between the toxicities reported on a weekly or cycle 
basis will be investigated.  The agreement between patients and clinicians assessment 
of the toxicity will be assessed using weighted ț statistic. 
Since PRO-CTCAE is a novel assessment strategy of the patient-reported outcomes, a 
preferred statistical methodology for the analyses of these data is still under 
investigation.  Therefore, additional analyses of the data will be considered if the new 
approaches emerge. 
The analyses dealing with the missing PRO-CTCAE data will be similar to the ones 
described in Section 14.6.3.  The use of the clinician-reported AE data as an approach 
to missing patient-reported data will also be considered (Basch 2016). 
14.7 
Gender/Ethnicity/Race Distribution 
Possible racial and ethnic variation in response to the treatment under consideration is of great 
concern to African-Americans.  Researchers have noted poorer survival rates for African-
American breast cancer patients as compared to Caucasians (Baquet 1986, Youn 1984).  This 
difference has been attributed to many factors, including more advanced disease at the time of 
diagnosis (Satariano 1986), social and economic factors (Bassett 1986), or specific tumor 
characteristics such as ER status (Crowe 1986, Mohla 1982).  Although outcomes tend to be less 
favorable for African-Americans, significant race-by-treatment interactions have not been 
previously reported suggesting that, where treatment efficacy exists, both groups appear to 
benefit.  Previous NSABP investigations of the relationship between race and prognosis support 
these conclusions (Dignam 1997, Costantino 1987). 
Potential for the enrollment of minority patients in this protocol is enhanced by NRG Oncology's 
recognition of the importance of increasing minority accrual.  To this end, we provide educational 
opportunities for NRG Oncology investigators and coordinators to increase their awareness and 
skills related to recruitment of racial and ethnic minority populations.  The distributions of 
ethnicity and race for BR004 are projected from the North American participants of the 
CLEOPATRA study (Roche 2016).  The ethnicity distribution of the US participants of the 
CLEOPATRA study consists of 9.6% Hispanic and 90.4% non-Hispanic.  The racial distribution 
in the US CLEOPATRA population is 83% white; 11% black, not of Hispanic origin; 3% Asian; 
0% American Indian or Alaskan Native, and 3% others.  Note that the majority of non-US North 
American CLEOPATRA participants were from countries other than Canada from where most of 
international participants of this study come, the expected distributions of race and ethnicity for 
international participants of BR004 are estimated based on those distributions of both US and 
non-US CLEOPATRA populations. 
Use of this document is governed by the terms of use on the first page of this document.

Use of this document is governed by the terms of use on the first page of this document.

 
NRG-BR004 
162 
NCI Version Date: August 15, 2022 
14.8 
Amended Statistical Considerations 
Patient accrual was permanently closed, and atezolizumab/placebo was discontinued on May 20, 
2022, due to an imbalance of Grade 5 toxicities coupled with continued slow accrual rates that 
had not improved following protocol modifications to address identified barriers.  Patients were 
also unblinded on June 21, 2022, and notified of treatment assignment.  We plan to follow 
enrolled patients for an additional 2 years to assess progression-free survival and overall survival 
in the control and intervention arms.  The following statistical considerations reflect this change. 
14.8.1 Study Design 
NRG-BR004 was designed as a Phase III randomized, placebo-controlled, and double-blinded 
clinical trial.  One hundred and ninety patients were randomized in a 1:1 ratio to receive a 
regimen of pertuzumab and trastuzumab with a taxane (paclitaxel or docetaxel) and either 
atezolizumab or placebo.  By May 20, 2022, 93 patients were randomized to receive placebo and 
the other 97 patients were randomized to receive atezolizumab. 
Patients were stratified by 1) prior neoadjuvant or adjuvant therapy with trastuzumab (no; yes), 2) 
estrogen receptor status (positive; negative), 3) PD-L1 status (positive; negative or 
indeterminant), 4) disease sites (visceral without brain metastasis; non-visceral only without brain 
metastasis; brain metastasis), and 5) choice of taxane (paclitaxel; docetaxel).  A stratified random 
permuted blocks scheme was followed for the treatment assignment. 
14.8.2 Study Endpoints 
14.8.2.1 Primary Endpoint 
The primary endpoint is PFS, defined as the time from randomization to the first documented 
progressive disease, as determined by investigator using the current RECIST 1.1 criteria, or 
death from any causes, whichever occurs first. 
14.8.2.2 Secondary Endpoints 
x 
Overall survival (OS), defined as time from randomization to death from any cause. 
x 
Overall objective response (OR), defined as complete response or partial response 
according to the current RECIST 1.1 criteria, on two consecutive occasions t 4 weeks 
apart. 
x 
Frequencies of adverse events, including cardiac events and late immune-mediated 
toxicities, categorized using the NCI Common Terminology Criteria for Adverse Events 
Version 5.0 (CTCAE v5.0). 
14.8.3 Primary Objective and Primary Hypothesis 
14.8.3.1 Primary Objective 
The primary objective is to determine whether the addition of atezolizumab to a regimen of 
taxane chemotherapy (paclitaxel or docetaxel), administered with pertuzumab and trastuzumab 
will improve PFS in patients with newly documented HER2-positive measurable metastatic 
breast cancer. 
Use of this document is governed by the terms of use on the first page of this document.

 
NRG-BR004 
163 
NCI Version Date: August 15, 2022 
14.8.3.2 Primary Hypothesis 
The addition of atezolizumab to a regimen of taxane chemotherapy (paclitaxel or docetaxel), 
administered with pertuzumab and trastuzumab is superior to a regimen of taxane 
chemotherapy (paclitaxel or docetaxel) administered with pertuzumab and trastuzumab in 
patients with newly documented HER2-positive measurable metastatic breast cancer, as 
measured by PFS per RECIST 1.1 as assessed by investigators from the participating 
institutions. 
14.8.3.3 Power Justification 
In this trial, by May 20, 2022, 190 patients were randomized to receive a regimen of taxane 
chemotherapy (paclitaxel or docetaxel) administered with pertuzumab and trastuzumab with 
atezolizumab or a placebo.  In the CLEOPATRA study, the median PFS time was 16.5 months 
for patients with HER2-positive measurable MBC who were randomized to docetaxel, 
pertuzumab, and trastuzumab.  We assume that patients on the arm without atezolizumab have 
a similar PFS.  We plan to perform the definitive analysis with data closure on April 30, 2024. 
With a type I error rate of 0.05 (for a two-sided test), we would have 80% power to detect a 
PFS hazard ratio at 0.6 between the atezolizumab arm and the control arm at the primary 
analysis when about 121 PFS events are to be observed (Schoenfeld 1983).  The chance to 
detect a PFS hazard ratio at 0.733, as originally designed, would be about 43% at the primary 
analysis. 
14.8.4 
Statistical Analyses 
14.8.4.1 Analysis Populations 
The intent-to-treat (ITT) population is defined as all patients who are randomized in the study.  
Analyses of PFS and OS will be based on the ITT population.  Analyses of the overall objective 
response will be the sub-cohort of patients who were randomized six months or more prior to 
the study accrual closure to allow time for response assessment and confirmation as well as a 
reasonable exposure to study medication. 
The safety population includes all patients who have received study medication (atezolizumab 
or placebo) along with a taxane (paclitaxel or docetaxel), pertuzumab and trastuzumab and have 
at least one safety assessment on treatment. 
14.8.4.2 Analyses of Data on the Primary Endpoint 
The intention-to-treat principle will be used for primary analyses of the endpoints.  Therefore, 
the analyses will be performed on all randomized patients. 
The event time for PFS is defined as time from randomization to the first occurrence of 
documented disease progression, as determined using the current RECIST 1.1 criteria, or death 
from any causes.  PFS is censored at the last adequate tumor assessment using the RECIST 1.1 
criteria for patients who have not had disease progression and are still alive by the data closure 
date.  For patients who never have any tumor assessment or survival follow-up, their PFS is 
censored at time of randomization.  As the primary analysis, the stratified log-rank test will be 
used to compare the PFS between the two treatment arms with the following stratification 
factors: prior neoadjuvant or adjuvant therapy with trastuzumab (no; yes), estrogen receptor 
status (positive; negative), PD-L1 status (positive; negative or indeterminant), disease sites (any 
visceral without brain metastasis; non-visceral only without brain metastasis; brain metastasis), 
Use of this document is governed by the terms of use on the first page of this document.

 
NRG-BR004 
164 
NCI Version Date: August 15, 2022 
and choice of taxane (paclitaxel; docetaxel).  Because sparsity may pose a problem for the 
stratified log-rank test, we plan to collapse on choice of taxane and disease sites before 
performing the test because only seven patients had brain metastasis at study entry.  The 
Kaplan-Meier estimates will be calculated by treatment arms (Kaplan 1958).  We will use 
stratified Cox proportional hazards models to estimate the hazard ratio associated with the 
addition of atezolizumab vs placebo after adjusting for the stratification factors, and the 
following potential confounders: nature of the distant metastasis (de novo vs. recurrent), age, 
and number of metastatic sites (< 3,  3) (Cox 1975).  The Efron's method will be used to 
handle the ties in event times.  The underlying assumption of proportional hazards will be 
evaluated using Schoenfeld residuals and martingale residuals (Lin 1993).  If there is indication 
of assumption violation, time-dependent Cox models or Cox models with penalized smoothing 
spline will be explored (Kalbfleisch 2000).  Cox proportional hazards models will be further 
used to study the interactions between treatment and patient characteristics such as estrogen 
receptor status, disease site, nature of the distant metastasis (de novo vs. recurrent), age, 
number of metastatic sites (< 3,  3), and potential biomarkers for predicting the magnitude of 
superiority of atezolizumab to placebo in this study population. 
After this protocol amendment, disease progression status will be updated every six months 
until April 30, 2024.  Patients who discontinue all protocol therapy in the absence of 
progression should continue to be followed per study calendar. 
14.8.4.3 Analyses of Data on Overall Survival 
Overall survival (OS) is defined as time from randomization to death due to any cause.  After 
this protocol amendment, patients will be assessed every 6 months for survival.  For patients 
who are alive at the last follow-up, their OS is censored at the corresponding occasion.  For 
patients who never have any tumor assessment or survival follow-up, their OS is censored at 
time of randomization.  The intent-to-treat analyses will be performed for OS.  The stratified 
log-rank test will be used as the primary analysis to compare the OS between the two treatment 
arms, and a two-sided alpha level at 0.05 will be used for claiming statistical significance.  The 
stratification factors are the same as what are used in the stratified log-rank test for the primary 
analysis on PFS.  The Kaplan-Meier estimates will be calculated by treatment arms.  We will 
use stratified Cox proportional hazards models to estimate the hazard ratio associated with the 
addition of atezolizumab vs placebo after adjusting for the stratification factors and other 
potential confounders such as nature of the distant metastasis (de novo vs. recurrent), age, and 
number of metastatic sites (< 3,  3).  The Efron's method will be used to handle the ties in 
event times.  The underlying assumption of proportional hazards will be evaluated using 
Schoenfeld residuals and martingale residuals (Lin 1993).  Cox proportional hazards models 
will be further used to study the interactions between treatment and patient characteristics such 
as estrogen receptor status, disease site, nature of the distant metastasis (de novo vs. recurrent), 
age, number of metastatic sites (< 3,  3), and potential biomarkers for predicting the 
magnitude of superiority of atezolizumab to placebo in OS in this study population.  The 
analyses of OS will be performed at the same time as that for the primary analysis of PFS data. 
14.8.4.4 Analyses of Data on Other Secondary Efficacy Endpoints 
Following this protocol amendment, patients will be assessed every 6 months for survival, late 
immune toxicities, and use of subsequent immuno-oncology (IO) therapy.  Late IO toxicities 
will be collected up to final analysis of OS, death, or receipt of alternative IO therapy.   
The overall objective response is defined as CR or PR according to the current RECIST 1.1 
criteria, on two consecutive occasions,  4 weeks apart.  Patients with disease localized only to 
Use of this document is governed by the terms of use on the first page of this document.

 
NRG-BR004 
165 
NCI Version Date: August 15, 2022 
the bone will not be included in the analysis of objective response.  This analysis will be 
restricted to the sub-cohort of patients randomized six months or more prior to May 20, 2022.  
Only response data collected up to May 20, 2022, will be included in this analysis.  Patients 
who never have subsequent tumor assessment during the study will be regarded as non-
responders.  The stratified Cochran-Mantel-Haenszel test will be used to compare the object 
response between the treatment arms. 
All adverse events, including late immune-mediated events and cardiac toxicity, will be graded 
according to the CTCAE v5.0, and the endpoint for the safety analyses is the proportions of the 
highest grades in various adverse events categories.  Comparisons of the adverse events 
between the two treatment arms will be done by the Fisher’s exact test.  Immune-mediated 
adverse events will be tabulated.  Up to this protocol amendment, the DMC has reviewed safety 
data every 6 months after the study was activated. 
To assess the potential cardiac side effects due to trastuzumab, pertuzumab, and atezolizumab, 
we will perform LVEF assessments every 3 months during the first 2 years and monitor the 
overall distribution of LVEF assessments and by treatment arm. 
Analysis of the overall objective response, the adverse events data, including the late-immune 
mediated events data, will be performed at the definitive analysis of PFS.   
14.8.4.5 Evaluation of Potential Prognostic and Predictive Markers Retrieved from Tissue Samples 
The PD-L1 expression is determined by the VENTANA anti-PD-L1 (SP142) Rabbit 
Monoclonal Primary Antibody assay and scored in two categories: IC0 and IC1/2/3.  Tissue 
samples that are scored IC1/2/3 are called PD-L1 positive.  Clinical response to therapies 
targeting the PD1/PD-L1 axis has been shown to be associated with expression of PD-L1 in a 
number of cancers (Topalian 2012, Herbst 2014, Borghaei 2015, Fehrenbacher 2016, Herbst 
2016, Rosenberg 2016), including HER2-positive breast cancer (Loi 2017).  The expression of 
PD-L1 in at least one percent of tumoral immune cells using the SP142 PDL1 IHC assay has 
been associated with clinical response to atezolizumab in the OAK and POPLAR studies in 
metastatic NSCLC (Rittmeyer 2017, Fehrenbacher 2016), the IMvigor210 study in metastatic 
urethral carcinoma (Rosenberg 2016) and the IMmotion151 in metastatic renal cell carcinoma 
(Motzer 2018).  A retrospective analysis of the Phase 1 PDC4989g atezolizumab monotherapy 
clinical study suggests that PD-L1 expression in at least one percent of tumoral immune cells 
may be associated with improved overall response rate and overall survival in TNBC patients 
(Li 2018).  Based on these data, additional studies are testing the association of PD-L1 status 
(using this  1 percent immune cell cutoff for the SP142 PDL1 IHC assay) with benefit of 
atezolizumab treatment in breast cancer (Mittendorf 2018, Miles 2018). 
The PD-L1 status (positive vs. negative will be the primary predictive marker under 
investigation in this correlative science sub-study.  Patients with indeterminant PD-L1 status 
will be excluded in the following analysis.  At first, contingency table analyses will be used to 
explore the association between PD-L1 expression (positive vs negative, or in ordinal scale) 
and clinicopathological characteristics such as ER, tumor grade, disease sites.  Two-sample t-
test or the nonparametric Wilcoxon rank-sum test will be used to study the association between 
PD-L1 status (positive vs negative) and continuous clinicopathological characteristics such as 
age.  The stratified Cox proportional hazard model that includes treatment, the PD-L1 status 
and their interaction will be used to test whether the PD-L1 status is a predictor for the benefit 
in PFS from atezolizumab (vs control), in patients with newly documented HER2-positive 
measurable metastatic breast cancer treated with a regimen of paclitaxel or docetaxel, 
pertuzumab, and trastuzumab.  Potential confounders such as the nature of the distant 
metastasis (de novo vs. recurrent), age, and number of metastatic sites (< 3,  3) will be 
Use of this document is governed by the terms of use on the first page of this document.

 
NRG-BR004 
166 
NCI Version Date: August 15, 2022 
adjusted.  The likelihood ratio test will be used for testing the interaction term in the model and 
the alpha level for claiming statistical significance is 0.05.  Subsequently, interaction between 
treatment and PD-L1 expression in the ordinal scale or nominal scale will be explored in such 
Cox models to look for potential trend or cut-off in PD-L1 expression.  In case there is not 
enough evidence to support PD-L1 as a predictive marker for benefit from atezolizumab, 
stratified Cox models will be used to determine whether PD-L1 status is a prognostic marker 
for PFS, after adjusting for other potential confounders and treatment, in the study population.  
Similar analyses will be performed with OS as the endpoint.  Contingency table analyses and 
logistic regression models will be used to study the prognostic and predictive utility of PD-L1 
status on the overall objective response. 
We will further explore the prognostic and predictive utility (of the efficacy of atezolizumab) of 
potential immune biomarkers such as the immune-mediated gene expression signatures, 
antibodies status from multiplex immunofluorescence, cell-free circulating tumor DNA 
(ctDNA), stromal tumor infiltrating lymphocytes (sTIL), and intrinsic subtype of the tumor.  
Formal proposals with detailed statistical analysis plan will be submitted to CTEP for approval 
according to NCTN guidelines. 
14.8.4.6 Comparison in the incidence of subsequent brain metastasis 
Intent-to-treat analyses will be performed to compare the incidence of brain metastases between 
the two treatment arms.  Patients with brain metastasis at study entry will be excluded from the 
analysis on brain metastasis.  The event time is time from randomization to the occurrence of 
brain metastasis.  Patients who are alive or die without brain metastasis at their last follow-up 
are censored at their last follow-up.  Patients who never have any tumor assessment or survival 
follow-up are censored at time of randomization.  The stratified log-rank test will be used to 
compare the risk of brain metastasis between the two treatment arms.  The stratification factors 
are the same as what are adopted for the analysis on PFS.  The Kaplan-Meier estimates will be 
calculated by treatment arms.  We will use stratified Cox proportional hazards models to 
estimate the hazard ratio associated with the addition of atezolizumab after adjusting for the 
stratification factors and other potential confounders such as nature of the distant metastasis (de 
novo vs. recurrent), age, and number of metastatic sites (< 3,  3). 
14.8.5 Study Monitoring 
There will not be any interim analysis.  The study team will continue monitoring for late adverse 
immune mediated adverse events, progression events, and deaths and will provide a report every 
six months. 
14.8.6 Statistical consideration for the QOL and PRO-CTCAE substudy 
No formal statistical analyses of the collected QOL data will be performed.  The descriptive 
statistics for PROMIS Fatigue score, PROMIS PF scale scores, and FACT-B-TOI will be 
presented.  
Statistical Consideration for PRO-CTCAE substudy 
The feasibility of weekly assessment (Cycles 1-2) of toxicity with ePRO reporting will be 
assessed.  A cutoff of 25% of expected data missing will be used to determine feasibility.  A 
patient will be defined as compliant if he/she has submitted 75% or more of the scheduled 
assessments (at least 9 out of 12 weekly assessments), otherwise the patient will be considered to 
Use of this document is governed by the terms of use on the first page of this document.

Use of this document is governed by the terms of use on the first page of this document.

Use of this document is governed by the terms of use on the first page of this document.

 
NRG-BR004 
169 
NCI Version Date: August 15, 2022 
15.0 
PUBLICATION INFORMATION AND ADMINISTRATIVE AGREEMENTS 
The agent(s) supplied by CTEP, DCTD, NCI used in this protocol is/are provided to the NCI 
under a Collaborative Agreement (CRADA, CTA, CSA) between the Pharmaceutical 
Company(ies) (hereinafter referred to as ”Collaborator(s)”) and the NCI Division of Cancer 
Treatment and Diagnosis.  Therefore, the following obligations/guidelines, in addition to the 
provisions in the “Intellectual Property Option to Collaborator”  
(http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm) contained within the 
terms of award, apply to the use of the Agent(s) in this study: 
x 
Agent(s) may not be used for any purpose outside the scope of this protocol, nor can Agent(s) 
be transferred or licensed to any party not participating in the clinical study.  Collaborator(s) 
data for Agent(s) are confidential and proprietary to Collaborator(s) and shall be maintained 
as such by the investigators.  The protocol documents for studies utilizing Agent(s) contain 
confidential information and should not be shared or distributed without the permission of the 
NCI.  If a copy of this protocol is requested by a patient or patient’s family member 
participating on the study, the individual should sign a confidentiality agreement.  A suitable 
model agreement can be downloaded from: http://ctep.cancer.gov. 
x 
For a clinical protocol where there is an investigational Agent used in combination with 
(an)other  Agent(s), each the subject of different Collaborative Agreements, the access to and 
use of data by each Collaborator shall be as follows (data pertaining to such combination use 
shall hereinafter be referred to as "Multi-Party Data"): 
 
NCI will provide all Collaborator(s) with prior written notice regarding the 
existence and nature of any agreements governing their collaboration with NCI, 
the design of the proposed combination protocol, and the existence of any 
obligations that would tend to restrict NCI's participation in the proposed 
combination protocol. 
 
Each Collaborator shall agree to permit use of the Multi-Party Data from the 
clinical trial by any other Collaborator solely to the extent necessary to allow said 
other Collaborator to develop, obtain regulatory approval or commercialize its 
own Agent. 
 
Any Collaborator having the right to use the Multi-Party Data from these trials 
must agree in writing prior to the commencement of the trials that it will use the 
Multi-Party Data solely for development, regulatory approval, and 
commercialization of its own Agent. 
x 
Clinical Trial Data and Results and Raw Data developed under a Collaborative Agreement 
will be made available exclusively to Collaborator(s), the NCI, and the FDA, as appropriate 
and unless additional disclosure is required by law or court order as described in the IP 
Option to Collaborator 
(http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm).  Additionally, all 
Clinical Data and Results and Raw Data will be collected, used and disclosed consistent with 
all applicable federal statutes and regulations for the protection of human subjects, including, 
if applicable, the Standards for Privacy of Individually Identifiable Health Information set 
forth in 45 C.F.R. Part 164. 
Use of this document is governed by the terms of use on the first page of this document.

 
NRG-BR004 
170 
NCI Version Date: August 15, 2022 
x 
When a Collaborator wishes to initiate a data request, the request should first be sent to the 
NCI, who will then notify the appropriate investigators (Group Chair for Cooperative Group 
studies, or PI for other studies) of Collaborator's wish to contact them. 
x 
Any data provided to Collaborator(s) for Phase 3 studies must be in accordance with the 
guidelines and policies of the responsible Data Monitoring Committee (DMC), if there is a 
DMC for this clinical trial. 
x 
Any manuscripts reporting the results of this clinical trial must be provided to CTEP by the 
Group office for Cooperative Group studies or by the principal investigator for  
non-Cooperative Group studies for immediate delivery to Collaborator(s) for advisory review 
and comment prior to submission for publication.  Collaborator(s) will have 30 days from the 
date of receipt for review.  Collaborator shall have the right to request that publication be 
delayed for up to an additional 30 days in order to ensure that Collaborator’s confidential and 
proprietary data, in addition to Collaborator(s)’s intellectual property rights, are protected.  
Copies of abstracts must be provided to CTEP for forwarding to Collaborator(s) for courtesy 
review as soon as possible and preferably at least three (3) days prior to submission, but in 
any case, prior to presentation at the meeting or publication in the proceedings.  Press releases 
and other media presentations must also be forwarded to CTEP prior to release.  Copies of 
any manuscript, abstract and/or press release/media presentation should be sent to: 
 
 
 
 
E-mail: ncicteppubs@mail.nih.gov 
The Regulatory Affairs Branch will then distribute them to Collaborator(s).  No publication, 
manuscript or other form of public disclosure shall contain any of Collaborator’s confidential/ 
proprietary information. 
 
 
Use of this document is governed by the terms of use on the first page of this document.

 
NRG-BR004 
171 
NCI Version Date: August 15, 2022 
16.0 
REFERENCES 
Abbosh C, Birkbak NJ, Wilson GA, et al.  Phylogenetic ctDNA analysis depicts early-stage lung 
cancer evolution. Nature 2017; 545(7655):446-451. 
Adams S, Diamond JR, Hamilton EP, et al.  Phase 1b trial of atezolizumab in combination with 
nab-paclitaxel in patients with metastatic triple-negative breast cancer (mTNBC).  ASCO 2016; 
Abstr 1009. 
Adashek ML and Feldman M.  Cytokine release syndrome resulting from anti-programmed 
death-1 antibody: raising awareness among community oncologist.  J Oncol Practice 2019; 
15(19):502-504. 
Akbari O, Stock P, Singh AK, et al.  PD-L1 and PD-L2 modulate airway inflammation and 
iNKT-cell-dependent airway hyperreactivity in opposing directions.  Mucosal Immunol 2010; 
3(1):81-91.   
André F, O'Regan R, Ozguroglu M, et al.  Everolimus for women with trastuzumab-resistant, 
HER2-positive, advanced breast cancer (BOLERO-3): a randomized, double-blind, placebo-
controlled phase 3 trial.  Lancet Oncol 2015; 15:580-591.   
Arpino G, Gutierrez C, Weiss H, et al.  Treatment of human epidermal growth factor receptor 2-
overexpressing breast cancer xenografts with multiagent HER-targeted therapy.  J Natl Cancer 
Inst 2007; 99(9):694-705.   
Ayers M, Lunceford J, Nebozhyn M, et al.  IFN- Ȗ -related mRNA profile predicts clinical 
response to PD-1 blockade.  J Clin Invest 2017; 127(8):2930-2940. 
Baquet CR, Ringen K, Pollack ES, et al.  Cancer Among Blacks and Other Minorities: Statistical 
Profiles.  Bethesda MD: National Institutes of Health.  DHEW publication (NIH), 1986; 86:2785. 
Barok M, Isola J, Pályi-Krekk Z, et al.  Trastuzumab causes antibody-dependent cellular 
cytotoxicity-mediated growth inhibition of submacroscopic JIMT-1 breast cancer xenografts 
despite intrinsic drug resistance.  Mol Cancer Ther 2007; 6(7): 2065-6072.   
Basch E, Rogak LJ, Dueck AC.  Methods for implementing and reporting patient-reported 
outcome (PRO) measures of symptomatic adverse events in cancer clinical trials.  Clin Ther 
2016; 38(4):821-830. 
Basch E, Dueck AC, Rogak LJ, et al.  Feasibility assessment of patient reporting of symptomatic 
adverse events in multicenter cancer clinical trials.  JAMA Oncol 2017; Feb 16; doi: 10.1001/ 
jamaoncol.2016.6749. [Epub ahead of print]. 
Baselga J, Gelmon K, Verma S, et al.  Phase II trial of pertuzumab and trastuzumab in patients 
with human epidermal growth factor receptor 2-positive metastatic breast cancer that progressed 
during prior trastuzumab therapy.  J Clin Oncol 2010; 28(7):1138-1144.   
Baselga J, Cortés J, Kim SB, et al.  Pertuzumab plus trastuzumab plus docetaxel for metastatic 
breast cancer.  N Engl J Med 2012; 366(2):109-119.  
Bassett MT, Krieger N.  Social class and black-white differences in breast cancer survival.  Am J 
Public Health 1986; 76:1400-1403. 
Benson AB III, Ajani JA, Catalano RB, et al.  Recommended Guidelines for the Treatment of 
Cancer Treatment-Induced Diarrhea.  J Clin Oncol 2004: 22(14):2918-2926. 
Bianchini G, Gianni L.  The immune system and response to HER2-targeted treatment in breast 
cancer.  Lancet Oncol 2014; 15(2): e58-68.  
Use of this document is governed by the terms of use on the first page of this document.

 
NRG-BR004 
172 
NCI Version Date: August 15, 2022 
Bianchini G, Pusztai L, Pienkowski T, et al.  Immune modulation of pathologic complete 
response after neoadjuvant HER2-directed therapies in the NeoSphere trial.  Ann Oncol 2015; 
26(12):2429-2436.  
Bidard FC, Weigelt B, Reis-Filho JS.  Going with the flow: from circulating tumor cells to DNA.  
Sci Transl Med 2013; 5(207):207ps214. 
Blank C, Gajewski TF, Mackensen A.  Interaction of PD-L1 on tumor cells with PD-1 on tumor-
specific T cells as a mechanism of immune evasion: implications for tumor immunotherapy.  
Cancer Immunol Immunother 2005; 54:307-314. 
Blank C, Mackensen A.  Contribution of the PD-L/PD-1 pathway to T-cell exhaustion: an update 
on implications for chronic infections and tumor evasion.  Cancer Immunol Immunother 2007; 
56(5):739-745. 
Borghaei H, Paz-Ares L, Horn L, et al.  Nivolumab versus docetaxel in advanced nonsquamous 
non-small-cell lung cancer.  N Engl J Med 2015; 373:1627í1639. 
Bower JE.  Cancer-related fatigue--mechanisms, risk factors, and treatments.  Nat Rev Clin Oncol 
2014; 11(10):597-609. 
Brahmer JR, Lacchetti C, Schneider BJ, et al.  Management of immune-related adverse events in 
patients treated with immune checkpoint inhibitor therapy: American Society of Clinical 
Oncology Clinical Practice Guideline.  J Clin Oncol 2018; Feb 14:JCO2017776385.  doi: 
10.1200/JCO.2017.77.6385.  [Epub ahead of print]. 
Butte MJ, Keir ME, Phamduy TB, et al.  Programmed death-1 ligand 1 interacts specifically with 
the B7-1 costimulatory molecule to inhibit T cell responses.  Immunity 2007; 27(1):111–122.   
Cortes J, Baselga J, Im Y-H, et al.  Health-related quality-of-life assessment in CLEOPATRA, a 
phase III study combining pertuzumab with trastuzumab and docetaxel in metastatic breast 
cancer.  Ann Oncol 2013; 24(10):2630-2635. 
Costantino JP, Redmond CK, Wickerham D, et al.  A comparison of survival between white and 
black breast cancer patients: Results from NSABP B-09.  Proc Am Soc Clin Oncol 1987;  
6:230 Abstr 905. 
Cox D R (1975).  Partial Likelihood.  Biometrika 1975; 62:269–276. 
Crowe JP Jr, Gordon NH, Hubay CA, et al.  The interaction of estrogen receptor status and race 
in predicating prognosis for stage I breast cancer patients.  Surgery 1986; 100:599-605. 
Dang C, Iyengar N, Datko F, et al.  Phase II study of paclitaxel given once per week along with 
trastuzumab and pertuzumab in patients with human epidermal growth factor receptor 2-positive 
metastatic breast cancer.  J Clin Oncol 2015; 33(5):442-447. 
.  Personal Communication.  2017. 
Dawson SJ, Tsui DW, Murtaza M, et al.  Analysis of circulating tumor DNA to monitor 
metastatic breast cancer.  N Engl J Med 2013; 368(13):1199-1209. 
De Mattos-Arruda L, Cortes J, Santarpia L, et al.  Circulating tumour cells and cell-free DNA as 
tools for managing breast cancer.  Nat Rev Clin Oncol 2013; 10(7):377-389. 
Deng R, Bumbaca D, Pastuskovas CV, et al.  Preclinical pharmacokinetics, pharmacodynamics, 
tissue distribution, and tumor penetration of anti-PD-L1 monoclonal antibody, an immune 
checkpoint inhibitor.  MAbs 2016; 8:593-603. 
Use of this document is governed by the terms of use on the first page of this document.

 
NRG-BR004 
173 
NCI Version Date: August 15, 2022 
Denkert C, Wienert S, Poterie A, et al.  Standardized evaluation of tumor-infiltrating lymphocytes 
in breast cancer: Results of the ring studies of the international immuno-oncology biomarker 
working group.  Mod Pathol 2016; 29(10):1155-1164.   
Di Giacomo AM, Biagioli M, Maio M.  The emerging toxicity profiles of anti-CTLA-4 
antibodies across clinical indications.  Semin Oncol 2010; 37:499-507. 
Dignam JJ, Redmond CK, Fisher B, et al.  Prognosis among African-American women and white 
women with lymph node-negative breast carcinoma: Findings from two randomized clinical trials 
of the National Surgical Adjuvant Breast and Bowel Project (NSABP).  Cancer 1997;  
80(1):80-90. 
Dong H, Zhu G, Tamada K, et al.  B7-H1, a third member of the B7 family, co-stimulates T-cell 
proliferation and interleukin-10 secretion.  Nat Med 1999; 5(12):1365–1369.   
Donovan KA, Stein KD, Lee M, et al.  Systematic review of the multidimensional fatigue 
symptom inventory-short form.  Support Care Cancer 2015; 23(1):191-212. 
Eisenhauer EA, Therasse P, Bogaerts J, et al.  New response evaluation criteria in solid tumours: 
revised RECIST guideline (version 1.1).  Eur J Cancer 2009; 45(2):228-247. 
El-Sahwi K, Bellone S, Cocco E, et al.  In vitro activity of pertuzumab in combination with 
trastuzumab in uterine serous papillary adenocarcinoma.  Br J Cancer 2010; 102(1):134-143.   
Emens LA, Braiteh FS, Cassier P, et al.  Inhibition of PD-L1 by MPDL3280A leads to clinical 
activity in patients with metastatic triple-negative breast cancer (TNBC).  Cancer Res 2015; 
75(15 Suppl):Abstr 2859.  
Fehrenbacher L, Spira A, Ballinger M, et al.  Atezolizumab versus docetaxel for patients with 
previously treated non-small-cell lung cancer (POPLAR): a multicentre, open label, phase 2 
randomised controlled trial.  Lancet 2016; 387:1837í1846. 
Fleming TR, Harrington DP, O'Brien PC.  Design for group sequential tests.  Control Clin Trials 
1984; 5:348-361. 
Food and Drug Administration/Center for Drug Evaluation and Research.  (2009).  Guidance for 
Industry Drug-Induced Liver Injury: Pre Marketing Clinical Evaluation.  
http://www.fda.gov/ucm/groups/fdagov-public/@fdagov-drugs-
gen/documents/document/ucm174090.pdf 
Genentech A Member of the Roche Group.  Personal communication, 2018. 
Gennari R, Menard S, Fagnoni F, et al.  Pilot study of the mechanism of action of preoperative 
trastuzumab in patients with primary operable breast tumors overexpressing HER2.  Clin Cancer 
Res 2004; 10(17):5650-5655.   
Geyer FC, Weigelt B, Natrajan R, et al.  Molecular analysis reveals a genetic basis for the 
phenotypic diversity of metaplastic breast carcinomas.  J Pathol 2010; 220(5):562-573. 
Gray R.  Flexible Methods for Analyzing Survival Data Using Splines, With Applications to 
Breast Cancer Prognosis.  Journal of the American Statistical Association 1992; 87(420):942-951. 
Hamanishi J, Mandai M, Iwasaki M, et al.  Programmed cell death 1 ligand 1 and tumor-
infiltrating CD8+ T lymphocytes are prognostic factors of human ovarian cancer.  Proc Natl Acad 
Sci USA 2007; 104:3360-3365. 
Hendry S, Salgado R, Gevaert T, et al.  Assessing Tumor-infiltrating Lymphocytes in Solid 
Tumors: A Practical Review for Pathologists and Proposal for a Standardized Method from the 
International Immunooncology Biomarkers Working Group: Part 1: Assessing the Host Immune 
Use of this document is governed by the terms of use on the first page of this document.

 
NRG-BR004 
174 
NCI Version Date: August 15, 2022 
Response, TILs in Invasive Breast Carcinoma and Ductal Carcinoma In Situ, Metastatic Tumor 
Deposits and Areas for Further Research.  Adv Anat Pathol 2017; 24(5):235-251. 
Herbst RS, Soria J-C, Kowanetz M, et al.  Predictive correlates of response to the anti-PD-L1 
antibody MPDL3280A in cancer patients.  Nature 2014; 515:563-567. 
Herbst RS, Baas P, Kim D-W, et al.  Pembrolizumab versus docetaxel for previously treated PD-
L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled 
trial.  Lancet 2016; 387:1540í1550. 
Hino R, Kabashima K, Kato Y, et al.  Tumor cell expression of programmed cell death-1 ligand 1 
is a prognostic factor for malignant melanoma.  Cancer 2010; 116:1757-1766. 
Howlader N, Chen VW, Ries LA, et al.  Overview of breast cancer collaborative stage data items-
their definitions, quality, usage, and clinical implications: a review of SEER data for 2004-2010.  
Cancer 2014; 120(Suppl 23):3771-3780. 
Huober J, Barrios CH, Niikura N, et al.  IMpassion050: A phase III study of neoadjuvant 
atezolizumab + pertuzumab + trastuzumab + chemotherapy (neoadj A + PH + CT) in high-risk, 
HER2-positive early breast cancer (EBC).  ESMO Virtual Plenary 6-2021: June 17, 2021 
DOI:https://doi.org/10.1016/j.annonc.2021.05.800. 
Huober J, Barrios CH, Niikura N, et al.  Atezolizumab With Neoadjuvant Anti-Human Epidermal 
Growth Factor Receptor 2 Therapy and Chemotherapy in Human Epidermal Growth Factor 
Receptor 2-Positive Early Breast Cancer: Primary Results of the Randomized Phase III 
IMpassion050 Trial.  J Clin Oncol 2022; Jun 28:JCO2102772. doi: 10.1200/JCO.21.02772. Epub 
ahead of print. 
Hurvitz SA, Andre F, Jiang Z, et al.  Combination of everolimus with trastuzumab plus paclitaxel 
as first-line treatment for patients with HER2-positive advanced breast cancer (BOLERO-1): a 
phase 3, randomized, double-blind, multicenter trial.  Lancet Oncol 2015; 16:816-829.   
Investigator’s Brochure, Atezolizumab (MPDL3280A).  Version 9, August 2016. 
Iwai Y, Ishida M, Tanaka Y, et al.  Involvement of PD-L1 on tumor cells in the escape from host 
immune system and tumor immunotherapy by PD-L1 blockade.  Proc Natl Acad Sci USA 2002; 
99(19):12293-12297. 
Jacobsen PB.  Assessment of fatigue in cancer patients.  J Natl Cancer Inst Monogr 2004; 
2004(32):93-97.  
Jensen R, Potosky A, Reeve B, et al.  Validation of the PROMIS physical function measures in a 
diverse US population-based cohort of cancer patients.  Qual Life Res 2015; 24(10):2333-2344. 
Kalbfleisch JD, and Prentice RL.  The Statistical Analysis of Failure Time Data.  Second edition, 
New York: John Wiley & Sons, 2002. 
Kaplan EL, Meier P.  Nonparametric estimation from incomplete observations.  J Amer Statist 
Assn 1958; 53(282):457–481. 
Keir ME, Butte MJ, Freeman GJ, et al.  PD-1 and its ligands in tolerance and immunity.  Annual 
Rev Immunol 2008; 26:677-704. 
Kluetz PG, Slagle A, Papadopoulos E, et al.  Focusing on Core Patient-Reported Outcomes in 
Cancer Clinical Trials: Symptomatic Adverse Events, Physical Function, and Disease-Related 
Symptoms.  Clin Cancer Res 2016; 22:1553-1558. 
Use of this document is governed by the terms of use on the first page of this document.

 
NRG-BR004 
175 
NCI Version Date: August 15, 2022 
Kute TE, Savage L, Stehle JR Jr, et al.  Breast tumor cells isolated from in vitro resistance to 
trastuzumab remain sensitive to trastuzumab anti-tumor effects in vivo and to ADCC killing.  
Cancer Immunol Immunother 2009; 58(11): 1887-1896.  Epub 2009 Apr 2.  
Lai J, Cella D, Yanez B, et al.  Linking fatigue measures on a common reporting metric. J Pain 
Symptom Manage 2014; 48(4):639-648. 
Le DT, Uram JN, Wang H, et al.  PD-1 Blockade in Tumors with Mismatch-Repair Deficiency.  
N Engl J Med 2015; 372(26):2509-20.   
Lee SC, Srivastava RM, López-Albaitero A, et al.  Natural killer (NK): dendritic cell (DC) cross 
talk induced by therapeutic monoclonal antibody triggers tumor antigen-specific T cell immunity.  
Immunol Res 2011; 50(2-3):248-254.  
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(4):625-638. 
Lee-Hoeflich ST, Crocker L, Yao E, et al.  A central role for HER3 in HER2-amplified breast 
cancer: implications for targeted therapy.  Cancer Res 2008; 68(14):5878-5887.   
Li Y, Chang C-W, Tran D, et al.  Prevalence of PDL1 and tumor infiltrating lymphocytes (TILs) 
in primary and metastatic TNBC.  Cancer Res. February 15 2018 (78) (4 Supplement) PD6-01. 
Lin DY, Wei LJ, Ying Z.  Checking the Cox model with cumulative sums of martingale-based 
residuals.  Biometrika 1993; 80(3):557-572. 
Loi S, Giobbe-Hurder A, Gombos A, et al.  Phase Ib/II study evaluating safety and efficacy of 
pembrolizumab and trastuzumab in patients with trastuzumab-resistant HER2-positive metastatic 
breast cancer: Results from the PANACEA (IBCSG 45-13/KEYNOTE-014) study.  San Antonio 
Breast Cancer Symposium. 6 December 2017. GS2-06. 
Luen SJ, Salgado R, Fox S, et al.  Tumour-infiltrating lymphocytes in advanced HER2-positive 
breast cancer treated with pertuzumab or placebo in addition to trastuzumab and docetaxel: a 
retrospective analysis of the CLEOPATRA study.  Lancet Oncol 2017; 18(1):52–62. 
Matsumoto K, Fukuyama S, Eguchi-Tsuda M, et al.  B7-DC induced by IL-13 works as a 
feedback regulator in the effector phase of allergic asthma.  Biochem Biophys Res Commun 
2008; 365(1):170-175.  
McClain, K.L and O. Eckstein.  (2017).  Clinical features and diagnosis of hemaphagocytic 
lymphohistiocytosis. Available from: https://www.uptodate.com/contents/clinicalဨfeaturesဨandဨ
diagnosisဨofဨhemophagocyticဨlymphohistiocytosis. 
Miles D, André F, Gligorov J, et al.  IMpassion131: A phase III study comparing 1L 
atezolizumab with paclitaxel vs placebo with paclitaxel in treatment-naive patients with 
inoperable locally advanced or metastatic triple negative breast cancer (TNBC) [abstract]. 
Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, 
TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr OT1-01-01. 
Miles DW, Gligorov J, André F, et al.  Primary results from IMpassion131, a double-blind 
placebo-controlled randomised phase III trial of first-line paclitaxel (PAC) ± atezolizumab (atezo) 
for unresectable locally advanced/metastatic triple-negative breast cancer (mTNBC).  Ann Oncol 
2020; 31(suppl_4): S1142-S1215. 
Mittendorf E, Barrios CH, Harbeck N, et al.  IMpassion031: A phase III study comparing 
neoadjuvant atezolizumab vs placebo in combination with nab-paclitaxel–based chemotherapy in 
early triple-negative breast cancer (TNBC) [abstract]. In: Proceedings of the 2017 San Antonio 
Use of this document is governed by the terms of use on the first page of this document.

 
NRG-BR004 
176 
NCI Version Date: August 15, 2022 
Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer 
Res 2018;78(4 Suppl):Abstract nr OT2-07-03. 
Mohla S, Sampson CC, Khan T, et al.  Estrogen and progesterone receptors in breast cancer in 
black Americans: Correlation of receptor data with tumor differentiation.  Cancer 1982;  
50(3):552-559. 
Motzer RJ, Powles T, Atkins MB, et al.  IMmotion151: A randomized phase III study of 
atezolizumab plus bevacizumab vs sunitinib in untreated metastatic renal cell carcinoma (mRCC).  
J Clin Oncol 36 no. 6 suppl (February 20 2018) 578. 
Murtaza M, Dawson SJ, Tsui DW, et al.  Non-invasive analysis of acquired resistance to cancer 
therapy by sequencing of plasma DNA.  Nature 2013; 497(7447):108-112. 
Nahta R, Hung M, Esteva F.  The HER-2-targeting antibodies trastuzumab and pertuzumab 
synergistically inhibit the survival of breast cancer cells.  Cancer Res 2004; 64(7):2343-2346.  
Nanda R, Chow LQ, Dees ER, et al.  A phase Ib study of pembrolizumab (MK-3475) in patients 
with advanced triple-negative breast cancer.  Ann San An Breast Can Symp 2014. Abstr: S1-09.   
National Comprehensive Cancer Network: Breast Cancer.  NCCN Clinical Practice Guidelines in 
Oncology 2015 (3.2015).  http://www.nccn.org/professionals/physician_gls/pdf/breast.pdf. 
Newman AM, Liu CL, Green MR, et al.  Robust enumeration of cell subsets from tissue 
expression profiles.  Nat Methods 2015; 12(5):453-457. 
Okazaki T, Honjo T.  PD-1 and PD-1 ligands: from discovery to clinical application.  Int 
Immunol 2007; 9:813-824. 
Park JJ, Omiya R, Matsumura Y, et al.  B7-H1/CD80 interaction is required for the induction and 
maintenance of peripheral T-cell tolerance.  Blood 2010; 116(8):1291–1298.   
Park S, Jiang Z, Mortenson ED, et al.  The therapeutic effect of anti-HER2/neu antibody depends 
on both innate and adaptive immunity.  Cancer Cell 2010; 18(2):160-170.  
Paterson AM, Brown KE, Keir ME, et al.  The programmed death-1 ligand 1:B7-1 pathway 
restrains diabetogenic effector T cells in vivo.  J Immunol 2011; 187(3):1097-1105.   
Portera C, Walshe J, Rosing D, et al.  Cardiac toxicity and efficacy of trastuzumab combined with 
pertuzumab in patients with trastuzumab-insensitive human epidermal growth factor receptor 2-
positive metastatic breast cancer.  Clin Cancer Res 2008; 14(9):2710-2716.    
Powles T, Eder JP, Fine GD, et al.  MPDL3280A (anti-PD-L1) treatment leads to clinical activity 
in metastatic bladder cancer.  Nature 2014; 515(7528):558-562.   
Ravelli A, Minoia F, Davì S, et al.  Classification criteria for macrophage activation syndrome 
complicating systemic juvenile idiopathic arthritis: A European League Against 
Rheumatism/American College of Rheumatology/Paediatric Rheumatology International Trials 
Organisation Collaborative Initiative.  Arthritis Rheumatol 2016; 68(3):566-576. 
Reeve BB, Mitchell SA, Dueck AC, et al.  Recommended patient-reported core set of symptoms 
to measure in adult cancer treatment trials.  J Natl Cancer Inst 2014; 106(7): pii: dju129. 
Riegler LL, Jones GP, and 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  15:323-335. 
Rittmeyer A, Barlesi F, Waterkamp D, et al.  Atezolizumab versus docetaxel in patients with 
previously treated non-small-cell lung cancer (OAK): a phase 3, open-label, multicentre 
randomised controlled trial.  Lancet 2017; 389:255-265. 
Use of this document is governed by the terms of use on the first page of this document.

 
NRG-BR004 
177 
NCI Version Date: August 15, 2022 
Roche.  Personal communication, 2016. 
Rosenberg JE, Hoffman-Censits J, Powles T, et al.  Atezolizumab in patients with locally 
advanced and metastatic urothelial carcinoma who have progressed following treatment with 
platinum-based chemotherapy: a single-arm, multicentre, phase 2 trial.  Lancet 2016; 
387:1909í1920. 
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. 
Rugo HS, Barry WT, Moreno-Aspitia A, et al.  Randomized phase III trial of paclitaxel once per 
week compared with nanoparticle albumin-bound nab-paclitaxel once per week or ixabepilone 
with bevacizumab as first-line therapy for locally recurrent or metastatic breast cancer: CALGB 
40502/NCCTG N063H (Alliance).  J Clin Oncol 2015; 33(21):2361-2369.   
Satariano WA, Belle SH, Swanson GM.  The severity of breast cancer at diagnosis: A comparison 
of age and extent of disease in black and white women.  Am J Public Health 1986; 76(7):779-
782. 
Scheuer W, Friess T, Burtscher H, et al.  Strongly enhanced antitumor activity of trastuzumab and 
pertuzumab combination treatment on HER2-positive human xenograft tumor models.  Cancer 
Res 2009; 69(24):9330-9336.  
Schmid P, Cruz C, Braitch FS, et al.  Atezolizumab in metastatic TNBC (mTNBC): Long-term 
clinical outcomes and biomarker analyses.  American Association for Cancer Research Annual 
Meeting, Wash DC 2017; 58:Abstr. 2986. 
Schmid P, Adams S, Rugo HS, et al.  Atezolizumab and nab-paclitaxel in advanced triple-
negative breast cancer.  N Engl J Med 2018; 379(22):2108-2121. 
Schoenfeld DA.  Sample-size formula for the proportional-hazards regression model.  Biometrics 
1983; 39(2):499-503.   
Slamon DJ, Leyland-Jones B, Shak S, et al.  Use of chemotherapy plus a monoclonal antibody 
against HER2 for metastatic breast cancer that overexpresses HER2.  N Engl J Med 2001; 
344(11):783-792.   
Stagg J, Loi S, Divisekera U, et al.  Anti-ErbB-2 mAb therapy requires type I and II interferons 
and synergizes with anti-PD-1 or anti-CD137 mAb therapy.  Proc Natl Acad Sci U S A 2011; 
108(17):7142-7147.  Epub 2011 Apr 11.   
Strome SE, Dong H, Tamura H, et al.  B7-H-1 blockade augments adoptive T-cell 
immunotherapy for squamous cell carcinoma.  Cancer Res 2003; 63(19):6501-6505. 
Swain S, Baselga J, Kim S-B, et al.  Pertuzumab, trastuzumab, and docetaxel in HER2-positive 
metastatic breast cancer.  N Engl J Med 2015; 372:724-734.  
Temple R.  Hy's law: predicting serious hepatotoxicity.  Pharmacoepidemiol Drug Safety 2006; 
15(4):241-243. 
Therneau TM, and Grambsch P M.  Modeling Survival Data: Extending the Cox Model.  New 
York: Springer-Verlag, 2000. 
Thompson RH, Kuntz SM, Leibovich BC, et al.  Tumor B7-H1 is associated with poor prognosis 
in renal cell carcinoma patients with long-term follow-up.  Cancer Res 2006; 66:3381-3385. 
Topalian SL, Hodi FS, Brahmer JR, et al.  Safety, activity, and immune correlates of antiíPD-1 
antibody in cancer.  N Engl J Med 2012; 366:2443í2454. 
Use of this document is governed by the terms of use on the first page of this document.

 
NRG-BR004 
178 
NCI Version Date: August 15, 2022 
Turner NC, Garcia-Murillas I, Schiavon G, et al.  Tracking tumor-specific mutations in 
circulating-free DNA to predict early relapse after treatment of primary breast cancer.  J Clin 
Oncol 2014; 32(5s):Abstr 511. 
Varadan V, Gilmore HL, Miskimen KL, et al.  Immune signatures following single dose 
trastuzumab predict pathologic response to preoperative trastuzumab and chemotherapy in HER2-
positive early breast cancer.  Clin Cancer Res 2016 Feb 3. pii: clincanres.2021.2015.  [Epub 
ahead of print] 
Varchetta S, Gibelli N, Oliviero B, et al.  Elements related to heterogeneity of antibody-
dependent cell cytotoxicity in patients under trastuzumab therapy for primary operable breast 
cancer overexpressing HER2.  Cancer Res 2007; 67(24):11991-11999.  
Wolchok JD, Hoos A, O’Day S, et al.  Guidelines for the evaluation of immune therapy activity 
in solid tumors: immune-related response criteria.  Clin Can Res2009; 15:7412-7420. 
Wolff AC, Hammond ME, Allsion 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; May 30:JCO2018778738. doi: 
10.1200/JCO.2018.77.8738. [Epub ahead of print]..  
Yang J, Riella LV, Chock S, et al.  The novel costimulatory programmed death ligand 1/B7.1 
pathway is functional in inhibiting alloimmune responses in vivo.  J Immunol 2011; 
187(3):1113–1119.  
Yost KJ, Eton DT, Garcia SF, et al.  Minimally important differences were estimated for six 
Patient-Reported Outcomes Measurement Information System-Cancer scales in advanced-stage 
cancer patients.  J Clin Epidemiol 2011; 64(5):507-516. 
Youn JL Jr, Ries LG, Pollack ES.  Cancer patient survival among ethnic groups in the United 
States.  J Natl Cancer Inst 1984; 73(2):341-352. 
Zhao H. and Tsiatis A.A.  Testing equality of survival functions of quality-adjusted lifetime.  
Biometrics 2001; 57:861-867. 
 
Use of this document is governed by the terms of use on the first page of this document.

 
NRG-BR004 
179 
NCI Version Date: August 15, 2022 
APPENDIX A 
ASSESSMENT OF PERFORMANCE STATUS AND ACTIVITIES OF DAILY LIVING 
1.0 
PERFORMANCE STATUS 
ECOG or Zubrod Scale 
 
Karnofsky Score 
0 
Fully active; able to carry on all 
pre-disease performance without 
restriction 
90-100% 
1 
Restricted in physically 
strenuous activity but 
ambulatory 
70-80% 
2 
Ambulatory and capable of  
self-care; but unable to carry out 
any work activities 
50-60% 
3 
Capable of only limited self-
care; confined to bed or chair 
more than 50% of waking hours 
30-40% 
4 
Completely disabled 
10-20% 
 
 
2.0 
ACTIVITIES OF DAILY LIVING 
The following definitions for activities of daily living (ADL) should be used when the  
CTCAE v5.0 grading criteria are based on ADL: 
x 
Instrumental ADL refer to preparing meals, shopping for groceries or clothes, using the 
telephone, managing money, etc. 
x 
Self-care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, taking 
medications, and not bedridden.
Use of this document is governed by the terms of use on the first page of this document.

 
NRG-BR004 
180 
NCI Version Date: August 15, 2022 
APPENDIX B 
MEDIDATA PATIENT CLOUD ePRO OPERATIONAL PROCEDURES 
In this document ePRO application refers to the application accessed by the site via iMedidata 
and Rave, and ePRO mobile app refers to the app accessed by the patient on a mobile device. 
1.0 
Introduction 
Electronic collection of patient-reported outcomes (ePRO) through Medidata's ePRO application 
is preferred for collection of PRO-CTCAE in patients who read or understand English, Spanish, 
or French and were enrolled in the PRO-CTCAE substudy prior to Amendment #3 and for 
collection of QOL for all patients who read or understand English, Spanish, or French.  Sites are 
not permitted to delete the ePRO component from the protocol or from the informed consent 
form.  Traditional paper submission is the other option.  Patients who will be submitting PRO 
data via the ePRO mobile app must be registered to the ePRO application by an authorized site 
staff after the patient has been registered to the study.  Patients may use their own mobile device 
or one provisioned by the site.  
Sites can use a site-specific tablet for multiple study participants.  If a site-specific tablet is used, 
CRAs need to setup the tablet for multiple users.  Multi-user mode lets multiple study participants 
log in to the ePRO mobile app with their passwords or their PIN codes on the same device. 
2.0 
ePRO Mobile Application Download 
Note that there are multiple versions of the ePRO mobile app.  Patients should be instructed to 
download the version chosen by the study team for the protocol.  The patient will receive an error 
upon logging into the ePRO mobile app if the wrong version is downloaded. The version being 
used on this trial is: 
Patient Cloud 
 
 
 
3.0 
CRA Site Users 
Site staff require access to the ePRO application.  This access is granted through iMedidata and is 
similar to the process of obtaining access to Rave studies.  Site staff will receive an invitation to 
the ePRO application which they must accept in order to begin registering patients.  Staff who 
have not previously activated their iMedidata/Rave account at the time of initial approval of site 
registration will also receive a separate invitation from iMedidata to activate their account.  
Medidata Account Activation and Study Invitation Acceptance instructions are located on the 
CTSU members' website under Data Management > Rave Home > Learn More About Rave > 
Medidata Account Activation and Study Invitation Acceptance.  Site staff will not be able to 
access the study in the ePRO application until all required Rave and study specific trainings 
(eLearnings assigned in iMedidata) are completed. 
Additional information on iMedidata/Rave is available on the CTSU members’ website under the 
Data Management tab and further under the Rave subtab or by contacting the CTSU Help Desk at 
1-888-823-5923 or by e-mail at ctsucontact@westat.com.   
Use of this document is governed by the terms of use on the first page of this document.

 
NRG-BR004 
181 
NCI Version Date: August 15, 2022 
4.0 
CRA Instructions for Setting the Patient Cloud Mobile App to Multi-User Mode 
Sites conducting studies entirely on-premise, where participants travel to the sites to fill out 
questionnaires, can use multi-user mode.  Multi-user mode lets multiple study participants log in 
to the ePRO mobile app with their passwords or their PIN codes on the same device.  If patients 
will be using devices supplied by the institution, site staff will need to help the patient to access 
the device if the device is locked. 
The study provider will download the ePRO mobile app to the device and set the ePRO mobile 
app to multi-user mode if applicable.  **Verify the correct ePRO mobile app (Patient Cloud OR 
Patient Cloud ePRO) is downloaded per the protocol requirements.  Note only 1 version of the 
app is active per protocol.  On this protocol the app is named Patient Cloud and its icon is: 
 
Patient Cloud 
 
To switch from personal mode (default setting) to multi-user mode: 
1. Tap About at the bottom of the log in screen. 
2. Scroll to the bottom and tap Advanced User. 
3. Tap Mode, then select Multi-User. 
4. Tap Yes to confirm. 
5. Tap the back arrows to return to the log in screen. 
Note: If enabling multi-user mode on a device, it is highly recommended that completion 
reminders are turned off on that device. 
5.0 
Patient Users 
To use the ePRO mobile app, patients will need to use their own device (IOS, Android phone, or 
tablet) or one provided at the site.  For instructions for patients using their own device refer to 
section #6 below.  Short term data will only appear on the patient’s device until responses are 
completed and submitted.  The patient data will import directly into the database once the patient 
selects the “Submit” button and will no longer be visible on the patient's device.  
Sites can provide a site-specific tablet for multiple study participant use on site.  If a site-specific 
tablet is used, study staff need to setup the tablet for multiple users.  Multi-user mode lets 
multiple study participants log into the ePRO mobile app with their passwords or their PIN codes 
on the same device.  Refer to Section 4.0 above on Setting the Patient Cloud App to Multi-
User Mode. 
6.0 
Patient Instructions for Accessing the Patient Cloud Using Your Personal Device 
Downloading the Patient Cloud ePRO Mobile App 
If you are using your personal device, and you do not have the ePRO mobile app with the 
icon shown below, use the following instructions.  When downloading the app, you must 
use the Apple ID or Google account associated with the device.  If the ePRO mobile app 
is already on the device, or if you are using a provider's device, you can skip this section.  
There are multiple versions of the ePRO mobile app available.  Ensure that the correct 
version of the ePRO mobile app is downloaded.  For this study the app is named Patient 
Cloud and its icon looks like this: 
Use of this document is governed by the terms of use on the first page of this document.

 
NRG-BR004 
182 
NCI Version Date: August 15, 2022 
 
Patient Cloud 
 
You will need an email address that you agree to use for this purpose.  The email address 
is needed to uniquely identify you on the ePRO Application, and to reset your password 
if needed.  Your email address will only be used for this survey study and will not be 
used for mail or marketing purposes. 
If you decide to use the electronic method to complete the questionnaires, and do not 
have an email address, you may sign up for one at no charge at many different websites.  
A few sites that are commonly used and will allow you to create an email address very 
easily are Yahoo, Gmail, and Outlook. 
For iOS (when using an Apple device):  
1. An Apple ID is required for downloading the ePRO mobile app. 
2. Tap the App Store icon on your device. 
3. Search for the appropriate ePRO mobile app ("Patient Cloud" see the icon 
above) and follow the installation instructions. 
 For Android: 
1. A Google account is required for downloading the ePRO mobile app. 
2. Tap the Play Store icon. 
3. Search for the appropriate ePRO mobile app ("Patient Cloud", see the icon 
above) and follow the installation instructions. 
Registering 
You must register in order to complete and submit your study forms.  When you register, 
you will create a username, which is your email address, and a password that allows you 
to log in to the ePRO mobile app. 
Note: You must have an activation code to begin this process.  If you do not have an 
activation code, please contact your provider.  
There are two possible ways to register.  Your provider may have sent you a link to a web 
address where you may register from any web browser, including the one on your device.  
The other way to register is on the ePRO mobile app. 
1. If registering from the ePRO mobile app, open the Patient Cloud app, tap 
Register on the bottom of the log in page.  If registering on the web, open the 
URL https://shield.imedidata.com on a web browser. 
2. Enter your activation code and tap Activate. 
3. On the next page, read the instructions and tap Next. 
4. Read the privacy notice and tap I agree.  Then tap OK to confirm. 
5. Enter and confirm your email address.  Tap Next. 
6. Enter and confirm your password.  Tap Next. 
7. Choose a security question by scrolling through the dropdown menu to display 
the question of your choice. 
8. Enter your response to the security questions. 
Use of this document is governed by the terms of use on the first page of this document.

NRG-BR004
183
NCI Version Date: August 15, 2022
9.
Tap Create my account to complete your registration.
If you registered on the ePRO mobile app, it automatically logs you out.  If you registered 
on the web, you are presented with the option to download the ePRO mobile app (Patient 
Cloud). You can then proceed to log in with the credentials you created.
Logging in to the ePRO Mobile App
1.
Enter your Email and Password that you created during the registration process.  (If 
you previously set a PIN code, just enter your four-digit PIN.)
2.
Tap Log in. 
Note: If you do not remember your password, tap Forgot Password, and follow the 
instructions provided.
Setting a PIN Code
The first time you log in to the ePRO mobile app, you are given the option to create a 
PIN code.  A PIN code allows you to bypass the step of entering your email and 
password every time you need to log in to the ePRO mobile app (Patient Cloud).  Instead, 
you can enter a four-digit PIN.
1.
If you wish to set a PIN code the first time you log in, tap Yes when prompted.
2.
Note: You can also set your PIN at a later time by tapping the options menu on 
the top right of most pages and selecting Set PIN. 
3.
Enter a four-digit PIN.
4.
Re-enter the four-digit PIN to confirm.
If you forget your PIN code, tap Forgot PIN and you can access the app using your email 
and password. You may reset your PIN by tapping the options menu (3 vertical dots) on 
the top right of most pages and selecting Set PIN. 
Resetting Your Password
You can reset your password by using the options menu at the top right of most pages.
1.
Tap the Options menu icon (3 vertical dots). 
2.
Tap Reset Password. 
3.
Follow the instructions to reset your password.
Completing and Submitting Forms
Once logged into the ePRO mobile app, forms related to your study are displayed on the 
Tasks List page.  Select a form, and complete and submit the form. New forms can 
appear on the Tasks Lists page at any time, depending on how the study is designed.
There are two types of forms displayed on the Tasks List page:
x
Scheduled Forms (with a 
icon): These forms have a "Due Date" indicator in them 
so you are aware of the last day by which you will need to complete the form.  If the 
form is due in less than one day, you will see the due time in hours.
x
Anytime Forms (with a 
 icon): These forms have "Last Completed Time" indicator 
on them which tells the most recent date or time when you completed the form.  If 
you start a form, but do not complete it, you will see an "Incomplete" status beneath 
the form name, along with a half-moon icon. 
Use of this document is governed by the terms of use on the first page of this document.

 
NRG-BR004 
184 
NCI Version Date: August 15, 2022 
To complete and submit form(s): 
1. Select the appropriate form. 
2. Follow the on-screen instructions until you reach the end of the form where you 
may be given the opportunity to review and change your responses prior to 
submitting. 
3. If given the opportunity to review and update, review your responses by scrolling 
down the list: if you need to change an answer, tap the question to go back and 
change the answer. 
4. When you are ready to submit, tap Submit Your Data. 
Note: Once a form is submitted, you will be unable to edit any of your responses.  In 
some cases, you may be asked to acknowledge your submission by entering your 
password.  
7.0 
Patient Compliance 
The patient data imports directly from a device into the Rave database.  There are no documents 
to audit.  The patient-submitted electronic responses are the source documentation. 
8.0 
Security 
All data is encrypted on the device (256 bit encryption and Hyper Text Transfer Protocol Secure 
[https]) and the app requires each user to have a unique username and password for access.  If the 
user is idle for too long (5 minutes inactivity time), the app will time out, and the user will need to 
log in again. 
The data will only reside on the device for a short period of time.  Once the user clicks “Submit,” 
the data is securely transferred over HTTPS between the device and internal relay to the Rave 
database.  Except for the patient's email address, no identifying information is stored in 
iMedidata.  The patient's email links the device (used) and (ePRO) account to where the data is 
stored.  The patient's email is not visible to anyone in the system. 
The Patient information (email/password) does not reside in Medidata Rave EDC, and the patient 
accounts are hidden in iMedidata from sites and LPOs. 
The ePRO application is 21 CFR Part 11 compliant and acts as a gateway between the device and 
Medidata Clinical Cloud (MCC).   
Messages and information communicated to and from the Patient Cloud are encrypted and 
therefore this information cannot be read if intercepted while in transit. 
9.0 
Site checklist for activities prior to consenting a patient 
 Accept study invitation at iMedidata.com. 
o Site staff must be rostered in RSS and have received an invitation to the ePRO 
application. 
 Site staff must have already completed required eLearning assigned in iMedidata for the 
ePRO application before gaining access to the study in Rave.  Contact the LPO to request 
appropriate Rave access to register patients in the ePRO application. 
 Verify the IOS or Android operating system is using the most current version. 
 Verify that the correct ePRO mobile app is being used.  Note only 1 version of the ePRO 
mobile app is active per protocol. 
 If using institutional shared devices, first patient only: Verify the ePRO mobile app is in 
Multi-User mode. 
Use of this document is governed by the terms of use on the first page of this document.

 
NRG-BR004 
185 
NCI Version Date: August 15, 2022 
 See the following webpage for more information about Patient Cloud iOS and Android ePRO 
apps.  The landing page contains general information as well as links to additional resources 
on the left side of the screen https://learn.mdsol.com/patient-cloud/ecoa/en/get-started-with-
patient-cloud-ios-and-android-apps-125282823.html. 
Note: Sites should consider copying this site checklist and placing it in the clinic or area where 
site is consenting patients to ePRO and also copy the correct image and name of the ePRO 
mobile app version with it to help remind staff and patients of the correct version being used in 
the protocol.  The correct version for this protocol is named “Patient Cloud” and has an icon 
with a cloud and a sun. 
 
 
Patient Cloud 
 
Use of this document is governed by the terms of use on the first page of this document.