A Randomized, Multicenter, Double-blind, Placebo-controlled Phase 3 Study of Nivolumab Versus Placebo in Combination With Neoadjuvant Chemotherapy and Adjuvant Endocrine Therapy in Patients With High-risk, Estrogen Receptor-Positive (ER+), Human Epidermal Growth Factor Receptor 2-Negative (HER2-) Primary Breast Cancer
Phase: PHASE3
Conditions: Breast Cancer
Sponsor: Bristol-Myers Squibb

Page:
1
Protocol Number:
CA2097FL
IND Number:
136,843
EX-US
Non-IND
EUDRACT Number:
2019-002469-37
Date:
01-Jul-2019
Revised Date:
27-Jun-2022
CLINICAL PROTOCOL CA2097FL
A Randomized, Multicenter, Double-blind, Placebo-controlled Phase 3 Study of Nivolumab 
Versus Placebo in Combination With Neoadjuvant Chemotherapy and Adjuvant Endocrine 
Therapy in Patients With High-risk, Estrogen Receptor-Positive (ER+), Human Epidermal 
Growth Factor Receptor 2-Negative (HER2-) Primary Breast Cancer
(CheckMate 7FL: CHECKpoint pathway and nivoluMAb clinical Trial Evaluation 7FL)
Short Title:
Nivolumab or Placebo with Neoadjuvant Chemotherapy and Adjuvant Endocrine Therapy in ER+, 
HER2- Breast Cancer
Protocol Amendment 03
Incorporates Administrative Letters 06, 07, and 08
Medical Monitoring Contact Information
Sr Clinical Trial Physician
Bristol-Myers Squibb Company
3401 Princeton Pike Lawrenceville, NJ 08648
Phone: 
Email: 
Sr Clinical Scientist
Bristol-Myers Squibb Company
86 Morris Ave, Summit, NJ 07901
Phone:
Email: 
 
24-hr Emergency Telephone Number
USA: 
Bristol-Myers Squibb Research and Development
3401 Princeton Pike
Lawrenceville, NJ 08648
Avenue de Finlande 4
B-1420 Braine-l’Alleud, Belgium
This document is the confidential and proprietary information of Bristol-Myers Squibb 
Company and its global affiliates (BMS). By reviewing this document, you agree to keep it 
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Protocol Amendment No.: 03
Date: 27-Jun-2022
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confidential and to use and disclose it solely for the purpose of assessing whether your 
organization will participate in and/or the performance of the proposed BMS sponsored 
study. Any permitted disclosures will be made only on a confidential "need to know" basis 
within your organization or to your independent ethics committee(s)(IEC). Any other use, 
copying, disclosure or dissemination of this information is strictly prohibited unless expressly 
authorized in writing by BMS. Any supplemental information (eg, amendments) that may 
be added to this document is also confidential and proprietary to BMS and must be kept in 
confidence in the same manner as the contents of this document. Any person who receives 
this document without due authorization from BMS is requested to return it to BMS or 
promptly destroy it. All other rights reserved. References to BMS in this protocol may apply 
to partners to which BMS has transferred obligations, eg, a Contract Research Organization 
(CRO).
© 2022 Bristol-Myers Squibb Company
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Protocol Amendment No.: 03
Date: 27-Jun-2022
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DOCUMENT HISTORY
Document
Date of Issue
Summary of Change
Protocol 
Amendment 03
27-Jun-2022
Key changes in Protocol Amendment 03 include the following:
•
Details of study enrollment closure with provision for enrolled
participants on treatment to continue in the study.
•
The primary endpoint of the trial was updated to focus solely on
pathological complete response (pCR) in the intent-to-treat (ITT)
population. Event-free survival (EFS) was moved from primary to
exploratory endpoint and will be evaluated up to long-term follow-up
at approximately 12 months (± 2 months) post-Surgery visit. pCR in
the programmed death-ligand 1-positive (PD-L1+) population will be
evaluated as a secondary endpoint. The study will remain blinded
through the neoadjuvant treatment and surgery phases, and will
transition to open label when participants enter into adjuvant treatment.
•
Removal of nivolumab placebo infusion at Adjuvant phase for
participants in Arm B.
•
Removal of pharmacokinetic and immunogenicity samples collection
at Adjuvant phase for participants in Arm B.
•
The study will follow participants until completion of safety follow-up
Visits 1 and 2 and a single long-term follow-up visit at approximately
12 months (± 2 months) post-Surgery. Subsequent long-term follow-up
visits have been removed.
•
The study objectives, endpoints, and statistical analysis have been
updated and clarified.
Administrative 
Letter 08
01-Apr-2022
Updated BMS study contact information.
Administrative
Letter 07
27-Jul-2021
Corrected an error found in the Exclusion Criteria 1b to ensure proper 
alignment throughout the protocol.
Administrative 
Letter 06
15-Jun-2021
Corrected protocol footer to reflect change from revised protocol to 
protocol amendment.
Protocol 
Amendment 02
21-May-2021
•
Updated BMS study contact information.
•
Aligned dose modification criteria and IO management algorithms with
CTCAE v5.
•
Incorporated additional revisions to improve alignment across protocol
sections and/or clarify expectations for eligibility, assessments, sample
collection, and treatment administration.
•
Added surgical clips placement prior starting neoadjuvant treatment.
•
Incorporated Administrative Letters 03, 04 and 05.
Administrative 
Letter 05
22-Jan-2021
•
Updated BMS medical monitor information.
Administrative 
Letter 04
02-Nov-2020
•
Updated BMS medical monitor information.
Administrative 
Letter 03
20-Jul-2020
•
Updated BMS study contact information.
•
Clarified cortisol result requirement and sample collection.
•
Clarified on bilateral breast imaging to align with Section 9.1.5.1.
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Protocol Amendment No.: 03
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Document
Date of Issue
Summary of Change
•
Corrected inconsistency on how to manage participants who may not
proceed to definitive surgery between Sections 5.1.2.1 and 9.1.2.
Revised 
Protocol 01
24-Mar-2020
•
Clarified and/or update some of the study procedures to align with
local practice.
•
Aligned with recent ASCO-CAP Guidelines for estrogen and
progesterone testing in breast cancer.
•
Removed requirements related to RECIST v1.1. to allow for
unidimensional methods for assessing response with a modification of
RECIST criteria in the neoadjuvant setting.
•
Clarified menopausal status definitions, contraception requirements,
and timing for prohibition of concurrent hormonal contraception.
•
Updated exclusion criteria related to HIV status to allow increased
opportunity for potential enrollment.
•
Updated window for tumor sample to be ≤90 day prior to enrollment
for FFPE block or ≤60 day for unstained slides from primary breast
lesion submitted at baseline.
•
Allowed option for concomitant administration of adjuvant systemic
treatment with nivolumab/nivolumab placebo plus endocrine therapy
and radiotherapy for participant requiring radiotherapy.
•
Clarified eCOA capture methods and remove FACIT-GP5 COA
assessments on Days 8,15, and 22.
•
Included assessment of PD-L1 expression by combined positive score
(CPS) as an exploratory objective.
•
Clarified dose modification expectations for the different study
treatments.
•
Clarified prohibited/restricted and permitted concomitant therapies
including growth factors, LHRH agonists, and bisphosphonates.
•
Incorporated Administrative Letters 01 and 02.
Administrative 
Letter 02
26-Aug-2019
•
Updated BMS Medical Monitor information.
•
Provided clarification on luteinizing hormone-releasing hormone
agonists.
•
Corrected inconsistency regarding start of adjuvant treatment in
participants not receiving radiotherapy.
Administrative 
Letter 01
25-Jul-2019
Removed France from the country specific requirement.
Original 
Protocol
01-Jul-2019
Not applicable
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OVERALL RATIONALE FOR PROTOCOL AMENDMENT 03:
 
 
 
 
 
 
 
 On 07-Apr-2022, Bristol-Myers Squibb (BMS) informed sites 
and the steering committee of the decision to stop new enrollment to the CA2097FL study. The 
study committee was supportive of the decision. Participants who had signed study consent prior 
to this decision and were undergoing screening were permitted to be randomized to study 
treatment. The decision to stop new enrollment was not based on any safety signal or review of 
any efficacy data. There has been no change in the understanding of the safety profile of nivolumab 
in combination with paclitaxel, cyclophosphamide, epirubicin/doxorubicin, and endocrine therapy.
Key changes in Protocol Amendment 03 include the following:
•
Details of study enrollment closure with provision for enrolled participants on treatment to
continue in the study.
•
The primary endpoint of the trial was updated to focus solely on pathological complete
response (pCR) in the intent-to-treat (ITT) population. Event-free survival (EFS) was moved
from primary to exploratory endpoint and will be evaluated up to long-term follow-up at 12
months (± 2 months) post-Surgery visit. pCR in the programmed death-ligand 1-positive
(PD-L1+) population will be evaluated as a secondary endpoint. The study will remain blinded
through the neoadjuvant treatment and surgery phases and will transition to open label when
participants enter into adjuvant treatment.
•
Removal of nivolumab placebo infusion at Adjuvant phase for participants in Arm B.
•
Removal of pharmacokinetic and immunogenicity samples collection at Adjuvant phase for
participants in Arm B.
•
The study will follow participants until completion of safety follow-up visits 1 and 2 and a
single long-term follow-up visit at approximately 12 months (± 2 months) post-surgery.
Subsequent long-term follow-up visits have been removed.
•
The study objectives, endpoints, and statistical analysis have been updated and clarified.
Additional revisions, including to the Protocol Synopsis, have been made to align the protocol 
amendment with respect to these changes.
Other clarifications and editorial updates were made throughout the protocol to improve clarity 
and readability and to keep consistency throughout the document.
Changes instituted in Protocol Amendment 03 should override any existing protocol requirements
in the event of any apparent discrepancies.
Protocol Amendment No.: 03
Date: 27-Jun-2022
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This amendment also incorporates the changes from the approved Administrative Letters 06, 07, 
and 08, which are detailed in the Document History but not listed in the Summary of Key Changes 
below.
SUMMARY OF KEY CHANGES FOR PROTOCOL AMENDMENT 03
Section Number & Title
Description of Change
Brief Rationale
Table 2-1: Screening Procedural 
Outline (CA2097FL)
The screening procedures are not 
applicable as of Protocol 
Amendment 03 as the study has 
been closed to enrollment. This is 
clarified in footnote “a” as well.
Because the study is unlikely to 
complete enrollment in a reasonable 
timeframe and may no longer be able 
to achieve the scientific objectives of 
the trial, BMS decided to stop new 
enrollment to the CA2097FL study.
Table 2-2: On-treatment 
Neoadjuvant (Pre-surgery) 
Procedural Outline (CA2097FL) 
with PTX and AC Q2W 
Schedule
Table 2-5: Follow-up Procedural 
Outline (CA2097FL)
 
 
 
 
 
For consistency within protocol.
Table 2-5: Follow-up Procedural 
Outline (CA2097FL)
Section 5.1: Overall Design
Section 5.1.3.2: Long-term 
Follow-up Visit
 
 
In Protocol Amendment 03, Long-
term Follow-up has been changed to 
a single visit at 12 months (± 2 
months) post-Surgery. There will be 
no further follow-up beyond this 
visit.
Ten-year long-term follow-up visits 
are not required.
Table 2-4: On-treatment 
Adjuvant (Post-surgery) 
Procedural Outline (CA2097FL)
“Mammogram or breast MRI for 
participants with remaining breast 
tissue post-surgery” row was 
removed.
Mammogram or breast MRI
assessment will not be performed 
before 1 year post-surgery.
Table 2-5: Follow-up Procedural 
Outline (CA2097FL)
In the row for Mammogram or 
breast MRI, the notes were updated 
to add that for participants that 
already performed a mammogram or 
breast MRI at 1-year post-surgery, a 
second examination is not required.
Further clarify mammogram or breast 
MRI at 1 year post-surgery.
Table 2-2: On-treatment 
Neoadjuvant (Pre-surgery) 
Procedural Outline (CA2097FL) 
with PTX and AC Q2W 
Schedule
Table 2-3: On-treatment 
Neoadjuvant (Pre-surgery) 
Procedural Outline (CA2097FL) 
with PTX and AC Q3W 
Schedule
Changed the requirements of 
completion of Clinical Outcome 
Assessments. “COAs will be 
completed by the participants and 
should be completed before the 
participant sees the physician and 
any study related procedures are 
performed.” 
Completion of COAs is recommended 
before the participant sees the 
physician and any study-related 
procedures are performed.
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SUMMARY OF KEY CHANGES FOR PROTOCOL AMENDMENT 03
Section Number & Title
Description of Change
Brief Rationale
Table 2-4: On-treatment 
Adjuvant (Post-surgery) 
Procedural Outline (CA2097FL)
Section 3: Introduction
Section 5.1.1: Screening Period
Section 6: Study Population
Table 7-1: Study Treatments for 
CA2097FL
Added statement regarding study 
enrollment closure as of 07-Apr-
2022.
BMS decided to stop new enrollment 
to the CA2097FL study.
Section 3: Introduction
Modification of the primary 
endpoints to move EFS to an 
exploratory endpoint.
Ten-year long-term follow-up visits 
are not required for this study.
Section 3.1.1: Research 
Hypothesis
Added text that nivolumab added to 
anthracycline-taxane-based 
neoadjuvant will increase pCR.
Updated research hypothesis.
Section 3.1.2: Changes per 
Protocol Amendment 03
New section added. Background 
information for the changes in 
Protocol Amendment 03 has been 
provided.
This section is added to provide key 
changes and rationales.
Section 3.2.5: Background for 
Endocrine Adjuvant Therapy
Section 3.3.5: Nivolumab and 
Endocrine Therapy Combination 
Safety Profile
Data (efficacy and safety) from 
MonarchE study with adjuvant 
abemaciclib has been added. 
In Oct-2021, FDA approved 
abemaciclib in combination with ET 
as adjuvant therapy for high-risk HR+, 
HER2- early BC.
Toxicity observed with concurrent 
administration of abemaciclib with 
pembrolizumab.
Section 3.3: Benefit/Risk
Assessment
Benefit/risk of the trial are 
re-assessed with changes to 
endpoints and unblinding in 
Adjuvant phase.
Benefit/risk of the trial was reassessed 
as new adjuvant treatment landscape 
has evolved.
Section 4: Objectives and 
Endpoints
Section 8.1.4: Post-study 
Treatment Follow-up
Multiple changes were made to the 
objectives and endpoints:
•
EFS has moved from a primary
endpoint to an exploratory
endpoint.
•
Pathological complete response
in the PD-L1+ population has
been moved to a secondary
endpoint.
•
Secondary quality of life
endpoints have been removed.
•
Reduced number of exploratory
biomarker endpoints.
New enrollment to the study is 
stopped; therefore, the study 
objectives and endpoints were 
updated.
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Date: 27-Jun-2022
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SUMMARY OF KEY CHANGES FOR PROTOCOL AMENDMENT 03
Section Number & Title
Description of Change
Brief Rationale
Table 2-4: On-treatment 
Adjuvant (Post-surgery) 
Procedural Outline 
(CA2097FL), footnote “c”
Section 5.1: Overall Design
Section 5.1.2.4: Adjuvant (Post-
surgery) Phase
Section 7.1.3: Adjuvant (Post-
surgery) Phase
As of Protocol Amendment 03, 
treatment in the Adjuvant phase will 
be open label and no crossover is 
allowed on the protocol.
The study design transitioned to open
label at Adjuvant phase per Protocol 
Amendment 03.
Section 5.1: Overall Design
The total duration of the study is 4 
years, with the changes to long-term 
follow-up length.
The duration of study was recalculated 
from first randomized participant to 
the last study visit at 1 year after 
surgery.
Figure 5.1-1: Study Design 
Schema
Schema has been updated to reflect 
the changes in Protocol Amendment 
03.
Treatment assignment was unblinded 
at Adjuvant phase.
Long-term follow-up visits are 
changed to 1 long-term follow-up visit 
at 1 year post-surgery.
Nivolumab placebo removed from 
Adjuvant phase.
Section 5.1.2.3: Radiotherapy
More detail has been provided 
regarding timing of when adjuvant 
systemic therapy may start.
To further clarify when adjuvant 
therapy can be started along with RT.
Section 5.1.2.1: Neoadjuvant 
(Pre-surgery) Phase
Section 5.1.2.4: Adjuvant (Post-
surgery) Phase
Table 7.1-3: Selection and 
Timing of Dose - Adjuvant 
(Post-surgery) Phase
Section 7.1.1:
Nivolumab/Nivolumab Placebo 
Dosing
Section 7.1.3: Adjuvant (Post-
surgery) Phase
As of Protocol Amendment 03, 
participants randomized to Arm B 
will no longer receive nivolumab 
placebo infusion treatment in the 
Adjuvant phase.
To align with nivolumab placebo 
being removed from the Adjuvant 
phase.
Section 5.1.2.4: Adjuvant (post-
surgery) Phase
Two clarifications were made:
Description of no further nivolumab 
placebo infusion adjuvant treatment 
except endocrine treatment (ET) for 
Arm B participants was provided.
Ovarian function suppression is 
allowed to be used with ET.
To align with nivolumab placebo 
being removed from the Adjuvant 
phase.
Section 5.2: Number of 
Participants
An updated number of participants 
screened and randomized has been 
provided.
New enrollment to the study was 
stopped on 07-Apr-2022.
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SUMMARY OF KEY CHANGES FOR PROTOCOL AMENDMENT 03
Section Number & Title
Description of Change
Brief Rationale
Section 5.4.5: Rationale for 
Stratification Factors
Removed maximum number of 
participants who must have PD-L1 
< 1% as the study has closed to 
enrollment.
As this cap of stratification factor is no
longer applicable.
Section 6.1: Inclusion Criteria 2) 
a) i)
Deleted mention of “clinical” before 
the node.
The criteria is for pathological
assessment of nodes.
Section 7.3: Blinding
Language has been added regarding 
the open label treatment/unblinding 
in the Adjuvant phase of the study.
Treatment assignment is transitioned 
to open label at Adjuvant phase.
Section 7.4.2.1: Dose Delay for 
Paclitaxel Therapy
Changed the number of neutrophils 
for febrile neutropenia from 
1500 cells/mm3 down to 
1000 cells/mm3 for > 1 week to dose 
delay.
To correct typographical error.
Section 7.7.1.1: Prohibited 
and/or Restricted Treatments for 
Nivolumab
Section 7.7.1.2: Prohibited 
and/or Restricted Treatments for 
Chemotherapy and Endocrine 
Therapy
CDK4/6 inhibitors are listed as 
examples of anti-neoplastic therapy 
that cannot be administered 
concurrently with nivolumab.
Toxicity observed when abemaciclib 
is concurrently administered with 
pembrolizumab.
Section 8: Discontinuation 
Criteria
Section 8.1: Discontinuation 
from Study Treatment
Start of subsequent cancer therapy 
and unblinding prior to Adjuvant 
phase are newly added 
discontinuation criteria.
Emergency unblinding through IRT 
system prior to Adjuvant phase 
disqualifies the participant to continue
to stay on study treatment.
Table 2-4: On-treatment 
Adjuvant (Post-surgery) 
Procedural Outline (CA2097FL)
Section 9.5: Pharmacokinetics
and Immunogenicity
Table 9.5-1: Pharmacokinetic 
and Anti-drug Antibody 
Sampling Schedule for All 
Participants (CA2097FL)
For participants randomized to Arm 
B, PK and immunogenicity samples 
are no longer required to be 
collected at Adjuvant phase.
Nivolumab placebo is removed from 
Adjuvant phase, so PK and 
immunogenicity samples will only be 
collected in Arm A.
Section 5.1: Overall Design
Section 5.4.5: Rationale for 
Stratification Factors
Section 5.4.5.1: PD-L1 Status
Section 9.8.2.1: PD-L1 
Expression
Provided additional details on 
determination of PD-L1 status.
To further clarify the methodologies 
used for determination of PD-L1 
expression.
Section 9.8.3.4: Plasma for 
Circulating Tumor DNA
Updated wording provided for 
circulating tumor DNA (ctDNA)
testing.
For further clarification.
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SUMMARY OF KEY CHANGES FOR PROTOCOL AMENDMENT 03
Section Number & Title
Description of Change
Brief Rationale
Section 10.1: Sample Size 
Determination
Table 10.1-1: Power 
Assumptions
Sample size and power calculations 
have been updated based on 
changes to the primary endpoint and 
enrollment closure of the study.
Timing for final analysis of pCR 
was added.
New enrollment to the study is 
stopped and the timing for final pCR 
analysis is provided.
Table 10.2-1: Population for 
Analyses
Clarified that the randomized 
population is the ITT population
For clarification of ITT population.
Section 10.3.1: Efficacy 
Analyses
Section 10.3.2: Safety Analyses
The endpoints and statistical 
analysis methods were updated 
based on the changes to the 
objectives of the protocol.
To align study endpoints and 
statistical analysis across the protocol.
Section 10.3.5.1: Futility 
Analysis Based on pCR
Timing of futility analysis was 
noted in the protocol and details of 
interim analyses were removed.
To provide the timing and clarification 
for futility analysis.
Section 11: References
Reference list updated.
Added emergent data/literature about 
PD-L1.
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TABLE OF CONTENTS 
TITLE PAGE ................................................................................................................ 
DOCUMENT HISTORY .............................................................................................. 
OVERALL RATIONALE FOR PROTOCOL AMENDMENT 03 ............................ 
SUMMARY OF KEY CHANGES FOR PROTOCOL AMENDMENT 03 ................ 
TABLE OF CONTENTS .............................................................................................. 
1 SYNOPSIS ................................................................................................................. 
2 SCHEDULE OF ACTIVITIES.................................................................................. 
3 INTRODUCTION ..................................................................................................... 
3.1 Study Rationale ................................................................................................. 
3.1.1 Research Hypothesis ................................................................................ 
3.1.2 Changes per Protocol Amendment 03 ..................................................... 
3.2 Background ....................................................................................................... 
3.2.1 ER+, HER2- Breast Cancer ..................................................................... 
3.2.2 Nivolumab Mechanism of Action ............................................................. 
3.2.3 Clinical Experience with Nivolumab ....................................................... 
3.2.4 Neoadjuvant Chemotherapy ..................................................................... 
3.2.5 Background for Adjuvant Endocrine Therapy ......................................... 
3.3 Benefit/Risk Assessment .................................................................................. 
3.3.1 Nivolumab Safety Profile ......................................................................... 
3.3.2 Anthracycline-Taxane-Based Chemotherapy Safety Profile ................... 
3.3.3 Endocrine Therapy Safety Profile ............................................................ 
3.3.4 Nivolumab and Anthracycline-Taxane-Based Chemotherapy 
Combination Safety Profile ......................................................................... 
3.3.5 Nivolumab and Endocrine Therapy Combination Safety Profile ............ 
4 OBJECTIVES AND ENDPOINTS ........................................................................... 
5 STUDY DESIGN....................................................................................................... 
5.1 Overall Design .................................................................................................. 
5.1.1 Screening Period ...................................................................................... 
5.1.2 Treatment Period ..................................................................................... 
5.1.2.1 Neoadjuvant (Pre-surgery) Phase .................................................. 
5.1.2.2 Surgery ............................................................................................ 
5.1.2.3 Radiotherapy ................................................................................... 
5.1.2.4 Adjuvant (Post-surgery) Phase ....................................................... 
5.1.3 Follow-up Period ..................................................................................... 
5.1.3.1 Safety Follow-up Visits ................................................................... 
5.1.3.2 Long-term Follow-up Visit .............................................................. 
5.1.4 External Committees ................................................................................ 
5.1.4.1 Independent Data Monitoring Committee ...................................... 
5.1.4.2 Study Steering Committee ............................................................... 
5.2 Number of Participants ..................................................................................... 
5.3 End of Study Definition .................................................................................... 
5.4 Scientific Rationale for Study Design............................................................... 
5.4.1 Rationale for Choice of Patient Population............................................. 
5.4.2 Rationale for Choice of Endpoints ........................................................... 
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Clinical Protocol
BMS-936558
CA2097FL
nivolumab
Protocol Amendment No.: 03
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5.4.3 Rationale for Chemotherapy Plus PD-1 Inhibition ................................. 
 
5.4.4 Rationale for Endocrine Therapy Plus PD-1 Inhibition .......................... 
 
5.4.5 Rationale for Stratification Factors ......................................................... 
 
5.4.5.1 PD-L1 Status ................................................................................... 
 
5.4.5.2 Tumor Grade ................................................................................... 
 
5.4.5.3 Axillary Nodal Status ...................................................................... 
 
5.4.5.4 Anthracycline-Cyclophosphamide Dose Frequency ....................... 
 
5.5 Justification for Dose ........................................................................................ 
 
5.5.1 Justification for Dose of Nivolumab ........................................................ 
 
5.5.1.1 Nivolumab 240-mg Every-2-Week Dosing Regimen....................... 
 
5.5.1.2 Nivolumab 360-mg Every-3-Week Dosing Regimen....................... 
 
5.5.1.3 Nivolumab 480-mg Every-4-Week Dosing Regimen....................... 
 
5.5.2 Justification for Dose of Chemotherapy Agents ...................................... 
 
5.5.3 Justification for Dose of Endocrine Therapy ........................................... 
 
6 STUDY POPULATION ............................................................................................ 
 
6.1 Inclusion Criteria .............................................................................................. 
 
6.2 Exclusion Criteria ............................................................................................. 
 
6.3 Lifestyle Restrictions ........................................................................................ 
 
6.4 Screen Failures .................................................................................................. 
 
6.4.1 Retesting During Screening ..................................................................... 
 
7 TREATMENT ........................................................................................................... 
 
7.1 Treatments Administered .................................................................................. 
 
7.1.1 Nivolumab/Nivolumab Placebo Dosing ................................................... 
 
7.1.2 Neoadjuvant (Pre-surgery) Phase ........................................................... 
 
7.1.3 Adjuvant (Post-surgery) Phase ................................................................ 
 
7.1.4 Chemotherapy Dosing ............................................................................. 
 
7.1.4.1 Paclitaxel ........................................................................................ 
 
7.1.4.2 Anthracycline and Cyclophosphamide ........................................... 
 
7.1.5 Endocrine Therapy Dosing ...................................................................... 
 
7.2 Method of Treatment Assignment .................................................................... 
 
7.3 Blinding............................................................................................................. 
 
7.4 Dosage Modification ......................................................................................... 
 
7.4.1 Dose Modifications for Nivolumab .......................................................... 
 
7.4.1.1 Dose Delay Criteria for Nivolumab ................................................ 
 
7.4.1.2 Criteria to Resume Treatment with Nivolumab .............................. 
 
7.4.1.3 Treatment of Nivolumab Infusion Reaction .................................... 
 
7.4.2 Dose Modifications for Chemotherapy .................................................... 
 
7.4.2.1 Dose Delay for Paclitaxel Therapy ................................................. 
 
7.4.2.2 Dose Reductions for Paclitaxel Chemotherapy .............................. 
 
7.4.2.3 Criteria to Resume Treatment with Paclitaxel Chemotherapy ....... 
 
7.4.2.4 Dose Delay for Anthracycline and Cyclophosphamide 
Chemotherapy ....................................................................................... 
 
7.4.2.5 Dose Reductions for Anthracycline-Cyclophosphamide 
Chemotherapy ....................................................................................... 
 
7.4.2.6 Criteria to Resume Treatment with Anthracycline-
Cyclophosphamide Chemotherapy ....................................................... 
 
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Clinical Protocol
BMS-936558
CA2097FL
nivolumab
Protocol Amendment No.: 03
Date: 27-Jun-2022
12
4.0
Approved
930139564
4.0
v
Approved
1.0
v

7.4.3 Dose Modifications for Investigator’s Choice Endocrine Therapy ......... 
7.4.3.1 Dose Delay for Investigator’s Choice Endocrine Therapy ............. 
7.4.3.2 Criteria to Resume Treatment with Investigator’s Choice Endocrine 
Therapy ................................................................................................. 
7.5 Preparation/Handling/Storage/Accountability .................................................. 
7.6 Treatment Compliance ...................................................................................... 
7.7 Concomitant Therapy........................................................................................ 
7.7.1 Prohibited and/or Restricted Treatments................................................. 
7.7.1.1 Prohibited and/or Restricted Treatments for Nivolumab ............... 
7.7.1.2 Prohibited and/or Restricted Treatments for Chemotherapy and 
Endocrine Therapy ................................................................................ 
7.7.2 Other Restrictions and Precautions ......................................................... 
7.7.2.1 Imaging Restriction and Precautions ............................................. 
7.7.3 Permitted Therapy ................................................................................... 
7.8 Treatment After the End of the Study ............................................................... 
8 DISCONTINUATION CRITERIA ........................................................................... 
8.1 Discontinuation from Study Treatment ............................................................ 
8.1.1 Nivolumab Dose Discontinuation ............................................................ 
8.1.2 Chemotherapy Dose Discontinuation ...................................................... 
8.1.3 Endocrine Therapy Dose Discontinuation ............................................... 
8.1.4 Post-study Treatment Study Follow-up .................................................... 
8.2 Discontinuation from the Study ........................................................................ 
8.3 Lost to Follow-up .............................................................................................. 
9 STUDY ASSESSMENTS AND PROCEDURES ..................................................... 
9.1 Efficacy Assessments ........................................................................................ 
9.1.1 Pathological Assessment of Effect ........................................................... 
9.1.1.1 Pathological Complete Response Determination ........................... 
9.1.1.2 Residual Cancer Burden Determination ......................................... 
9.1.2 Definition of Event-free Survival ............................................................. 
9.1.3 Definition of Disease-free Survival .......................................................... 
9.1.4 Definition of Distant Metastasis-free Survival ........................................ 
9.1.5 Imaging Assessment for the Study............................................................ 
9.1.5.1 Objective Response Rate ................................................................. 
9.1.6 Clinical Response by Physical Examination ............................................ 
9.1.7 Breast-conserving Surgery Rate .............................................................. 
9.1.8 Clinical Outcomes Assessments ............................................................... 
9.1.8.1 EORTC QLQ-C30 ........................................................................... 
9.1.8.2 EORTC QLQ-BR23 ......................................................................... 
9.1.8.3 FACIT GP5 ..................................................................................... 
9.1.8.4 EQ-5D-5L ....................................................................................... 
9.2 Adverse Events ................................................................................................. 
9.2.1 Immune-mediated Adverse Events ........................................................... 
9.2.2 Time Period and Frequency for Collecting AE and SAE Information .... 
9.2.3 Method of Detecting AEs and SAEs ......................................................... 
9.2.4 Follow-up of AEs and SAEs ..................................................................... 
9.2.5 Regulatory Reporting Requirements for SAEs ......................................... 
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Clinical Protocol
BMS-936558
CA2097FL
nivolumab
Protocol Amendment No.: 03
Date: 27-Jun-2022
13
4.0
Approved
930139564
4.0
v
Approved
1.0
v

9.2.6 Pregnancy ................................................................................................ 
9.2.7 Laboratory Test Result Abnormalities ..................................................... 
9.2.8 Potential Drug Induced Liver Injury ....................................................... 
9.2.9 Other Safety Considerations .................................................................... 
9.2.10 Management Algorithms for Nivolumab ................................................ 
9.3 Overdose ........................................................................................................... 
9.4 Safety ................................................................................................................ 
9.4.1 Physical Examinations ............................................................................. 
9.4.2 Vital Signs ................................................................................................ 
9.4.3 Electrocardiograms and ECHO or MUGA ............................................. 
9.4.4 Clinical Safety Laboratory Assessments .................................................. 
9.4.5 Imaging Safety Assessment ...................................................................... 
9.5 Pharmacokinetics and Immunogenicity ............................................................ 
 
 
9.8 Biomarkers ........................................................................................................ 
 
9.8.2 Tumor-based Biomarkers ......................................................................... 
9.8.2.1 PD-L1 Expression ........................................................................... 
 
 
 
 
 
 
 
 
 
9.8.4 Additional Research Collection ............................................................... 
9.9 Health Economics OR Medical Resource Utilization and Health Economics . 
10 STATISTICAL CONSIDERATIONS .................................................................... 
10.1 Sample Size Determination ............................................................................. 
10.2 Populations for Analyses ................................................................................ 
10.3 Statistical Analyses ......................................................................................... 
10.3.1 Efficacy Analyses ................................................................................... 
10.3.2 Safety Analyses....................................................................................... 
10.3.3 Clinical Outcomes Assessments ............................................................. 
10.3.3.1 EORTC QLQ-C30 and EORTC QLQ-BR23 ................................. 
10.3.3.2 EQ-5D-5L ..................................................................................... 
10.3.3.3 FACIT GP5 ................................................................................... 
10.3.4 Other Analyses ....................................................................................... 
10.3.4.1 Pharmacokinetic Analyses ............................................................ 
10.3.4.2 Immunogenicity Analyses.............................................................. 
 
10.3.5 Interim Analyses ..................................................................................... 
10.3.5.1 Futility Analysis Based on pCR .................................................... 
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Clinical Protocol
BMS-936558
CA2097FL
nivolumab
Protocol Amendment No.: 03
Date: 27-Jun-2022
14
4.0
Approved
930139564
4.0
v
Approved
1.0
v

11 REFERENCES ........................................................................................................ 
 
12 APPENDICES ......................................................................................................... 
 
APPENDIX 1 ABBREVIATIONS AND TRADEMARKS ........................................ 
 
APPENDIX 2 STUDY GOVERNANCE CONSIDERATIONS ................................. 
 
APPENDIX 3 ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS: 
DEFINITIONS AND PROCEDURES FOR RECORDING, EVALUATING, 
FOLLOW UP AND REPORTING ......................................................................... 
 
APPENDIX 4 WOMEN OF CHILDBEARING POTENTIAL DEFINITIONS AND 
METHODS OF CONTRACEPTION ..................................................................... 
 
APPENDIX 5 ECOG PERFORMANCE STATUS ..................................................... 
 
APPENDIX 6 MANAGEMENT ALGORITHMS ....................................................... 
 
APPENDIX 7 RADIOTHERAPY GUIDELINES ....................................................... 
 
APPENDIX 8 RESPONSE EVALUATION CRITERIA IN SOLID TUMORS 
GUIDELINES (VERSION 1.1) WITH BMS MODIFICATIONS FOR 
NEOADJUVANT BREAST CANCER ................................................................. 
 
APPENDIX 9 COUNTRY-SPECIFIC REQUIREMENTS/DIFFERENCES.............. 
 
APPENDIX 10 NYHA FUNCTIONAL CLASSIFICATION ..................................... 
 
APPENDIX 11 PROTOCOL AMENDMENT SUMMARY OF CHANGE HISTORY
................................................................................................................................. 
 
 
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Clinical Protocol
BMS-936558
CA2097FL
nivolumab
Protocol Amendment No.: 03
Date: 27-Jun-2022
15
4.0
Approved
930139564
4.0
v
Approved
1.0
v

Clinical Protocol
CA2097FL
BMS-936558
nivolumab
1
SYNOPSIS
Protocol Title: A Randomized, Multicenter, Double-blind, Placebo-controlled Phase 3 Study of 
Nivolumab Versus Placebo in Combination With Neoadjuvant Chemotherapy and Adjuvant 
Endocrine Therapy in Patients With High-risk, Estrogen Receptor-Positive (ER+), Human 
Epidermal Growth Factor Receptor 2-Negative (HER2-) Primary Breast Cancer
Short Title:
Nivolumab or Placebo with Neoadjuvant Chemotherapy and Adjuvant Endocrine Therapy in ER+, 
HER2- Breast Cancer
Study Phase: 3
Rationale:
Neoadjuvant therapy is used increasingly in patients with primary breast cancer (BC) to improve 
the likelihood of local tumor control, assess the treatment sensitivity of the disease in vivo, and 
increase the potential for curable disease by targeting the micrometastatic disease burden. Robust 
individual patient-level data meta-analyses from well-conducted clinical trials suggest that 
achieving a pathological complete response (pCR) is positively associated with improvement in 
event-free survival (EFS) and overall survival (OS); these associations are more robust within 
populations with high-risk BC subtypes. Further, use of the neoadjuvant setting as a research 
platform permits rapid assessment of drug efficacy and may expedite clinical development of new 
agents in this setting. Agents that positively and substantially impact pCR rates may have a 
reasonable expectation of meaningful improvement in EFS.
Current neoadjuvant standard of care (SOC), consisting of anthracycline-taxane-based 
chemotherapy, is effective and tolerable among most patients with primary BC. Chemotherapy is 
effective in high-risk, primary estrogen receptor-positive (ER+), human epidermal growth factor 
receptor 2-negative (HER2-) disease and pCR rates range from 7-16%, which are lower than those 
achieved in human epidermal growth factor receptor 2-positive (HER2+) and triple-negative breast 
cancer (TNBC) subtypes through chemotherapy with or without human epidermal growth factor 
receptor 2 (HER2) blockade, respectively (30-50%). In addition, SOC clinical management of 
patients with ER+ BC also includes endocrine therapy (ET) for up to a 10-year period. In the 
setting of a high-risk disease population receiving neoadjuvant chemotherapy, ET is administered 
in the adjuvant setting, with the 2 treatment modalities not being administered concomitantly.
Programmed cell death-1 (PD-1) pathway inhibition has demonstrated clinical activity across 
multiple tumor types, including BC. An accumulating body of preclinical and clinical data supports 
the combination of anti-PD-1 agents and chemotherapy to improve clinical outcomes in early and 
advanced settings across BC subtypes; such data culminated recently in the first approval of a 
programmed death-ligand 1 (PD-L1) inhibitor, atezolizumab, coupled with single-agent 
chemotherapy for patients with newly diagnosed, programmed death-ligand 1-positive (PD-L1+; 
assessed in the immune-cell component of the disease) metastatic TNBC. Preliminary clinical data 
from a Phase 2 adaptive-design neoadjuvant trial (I-SPY2) in participants with HER2- BC (ER+, 
HER2-, and TNBC cohorts) assessed an anti-PD-1 agent added to standard paclitaxel 
Protocol Amendment No.: 03
Date: 27-Jun-2022
16
4.0
Approved
930139564
4.0
v
Approved
1.0
v

Clinical Protocol
CA2097FL
BMS-936558
nivolumab
chemotherapy and demonstrated clinically meaningful improvements in pCR relative to historical 
controls. These and other early clinical trials support currently ongoing Phase 3 
neoadjuvant-adjuvant trials that are evaluating anti-PD-1 agents in the HER2- population.
 
 
 
 
 
 
 
On 07-Apr-2022, Bristol-Myers Squibb (BMS) 
informed sites and the steering committee to stop new enrollment into the CA2097FL study. The 
study steering committee was supportive of the decision. The decision to stop new enrollment was
not based on any safety signal or review of any efficacy data. There has been no change in our 
understanding of the safety profile of nivolumab in combination with paclitaxel, 
cyclophosphamide, epirubicin/doxorubicin, and endocrine therapy.
The trial will continue with the participants currently enrolled and the primary endpoint will be 
amended to focus solely on pCR. 
Study Population:
Newly diagnosed, treatment-naive, high-risk, ER+, HER2- BC.
Objectives and Endpoints:
Objectives
Endpoints
Primary
•
To 
compare 
efficacy 
of 
nivolumab 
plus 
chemotherapy 
vs 
nivolumab 
placebo 
plus 
chemotherapy as neoadjuvant treatment in terms 
of the absence of residual tumor disease in 
participants with untreated, high-risk ER+, HER2-
BC.
•
pCR, defined as no invasive residual disease in breast 
and lymph nodes (ie, ypT0/is, ypN0) by a local 
pathologist (ITT population).
Key Secondary
•
To 
compare 
efficacy 
of 
nivolumab 
plus 
chemotherapy 
vs 
nivolumab 
placebo 
plus 
chemotherapy as neoadjuvant treatment in terms 
of the absence of residual tumor disease in 
participants with untreated, high-risk ER+, HER2-
BC in the PD-L1+ subgroup.
•
pCR, defined as no invasive residual disease in breast 
and lymph nodes (ie, ypT0/is, ypN0) by a local 
pathologist (PD-L1+ population).
•
To assess the efficacy of nivolumab and
nivolumab 
placebo 
in 
combination 
with 
neoadjuvant chemotherapy in terms of RCB.
•
RCB class (0, I, II, III) frequency, for RCB assessed 
by a local pathologist in ITT
and PD-L1+
populations.
•
To evaluate the safety and tolerability of 
nivolumab and nivolumab placebo in combination 
with neoadjuvant chemotherapy.
•
Incidence of AEs, drug-related AEs, AEs leading to 
discontinuation, 
and 
SAEs
as 
defined 
by 
NCI CTCAE v5.0.
Protocol Amendment No.: 03
Date: 27-Jun-2022
17
4.0
Approved
930139564
4.0
v
Approved
1.0
v

Clinical Protocol
CA2097FL
BMS-936558
nivolumab
Objectives
Endpoints
•
Incidence of deaths.
Key Tertiary/Exploratory
•
To assess the efficacy of nivolumab and
nivolumab
placebo 
in 
combination 
with
neoadjuvant chemotherapy in terms of pCR by
alternative definitions.
•
pCR, defined as no invasive or in situ residual
disease in breast and lymph nodes (ie, ypT0 ypN0)
by a local pathologist in ITT
and PD-L1+
populations.
•
pCR, defined as no invasive residual disease in the
breast irrespective of in situ or nodal involvement
(ypT0/is) by a local pathologist in ITT and PD-L1+
populations.
•
To assess the efficacy of nivolumab and
nivolumab 
placebo 
in 
combination 
with
neoadjuvant chemotherapy in terms of ORR by
investigator.
•
ORR,
defined as investigator-assessed tumor
response rate per radiologic-based assessment
(RECIST v1.1) in the Neoadjuvant (pre-surgery)
phase in ITT and PD-L1+ populations.
•
To assess the efficacy of nivolumab and
nivolumab 
placebo 
in 
combination 
with
neoadjuvant chemotherapy and adjuvant ET in
terms of EFS, survival, DFS, and DMFS.
•
EFS in ITT population
•
OS in ITT population.
•
DFS in ITT population.
•
DMFS in ITT population.
•
To characterize the PK and IMG of nivolumab
when 
administered 
in 
combination 
with
neoadjuvant chemotherapy.
•
Nivolumab PK and IMG parameters.
•
To characterize the PK and IMG of nivolumab
when administered in combination with adjuvant
ET.
•
Nivolumab PK and IMG parameters.
•
To assess the efficacy of nivolumab and
nivolumab 
placebo 
in 
combination 
with
neoadjuvant chemotherapy and adjuvant ET in
subgroups based on PD-L1 expression by IHC
28-8 CPS.
•
Clinical efficacy endpoints (eg, pCR, RCB, ORR) by
PD-L1 expression using PD-L1 IHC 28-8 CPS.
•
To assess cancer-specific symptoms and QOL
domains across treatment groups.
•
Mean EORTC QLQ-C30 and QLQ-BR23 subscale
scores and post-baseline score changes.
•
To 
assess
perceptions 
of 
the 
overall
bothersomeness of symptomatic AEs.
•
Mean FACIT GP5 item scores and post-baseline
score changes.
•
To evaluate perceived general health status and
utility between treatment groups.
•
Mean EQ-5D-5L VAS and utility index scores and
post-baseline score changes.
Protocol Amendment No.: 03
Date: 27-Jun-2022
18
4.0
Approved
930139564
4.0
v
Approved
1.0
v

Clinical Protocol
CA2097FL
BMS-936558
nivolumab
Objectives
Endpoints
Abbreviations: AE, adverse event; BC, breast cancer; CPS, combined positive score; CTCAE, Common Terminology 
Criteria 
for 
Adverse 
Events; 
DFS, 
disease-free 
survival; 
DMFS,
distant metastasis-free 
survival; 
EFS, event-free survival; EORTC, European Organisation for Research and Treatment of Cancer; EQ-5D-5L, 5-Level 
EQ-5D; ER+, estrogen receptor-positive; ET, endocrine therapy; FACIT GP5, Functional Assessment of Chronic 
Illness Treatment General Physical Item 5; HER2-, human epidermal growth factor receptor 2-negative; IgG, 
immunoglobulin G; IHC, immunohistochemistry assay; IMG, immunogenicity; ITT, intent to treat; NCI, National 
Cancer Institute; ORR, objective response rate; OS, overall survival; pCR, pathological complete response; 
PD-L1, programmed death-ligand 1; PD-L1+, programmed death-ligand 1-positive; PK, pharmacokinetic; 
QLQ-BR23, Quality of Life Questionnaire-Breast Cancer-specific Module; QLQ-C30, Quality of Life Questionnaire-
Core 30; QOL, quality of life; RCB, residual cancer burden; SAE, serious adverse event; SARS-CoV-2, severe acute 
respiratory syndrome-coronavirus-2; VAS, visual analog scale; vs, versus.
Overall Design:
This is a randomized, double-blind, placebo-controlled, multicenter, global Phase 3 study. The 
study is designed to evaluate nivolumab vs nivolumab placebo in combination with neoadjuvant 
chemotherapy and adjuvant ET in newly diagnosed, treatment-naive participants with high-risk 
(defined as Grade 3 disease or Grade 2 disease with low ER expression of 1-10%) BC that is ER+ 
and HER2-. Participants must have histologically confirmed invasive ductal breast carcinoma 
meeting the characteristics of the Inclusion Criteria.
The study is divided into 3 periods: Screening Period, Treatment Period (Neoadjuvant, Surgery, 
and Adjuvant Phases), and Follow-up Period. Following the confirmation of eligibility, 
participants will be randomized to either Arm A or Arm B in a 1:1 ratio.
The Treatment Period will consist of the following phases:
•
Neoadjuvant (Pre-surgery) Phase: maximum of 8 cycles
−
Paclitaxel (PTX) Cycles 1-4 (1 cycle = every 3 weeks [Q3W]): nivolumab or nivolumab 
placebo + weekly paclitaxel
Followed by
−
Anthracycline-Cyclophosphamide (AC) Cycles 1-4 (1 cycle = every 2 weeks [Q2W] or 
Q3W [dosing frequency to be determined by the Investigator]): nivolumab or nivolumab 
placebo + AC
•
Surgery
•
Adjuvant (Post-surgery) Phase: maximum of 7 cycles
−
Adjuvant Cycles 1-7 (1 cycle = every 4 weeks [Q4W]): nivolumab + ET or ET alone (per 
Protocol Amendment 03)
Treatment will start with the Neoadjuvant (Pre-surgery) Phase, in which participants will be 
randomized to receive an intended 4 cycles of nivolumab or nivolumab placebo in combination 
with weekly paclitaxel, followed by an intended 4 cycles of nivolumab or nivolumab placebo in 
combination with anthracycline (doxorubicin or epirubicin) + cyclophosphamide. Following 
Protocol Amendment No.: 03
Date: 27-Jun-2022
19
4.0
Approved
930139564
4.0
v
Approved
1.0
v

Clinical Protocol
CA2097FL
BMS-936558
nivolumab
completion of the Neoadjuvant (Pre-surgery) Phase of treatment, participants who remain 
operative candidates will undergo breast surgery (per local standards) within 4 weeks. In cases 
when surgery does not occur within 4 weeks, surgery is permitted at a later date. The investigator 
must document the reason for delay of surgery in the CRF and the medical record.
Participants will return to the site within 7-14 days following surgery to begin their Adjuvant 
(Post-surgery) Phase of treatment, consisting of a maximum of 7 cycles of nivolumab +ET or with 
Investigator’s choice of ET alone (per Protocol Amendment 03). The post-surgery visit and the 
first cycle of adjuvant treatment may be combined if adjuvant treatment starts within 7-14 days 
after the breast cancer surgery.
As of Protocol Amendment 03, the Adjuvant phase of the study will be converted to open label, 
and participants will be unblinded when they reach the Adjuvant phase of the study. Participants 
already on adjuvant treatment or in follow-up when Protocol Amendment 03 is approved will also 
be unblinded. No crossover to adjuvant nivolumab will be allowed for participants enrolled in Arm 
B. Adjuvant systemic therapy should be started no later than 6 weeks following Surgery in
participants not receiving radiotherapy (RT). In participants receiving RT, adjuvant systemic
therapy may start at the same time as RT or no later than 1 to 2 weeks after completion of RT per
local standards. Starting adjuvant systemic therapy for a few adjuvant cycles then stopping or
pausing therapy to administer RT then restarting adjuvant systemic therapy for remaining adjuvant
cycles will not be permitted.
Randomized participants in the study will be stratified by the following factors:
1) PD-L1 on immune cells (≥1% or < 1%);
2) Tumor grade (2 or 3);
3) Axillary nodal status (pathological review positive versus radiographic and/or pathologic
review negative); and
4) AC dose-frequency chemotherapy regimen (Q2W or Q3W).
PD-L1 status, used for stratification, is determined by qualitative immunohistochemical assay 
using rabbit monoclonal anti-PD-L1 clone SP142 on the proportion of tumor area occupied by 
PD-L1-expressing tumor-infiltrating immune cells (% IC) of any intensity.
Clinical outcomes assessments (COAs) will be assessed throughout the study at the timepoints 
defined in the Schedule of Activities.
Participants who discontinue study treatment must continue to be followed in this study for 
collection of outcome and/or survival follow-up data, as required, until death or the conclusion of 
the study.
Safety Follow-up Visits will occur after the last Adjuvant (Post-surgery) Phase treatment. As of 
Protocol Amendment 03, the Long-term Follow-up visit will occur 12 months (± 2 months)
following surgery. The Long-term Follow-up visit will be the final visit of the study. For 
participants in follow-up at the time of Protocol Amendment 03, the final study visit will happen 
at the time of the next previously scheduled study visit.
Protocol Amendment No.: 03
Date: 27-Jun-2022
20
4.0
Approved
930139564
4.0
v
Approved
1.0
v

Clinical Protocol
CA2097FL
BMS-936558
nivolumab
The total duration of the study is approximately 4 years from randomization of the first participant. 
The study may be terminated at any time by the Sponsor.
The study design schematic is presented in the figure below.
Protocol Amendment No.: 03
Date: 27-Jun-2022
21
4.0
Approved
930139564
4.0
v
Approved
1.0
v

Clinical Protocol
CA2097FL
BMS-936558
nivolumab
Study Design Schematic
Key Inclusion Criteria:
• Newly diagnosed
ER+, HER2- BC
• Confirmed ER+ BC
• T1c-T2, cN0-cN2 or
T3-T4, cN0-cN2
• Grade 3 or
Grade 2 with ER
1-10%
• Adequate organ
function
• Tissue available for
biomarker 
assessments
• ECOG PS 0-1
Screening
Treatment
Follow-Up
R
A
N
D
O
M
I
Z
A
T
I
O
N
Nivo 360 mg 
Q3W + PTX QW
Nivo PBO Q3W + 
PTX QW
Safety 
Follow-up
30-Day
100-Day
Long-term 
Follow-up 
(12 months 
post Surgery)
*Investigator’s choice anthracycline; dosing frequency of Q2W or Q3W for AC cycles determined by the
Investigator.
†Available ET agents include tamoxifen, anastrozole, letrozole, and exemestane.
Abbreviations: AC = anthracycline + cyclophosphamide; BC = breast cancer; Cy = cycle; ECOG PS =
Eastern Cooperative Oncology Group performance status; ET = endocrine therapy; IC = immune cells;
PBO = placebo; PTX = paclitaxel; Q2W = every 2 weeks; Q3W = every 3 weeks; QW = every week
**In Adjuvant phase, the study treatment will be open-label. Participants in Arm B will not receive Nivo
PBO infusion
Stratification Factors: 
•
PD-L1 IC (> 1% or <1%)
•
Tumor Grade (3 or 2)
•
Axillary Nodal Status (+ or -)
•
AC (Q3W or Q2W)
Neoadjuvant Phase
(Pre-Surgery) 
Surgery
Adjuvant Phase**
(Post-Surgery)
Surgery
Surgery
Nivo 480 mg 
Q4W + 
Investigator’s 
Choice ET†
Investigator’s 
Choice ET†
Nivo 360 mg 
Q3W + AC Q3W 
Or
Nivo 240 mg 
Q2W + AC Q2W
Nivo PBO Q3W + 
AC Q3W 
Or
Nivo PBO Q2W + 
AC Q2W
PTX Cycles 1-4
1 Cy = 3 wks
AC Cycles 1-4
1 Cy = 2 or 3 wks*
Adjuvant Cycles 1-7
1 Cy = 4 wks
1:1
ARM A
ARM B
Protocol Amendment No.: 03
Date: 27-Jun-2022
22
4.0
Approved
930139564
4.0
v
Approved
1.0
v

Clinical Protocol
CA2097FL
BMS-936558
nivolumab
Number of Participants:
The study is closed to new enrollment on 07-Apr-2022. As of 16-May-2022, 831 participants are 
screened and 521 participants are randomized. 
Treatment Arms and Duration:
The selection and timing of dose for each participant is provided in the tables below.
Selection and Timing of Dose - Neoadjuvant (Pre-surgery) Phase - PTX
Arm
Study Treatment
Dosage Level
Frequency of 
Administration
Start and Duration 
of Treatment
Route of 
Administration
A
Nivolumab
360 mg
Q3W
PTX Cycles 1-4
IV
Paclitaxel
80 mg/m2
QW
PTX Cycles 1-4
IV
B
Nivolumab 
Placebo
NA
Q3W
PTX Cycles 1-4 
IV
Paclitaxel
80 mg/m2
QW
PTX Cycles 1-4
IV
Abbreviations: IV, intravenous; m2, square meter; mg, milligram; NA, not applicable; PTX, paclitaxel; QW, every 
week; Q3W, every 3 weeks.
Selection and Timing of Dose - Neoadjuvant (Pre-surgery) Phase - AC
Arm
Study Treatment
Dosage Level
Frequency of 
Administration
Start and Duration 
of Treatment
Route of 
Administration
A
Nivolumab
360 mg
Q3W
AC Cycles 1-4
IV
ORa
240 mg
Q2W
Doxorubicinb
60 mg/m2
Q3W or Q2Wa,c
AC Cycles 1-4
IV
Epirubicinb
90 mg/m2
Q3W or Q2Wa,c
AC Cycles 1-4
IV
Cyclophosphamide
600 mg/m2
Q3W or Q2Wa,c
AC Cycles 1-4
IV
B
Nivolumab 
Placebo
NA
Q3W or Q2Wa
AC Cycles 1-4
IV
Doxorubicinb
60 mg/m2
Q3W or Q2Wa,c
AC Cycles 1-4
IV
Epirubicinb
90 mg/m2
Q3W or Q2Wa,c
AC Cycles 1-4
IV
Cyclophosphamide
600 mg/m2
Q3W or Q2Wa,c
AC Cycles 1-4
IV
Abbreviations: AC, anthracycline + cyclophosphamide; IV, intravenous; m2, square meter; mg, milligram; NA, not 
applicable; Q2W, every 2 weeks; Q3W, every 3 weeks.
a Dosing frequency of Q2W or Q3W for AC cycles to be determined by the Investigator.
b Choice of anthracycline, either doxorubicin or epirubicin, to be determined by the Investigator.
c Prophylaxis with growth factors is required for the AC 2QW schedule .
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Clinical Protocol
CA2097FL
BMS-936558
nivolumab
Selection and Timing of Dose - Adjuvant (Post-surgery) Phase
Arm
Study Treatment
Dosage Level
Frequency of 
Administration
Start and Duration 
of Treatment
Route of 
Administration
A
Nivolumab
480 mg
Q4W
Cycles 1-7
IV
Investigator’s 
Choice ET
See Notea
See Notea
Cycles 1-7
See Notea
B
Investigator’s 
Choice ET
See Notea
See Notea
Cycles 1-7
See Notea
Abbreviations: ET, endocrine therapy; IV, intravenous; mg, milligram; NA, not applicable; Q4W, every 4 weeks.
a May include tamoxifen, letrozole, anastrozole, or exemestane, to be administered per the respective package inserts.
All participants should begin study treatment within 3 days of randomization.
Study Treatment:
Study Drugs for CA2097FL
Medication
Potency
IP/Non-IP
Nivolumab Injectiona
10 mg/mL;
100-mg fill volume
and
10 mg/mL;
40-mg fill volume
IP
Paclitaxel Solution for Injectionb
6 mg/mL; 100 mg fill 
volume
IP
Doxorubicin Hydrochloride Injectionb
2 mg/mL; 200 mg fill 
volume
IP
Epirubicin Solution for Injectionb
2 mg/mL; 200 mg fill 
volume
IP
Cyclophosphamide Injectionb
1 g vial
IP
0.9% Sodium Chloride for Injection
NA
IP
5% Dextrose for Injection
NA
IP
Tamoxifen Tabletsb
Various strengths
IP
Letrozole Tabletsb
2.5 mg
IP
Anastrozole Tabletsb
1 mg
IP
Exemestane Tabletsb
25 mg
IP
Granulocyte colony-stimulating factor 
(G-CSF)c
Various strengths
Non-IP
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Clinical Protocol
CA2097FL
BMS-936558
nivolumab
Study Drugs for CA2097FL
Medication
Potency
IP/Non-IP
Granulocyte-macrophage colony-
stimulating factor (GM-CSF)c
Various strengths
Non-IP
Abbreviations: g, gram; IP, investigational product; mg, milligram; mL, milliliter; NA, not applicable; SmPC, 
summary of product characteristics.
a May be labeled as either “BMS-936558-01” or “Nivolumab.”
b These products may be obtained by the investigational sites as local commercial product in certain countries if
allowed by local regulations. In these cases, products may be a different pack size/potency than listed in the table. 
These products should be prepared/stored/administered in accordance with the package insert or SmPC or according 
to local standards.
c To be sourced locally by investigational sites. These products should be prepared/stored/administered in accordance
with their package insert or SmPC or according to local standards.
Independent Data Monitoring Committee: Yes
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Clinical Protocol
CA2097FL
BMS-936558
nivolumab
2
SCHEDULE OF ACTIVITIES
Table 2-1:
Screening Procedural Outline (CA2097FL) - Not Applicable per Protocol Amendment 03
Procedurea
Screening
Visit
Notes
All windows are based on calendar days.
Eligibility Assessments
Informed Consent
X
Must be obtained prior to any study-related procedures.
Register in IRT system to obtain participant number.
Inclusion/Exclusion Criteria
X
Must be confirmed prior to randomization. See Section 6 (Study Population).
Medical History
X
All medical history relevant to the disease under study, including tobacco history and TNM 
staging.
Disease Biomarkers
X
Document hormonal receptors (ER, PgR) and HER2 status from local testing.
Document results for mutation status (eg, BRCA1/2, PALB2, PIK3CA), if known.
Document results, if known, of genomic test(s) for prognostic (eg, Oncotype, MammaPrint, 
Prosigna).
Documentation of Menopausal Status
(Women only)
X
Document menopausal status. See Section 5.1.1 (Screening Period) for definitions.
Pretreatment Tumor Sample Submission
X
A recent archival primary breast tumor biopsy is required in the format of 1 FFPE tissue 
block (strongly preferred) containing 20 mm3 of tissue, collected ≤90 days prior to
enrollment or unstained tumor tissue sections (22 slides) prepared ≤ 60 days prior to 
enrollment from a tissue sample collected ≤ 90 days prior to enrollment.
If a recent breast tumor specimen is not available, a fresh breast tumor biopsy collection is 
required. If < 22 slides are available, a minimum of 15 unstained slides must be submitted for 
a participant to be eligible. If < 15 unstained slides are available, the participant is not 
eligible.
For participant with planned BCS, surgical clip(s) should be placed preferably prior to starting 
neoadjuvant treatment but no later than PTX C2D1. For participant with planned mastectomy, 
placement of surgical clip(s) is strongly recommended. Placement of surgical clip(s) marks the 
tumor bed to ensure its appropriate localization at the time of the surgery and to enable accurate 
sampling of the specimen by the pathologist. (Refer to pathology manual for additional details).
Central laboratory results for PD-L1 status, ER status, and ER expression level must be 
available prior to randomization.
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Clinical Protocol
CA2097FL
BMS-936558
nivolumab
Table 2-1:
Screening Procedural Outline (CA2097FL) - Not Applicable per Protocol Amendment 03
Procedurea
Screening
Visit
Notes
All windows are based on calendar days.
For additional details, see 
 
Laboratory Manual.
Safety Assessments
PE, Measurements, Vital Signs, and 
ECOG PS
X
Complete PE (including review of systems), height, weight, temperature, BP, heart rate, RR, 
and ECOG PS (Appendix 5). Must be collected within 14 days prior to randomization.
ECG (12-lead)
X
Must be performed within 14 days prior to randomization.
ECHO (Preferred) or MUGA
X
Must be performed within 28 days prior to randomization.
ECHO is the preferred method of assessment. The method used for the baseline assessment 
should be used consistently for additional assessments.
Assessment of Signs and Symptoms
X
Must be performed within 14 days prior to randomization.
Concomitant Medication Use
X
Must be collected within 28 days prior to randomization.
Vaccine use within 30 days prior to randomization.
SAE Assessment
X
Must be collected from the time of consent.
All AEs (SAEs or non-serious AEs) associated with SARS-CoV-2 infection collected from 
time of consent.
Laboratory Tests
CBC with Differential, Chemistry, and 
Serology
X
Must be performed within 14 days prior to randomization.
Serology must be completed within 28 days prior to randomization.
See Section 9.4.4 (Clinical Safety Laboratory Assessments) for a list of laboratory tests.
Cortisolc
X
Must be performed within 14 days prior to randomization.
Pregnancy Test (WOCBP only)
X
Serum or urine pregnancy test (minimum sensitivity of 25 IU/L or equivalent units of HCG) 
to be done at screening and repeated within 24 hours prior to the first dose of study therapy.
An extension up to 72 hours prior to the start of study treatment is permissible in the 
situations where results cannot be obtained within the standard 24-hour window.
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Date: 27-Jun-2022
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Clinical Protocol
CA2097FL
BMS-936558
nivolumab
Table 2-1:
Screening Procedural Outline (CA2097FL) - Not Applicable per Protocol Amendment 03
Procedurea
Screening
Visit
Notes
All windows are based on calendar days.
 
 
Efficacy Assessments
Documentation of Planned Surgery
X
Record type of planned BC surgery (ie, BCS, mastectomy).
Clinical Breast Examination
X
Perform clinical breast examination by palpation of breast and axilla.
Bilateral Ultrasound or Mammogram of 
Breast and Axilla or Breast MRI
X
Perform bilateral ultrasound or mammogram of breast and axilla or breast MRI per local 
standards within 45 days prior to randomization. See Section 9.1.5 (Imaging Assessment for 
the Study).
The method used for the baseline assessment should be used consistently for additional 
assessments during the neoadjuvant phase.
Other Imaging (eg, ultrasound, X-ray, CT, 
MRI, PET)
X
Permitted if clinically indicated and per local standards. See Section 9.1 (Efficacy 
Assessments) for further details.
Axillary Lymph Nodes Fine Needle Biopsy 
or Core Biopsy
X
This procedure at screening will be omitted if there is no suspicion for positive axillary lymph 
node(s) radiographically, or if a pathological report of suspicious lymph nodes of the results 
of a fine needle biopsy or core biopsy is available prior to the Screening Period.
Abbreviations: AE, adverse event; BC, breast cancer; BCS, breast-conserving surgery; BP, blood pressure; CBC, complete blood count; CT, computed tomography; 
ECG, electrocardiogram; ECHO, echocardiogram; ECOG, Eastern Cooperative Oncology Group; eCRF, electronic case report form; ER+, estrogen receptor-
positive; FFPE, formalin-fixed paraffin-embedded; HCG, human chorionic gonadotropin; HER2-, human epidermal growth factor receptor 2-negative; IRT,
interactive response technology; IU, international unit; L, liter; MRI, magnetic resonance imaging; MUGA, multiple-gated acquisition; PD-L1, programmed death-
ligand 1; PE, physical examination; PET, positron emission tomography; PS, performance status; PTX, paclitaxel; RR, respiratory rate; SAE, serious adverse event; 
SARS-CoV-2, severe acute respiratory syndrome-coronavirus-2; TNM, tumor, node, metastasis; WOCBP, women of childbearing potential.
a Some of the assessments referred to in this section may not be captured as data on the eCRF. They are intended to be used as safety monitoring by the treating 
physician. Additional testing or assessments may be performed as clinically necessary or where required by institutional or local regulations. As of 07-Apr-2022, 
this study is closed to new participant enrollment. 
 
 
c Cortisol must be collected at AC C1D1 (predose) and prior to surgery. Result is not required prior to dosing.
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Clinical Protocol
CA2097FL
BMS-936558
nivolumab
Table 2-2:
On-treatment Neoadjuvant (Pre-surgery) Procedural Outline (CA2097FL) with PTX and AC Q2W 
Schedule
Procedurea
Neoadjuvant Treatmentb
Pre-
surgeryd
Notesc
All windows are based on calendar days.
PTX Cycles 1-4
(1 cycle = 3 weeks)
End of 
PTXe
AC Cycles 1-4
(1 cycle = 2 weeks)
D1
D8
D15
D1
Safety Assessments
Targeted PE, Measurements, 
Vital Signs, and ECOG PS
X
X
Weight, BP, heart rate, temperature, and 
ECOG PS (Appendix 5).
ECHO (Preferred) or MUGA
X
ECHO is the preferred method of assessment. 
The method used for the baseline assessment 
should be used consistently for additional 
assessments.
AEs Assessment
(Including SAEs)
Continuously.
Record at each visit.
All SAEs and non-serious AEs should be 
collected continuously during the treatment 
period and for a minimum of 100 days 
following discontinuation of study treatment.
Participants will be followed for all SAEs, non-
serious AEs of special interest (as defined in 
Section 9.2), and all AEs (SAEs and non-
serious AEs) associated with confirmed or 
suspected SARS-CoV-2 infection until 
resolution, the condition stabilizes, the event is 
otherwise explained, the event is deemed 
irreversible, the participant is lost to follow-up 
(as defined in Section 8.3), or for suspected 
cases, until SARS-CoV-2 infection is ruled out.
Concomitant Medication Use
Continuously.
Record at each visit.
Laboratory Tests
CBC with Differential and
Chemistry
X
X
See Section 9.4.4 (Clinical Safety Laboratory 
Assessments) for a list of laboratory tests.
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Clinical Protocol
CA2097FL
BMS-936558
nivolumab
Table 2-2:
On-treatment Neoadjuvant (Pre-surgery) Procedural Outline (CA2097FL) with PTX and AC Q2W 
Schedule
Procedurea
Neoadjuvant Treatmentb
Pre-
surgeryd
Notesc
All windows are based on calendar days.
PTX Cycles 1-4
(1 cycle = 3 weeks)
End of 
PTXe
AC Cycles 1-4
(1 cycle = 2 weeks)
D1
D8
D15
D1
Must be performed within 3 calendar days prior 
to dosing and results must be available prior to 
dosing for all timepoints, except PTX C1D1 
which does not need to be repeated if baseline 
assessment performed within 7 days prior to 
first dose.
Cortisol
X
X
Cortisol must be collected at AC C1D1 
(predose) and prior to surgery. Result is not 
required prior to dosing.
 
 
 
 
 
 
 
 
 
 
 
Pregnancy Test 
(WOCBP Only)
See Notes.
Serum or urine pregnancy test (minimum 
sensitivity 25 IU/L or equivalent units of HCG) 
to be done within 24 hours prior to D1 of each 
PTX cycle and prior to D1 of AC C1 and AC 
C3. An extension up to 72 hours prior to the 
start of study treatment is permissible in 
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Clinical Protocol
CA2097FL
BMS-936558
nivolumab
Table 2-2:
On-treatment Neoadjuvant (Pre-surgery) Procedural Outline (CA2097FL) with PTX and AC Q2W 
Schedule
Procedurea
Neoadjuvant Treatmentb
Pre-
surgeryd
Notesc
All windows are based on calendar days.
PTX Cycles 1-4
(1 cycle = 3 weeks)
End of 
PTXe
AC Cycles 1-4
(1 cycle = 2 weeks)
D1
D8
D15
D1
situations where results cannot be obtained 
within the standard 24-hour window.
Efficacy Assessments
Clinical Breast Examination
X
X
Perform clinical breast examination by 
palpation of breast and axilla after the last PTX 
cycle and prior to surgery.
Bilateral Ultrasound or 
Mammogram of Breast and 
Axilla or Breast MRI
X
Perform after completion of neoadjuvant 
treatment, or as clinically indicated.
The method used for the baseline assessment 
should be used consistently for additional 
assessments during the neoadjuvant phase.
Other Imaging 
(eg, ultrasound, X-ray, CT, 
contrast-enhanced MRI, PET)
See Notes.
Permitted as clinically indicated and per local 
standards. See Section 9.1 (Efficacy 
Assessments) for further details.
Tumor Biopsy
See Notes.
Tumor biopsy collection is optional on 
PTX C2D1 (± 2 days) and required at the time 
of surgery.
 
Clinical Outcomes Assessments
EORTC QLQ-C30
X
X
X
COAs will be completed by the participants 
and should be completed before the participant 
sees the physician and any study-related 
procedures are performed.
See Section 9.1.8 (Clinical Outcomes 
Assessments) for details.
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Clinical Protocol
CA2097FL
BMS-936558
nivolumab
Table 2-2:
On-treatment Neoadjuvant (Pre-surgery) Procedural Outline (CA2097FL) with PTX and AC Q2W 
Schedule
Procedurea
Neoadjuvant Treatmentb
Pre-
surgeryd
Notesc
All windows are based on calendar days.
PTX Cycles 1-4
(1 cycle = 3 weeks)
End of 
PTXe
AC Cycles 1-4
(1 cycle = 2 weeks)
D1
D8
D15
D1
EORTC QLQ-BR23
X
X
X
COAs will be completed by the participants 
and should be completed before the participant 
sees the physician and any study-related 
procedures are performed.
See Section 9.1.8 (Clinical Outcomes 
Assessments) for details.
EQ-5D-5L
X
X
X
COAs will be completed by the participants 
and should be completed before the participant 
sees the physician and any study-related 
procedures are performed.
See Section 9.1.8 (Clinical Outcomes 
Assessments) for details.
FACIT GP5
X
X
X
COAs will be completed by the participants 
and should be completed before the participant 
sees the physician and any study-related 
procedures are performed.
See Section 9.1.8 (Clinical Outcomes 
Assessments) for details.
Healthcare Resource Utilization
Healthcare Resource 
Utilization
X
X
X
Must be completed by site staff and recorded 
on the eCRF.
See Section 9.9 (Health Economics OR 
Medical Resource Utilization and Health 
Economics) for details.
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Clinical Protocol
CA2097FL
BMS-936558
nivolumab
Table 2-2:
On-treatment Neoadjuvant (Pre-surgery) Procedural Outline (CA2097FL) with PTX and AC Q2W 
Schedule
Procedurea
Neoadjuvant Treatmentb
Pre-
surgeryd
Notesc
All windows are based on calendar days.
PTX Cycles 1-4
(1 cycle = 3 weeks)
End of 
PTXe
AC Cycles 1-4
(1 cycle = 2 weeks)
D1
D8
D15
D1
PK and IMG Assessments
See Notes.
See Table 9.5-1 for PK/IMG sample collection 
schedule.
 
Optional Tumor Tissue 
Sample Collection Upon 
Recurrence and/or 
Progression
At disease recurrence and/or progression (within 40 days).
If biopsy or surgical resection is performed at 
recurrence and/or progression, submit a tumor 
sample (1 FFPE block or 22 unstained slides)
to the central laboratory.
Study Treatment
Randomization
X
IRT Drug Assignment
X
X
X
X
Administer Nivolumab or 
Nivolumab Placebo
X
X
Treatment must be administered within 
3 calendar days after randomization.
Administer PTX
X
X
X
Administer Anthracycline
X
Anthracycline may be doxorubicin or 
epirubicin. See Table 7.1-1 for dose regimens.
G-CSF or GM-CSF prophylaxis per
international guidelines is required for
dose-dense administration of AC.
Administer 
Cyclophosphamide
X
G-CSF or GM-CSF prophylaxis per
international guidelines is required for
dose-dense administration of AC.
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Clinical Protocol
CA2097FL
BMS-936558
nivolumab
Table 2-2:
On-treatment Neoadjuvant (Pre-surgery) Procedural Outline (CA2097FL) with PTX and AC Q2W 
Schedule
Procedurea
Neoadjuvant Treatmentb
Pre-
surgeryd
Notesc
All windows are based on calendar days.
PTX Cycles 1-4
(1 cycle = 3 weeks)
End of 
PTXe
AC Cycles 1-4
(1 cycle = 2 weeks)
D1
D8
D15
D1
Documentation of Actual 
Breast Surgery
X
Record the actual type of BC surgery (ie, BCS, 
mastectomy) on day of or within 7 days after 
surgery.
Surgery (SOC)
X
Surgery per local SOC should be performed 
within 4 weeks after the completion of the 
neoadjuvant treatment phase (ie, 6-7 weeks after 
last neoadjuvant dose depending on AC 
treatment schedule).
In cases, when surgery does not occur within 4 
weeks surgery is permitted at a later date. The 
investigator must document reason for delay of 
surgery in the eCRF and the medical record.
Surgery may be either BCS or mastectomy as 
determined by the participant and surgeon as 
per local SOC. 
Appropriate PE, pathologic TNM staging (after 
resection) and laboratory assessments should be 
performed as per local SOC prior to surgery.
 
 
 
Refer to Pathology Manual for a detailed listing 
of surgical specimen details to be included on 
the participant pathology report and in the 
eCRF.
Abbreviations: AC, anthracycline + cyclophosphamide; AE, adverse event; BC, breast cancer; BCS, breast-conserving surgery; BP, blood pressure; C, cycle; 
CBC, complete blood count; COA, clinical outcomes assessment; CT, computed tomography; D, day; ECHO, echocardiogram; ECOG, Eastern Cooperative 
Oncology Group; eCRF, electronic case report form; EORTC, European Organisation for the Research and Treatment of Cancer; EQ-5D-5L, 5-Level EQ-5D; 
FACIT GP5, Functional Assessment of Chronic Illness Therapy General Physical Item 5; G-CSF,= granulocyte-colony stimulating factor; GM-CSF, granulocyte-
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Clinical Protocol
CA2097FL
BMS-936558
nivolumab
macrophage 
colony-stimulating 
factor;
HCG,
human 
chorionic 
gonadotropin;
IgG,
immunoglobulin 
G;
IMG,
immunogenicity; 
IRT, interactive response technology; IU,
international unit; L,
liter; MRI,
magnetic resonance imaging; MUGA,
multiple-gated acquisition;
PE, physical examination; PET, positron emission tomography; PK, pharmacokinetic; PS, performance status; PTX, paclitaxel; Q2W, every 2 weeks; QLQ-BR23,
Quality of Life Questionnaire-Breast Cancer-specific Module; QLQ-C30, Quality of Life Questionnaire-Core 30; SAE, serious adverse event; SARS-CoV-2,
severe acute respiratory syndrome-coronavirus-2;SOC, standard of care; TNM, tumor, node, metastasis; WOCBP, women of childbearing potential.
a If a dose is delayed, the procedures schedule for that same timepoint should also be delayed to coincide with when that timepoint’s dosing actually occurs, with
the exception of the optional tissue sample collection.
b On-treatment procedures may generally be performed within a ± 3-day visit window, unless otherwise specified (eg, breast ultrasound or mammogram or breast
MRI, tumor biopsy).
c Some of the assessments referred to in this section may not be captured as data on the eCRF. They are intended to be used as safety monitoring by the treating 
physician. Additional testing or assessments may be performed as clinically necessary or where required by institutional or local regulations.
d Between end of neoadjuvant treatment and before surgery.
e End of PTX is defined as 3 weeks after PTX C4D1 or sooner if participant discontinues prior to completion of the 4 PTX cycles.
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Clinical Protocol
CA2097FL
BMS-936558
nivolumab
Table 2-3:
On-treatment Neoadjuvant (Pre-surgery) Procedural Outline (CA2097FL) with PTX and AC Q3W 
Schedule
Procedurea
Neoadjuvant Treatmentb
Pre-
surgeryd
Notesc
All windows are based on calendar days.
PTX Cycles 1-4
(1 cycle = 3 weeks)
End of 
PTXe
AC Cycles 1-4
(1 cycle = 3 weeks)
D1
D8
D15
D1
Safety Assessments
Targeted PE, Measurements, Vital 
Signs, and ECOG PS
X
X
Weight, BP, heart rate, temperature, and 
ECOG PS (Appendix 5).
ECHO (Preferred) or MUGA
X
ECHO is the preferred method of assessment. 
The method used for the baseline assessment 
should be used consistently for additional 
assessments.
AEs Assessment 
(Including SAEs)
Continuously.
Record at each visit.
All SAEs and non-serious AEs should be 
collected continuously during the treatment 
period and for a minimum of 100 days 
following discontinuation of study treatment.
Participants will be followed for all SAEs, 
non-serious AEs of special interest (as defined 
in Section 9.2), and all AEs (SAEs and non-
serious AEs) associated with confirmed or 
suspected SARS-CoV-2 infection until 
resolution, the condition stabilizes, the event 
is otherwise explained, the event is deemed 
irreversible, the participant is lost to follow-up 
(as defined in Section 8.3), or for suspected 
cases, until SARS-CoV-2 infection is ruled 
out.
Concomitant Medication Use
Continuously.
Record at each visit.
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Clinical Protocol
CA2097FL
BMS-936558
nivolumab
Table 2-3:
On-treatment Neoadjuvant (Pre-surgery) Procedural Outline (CA2097FL) with PTX and AC Q3W 
Schedule
Procedurea
Neoadjuvant Treatmentb
Pre-
surgeryd
Notesc
All windows are based on calendar days.
PTX Cycles 1-4
(1 cycle = 3 weeks)
End of 
PTXe
AC Cycles 1-4
(1 cycle = 3 weeks)
D1
D8
D15
D1
Laboratory Tests
CBC with Differential and 
Chemistry
X
X
See Section 9.4.4 (Clinical Safety Laboratory 
Assessments) for a list of laboratory tests.
Must be performed within 3 calendar days 
prior to dosing and results must be available 
prior to dosing for all timepoints, except 
PTX C1D1 which does not need to be 
repeated if baseline assessment performed 
within 7 days prior to first dose.
Cortisol
X
X
Cortisol must be collected at AC C1D1 
(predose) and prior to surgery. Result is not 
required prior to dosing.
 
 
 
 
 
 
 
 
 
 
 
Protocol Amendment No.: 03
Date: 27-Jun-2022
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v

Clinical Protocol
CA2097FL
BMS-936558
nivolumab
Table 2-3:
On-treatment Neoadjuvant (Pre-surgery) Procedural Outline (CA2097FL) with PTX and AC Q3W 
Schedule
Procedurea
Neoadjuvant Treatmentb
Pre-
surgeryd
Notesc
All windows are based on calendar days.
PTX Cycles 1-4
(1 cycle = 3 weeks)
End of 
PTXe
AC Cycles 1-4
(1 cycle = 3 weeks)
D1
D8
D15
D1
Pregnancy Test (WOCBP Only)
X
X
Serum or urine pregnancy test (minimum 
sensitivity 25 IU/L or equivalent units of 
HCG) to be done within 24 hours prior to D1 
of each cycle. An extension up to 72 hours 
prior to the start of study treatment is 
permissible in situations where results cannot 
be obtained within the standard 24-hour 
window.
Efficacy Assessments
Clinical Breast Examination
X
X
Perform clinical breast examination by 
palpation of breast and axilla after the last 
PTX cycle and prior to surgery.
Bilateral Ultrasound or 
Mammogram of Breast and Axilla 
or Breast MRI
X
Perform after completion of neoadjuvant 
treatment, or as clinically indicated.
The method used for the baseline assessment 
should be used consistently for additional 
assessments.
Other Imaging 
(eg, ultrasound, X-ray, CT, 
contrast enhanced MRI, PET)
See Notes.
Permitted as clinically indicated and per local 
standards. See Section 9.1 (Efficacy 
Assessments) for further details.
Tumor Biopsy
See Notes.
Tumor biopsy collection is optional on 
PTX C2D1 (± 2 days) and required at the time 
of surgery.
 
Protocol Amendment No.: 03
Date: 27-Jun-2022
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4.0
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4.0
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1.0
v

Clinical Protocol
CA2097FL
BMS-936558
nivolumab
Table 2-3:
On-treatment Neoadjuvant (Pre-surgery) Procedural Outline (CA2097FL) with PTX and AC Q3W 
Schedule
Procedurea
Neoadjuvant Treatmentb
Pre-
surgeryd
Notesc
All windows are based on calendar days.
PTX Cycles 1-4
(1 cycle = 3 weeks)
End of 
PTXe
AC Cycles 1-4
(1 cycle = 3 weeks)
D1
D8
D15
D1
Clinical Outcomes Assessments
EORTC QLQ-C30
X
X
X
COAs will be completed by the participants 
and should be completed before the 
participant sees the physician and any study
related procedures are performed.
See Section 9.1.8 (Clinical Outcomes 
Assessments) for details.
EORTC QLQ-BR23
X
X
X
COAs will be completed by the participants 
and should be completed before the 
participant sees the physician and any study
related procedures are performed.
See Section 9.1.8 (Clinical Outcomes 
Assessments) for details.
EQ-5D-5L
X
X
X
COAs will be completed by the participants 
and should be completed before the 
participant sees the physician and any study
related procedures are performed.
See Section 9.1.8 (Clinical Outcomes 
Assessments) for details.
FACIT GP5
X
X
X
COAs will be completed by the participants 
and should be completed before the 
participant sees the physician and any study
related procedures are performed.
See Section 9.1.8 (Clinical Outcomes 
Assessments) for details.
Protocol Amendment No.: 03
Date: 27-Jun-2022
39
4.0
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930139564
4.0
v
Approved
1.0
v

Clinical Protocol
CA2097FL
BMS-936558
nivolumab
Table 2-3:
On-treatment Neoadjuvant (Pre-surgery) Procedural Outline (CA2097FL) with PTX and AC Q3W 
Schedule
Procedurea
Neoadjuvant Treatmentb
Pre-
surgeryd
Notesc
All windows are based on calendar days.
PTX Cycles 1-4
(1 cycle = 3 weeks)
End of 
PTXe
AC Cycles 1-4
(1 cycle = 3 weeks)
D1
D8
D15
D1
Healthcare Resource Utilization
Healthcare Resource Utilization
X
X
X
Must be completed by site staff and recorded 
on eCRF.
See Section 9.9 (Health Economics OR 
Medical Resource Utilization and Health 
Economics) for details.
PK and IMG Assessments
See Notes.
See Table 9.5-1 for PK/IMG sample 
collection schedule.
 
Optional Tumor Tissue Sample 
Collection Upon Recurrence 
and/or Progression
At recurrence and/or disease progression (within 40 days).
If biopsy or surgical resection is performed at 
recurrence and/or progression, submit a tumor 
sample (1 FFPE block or 22 unstained slides)
to the central laboratory.
Study Treatment
Randomization
X
IRT Drug Assignment
X
X
X
X
Administer Nivolumab or 
Nivolumab Placebo
X
X
Treatment must be administered within 
3 calendar days after randomization.
Administer PTX
X
X
X
Administer Anthracycline
X
Anthracycline may be doxorubicin or 
epirubicin. See Table 7.1-1 for dose regimens.
Administer Cyclophosphamide
X
Protocol Amendment No.: 03
Date: 27-Jun-2022
40
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930139564
4.0
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Approved
1.0
v

Clinical Protocol
CA2097FL
BMS-936558
nivolumab
Table 2-3:
On-treatment Neoadjuvant (Pre-surgery) Procedural Outline (CA2097FL) with PTX and AC Q3W 
Schedule
Procedurea
Neoadjuvant Treatmentb
Pre-
surgeryd
Notesc
All windows are based on calendar days.
PTX Cycles 1-4
(1 cycle = 3 weeks)
End of 
PTXe
AC Cycles 1-4
(1 cycle = 3 weeks)
D1
D8
D15
D1
Documentation of Actual Breast 
Surgery
X
Record the actual type of BC surgery (ie, 
BCS, mastectomy) on day of or within 7 days 
after surgery.
Surgery (SOC)
X
Surgery per local SOC should be performed 
within 4 weeks after the completion of the 
neoadjuvant treatment phase (ie, 6-7 weeks 
after last neoadjuvant dose depending on AC 
treatment schedule).
In cases, when surgery does not occur within 4 
weeks surgery is permitted at a later date. The 
investigator must document reason for delay of 
surgery in the eCRF and the medical record.
Surgery may be either BCS or mastectomy as 
determined by the participant and surgeon as 
per local SOC. 
Appropriate PE, pathologic TNM staging,(after 
resection) and laboratory assessments should 
be performed as per local SOC prior to 
surgery.
 
 
 
Refer to Pathology Manual for a detailed 
listing of surgical specimen details to be 
included on the participant pathology report 
and in the eCRF.
Abbreviations: AC, anthracycline + cyclophosphamide; AE, adverse event; BC, breast cancer; BCS, breast-conserving surgery; BP, blood pressure; C, cycle; 
CBC, complete blood count; COA, clinical outcomes assessment; CT, computed tomography; D, day; ECHO, echocardiogram; ECOG, Eastern Cooperative 
Oncology Group; eCRF, electronic case report form; EORTC, European Organisation for the Research and Treatment of Cancer; EQ-5D-5L, 5-Level EQ-5D; 
Protocol Amendment No.: 03
Date: 27-Jun-2022
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4.0
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Clinical Protocol
CA2097FL
BMS-936558
nivolumab
FACIT GP5, Functional Assessment of Chronic Illness Therapy General Physical Item 5; G-CSF, granulocyte-colony stimulating factor; GM-CSF, granulocyte-
macrophage 
colony-stimulating 
factor; 
HCG,
human 
chorionic 
gonadotropin; 
IgG,
immunoglobulin 
G; 
IMG,
immunogenicity; 
IRT, interactive response technology;
IU,
international unit; L,
liter;
MRI,
magnetic resonance imaging; MUGA,
multiple-gated acquisition; 
PE, physical examination; PET, positron emission tomography; PK, pharmacokinetic; PS, performance status; PTX, paclitaxel; Q3W, every 3 weeks; QLQ-BR23,
Quality of Life Questionnaire-Breast Cancer-specific Module; QLQ-C30, Quality of Life Questionnaire-Core 30; SAE, serious adverse event; SARS-CoV-2,
severe acute respiratory syndrome-coronavirus-2; SOC, standard of care; TNM, tumor node metastasis; WOCBP, women of childbearing potential.
a If a dose is delayed, the procedures schedule for that same timepoint should also be delayed to coincide with when that timepoint’s dosing actually occurs, with
the exception of the optional tissue sample collection.
b On-treatment procedures may generally be performed within a ± 3-day visit window, unless otherwise specified (eg, breast ultrasound or mammogram or breast
MRI, tumor biopsy).
c Some of the assessments referred to in this section may not be captured as data on the eCRF. They are intended to be used as safety monitoring by the treating 
physician. Additional testing or assessments may be performed as clinically necessary or where required by institutional or local regulations.
d Between end of neoadjuvant treatment and before surgery.
e End of PTX is defined as 3 weeks after PTX C4D1 or sooner if participant discontinues prior to completion of the 4 PTX cycles.
Protocol Amendment No.: 03
Date: 27-Jun-2022
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4.0
Approved
930139564
4.0
v
Approved
1.0
v

Clinical Protocol
CA2097FL
BMS-936558
nivolumab
Table 2-4:
On-treatment Adjuvant (Post-surgery) Procedural Outline (CA2097FL)
Procedurea
Post-surgery 
Visitb
Adjuvant Treatmentc
Cycles 1-7 (1 cycle = 4 weeks)
End of 
Adjuvante
Notesd
All windows are based on calendar days.
Post-surgery 
(within 7-14 days)
D1
Safety Assessments
Targeted PE, 
Measurements, Vital Signs, 
and ECOG PS
X
X
Weight, BP, heart rate, temperature, and ECOG PS 
(Appendix 5).
Documentation of 
Menopausal Status 
(Women only)
X
Document menopausal status in participants who were 
premenopausal at screening/baseline. See Section 5.1.2.4
[Adjuvant (Post-surgery) Phase] for definition.
ECHO (Preferred) or 
MUGA
X
Perform assessment upon completion of adjuvant 
treatment, or as clinically indicated.
ECHO is the preferred method of assessment. The 
method used for the baseline assessment should be used 
consistently for additional assessments.
AEs Assessment 
(Including SAEs)
Continuously.
Record at each visit.
Collect continuously throughout the Treatment Period 
and for a minimum of 100 days after last dose of study 
treatment.
All AEs (SAE or non-serious AE) related to the protocol-
specified definitive breast surgery should be collected 
continuously during the treatment period and for a 
minimum of 100 days after last dose of study treatment.
Participants will be followed for all SAEs, non-serious 
AEs of special interest (as defined in Section 9.2), and all 
AEs (SAEs and non-serious AEs) associated with 
confirmed or suspected SARS-CoV-2 infection until 
resolution, the condition stabilizes, the event is otherwise 
explained, the event is deemed irreversible, the 
participant is lost to follow-up (as defined in Section 
Protocol Amendment No.: 03
Date: 27-Jun-2022
43
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930139564
4.0
v
Approved
1.0
v

Clinical Protocol
CA2097FL
BMS-936558
nivolumab
Table 2-4:
On-treatment Adjuvant (Post-surgery) Procedural Outline (CA2097FL)
Procedurea
Post-surgery 
Visitb
Adjuvant Treatmentc
Cycles 1-7 (1 cycle = 4 weeks)
End of 
Adjuvante
Notesd
All windows are based on calendar days.
Post-surgery 
(within 7-14 days)
D1
8.3), or for suspected cases, until SARS-CoV-2 infection 
is ruled out.
Concomitant Medication 
Use
Continuously.
Record at each visit.
Radiotherapy
See Notes.
Post-operative RT is required if BCS is subsequent 
treatment.
Post-operative RT is optional if mastectomy is 
subsequent treatment and should follow local practice.
Laboratory Tests
CBC with Differential and
Chemistry
X
X
See Section 9.4.4 (Clinical Safety Laboratory 
Assessments) for a list of laboratory tests.
Estradiol
X
For pre-menopausal women ONLY.
Pregnancy Test (WOCBP 
only)
X
Serum or urine pregnancy test (minimum sensitivity 
25 IU/L or equivalent units of HCG) to be done within 
24 hours prior to D1 of each cycle. An extension up to 72 
hours prior to the start of study treatment is permissible 
in situations where results cannot be obtained within the 
standard 24-hour window.
Efficacy Assessments
Clinical Breast 
Examination
See Notes.
Perform clinical breast examination by palpation of 
breast and axilla as clinically indicated and per local 
standards. See Section 9.1 (Efficacy Assessments) for 
further details.
Other Imaging (eg, 
ultrasound, X-ray, CT, 
contrast-enhanced MRI, 
PET)
See Notes.
Permitted if clinically indicated and per local standards. 
See Section 9.1 (Efficacy Assessments) for further 
details.
Protocol Amendment No.: 03
Date: 27-Jun-2022
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4.0
Approved
930139564
4.0
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Approved
1.0
v

Clinical Protocol
CA2097FL
BMS-936558
nivolumab
Table 2-4:
On-treatment Adjuvant (Post-surgery) Procedural Outline (CA2097FL)
Procedurea
Post-surgery 
Visitb
Adjuvant Treatmentc
Cycles 1-7 (1 cycle = 4 weeks)
End of 
Adjuvante
Notesd
All windows are based on calendar days.
Post-surgery 
(within 7-14 days)
D1
Clinical Outcomes Assessments
EORTC QLQ-C30
X
X
X
COAs will be completed by the participants and should
be completed before the participant sees the physician 
and any study related procedures are performed.
See Section 9.1.8 (Clinical Outcomes Assessments) for 
details.
EORTC QLQ-BR23
X
X
X
COAs will be completed by the participants and should
be completed before the participant sees the physician 
and any study related procedures are performed.
See Section 9.1.8 (Clinical Outcomes Assessments) for 
details.
EQ-5D-5L
X
X
X
COAs will be completed by the participants and should
be completed before the participant sees the physician 
and any study related procedures are performed.
See Section 9.1.8 (Clinical Outcomes Assessments) for 
details.
FACIT GP5
X
X
X
COAs will be completed by the participants and should
be completed before the participant sees the physician 
and any study related procedures are performed.
See Section 9.1.8 (Clinical Outcomes Assessments) for 
details.
Healthcare Resource Utilization
Healthcare Resource 
Utilization
X
X
X
Must be completed by site staff and recorded on eCRF.
See Section 9.9 (Health Economics OR Medical 
Resource Utilization and Health Economics) for details.
PK and IMG Assessments
See Notes.
As of Protocol Amendment 03, PK/IMG sample 
collection is only to be performed in participants in Arm 
Protocol Amendment No.: 03
Date: 27-Jun-2022
45
4.0
Approved
930139564
4.0
v
Approved
1.0
v

Clinical Protocol
CA2097FL
BMS-936558
nivolumab
Table 2-4:
On-treatment Adjuvant (Post-surgery) Procedural Outline (CA2097FL)
Procedurea
Post-surgery 
Visitb
Adjuvant Treatmentc
Cycles 1-7 (1 cycle = 4 weeks)
End of 
Adjuvante
Notesd
All windows are based on calendar days.
Post-surgery 
(within 7-14 days)
D1
(Arm A only)
A. See Table 9.5-1 for PK/IMG sample collection
schedule.
 
Optional Tumor Tissue 
Sample Collection Upon 
Recurrence and/or 
Progression
At disease recurrence and/or progression (within 40 days).
If biopsy or surgical resection is performed at recurrence 
and/or progression, submit a tumor sample (1 FFPE 
block or 22 unstained slides) to the central laboratory.
 
Study Treatment
IRT Drug Assignment
X
Administer Nivolumab
(Arm A only)
X
Participants Not Receiving RT: Adjuvant systemic
therapy should be started no later than 6 weeks following 
Surgery.
Participants Receiving RT: Adjuvant systemic therapy 
may start at the same time as RT or no later than 1 week 
after completion of RT, per local standard. See Section 
5.1.2.3 (Radiotherapy) for guidance.
Dispense Investigator’s 
Choice ET and 
Provide/Review Patient 
Diary
See Notes.
To be administered PO. Dispense and review patient 
diary at each study visit.
 
 
 
Protocol Amendment No.: 03
Date: 27-Jun-2022
46
4.0
Approved
930139564
4.0
v
Approved
1.0
v

Clinical Protocol
CA2097FL
BMS-936558
nivolumab
Table 2-4:
On-treatment Adjuvant (Post-surgery) Procedural Outline (CA2097FL)
Procedurea
Post-surgery 
Visitb
Adjuvant Treatmentc
Cycles 1-7 (1 cycle = 4 weeks)
End of 
Adjuvante
Notesd
All windows are based on calendar days.
Post-surgery 
(within 7-14 days)
D1
 
 
 
 
 
Abbreviations: AE, adverse event; BCS, breast-conserving surgery; BP, blood pressure; C, cycle; CBC, complete blood count; COA, clinical outcomes assessment; 
CT, computed tomography; D, day; ECHO, echocardiogram; ECOG, Eastern Cooperative Oncology Group; eCRF, electronic case report form; 
EORTC, European Organisation for the 
Research 
and 
Treatment 
of 
Cancer;
EQ-5D-5L,
5-Level 
EQ-5D; 
ET,
endocrine 
therapy; 
FACIT GP5, Functional Assessment of Chronic Illness Therapy General Physical Item 5; HCG, human chorionic gonadotropin; IgG, immunoglobulin G; IMG,
immunogenicity; IRT, interactive response technology; IU, international unit; L, liter; MRI, magnetic resonance imaging; MUGA, multiple-gated acquisition; 
PE, physical examination; PET, positron emission tomography; PK, pharmacokinetic; PO, by mouth; PS, performance status; QLQ-BR23, Quality of Life 
Questionnaire-Breast Cancer-specific Module; QLQ-C30, Quality of Life Questionnaire-Core 30; RT, radiotherapy; SAE, serious adverse event; SARS-CoV-2,
severe acute respiratory syndrome-coronavirus-2; WOCBP, women of childbearing potential.
a If a dose is delayed, the procedures schedule for that same timepoint should also be delayed to coincide with when that timepoint’s dosing actually occurs.
b Post-surgery visit and first cycle of adjuvant treatment may be combined if adjuvant treatment starts within 7-14 days after the breast cancer surgery.
c On-treatment procedures may generally be performed within a ± 3-day window, unless otherwise specified (eg, breast ultrasound or mammogram or breast MRI, 
tumor biopsy). As of Protocol Amendment 03, all participants in the Adjuvant phase will be unblinded.
d Some of the assessments referred to in this section may not be captured as data on the eCRF. They are intended to be used as safety monitoring by the treating 
physician. Additional testing or assessments may be performed as clinically necessary or where required by institutional or local regulations.
e End of  adjuvant therapy is defined as 4 weeks after Adjuvant C7D1 or sooner if participant discontinues prior to completion of the 7 Cycles.
Protocol Amendment No.: 03
Date: 27-Jun-2022
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Approved
930139564
4.0
v
Approved
1.0
v

Clinical Protocol
CA2097FL
BMS-936558
nivolumab
Table 2-5:
Follow-up Procedural Outline (CA2097FL)
Procedure
30-Day Safety 
Follow-up 
Visit 1a
(FU1)
(± 7 days)
100-Day 
Safety 
Follow-up
Visit 2b
(FU2)
(± 7 days)
Long-term 
Follow-up Visitc
12 months post-
surgery
(± 2 months)
Notesd
Safety Assessments
Targeted PE, Measurements, Vital 
Signs, and ECOG PS
X
X
Weight, BP, heart rate, temperature, and ECOG PS 
(Appendix 5).
AE Assessment (Including SAEs)
X
X
See Notes.
Non-serious and serious AEs are collected continuously 
throughout the Treatment Period and for a minimum of 
100 days after the last dose of study treatment.
All AEs (SAE or non-serious AE) related to the protocol-
specified definitive breast surgery should be collected 
continuously during the treatment period and for a minimum 
of 100 days after last dose of study treatment.
Participants will be followed for treatment-related toxicities 
until these toxicities resolve, return to baseline, or are 
deemed irreversible.
SAEs to be collected after FU2, if the SAE is deemed to be 
related or residual toxicities are persisting.
AEs of special interest to be collected at Long-term Follow-
up visit. See Section 9.2.1 (Immune-mediated Adverse 
Events).
Participants will be followed for all SAEs, non-serious AEs 
of special interest (as defined in Section 9.2), and all AEs 
(SAEs and non-serious AEs) associated with confirmed or 
suspected SARS-CoV-2 infection until resolution, the 
condition stabilizes, the event is otherwise explained, the 
event is deemed irreversible, the participant is lost to follow-
up (as defined in Section 8.3), or for suspected cases, until 
SARS-CoV-2 infection is ruled out.
Protocol Amendment No.: 03
Date: 27-Jun-2022
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4.0
Approved
930139564
4.0
v
Approved
1.0
v

Clinical Protocol
CA2097FL
BMS-936558
nivolumab
Table 2-5:
Follow-up Procedural Outline (CA2097FL)
Procedure
30-Day Safety 
Follow-up 
Visit 1a
(FU1)
(± 7 days)
100-Day 
Safety 
Follow-up
Visit 2b
(FU2)
(± 7 days)
Long-term 
Follow-up Visitc
12 months post-
surgery
(± 2 months)
Notesd
Concomitant Medication
Concomitant Medication (including 
endocrine therapy) Use
X
X
See Notes.
All concomitant medications are collected at FU1 and FU2.
Record Investigator’s choice ET taken after the last dose of 
adjuvant treatment at FU1, FU2, and the Long-term Follow-
up visit.
Subsequent Cancer Treatment
X
X
X
Record at each visit any new surgery, RT, and systemic 
cancer therapy given for the disease under study.
Laboratory Tests
CBC with Differential and Chemistry
X
X
X
See Section 9.4.4 (Clinical Safety Laboratory Assessments) 
for a list of laboratory tests.
Must be performed at FU1. If study drug-related toxicities 
persist, must be repeated at FU2
If a participant has an abnormal TSH value while ‘on 
treatment’, TSH testing (with reflexive fT3 and fT4 testing 
for abnormal values) will be performed at FU1, FU2, and 12 
months (± 2 months) post-Surgery.
If the abnormal lab value resolves and falls within normal 
limits, then testing may be discontinued earlier than the 12 
months (± 2 months) post-Surgery.
 
 
 
Cortisol
X
X
X
If a participant has an abnormal value (1x ULN) while “on 
treatment”, additional tests will be performed at FU1, FU2, 
and 12 months (± 2 months) post-Surgery.
Protocol Amendment No.: 03
Date: 27-Jun-2022
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1.0
v

Clinical Protocol
CA2097FL
BMS-936558
nivolumab
Table 2-5:
Follow-up Procedural Outline (CA2097FL)
Procedure
30-Day Safety
Follow-up
Visit 1a
(FU1)
(± 7 days)
100-Day
Safety
Follow-up
Visit 2b
(FU2)
(± 7 days)
Long-term 
Follow-up Visitc
12 months post-
surgery
(± 2 months)
Notesd
If the abnormal lab value then resolves and falls within 
normal limits, then testing may be discontinued earlier than 
12 months (± 2 months) post-Surgery.
Pregnancy Test (WOCBP only)
X
X
Serum or urine pregnancy test (minimum sensitivity 25 IU/L 
or equivalent units of HCG) is required
Optional Tumor Tissue Sample 
Collection Upon Recurrence and/or 
Progression
At disease recurrence and/or progression (within 40 
days).
If biopsy or surgical resection is performed at recurrence 
and/or progression, a tumor sample (1 FFPE block or 
22 unstained slides) should be submitted to the central 
laboratory. 
 
Efficacy Assessments
Mammogram or Breast MRI for 
Participants with Remaining Breast 
Tissue Post-surgery
X
Imaging is not recommended for participants who underwent
bilateral mastectomy with or without breast reconstruction.
For patients who underwent unilateral mastectomy, with or 
without reconstruction, and for patients with breast 
conserving surgery, imaging of the remaining breast must be 
done 12 months (± 2 months) post-Surgery according to 
imaging method used per local SOC.
For participants that already performed a mammogram or 
breast MRI at 1-year post-Surgery, a second examination is 
not required.
Other Imaging (eg, ultrasound, X-
ray, CT, contrast-enhanced MRI, 
PET)
See Notes.
Permitted as clinically indicated and per local standards. See 
Section 9.1 (Efficacy Assessments) for further details.
Clinical Breast Examination/Survival 
Status
X
X
X
To be collected at FU1, FU2, and Long-term Follow-up 
Visit.
Protocol Amendment No.: 03
Date: 27-Jun-2022
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Approved
930139564
4.0
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Approved
1.0
v

Clinical Protocol
CA2097FL
BMS-936558
nivolumab
Table 2-5:
Follow-up Procedural Outline (CA2097FL)
Procedure
30-Day Safety 
Follow-up 
Visit 1a
(FU1)
(± 7 days)
100-Day 
Safety 
Follow-up
Visit 2b
(FU2)
(± 7 days)
Long-term 
Follow-up Visitc
12 months post-
surgery
(± 2 months)
Notesd
Clinical Outcomes Assessments
EORTC QLQ-C30
X
X
All Clinical Outcomes Assessments to be collected at FU1
and FU2.
EORTC QLQ-BR23
X
X
All Clinical Outcomes Assessments to be collected at FU1
and FU2.
EQ-5D-5L
X
X
All Clinical Outcomes Assessments to be collected at FU1
and FU2.
FACIT GP5
X
X
All Clinical Outcomes Assessments to be collected at FU1
and FU2.
Healthcare Resource Utilization
Healthcare Resource Utilization
X
X
All Clinical Outcomes Assessments to be collected at FU1
and FU2.
Abbreviations: AE, adverse event; BP, blood pressure; CBC, complete blood count; CT, computed tomography; ECOG, Eastern Cooperative Oncology Group; 
eCRF, electronic case report form; EORTC, European Organisation for the Research and Treatment of Cancer; EQ-5D-5L, 5-Level EQ-5D; ET, endocrine therapy;
FACIT GP5, Functional Assessment of Chronic Illness Therapy General Physical Item 5; FFPE, formalin-fixed paraffin-embedded; FU1, follow-up visit 1; FU2,  
follow-up visit 2; HCG, human chorionic gonadotropin; IgG, immunoglobulin G; IU, international unit; L, liter; MRI, magnetic resonance imaging; PE, physical 
examination; PET, positron emission tomography; PS, performance status; QLQ-BR23, Quality of Life Questionnaire-Breast Cancer-specific Module; 
QLQ-C30, Quality of Life Questionnaire-Core 30; RT, radiotherapy; SAE, serious adverse event; SARS-CoV-2, severe acute respiratory syndrome-coronavirus-
2; SOC, standard of care; WOCBP, women of childbearing potential.
a FU1 should occur 30 days from the last dose (± 7 days) of study treatment (refer to Table 7-1 for a list of study treatments) or can be performed on the date of 
discontinuation if that date is great than 42 days from the last dose of study treatment. The safety follow-up visit should be conducted in person.
b Participants must be followed for at least 100 days after the last dose of study treatment. As such, FU2 occurs approximately 100 days (± 7 days) from last dose 
of study treatment. The safety follow-up visit should be conducted in person.
c As of Protocol Amendment 03, a single Long-term Follow-up Visit will be conducted at 12 months (± 2 months) post-Surgery. The Long-term Follow-up Visit
should be conducted in person. FU2 and Long-term Follow-up Visit may be combined if the timing of the 2 visits overlap. For participants in follow-up at the 
time that Protocol Amendment 03 is approved, the final study visit will happen at the time of the next previously scheduled study visit under Protocol Amendment 
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02. Survival data must be collected on all randomized participants, unless a participant withdraws consent. The Sponsor may request that survival data be
collected on all participants outside of the specified windows. At the time of this request, each participant will be contacted to determine their survival status
unless the participant has withdrawn consent for all contact.
d Some of the assessments referred to in this section may not be captured as data on the eCRF. They are intended to be used as safety monitoring by the treating
physician. Additional testing or assessments may be performed as clinically necessary or where required by institutional or local regulations.
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3
INTRODUCTION
CA2097FL is a Phase 3, randomized, global study assessing the efficacy and safety of nivolumab 
or nivolumab
placebo combined with standard neoadjuvant anthracycline-taxane-based 
chemotherapy, followed by nivolumab combined with endocrine therapy (ET) or ET alone (per 
Protocol Amendment 03) as adjuvant treatment, in participants with high-risk, estrogen
receptor-positive (ER+), human epidermal growth factor receptor 2-negative (HER2-) primary 
breast cancer (BC).
The study originally aimed to demonstrate that treatment with nivolumab combined with standard 
neoadjuvant anthracycline-taxane-based chemotherapy, followed by nivolumab combined with 
ET as adjuvant treatment, improves clinical efficacy in terms of pathological complete response 
rate (pCR) and/or event-free survival (EFS), when compared to standard-of-care (SOC) treatment 
alone. On 07-Apr-2022, new enrollment to the study was stopped. As of Protocol Amendment 03, 
pCR is the only primary endpoint and EFS has been changed to an exploratory endpoint.
A detailed description of the chemistry, pharmacology, efficacy, and safety of the study treatments 
is provided in the respective Investigator’s Brochures (IBs) and package inserts.
3.1
Study Rationale
Neoadjuvant therapy is used increasingly in patients with primary BC to improve the likelihood 
of local tumor control, assess the treatment sensitivity of the disease in vivo, and increase the 
potential for curable disease by targeting the micrometastatic disease burden.1 Robust individual 
patient-level data meta-analyses from well-conducted clinical trials suggest that achieving a pCR 
is positively associated with improvement in EFS and overall survival (OS); these associations are 
more robust within populations with high-risk BC subtypes.2,3,4 Further, use of the neoadjuvant 
setting as a research platform permits rapid assessment of drug efficacy and may expedite clinical 
development of new agents in this setting. Agents that positively and substantially impact pCR 
rates may have a reasonable expectation of meaningful improvement in EFS.5,6
Current neoadjuvant SOC, consisting of anthracycline-taxane-based chemotherapy, is effective 
and tolerable among most patients with primary BC.7,8,9 Chemotherapy is effective in high-risk, 
primary ER+, HER2- disease and pCR rates range from 7-16%, which are lower than those 
achieved in human epidermal growth factor receptor 2-positive (HER2+) and triple-negative breast 
cancer (TNBC) subtypes through chemotherapy with or without human epidermal growth factor 
receptor 2 (HER2) blockade, respectively (30-50%).2 In addition, SOC clinical management of 
patients with ER+ BC also includes ET for up to a 10-year period. In the setting of a high-risk 
disease population receiving neoadjuvant chemotherapy, ET is administered in the adjuvant 
setting, with the 2 treatment modalities not being administered concomitantly.8,9
Programmed cell death-1 (PD-1) pathway inhibition has demonstrated clinical activity across 
multiple tumor types, including BC.10,11,12,13,14,15,16 An accumulating body of preclinical17 and 
clinical data10,11,12,16 supports the combination of anti-PD-1 agents and chemotherapy to improve 
clinical outcomes in early and advanced settings across BC subtypes; such data culminated 
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recently in the first approval of a programmed death-ligand 1 (PD-L1) inhibitor, atezolizumab,
coupled with single-agent chemotherapy for patients with newly diagnosed, programmed 
death-ligand 1-positive (PD-L1+; assessed in the immune-cell component of the disease) 
metastatic TNBC.11 Preliminary clinical data from a Phase 2 adaptive-design neoadjuvant trial 
(I-SPY2) in participants with HER2- BC (ER+, HER2-, and TNBC cohorts) assessed an anti-PD-1 
agent added to standard paclitaxel chemotherapy and demonstrated clinically meaningful 
improvements in pCR relative to historical controls.12 These and other early clinical trials support 
currently ongoing Phase 3 neoadjuvant-adjuvant trials that are evaluating anti-PD-1 agents in the 
HER2- population.18,19,20
3.1.1
Research Hypothesis
The original research hypothesis was that the combination of nivolumab with anthracycline-
taxane-based neoadjuvant chemotherapy followed by nivolumab with Investigator’s choice 
adjuvant ET will increase pCR rate and/or prolong EFS in participants with newly diagnosed, high-
risk, treatment-naive ER+, HER2- BC. As of Protocol Amendment 03, the new research hypothesis 
is that the addition of nivolumab to anthracycline-taxane-based neoadjuvant chemotherapy will 
increase the pCR rate.
3.1.2
Changes per Protocol Amendment 03
 
 
 
 
 
 
On 07-Apr-2022, Bristol-Myers Squibb 
(BMS) informed sites and the steering committee of the decision to stop new enrollment into the 
CA2097FL study. The study steering committee was supportive of the decision. As of 07-Apr-
2022, the following measures were put into effect:
•
Enrollment of new participants is closed.
•
Participants who had signed study consent prior to this decision and who were undergoing
screening were permitted to be randomized to study treatment.
•
Participants who are on treatment or in survival follow-up continued on the trial per protocol
until Protocol Amendment 03 is approved by the relevant Health Authorities and Ethics
Committees/Institutional Review Boards at the site.
Key changes in Protocol Amendment 03 include the following:
•
Details of closure of study enrollment with provision for participants currently on treatment to
continue in the study as per the current protocol.
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•
The primary endpoint of the trial will be focusing solely on pCR in the intent-to-treat (ITT)
population. EFS will be evaluated as an exploratory endpoint. pCR in the programmed death-
ligand 1-positive (PD-L1+) population will be evaluated as a secondary endpoint.
•
The study will remain blinded through the Neoadjuvant treatment and Surgery phases and will 
transition to open label when participants enter into the Adjuvant treatment phase.
•
Removal of nivolumab placebo infusions during the Adjuvant phase for participants in Arm 
B.
•
Removal of PK and immunogenicity samples collection during the Adjuvant phase for 
participants in Arm B.
•
The study will follow up participants until completion of safety follow-up phase and long-term 
follow-up 12 months (± 2 months) after surgery visit. The subsequent long-term follow-up 
visits are cancelled. For participants in follow-up at the time that Protocol Amendment 03 is 
approved, the final study visit will happen at the time of the next previously scheduled study 
visit.
•
The study objectives, endpoints, and statistical analysis have been updated and clarified (refer 
to Table 4-1 for detail).
The changes instituted in Protocol Amendment 03 should override any existing protocol
requirements in the event of any apparent discrepancies.
3.2
Background
3.2.1
ER+, HER2- Breast Cancer
ER+, HER2- disease is the most common BC subtype, occurring in ~70% of cases. BC ranks 
second as a cause of cancer-death in women after lung cancer.21,22,23,24 An estimated 42,170 BC 
deaths (41,760 women) are expected in 2020 in the United States (US).
In clinical practice, BC tumors are classified by the expression status of estrogen receptor (ER), 
progesterone receptor (PgR), and HER2. The BC subtypes, identified on the basis of these 
receptors, have been reported to bear distinct gene expression profiles,25,26 as well as different 
clinical behaviors, prognoses, and treatment vulnerabilities. Seventy percent of invasive BCs in 
women > 45 years of age express ER and/or PgR, but not HER2, and are termed hormone 
receptor-positive (HR+), HER2-.22 Seminal studies performed with gene expression profiling
(GEP) analysis of primary BC samples indicated that the tumors in the HR+, HER2- group are 
significantly enriched with cases showing high expression of genes related to the luminal 
phenotype (ER-responsive genes, luminal cytokeratins, and other luminal-associated markers). 
Consequently, HR+, HER2- BC was found to be significantly enriched with the so-called luminal 
BC intrinsic subtypes. Luminal A comprises 50-60% of all BC, showing higher dependence on 
ER signaling, slower proliferation rate, and an overall more indolent clinical course. Luminal B 
comprises 15-20% of all BC, showing lower dependence on ER signaling, higher proliferation 
rate, and overall, a more aggressive clinical course and worse prognosis compared with their
Luminal A counterparts.23 Patients with Luminal B disease are more likely to benefit from 
chemotherapy compared with the Luminal A subtype.7
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ER+, HER2- BC is emerging as a continuing challenge to balance outcomes with treatment 
options. This BC subtype is generally associated with lower recurrence rates than other BC 
subtypes within the first 5 years after diagnosis and is associated with a good prognosis when 
diagnosed early and appropriately treated. However, despite the availability of both chemotherapy 
and ET options, the risk of recurrence persists over time in participants with ER+, HER2- BC, 
arguing for additional treatment strategies for an unmet need in this population.24
3.2.2
Nivolumab Mechanism of Action
Cancer immunotherapy rests on the premise that tumors can be recognized as foreign rather than 
as self and can be effectively attacked by an activated immune system. An effective immune 
response in this setting is thought to rely on immunosurveillance of tumor antigens expressed on 
cancer cells that ultimately results in an adaptive immune response and cancer cell death. 
Meanwhile, tumor progression may depend upon acquisition of traits that allow cancer cells to 
evade immunosurveillance and escape effective innate and adaptive immune responses.27,28,29
Current immunotherapy efforts attempt to break the apparent tolerance of the immune system to 
tumor cells and antigens by either introducing cancer antigens by therapeutic vaccination or by 
modulating regulatory checkpoints of the immune system. T-cell stimulation is a complex process 
involving the integration of numerous positive as well as negative co-stimulatory signals in 
addition to antigen recognition by the T-cell receptor (TCR).30 Collectively, these signals govern 
the balance between T-cell activation and tolerance.
PD-1 is a member of the cluster of differentiation 28 (CD28) family of T-cell co-stimulatory 
receptors that also includes CD28, cytotoxic T-lymphocyte-associated protein-4 (CTLA-4), 
inducible T cell co-stimulator (ICOS), and B- and T-lymphocyte attenuator (BTLA).31 PD-1 
signaling has been shown to inhibit CD28-mediated upregulation of interleukin (IL)-2, IL-10, 
IL-13, interferon-γ (IFN-γ), and B-cell lymphoma-extra large (Bcl-xL). PD-1 expression has also 
been noted to inhibit T-cell activation and expansion of previously activated cells. Evidence for a 
negative regulatory role of PD-1 comes from studies of PD-1-deficient mice, which develop a 
variety of autoimmune phenotypes.32 These results suggest that PD-1 blockade has the potential 
to activate anti-self T-cell responses, but these responses are variable and dependent upon various 
host genetic factors. Thus, PD-1 deficiency or inhibition is not accompanied by a universal loss of 
tolerance to self-antigens.
In vitro, nivolumab (BMS-936558) binds to PD-1 with high affinity (EC50 0.39-2.62 nM), and 
inhibits the binding of PD-1 to its ligands PD-L1 and programmed death-ligand 2 (PD-L2; 
IC50 ± 1 nM). Nivolumab binds specifically to PD-1 and not to related members of the CD28 
family, such as CD28, ICOS, CTLA-4, and BTLA. Blockade of the PD-1 pathway by nivolumab 
results in a reproducible enhancement of both proliferation and IFN-γ release in the mixed 
lymphocyte reaction (MLR). Using a cytomegalovirus (CMV) re-stimulation assay with human 
peripheral blood mononuclear cells (PBMCs), the effect of nivolumab on antigen-specific recall 
response indicated that nivolumab augmented IFN-γ secretion from CMV specific memory T cells 
in a dose-dependent manner vs isotype-matched control. In vivo blockade of PD-1 by a murine 
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analog of nivolumab enhanced the anti-tumor immune response and resulted in tumor rejection in 
several immunocompetent mouse tumor models (MC38, SA1/N, and PAN02).33
A detailed description of the chemistry, pharmacology, efficacy, and safety of nivolumab is 
provided in the current IB.34
3.2.3
Clinical Experience with Nivolumab
The overall clinical safety experience with nivolumab, as either monotherapy or in combination 
with other therapeutics,
including cytotoxic chemotherapy,
is based on experience in 
approximately 17,700 participants with different tumor types.34 Nivolumab monotherapy is 
approved in multiple regions, including the US and Europe (EU), for unresectable or metastatic 
melanoma, previously treated metastatic non-small cell lung cancer (NSCLC), previously treated 
advanced renal cell carcinoma (RCC), previously treated relapsed or refractory classical Hodgkin 
lymphoma (cHL), previously treated advanced or metastatic urothelial carcinoma, and for the 
treatment of previously treated recurrent or metastatic squamous cell carcinoma of the head and 
neck (SCCHN); it is also approved for previously treated colorectal cancer (CRC), previously 
treated hepatocellular carcinoma (HCC), and the adjuvant treatment of melanoma in the US. In 
addition, nivolumab has been approved for use in combination with ipilimumab for RCC in the 
US and unresectable melanoma in multiple countries, including the US and EU.34
In 39 participants with heavily pretreated, metastatic TNBC, nivolumab alone or in combination 
with ipilimumab were tolerable without additional safety signals detected in the CheckMate 32 
study (unpublished data). In 66 participants with newly diagnosed or pretreated metastatic TNBC, 
nivolumab with or without various induction therapies, including different classes of low-dose 
cytotoxic chemotherapy (radiation therapy, cyclophosphamide, cisplatin, or doxorubicin) 
demonstrated objective response rates (ORRs) ranging from 17% without induction therapy to 
35% with doxorubicin induction therapy (TONIC trial).35 A number of clinical trials of nivolumab 
alone or in combination with other treatment modalities focused on participants with BC are 
currently ongoing.36,37,38
Details on the clinical safety and pharmacokinetic (PK) profile of nivolumab, including results 
from other clinical studies, are summarized in the nivolumab IB.34
3.2.4
Neoadjuvant Chemotherapy
Neoadjuvant (ie, preoperative) therapy is used increasingly in patients with primary BC to improve 
the likelihood of local tumor control, assess the treatment sensitivity of the disease in vivo, and 
increase the potential for curable disease by targeting earlier the micrometastatic disease burden.1
Neoadjuvant chemotherapy also enables anatomic down staging of the tumor and involved lymph 
nodes and may allow more conservative surgery of the breast and axilla. Furthermore, neoadjuvant 
chemotherapy facilitates research in identifying radiological, histological, and molecular 
predictors for response. Lastly, the neoadjuvant approach expedites the evaluation of new 
treatment strategies by using early surrogate endpoints, such as pCR.
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The use of neoadjuvant therapy for BC has been studied in several large randomized trials that 
have compared neoadjuvant chemotherapy with standard adjuvant treatment.39,40,41,42 The 
randomized studies evaluating neoadjuvant therapy, as well as meta-analyses of these studies, have 
shown that neoadjuvant therapy can improve breast conservation rates, decreasing the number of 
women needing to undergo mastectomy.43,44 A meta-analysis of 9 randomized studies comparing 
adjuvant with neoadjuvant systemic therapy for BC showed no difference in rates of death, disease 
progression, or distant disease recurrence based upon the timing of the systemic therapy.45 The 
aforementioned studies culminated in the neoadjuvant therapy being recommended in international 
guidelines for patients with high-risk/high-grade ER+, HER2- primary BC.
Neoadjuvant chemotherapy has been shown to be effective in primary BC. Robust meta-analyses 
of individual patient-level data from well-conducted clinical trials suggest that achieving a pCR is 
positively associated with improvement in EFS and OS; in particular, the Collaborative Trials in 
Neoadjuvant Breast Cancer (CTNeoBC) meta-analysis evaluated 11,955 individuals with primary 
BC treated with neoadjuvant chemotherapy as part of clinical trials.2 The results of this 
meta-analysis confirmed an association of pCR with favorable long-term outcomes in high-risk 
populations (ie, HER2+, high-grade HR+, and TNBC subtypes), although the magnitude of pCR 
improvement predictive of the long-term survival benefits could not be determined.2,3,4 Further, 
use of the neoadjuvant platform permits rapid assessment of drug efficacy and may expedite 
clinical development of new agents in this setting. Agents that positively and substantially impact 
pCR rate may have a reasonable expectation of meaningful improvement in EFS.5,6 This was
exemplified in Sep-2013, when Food and Drug Administration (FDA) granted accelerated 
approval of pertuzumab, an anti-HER2 monoclonal antibody, as part of a complete treatment 
regimen for patients with HER2+, locally advanced, inflammatory, or early-stage BC in the 
neoadjuvant setting.
A number of established chemotherapy regimens have activity in the neoadjuvant setting, 
including the following:
•
Dose-dense (Q2W) Adriamycin® (doxorubicin) or epirubicin + cyclophosphamide (ddAC), 
followed by paclitaxel weekly
•
AC every 3 weeks (Q3W) followed by paclitaxel weekly (QW)
•
AC followed by docetaxel Q3W
•
AC Q3W
•
Docetaxel + AC
•
ddAC
•
Cyclophosphamide + methotrexate + fluorouracil
•
Epirubicin + cyclophosphamide
•
Docetaxel + cyclophosphamide
According to the National Cancer Care Network (NCCN) Guidelines for BC,8 regimens 
recommended in the adjuvant setting may also be used in the neoadjuvant setting. In both settings, 
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the underlying aim remains the same: eradication or control of undiscovered distant 
micrometastases. Preferred regimens include anthracycline- and taxane-based regimens in patients 
with high-risk, ER+, HER2- BC.
3.2.5
Background for Adjuvant Endocrine Therapy
The prognosis of patients with primary BC has vastly improved since the first adjuvant 
chemo-endocrine therapy trials in the 1970s. This treatment modality was designed originally to 
address the problem of distant disease relapse due to micrometastases, which, once clinically 
established, are the ultimate cause of death for the majority of patients with relapsed BC. 
Incremental improvements in outcomes were achieved through systematic therapeutic escalation, 
including the use of treatment regimens of longer duration, the integration of novel agents, or the 
inclusion of a higher number of agents, albeit at the cost of greater toxicity.46
Adjuvant ET, corresponding to systemic treatment blocking of ER signaling, is the cornerstone of 
systemic treatment of individuals with primary ER+, HER2- BC.47 To date, numerous trials have 
established the survival benefit of adjuvant ET.44,46,47 Extended treatment of 5-10 years with 
tamoxifen or an aromatase inhibitor (AI) with or without ovarian suppression is now recommended 
for most patients, based on results from several landmark trials;48,49,50,51 these trials demonstrated
a 15-20% relative reduction in the risk of recurrence, which translates to a 2-4% absolute 
improvement in disease-free survival (DFS) for average-risk participants included in these trials.52
Further, among premenopausal women with early BC, the addition of ovarian suppression to 
tamoxifen resulted in significantly higher 8-year rates of DFS and OS than tamoxifen alone 
(83.2% vs 78.9%). The use of exemestane plus ovarian suppression resulted in even higher rates 
of DFS (85.9%).52,53,54
Since the adoption of adjuvant ET with tamoxifen and AIs (anastrozole, letrozole, and 
exemestane), current efforts now focus on how best to identify patients at risk for recurrence 
despite optimal adjuvant ET and how best to manage them. Current recommendations suggest that 
patients with ER+, HER2- primary BC who are at a higher risk of relapse occurrence (ie, higher 
grade, low levels of ER expression) receive treatment with chemotherapy followed by ET.
Recent data from the MonarchE study demonstrated benefit in terms of invasive disease̽free 
survival (iDFS) with the addition of adjuvant abemaciclib (an inhibitor of cyclin-dependent 
kinases 4 and 6 [CDK4/6i]) to endocrine treatment for high-risk HR-positive breast cancer 
patients. Abemaciclib plus ET demonstrated superior iDFS versus ET alone (p = 0.01; hazard ratio, 
0.75; 95% CI, 0.60 to 0.93), with 2-year iDFS rates of 92.2% versus 88.7%, respectively. This led 
to the US FDA approval on 12-Oct-2021, of abemaciclib in combination with ET (tamoxifen or 
an aromatase inhibitor) for the adjuvant treatment of adult patients with HR-positive, HER2-
negative, node-positive, early breast cancer at high risk of recurrence and a Ki-67 score Ӌ 20% as
determined by an FDA-approved test.55
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3.3
Benefit/Risk Assessment
Based on preclinical and clinical data, treatment of nivolumab in combination with
anthracycline-taxane-based chemotherapy or in combination with ET is expected to be tolerable,
and toxicities of the treatment are expected to be manageable and reversible upon dose reduction, 
treatment interruption, or discontinuation (see Section 5.4 [Scientific Rationale for Study Design]).
Participants in this study will be carefully monitored for key toxicities. Risks will be further 
minimized by adherence to inclusion and exclusion selection criteria (see Section 6 [Study 
Population]), avoidance of prohibited medication (see Section 7.7 [Concomitant Therapy]), close 
safety monitoring (see Section 9.2 [Adverse Events], Section 9.2.1 [Immune-mediated Adverse 
Events], and Section 9.4 [Safety]), and dose adjustment guidelines (see Section 7.4 [Dosage 
Modification]). These will also be clearly discussed and highlighted during site visits.
An Independent Data Monitoring Committee (IDMC; see Section 5.1.4.1 [Independent Data 
Monitoring Committee]) will be constituted and will monitor safety and efficacy as outlined in the 
protocol. A Study Steering Committee (SSC; see Section 5.1.4.2 [Study Steering Committee]) will 
be established, comprising of Investigators and Sponsor personnel participating in the trial, to 
ensure transparent management of the trial according to the protocol. A BMS Safety Management 
Team will review and evaluate all emerging data across the program for potential safety signal 
assessment in a timely manner.
More detailed information about the known and expected benefits and risks and reasonably 
anticipated adverse events (AEs) of study treatments may be found in the respective IBs, Patient 
Information Leaflets, Package Inserts,56,57,58,59,60,61,62,63,64 Development Safety Update Reports, 
or Summaries of Product Characteristics (SmPCs).65,66,67,68,69,70,71,72,73
Due to the need to develop improved therapies to improve pCR rates and/or prolong EFS or OS in 
ER+, HER2- BC, and on the basis of the clinical and nonclinical data in support of the current 
study, the benefit-risk profile of nivolumab in combination with anthracycline-taxane-based 
chemotherapy or in combination with ET in newly diagnosed, treatment-naive, high-risk ER+, 
HER2- primary BC is favorable for proceeding with the proposed randomized Phase 3 clinical 
trial.
Starting in Oct-2021, abemaciclib has been approved as an adjuvant treatment in several countries 
and it is expected that some participants may want to receive adjuvant abemaciclib if/when it is 
available. As of Protocol Amendment 03, participants will be unblinded to treatment assignment 
in the Adjuvant phase to enable treatment decision making. The primary endpoint has been 
amended to focus solely on pCR after neoadjuvant treatment, and EFS has been changed to an 
exploratory endpoint.
3.3.1
Nivolumab Safety Profile
Overall, the safety profile of nivolumab monotherapy is manageable and generally consistent 
across completed and ongoing clinical trials, with no maximum tolerated dose (MTD) reached at 
any dose tested up to 10 mg/kg. Most AEs were low-grade (Grade 1 to 2) with relatively few 
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related high-grade (Grade 3 to 4) AEs. There was no pattern in the incidence, severity, or causality 
of AEs with respect to nivolumab dose level.
A pattern of immune-related AEs has been defined, for which management algorithms have been 
developed; these are provided in Appendix 6. Most high-grade events were manageable with the 
use of corticosteroids or hormone replacement therapy (endocrinopathies) as instructed in these 
algorithms.
See Sections 6.2, 6.4.1, and 7.4.1 for specific severe acute respiratory syndrome-coronavirus-2 
(SARS-CoV-2) risk mitigation recommendations.
Additional details on the safety profile of nivolumab, including results from other clinical studies, 
are also available in the nivolumab IB.34
3.3.2
Anthracycline-Taxane-Based Chemotherapy Safety Profile
Overall, the safety profiles of anthracycline-taxane-based chemotherapy are manageable and 
generally consistent across completed and ongoing trials.74
Extensive details on the safety profiles of doxorubicin, epirubicin, cyclophosphamide, and 
paclitaxel are available in the respective Patient Information Leaflets, Package Inserts,57,58,59,60 or 
SmPCs.66,67,68,69
3.3.3
Endocrine Therapy Safety Profile
Overall, the safety profiles of tamoxifen and the AIs used in this study are manageable and 
generally consistent across completed and ongoing trials.52,53,54
Extensive details on the safety profiles of tamoxifen and the AIs (anastrozole, letrozole, and 
exemestane) are available in the respective Patient Information Leaflets, Package Inserts,61,62,63,64
or SmPCs.70,71,72,73,75,76
3.3.4
Nivolumab and Anthracycline-Taxane-Based Chemotherapy 
Combination Safety Profile
The safety profile of nivolumab is well characterized and manageable when administered alone or 
in combination with chemotherapy, targeted agents, as well as additional immuno-oncology (IO)
products across many tumor types. In particular, several clinical trials have assessed neoadjuvant 
chemotherapy plus checkpoint inhibition combination approaches for participants with primary 
BC. Relevant safety data from such studies are given below.
In a Phase 2 adaptive-design neoadjuvant trial (I-SPY2), 69 participants with primary HER2- (ER+ 
and TNBC) BC were randomized to pembrolizumab, a PD-1 inhibitor, given as 200 mg Q3W plus 
weekly paclitaxel, followed by anthracycline + cyclophosphamide (AC; every 2 weeks [Q2W] or 
Q3W) without pembrolizumab. A total of 46 participants underwent surgery as of Nov-2016. 
In the TNBC cohort (n = 29), pembrolizumab increased the raw and estimated pCR rates by > 50% 
and 40%, respectively. In the ER+, HER2- cohort (n = 40), the raw and estimated pCR rates
increased by 13% and 21%, respectively. Five participants had immune-related Grade 3 AEs,
including hypophysitis (n = 1) and adrenal insufficiency (n = 4). Of these, 4 participants presented 
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with the AE after completing the AC treatment (149-179 days after pembrolizumab was initiated); 
1 participant presented prior to the AC treatment (37 days after pembrolizumab was initiated). 
Seven participants had Grade 1 to 2 thyroid abnormalities reported. Overall, the safety profile of 
pembrolizumab was consistent with that observed in previously reported studies across tumors. 
However, adrenal insufficiency was observed at a higher rate than previously reported in advanced 
cancer. Resolution of symptoms of adrenal insufficiency with use of replacement therapy was 
reported.12
In the Phase 1b KEYNOTE-173 study, pembrolizumab was combined with neoadjuvant treatment 
consisting of weekly nab-paclitaxel  (with or without carboplatin area under the curve [AUC]6 
Q3W), followed by 4 cycles of AC Q3W in 20 participants with TNBC. In the nab-paclitaxel 
cohort, the pCR rate in breast and nodes (ypT0/Tis ypN0) was 60% (n = 10) and 90% (n = 10) in 
participants receiving carboplatin plus nab-paclitaxel. Dose-limiting toxicities (DLTs) of 
myelosuppression occurred in 7 participants and were unrelated to pembrolizumab. Grade 3/4 
treatment-related AEs occurred in 8 participants in the nab-paclitaxel cohort and in 10 participants 
in the nab-paclitaxel-carboplatin cohort, of which, none were fatal. Three participants discontinued 
for a treatment-related AE (alanine aminotransferase [ALT] elevations with pembrolizumab, 
n = 2; deep vein thrombosis with chemotherapy, n = 1). No DLT was attributed to 
pembrolizumab.10 In a recent update in 60 participants evaluating 6 treatment cohorts assessing 
either nab-paclitaxel or paclitaxel with or without carboplatin,77 22 (36.7%) participants had a 
DLT. Most DLTs were Grade 3 or 4, with neutropenia the most commonly reported (n = 9). One 
DLT was Grade 5 (septic shock), occurring in a nab-paclitaxel-carboplatin arm. Grade ≥ 3 
treatment-related AEs were reported in 54 (90%) participants. Grade 3/4 treatment-related AEs 
were neutropenia (73%), febrile neutropenia (22%), anemia (20%), and thrombocytopenia (8%). 
Eighteen participants (30%) had immune-mediated AEs (IMAEs; Grade 2 hypothyroidism, n = 4; 
Grade 1 hyperthyroidism, n = 3; Grade 3 colitis, n = 2; and Grade 3 rash, n = 2). Eleven 
participants discontinued pembrolizumab due to treatment-related AEs. As expected, toxicity was 
higher in the carboplatin groups.
The combination of neoadjuvant chemotherapy with PD-L1 inhibition has been assessed in 
GeparNuevo, a randomized, Phase 2 neoadjuvant study; a total of 174 participants with primary 
TNBC 
were 
randomized 
to 
receive 
neoadjuvant 
nab-paclitaxel, 
followed 
by 
epirubicin/cyclophosphamide chemotherapy with or without durvalumab, a PD-L1 inhibitor. 
A numerically higher, but statistically non-significant increase in pCR (44.2% vs 53.4%, odds ratio 
[OR] 1.53; p = 0.182) was reported. The addition of durvalumab to neoadjuvant chemotherapy 
was well tolerated. All received growth factor support during epirubicin/cyclophosphamide
treatment. Grade 3/4 hematologic AEs were similar in the 2 groups and included anemia (2.2% vs 
2.4%), neutropenia (37.1% vs 41.5%), thrombocytopenia (1.1% vs 2.4%), and febrile neutropenia 
(4.3% vs 2.4%) in the durvalumab and control arms, respectively. Immune-related AEs were 
higher in the durvalumab arm and included hypothyroidism (6.5% vs 2.4%) and hyperthyroidism 
(7.6% vs 0%), in the durvalumab and control arms, respectively.16
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In the Phase 3, randomized (2:1), placebo-controlled, KEYNOTE 522 study, pembrolizumab 
(200 mg Q3W) was combined with paclitaxel (80 mg/m2 QW) and carboplatin (AUC 5 Q3W or 
AUC 1.5 QW) followed by anthracycline (doxorubicin 60 mg/m2
or epirubicin 
90 mg/m2)-cyclophosphamide (600 mg/m2) neoadjuvant chemotherapy (8 cycles) and adjuvant 
pembrolizumab (200 mg Q3W for 9 cycles) in patients with untreated, primary TNBC.78 The 
addition of pembrolizumab to platinum-containing neoadjuvant chemotherapy resulted in a 
statistically significant and clinically meaningful absolute increase in pCR (ypT0/Tis ypN0) of 
13.6 percentage points (64.8% vs 51.2%, p = 0.00055). A consistent benefit also was observed 
with pCR defined as ypT0 ypN0 and ypT0/Tis. The benefit of pembrolizumab was independent of 
PD-L1 status using the combined positive score (CPS) method of assessment. Preliminary, early 
data suggest there was a favorable trend for EFS in the pembrolizumab arm (HR = 0.63 [95% CI, 
0.43-0.93]). Safety was consistent with the known profiles of each regimen albeit with only 9% of 
the total number of targeted EFS events. Dose-intensity, characterized by the mean number of 
doses administered and mean treatment duration, was similar across the treatment groups. Across 
neoadjuvant and adjuvant phases, Grade 3 or higher treatment-related AE rates were 78.0% in the 
pembrolizumab-chemotherapy group and 73.0% in the chemotherapy alone group, and the 
incidence of death was 0.4% vs 0.3%, respectively.78
The above studies suggest that the combination of anti-PD-(L)1 and SOC neoadjuvant 
multi-regimen chemotherapy is feasible in patients with primary BC. Thus, the potential benefit 
of combination therapy appears to outweigh the known risks of these agents and warrants 
clinical investigation.
More detailed information about the known and expected benefits and risks and reasonably 
anticipated AEs of the study treatments may be found in the respective IBs, Patient Information 
Leaflets, Package Inserts,56,57,58,59,60 Development Safety Update Report, or SmPCs.65,66,67,68,69
3.3.5
Nivolumab and Endocrine Therapy Combination Safety Profile
The safety profile of nivolumab is well characterized and manageable when administered alone or 
in combination with chemotherapy, targeted agents, as well as additional IO products. Similarly, 
extensive clinical trials have established the efficacy and safety of ET in participants with BC. The 
agents used for standard ET have extensive, established safety databases in this setting. No data 
are available evaluating the combination of nivolumab and ET (eg, tamoxifen, AIs).
One of the initial BC studies assessing checkpoint inhibitors was a Phase 1 study of tremelimumab, 
an anti-CTLA-4 antibody, combined with exemestane, in 26 women with heavily pretreated ER+ 
metastatic BC.79 Most treatment-related AEs were mild to moderate (Grade 1 or 2) in nature. 
The most common events included diarrhea (46%), pruritus (42%), constipation (23%), and 
fatigue (23%). DLTs were transient serum transaminase elevations (n = 1) and diarrhea (n = 4). 
The MTD of tremelimumab with exemestane was 6 mg/kg every 90 days, which was lower than 
in other tremelimumab trials. Among 13 participants treated at the MTD, none developed Grade 3 
or Grade 4 treatment-related diarrhea. No PK interaction was observed between tremelimumab 
and exemestane. At the time of the trial, algorithm-based management of immune-related 
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diarrhea/colitis was not yet available nor implemented in the trial; however, it cannot be ruled out 
that diarrhea may have been exacerbated by the combination. With regard to anti-tumor activity, 
no objective responses were noted; however 11 of the 26 participants experienced stable disease, 
including 4 participants who previously progressed on exemestane. Evidence of T-cell activation 
was reported in the periphery, as measured by ICOS expression. Treatment was associated with 
T-cell activation, as revealed by an increase in ICOS-expressing T cells in blood and a marked
increase in the ratio of ICOS-positive T cells to FoxP3-positive regulatory T cells (Tregs).79,80
Several ongoing studies are evaluating different endocrine agents in combination with checkpoint
inhibitors.81,82
Recent data from the MonarchE study demonstrated benefit in terms of iDFS with the addition of 
adjuvant abemaciclib to ET for high-risk HR-positive breast cancer. However, the combination of 
pembrolizumab (anti-PD-1) with abemaciclib (CDK4/6 inhibitor) was demonstrated to be not 
feasible because of dose-limiting toxicities. Concurrent administration of abemaciclib to 
pembrolizumab caused an increased incidence of pneumonitis/interstitial lung disease and 
increased rates of Grade 3-4 liver enzyme elevations.83,84,85 The incidence was above that which 
would be expected with either agent alone. Three treatment-related deaths associated with 
pneumonitis occurred.84,85 Increased toxicity rates were also observed in CheckMate-7A8 testing 
the combination of nivolumab plus palbociclib, the same class of drug (CDK4/6i) as 
abemaciclib.86 Based on the findings, it does not appear that anti-PD-1 and CDK4/6 inhibitors can 
be safely combined due to increased risk of hepatic and lung toxicities.
More detailed information about the known and expected benefits and risks and reasonably 
anticipated AEs of the study treatments may be found in the respective IBs,34 Patient Information 
Leaflets, Package Inserts,56,61,62,63,64 Development Safety Update Report, or SmPCs.65,70,71,72,73
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4
OBJECTIVES AND ENDPOINTS
Table 4-1:
Objectives and Endpoints
Objectives
Endpoints
Primary
•
To 
compare 
efficacy 
of 
nivolumab 
plus 
chemotherapy 
vs 
nivolumab 
placebo 
plus 
chemotherapy as neoadjuvant treatment in terms of 
the absence of residual tumor disease in participants 
with untreated, high-risk ER+, HER2- BC.
•
pCR, defined as no invasive residual disease in 
breast and lymph nodes (ie, ypT0/is, ypN0) by a 
local pathologist (ITT population).
Key Secondary
•
To 
compare 
efficacy 
of 
nivolumab 
plus 
chemotherapy 
vs 
nivolumab 
placebo 
plus 
chemotherapy as neoadjuvant treatment in terms of 
the absence of residual tumor disease in participants 
with untreated, high-risk ER+, HER2-BC in the 
PD-L1+ subgroup.
•
pCR, defined as no invasive residual disease in 
breast and lymph nodes (ie, ypT0/is, ypN0) by a 
local pathologist (PD-L1+ population).
•
To assess the efficacy of nivolumab and nivolumab 
placebo 
in 
combination 
with 
neoadjuvant 
chemotherapy in terms of RCB.
•
RCB class (0, I, II, III) frequency, for RCB assessed 
by a local pathologist in ITT and PD-L1+
populations.
•
To evaluate the safety and tolerability of nivolumab 
and
nivolumab placebo in combination with 
neoadjuvant chemotherapy.
•
Incidence of AEs, drug-related AEs, AEs leading to 
discontinuation, and SAEs as defined by NCI 
CTCAE v5.0.
•
Incidence of deaths.
Key Tertiary/Exploratory
•
To assess the efficacy of nivolumab and nivolumab
placebo 
in 
combination 
with 
neoadjuvant 
chemotherapy in terms of pCR by alternative 
definitions.
•
pCR, defined as no invasive or in situ residual 
disease in breast and lymph nodes (ie, ypT0 ypN0) 
by a local pathologist in ITT and PD-L1+
populations.
•
pCR, defined as no invasive residual disease in the 
breast irrespective of in situ or nodal involvement 
(ypT0/is) by a local pathologist in ITT and PD-L1+
populations.
•
To assess the efficacy of nivolumab and nivolumab 
placebo 
in 
combination 
with 
neoadjuvant 
chemotherapy in terms of ORR by investigator.
•
ORR, defined as investigator-assessed tumor 
response rate per radiologic-based assessment 
(RECIST v1.1) in the Neoadjuvant (Pre-surgery) 
Phase in ITT and PD-L1+ populations.
•
To assess the efficacy of nivolumab and nivolumab 
placebo 
in 
combination 
with 
neoadjuvant 
chemotherapy and adjuvant ET in terms of EFS,
survival, DFS, and DMFS.
•
EFS in ITT population
•
OS in ITT population.
•
DFS in ITT population.
•
DMFS in ITT population.
•
To characterize the PK and IMG of nivolumab 
when 
administered 
in 
combination 
with
neoadjuvant chemotherapy.
•
Nivolumab PK and IMG parameters.
•
To characterize the PK and IMG of nivolumab 
when administered in combination with adjuvant 
ET.
•
Nivolumab PK and IMG parameters.
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Table 4-1:
Objectives and Endpoints
Objectives
Endpoints
•
To assess the efficacy of nivolumab and nivolumab 
placebo 
in 
combination 
with 
neoadjuvant 
chemotherapy and adjuvant ET in subgroups based 
on PD-L1 expression by IHC 28-8 CPS.
•
Clinical efficacy endpoints (eg, pCR, RCB, ORR)
by PD-L1 expression using PD-L1 IHC 28-8 CPS.
•
To assess cancer-specific symptoms and QOL
domains across treatment groups.
•
Mean EORTC QLQ-C30 and QLQ-BR23 subscale 
scores and post-baseline score changes.
•
To assess perceptions of the overall bothersomeness 
of symptomatic AEs.
•
Mean FACIT GP5 item scores and post-baseline 
score changes.
•
To evaluate perceived general health status and 
utility between treatment groups.
•
Mean EQ-5D-5L VAS and utility index scores and 
post-baseline score changes.
Abbreviations: AE, adverse event; BC, breast cancer; CPS, combined positive score; CTCAE, Common Terminology 
Criteria 
for 
Adverse 
Events; 
DFS,
disease-free 
survival; 
DMFS,
distant metastasis-free 
survival; 
EFS, event-free survival; EORTC, European Organisation for Research and Treatment of Cancer; EQ-5D-5L, 5-Level 
EQ-5D; ER+, estrogen receptor-positive; ET, endocrine therapy; FACIT GP5, Functional Assessment of Chronic 
Illness Treatment General Physical Item 5; HER2-, human epidermal growth factor receptor 2; IgG, immunoglobulin 
G; IHC, immunohistochemistry assay; IMG, immunogenicity; ITT, intent to treat; NCI, National Cancer Institute; 
ORR, objective response rate; OS, overall survival; pCR, pathological complete response; PD-L1, programmed 
death-ligand 1; PD-L1+, programmed death-ligand 1-positive; PK, pharmacokinetic; QLQ-BR23, Quality of Life 
Questionnaire-Breast Cancer-specific Module; QLQ-C30, Quality of Life Questionnaire-Core 30; QOL, quality of 
life; RCB,
residual cancer burden; SAE, serious adverse event; SARS-CoV-2,
severe acute respiratory 
syndrome-coronavirus-2; VAS, visual analog scale; vs, versus.
5
STUDY DESIGN
5.1
Overall Design
This is a randomized, double-blind, placebo-controlled, multicenter, global Phase 3 study. The 
study is designed to evaluate nivolumab vs nivolumab placebo in combination with neoadjuvant 
chemotherapy and adjuvant ET in newly diagnosed, treatment-naive participants with high-risk 
ER+, HER2- BC. High-risk disease is defined as a participant having either Grade 3 disease or 
having Grade 2 disease with low ER expression of 1-10%. Participants must have histologically
confirmed invasive ductal breast carcinoma meeting the characteristics described in Section 6.1
(Inclusion Criteria).
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The study is divided into 3 periods: Screening Period, Treatment Period (Neoadjuvant 
[Pre-surgery] Phase, Surgery, and Adjuvant [Post-surgery] Phase), and Follow-up Period. 
Following the confirmation of eligibility, participants will be randomized to either Arm A or 
Arm B in a 1:1 ratio.
The Treatment Period will consist of the following phases:
•
Neoadjuvant (Pre-surgery) Phase: maximum of 8 cycles
−
Paclitaxel (PTX) Cycles 1-4 (1 cycle = Q3W): nivolumab or nivolumab placebo + weekly
paclitaxel
Followed by
−
Anthracycline-Cyclophosphamide (AC) Cycles 1-4 (1 cycle = every 2 weeks [Q2W] or
1 cycle = Q3W [dosing frequency to be determined by the Investigator]): nivolumab or
nivolumab placebo + AC cycles 1-4 (1 cycle = Q2W or 1 cycle = Q3W).
•
Surgery
•
Adjuvant (Post-surgery) Phase: maximum of 7 cycles
−
Adjuvant Cycles 1-7 (1 cycle = every 4 weeks [Q4W]): nivolumab + ET or ET alone (per
Protocol Amendment 03)
Treatment will start with the Neoadjuvant (Pre-surgery) Phase, in which participants will be 
randomized to receive an intended 4 cycles of nivolumab or nivolumab placebo in combination 
with weekly paclitaxel, followed by an intended 4 cycles of nivolumab or nivolumab placebo in 
combination with anthracycline (doxorubicin or epirubicin) + cyclophosphamide. Following 
completion of the Neoadjuvant (Pre-surgery) Phase of treatment, participants who remain 
operative candidates will undergo surgery of the breast and axilla (per local standards) within 
4 weeks. In cases when surgery does not occur within 4 weeks, surgery is permitted at a later date. 
The investigator must document the reason for delay of surgery in the CRF and the medical record.
Participants will return to the site within 7-14 days following surgery to begin their Adjuvant 
(Post-surgery) Phase of treatment, consisting of a maximum of 7 cycles of nivolumab with 
Investigator’s choice of ET or ET alone (per Protocol Amendment 03). The post-surgery visit and 
the first cycle of adjuvant treatment may be combined if adjuvant treatment starts within 7-14 days
after the breast cancer surgery.
As of Protocol Amendment 03, the Adjuvant phase will be converted to open label, and 
participants will be unblinded when they reach the Adjuvant phase of the study. Participants 
already on adjuvant treatment or in follow-up when Protocol Amendment 03 is approved will also 
be unblinded. No crossover to adjuvant nivolumab will be allowed for participants enrolled in Arm 
B. Adjuvant systemic therapy should be started no later than 6 weeks following Surgery in
participants not receiving radiotherapy (RT). In participants receiving RT, adjuvant systemic
therapy may start at the same time as RT or no later than 1 to 2 weeks after completion of RT per
local standards. Starting adjuvant systemic therapy for a few adjuvant cycles then stopping or
pausing therapy to administer RT then restarting adjuvant systemic therapy for remaining adjuvant
cycles will not be permitted.
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Randomized participants in the study will be stratified by the following factors:
1) PD-L1 on immune cells (≥1% or < 1%);
2) Tumor grade (2 or 3);
3) Axillary nodal status (pathological review positive versus radiographic and/or pathologic
review negative) and
4) AC dose-frequency chemotherapy regimen (Q2W or Q3W).
PD-L1 status, used for stratification, is determined by qualitative immunohistochemical assay 
using rabbit monoclonal anti-PD-L1 clone SP142 on the proportion of tumor area occupied by 
PD-L1-expressing tumor-infiltrating immune cells (% IC) of any intensity.
Clinical outcomes assessments (COAs) will be assessed throughout the study at the timepoints 
defined in the Schedule of Activities (Section 2).
Safety Follow-up Visits will occur per Table 2-5, after the last Adjuvant (Post-surgery) Phase 
treatment. As of Protocol Amendment 03, the Long-term Follow-up visit will occur 12 months (±
2 months) following surgery per Table 2-5. The Long-term Follow-up visit will be the final visit 
of the study. For participants in follow-up at the time of Protocol Amendment 03, the final study 
visit will happen at the time of the next previously scheduled study visit under Protocol 
Amendment 02 (see Table 2-5).
The total duration of the study is approximately 4 years from randomization of the first participant. 
The study may be terminated at any time by the Sponsor. See Section 5.1.3 (Follow-up Period)
and Section 8.1 (Discontinuation from Study Treatment) for additional details.
The study design schematic is presented in Figure 5.1-1.
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Figure 5.1-1:
Study Design Schematic
Key Inclusion Criteria:
• Newly diagnosed 
ER+, HER2- BC
• Confirmed ER+ BC
• T1c-T2, cN0-cN2 or 
T3-T4, cN0-cN2
• Grade 3 or 
Grade 2 with ER 
1-10% 
• Adequate organ 
function
• Tissue available for 
biomarker 
assessments
• ECOG PS 0-1
Screening
Treatment
Follow-Up
R
A
N
D
O
M
I
Z
A
T
I
O
N
Nivo 360 mg 
Q3W + PTX QW
Nivo PBO Q3W + 
PTX QW
Safety 
Follow-up
30-Day
100-Day
Long-term 
Follow-up 
(12 months 
post Surgery)
*Investigator’s choice anthracycline; dosing frequency of Q2W or Q3W for AC cycles determined by the 
Investigator. 
†Available ET agents include tamoxifen, anastrozole, letrozole, and exemestane.
Abbreviations: AC = anthracycline + cyclophosphamide; BC = breast cancer; Cy = cycle; ECOG PS = 
Eastern Cooperative Oncology Group performance status; ET = endocrine therapy; IC = immune cells; 
PBO = placebo; PTX = paclitaxel; Q2W = every 2 weeks; Q3W = every 3 weeks; QW = every week
**In Adjuvant phase, the study treatment will be open-label. Participants in Arm B will not receive Nivo
PBO infusion
Stratification Factors: 
•
PD-L1 IC (> 1% or <1%)
•
Tumor Grade (3 or 2)
•
Axillary Nodal Status (+ or -)
•
AC (Q3W or Q2W)
Neoadjuvant Phase
(Pre-Surgery) 
Surgery
Adjuvant Phase**
(Post-Surgery)
Surgery
Surgery
Nivo 480 mg 
Q4W + 
Investigator’s 
Choice ET†
Investigator’s 
Choice ET†
Nivo 360 mg 
Q3W + AC Q3W 
Or
Nivo 240 mg 
Q2W + AC Q2W
Nivo PBO Q3W + 
AC Q3W 
Or
Nivo PBO Q2W + 
AC Q2W
PTX Cycles 1-4
1 Cy = 3 wks
AC Cycles 1-4
1 Cy = 2 or 3 wks*
Adjuvant Cycles 1-7
1 Cy = 4 wks
1:1
ARM A
ARM B
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5.1.1
Screening Period
As of 07-Apr-2022, new participant enrollment to this study is closed. 
Participants will provide written informed consent to participate in the study, before completing 
any protocol-specified procedures or evaluations not considered to be part of the participants’ 
standard care. After signing the informed consent form (ICF), participants will be enrolled into 
Interactive Response Technology (IRT) and then be evaluated for eligibility. The screening 
assessments are shown in Table 2-1.
Documentation of the participant’s menopausal status at screening/baseline is required for women 
only, following the definitions provided below:
•
Premenopausal status is defined as < 12 months since last menstrual period and no prior
bilateral ovariectomy and not receiving estrogen replacement, or biochemical evidence of
premenopausal status, according to local standards.
•
Post-menopausal status is defined as ≥ 12 consecutive months since last menstrual period in a
woman over age 45 years (with no identified cause other than menopause), prior bilateral
oophorectomy, age < 55 years and amenorrheic for 12 or more consecutive months in the
absence 
of 
chemotherapy, 
tamoxifen, 
toremifene, 
or 
ovarian 
suppression 
and
follicle-stimulating hormone (FSH) > 40 mIU/mL and estradiol in the post-menopausal range.8
Participants must provide a pretreatment (baseline) primary tumor tissue sample meeting eligibility 
requirements as described in Section 6.1 (Inclusion Criteria). The tumor biopsy will be submitted 
to the central laboratory with a pathology report for determining PD-L1 and ER status as well as 
ER expression level. 
 
. Participants should not have received any local or
systemic anticancer therapy before or after the date that the submitted tumor tissue was obtained.
Prior to randomization, PD-L1, ER status and ER expression level percentage, disease grade, 
axillary nodal status, and AC frequency must be available in IRT. Participants with a PD-L1, ER, 
or HER2 status of unknown/not evaluable are not eligible (see Section 6.1 [Inclusion Criteria]). 
Treatment should begin within 3 calendar days following randomization.
The Screening Period for each participant ends with the confirmation of full eligibility of the 
participant or with the confirmation that the participant is a screen failure. This study permits the 
re-enrollment of a participant that has discontinued the study as a pretreatment failure 
(ie, participant has not been randomized). If re-enrolled, the participant must be re-consented.
5.1.2
Treatment Period
Schedules of on-treatment visits and assessments for the Neoadjuvant (Pre-surgery) Phase and 
Adjuvant (Post-surgery) Phase are provided in Table 2-2, Table 2-3, and Table 2-4.
5.1.2.1
Neoadjuvant (Pre-surgery) Phase
Following confirmation of eligibility, participants will be randomized to receive nivolumab or 
nivolumab placebo administered in combination with weekly paclitaxel chemotherapy for 
maximum 4 cycles (Paclitaxel Cycles 1-4; 1 cycle = 3 weeks). This will be followed by nivolumab 
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or nivolumab placebo in combination with anthracycline (doxorubicin or epirubicin) + 
cyclophosphamide chemotherapy for a maximum of 4 additional cycles (AC Cycles 1-4; 
1 cycle = 2 weeks or 3 weeks); the dose frequency will be selected by the treating physician prior 
to randomization and entered in IRT. Participants will be informed of their scheduled surgery prior
to the completion of the Neoadjuvant (Pre-surgery) Phase.
Dose reduction will not be allowed for nivolumab. Some participants may not receive all 8 cycles 
of planned neoadjuvant therapy (eg, toxicity, refusal to receive further therapy). However, 
participants should receive as much of the planned neoadjuvant therapy as possible. Such treatment 
decisions will be at the discretion of the Investigator and participant.
Additional guidance is given below regarding potential study conduct scenarios that may occur for 
some participants during the course of the Neoadjuvant Phase:
•
If a participant discontinues nivolumab or nivolumab placebo study treatment during the 
Neoadjuvant Phase and continues with chemotherapy study treatment, the participant may 
continue on-study, to receive surgery, and transition to the Adjuvant phase to receive endocrine 
therapy and nivolumab or ET study treatment alone (per Protocol Amendment 03), unless 
consent is withdrawn and/or medical conditions necessitate the participant to discontinue study 
treatment. See Section 7 (Treatment) for additional details.
•
If a participant discontinues paclitaxel during the Neoadjuvant Phase, the participant may 
continue on-study to receive neoadjuvant AC and nivolumab or nivolumab placebo study 
treatment or may transition to the Adjuvant Phase, after Surgery, to receive endocrine therapy 
and nivolumab or ET study treatment alone (per Protocol Amendment 03) at an earlier 
timepoint, unless consent is withdrawn and/or medical conditions necessitate the participant to 
discontinue the study treatment. See Section 7 (Treatment) for additional details.
•
If a participant discontinues the AC treatment during the Neoadjuvant Phase, nivolumab or 
nivolumab placebo must also be discontinued and the participant may continue on study to 
receive Surgery and transition to the Adjuvant Phase to receive endocrine therapy and 
nivolumab or ET study treatment alone (per Protocol Amendment 03), unless consent is 
withdrawn and/or medical conditions necessitate the participant to discontinue study treatment.
•
If chemotherapy is delayed, nivolumab or nivolumab placebo is also delayed. Nivolumab or 
nivolumab placebo can resume within 3 days of the scheduled chemotherapy dose if 
chemotherapy re-treatment criteria are met.
If participant has worsening of disease or disease progression during the Neoadjuvant Phase that 
precludes definitive surgery or results in metastatic disease the event is recorded as an EFS event, 
and the participant continues in the follow-up period. See Section 5.1.3 (Follow-up Period).
Participants who discontinue study treatment must continue to be followed in this study for 
collection of outcome and/or survival follow-up data, as required and in line with Section 5 (Study 
Design), until death, withdrawal of consent, or the conclusion of the study.
5.1.2.2
Surgery
Following the completion of the neoadjuvant treatment phase (completion of paclitaxel cycles 1-4, 
1 cycle = 3 weeks and AC cycles 1-4, 1 cycle = Q2W or Q3W), all participants who remain 
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operative candidates will undergo surgery of the breast and axilla (per local standards) within 
4 weeks of the completion of the neoadjuvant treatment phase (ie, 6-7 weeks after last neoadjuvant 
dose depending on AC treatment schedule).
In cases when surgery does not occur within 4 weeks of the completion of the neoadjuvant 
treatment phase, surgery is permitted at a later date. The investigator must document the reason 
for the delay of surgery in the eCRF and the medical record.
For participants who undergo BCS, the margins of the resected surgical specimen must be 
histologically free of invasive tumor as well as ductal carcinoma in situ (DCIS) as determined by 
the local pathologist. If pathologic examination demonstrates tumor at the line of resection, 
additional operative procedures may be performed at the discretion of the treating physician to 
obtain clear margins. If tumor is still present at the resected margin after potential subsequent 
re-excision(s), the participant must undergo total mastectomy to be eligible for the Adjuvant 
(Post-surgery) Phase. Participants with margins positive for lobular carcinoma in situ (LCIS) are 
eligible for the Adjuvant Phase without additional resection.
For participants who undergo mastectomy (and/or nipple- or skin-sparing mastectomy), margins 
must be free of gross residual tumor. It is recommended that participants should have a negative 
microscopic margin in accordance with local pathology protocol. Participants with a microscopic 
positive deep margin are eligible for the Adjuvant Phase. Information on the type of surgery 
performed and reason why different from the planned surgery at baseline will be collected and 
recorded in the eCRF and in the patient medical record.
Surgery specimens will be collected for histological examination of pCR, as well as other 
pathology parameters and endpoint analyses, as outlined in Section 4 (Objectives and Endpoints).
For additional details, please refer to the Pathology Manual.
5.1.2.3
Radiotherapy
Post-operative RT is required if breast-conserving surgery (BCS) is performed, per international 
guidelines and/or local standards. In the event of mastectomy, administration of adjuvant RT
should follow local clinical practice.
In participants receiving RT, adjuvant systemic therapy (nivolumab + endocrine therapy [ET] or 
ET alone [per Protocol Amendment 03]) may start:
1) Any time from the post-surgery visit or
2) At the same time as RT or
3) During RT or
4) Within 1 to 2 weeks of completion of RT per local standards.
Note: Starting adjuvant systemic therapy, then stopping or pausing to administer RT, and then 
restarting adjuvant systemic therapy for remaining adjuvant cycles will not be permitted.
In participants not receiving RT, adjuvant systemic therapy should be started no later than 6 weeks 
following surgery.
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In cases of BCS, breast RT after complete local excision is mandatory. Breast RT may be 
contraindicated in participants with significant comorbidity (for example, scleroderma and 
systemic lupus erythematosus). Reasons for not delivering breast RT after complete local excision 
of the primary breast cancer should be discussed with the Medical Monitor (or designee) and 
documented in the eCRF.
Recommendations for post-surgical RT are described in Appendix 7 (Radiotherapy Guidelines).
5.1.2.4
Adjuvant (Post-surgery) Phase
Participants will return to the clinic within 7-14 days following Surgery for a post-surgical visit.
The post-surgery visit and the first cycle of adjuvant treatment may be combined if adjuvant 
treatment starts within 7-14 days after the breast cancer surgery.
Documentation of the participant’s menopausal status at the post-surgical visit for participants who 
were premenopausal at baseline is required, following the definition provided below:
•
Premenopausal status is defined as < 12 months since last menstrual period and no prior
bilateral ovariectomy and not receiving estrogen replacement, or biochemical evidence of
premenopausal status, according to local standards.8
As of Protocol Amendment 03, treatment in the Adjuvant phase will be open label; participants 
will be treated according to their unblinded randomized treatment assignment. No crossover is 
allowed per protocol.
Adjuvant (Post-surgery) Phase of treatment will begin with the administration of nivolumab in 
combination with Investigator’s choice ET (Arm A) or Investigator’s choice ET only (Arm B) for 
a maximum of 7 cycles (Cycles 1 to 7; 1 cycle = 4 weeks), except in the event of disease recurrence 
or progression, withdrawal of consent, death, unacceptable toxicity, or symptomatic deterioration. 
Participants who discontinue study treatment for reasons other than death or withdrawal of consent 
will proceed to the Follow-Up Period of the study.
Besides the ET (Arm B) and ET in combination with nivolumab (Arm A), no further adjuvant 
treatment (chemotherapy, iCDK4/6 inhibitor, or any drug administered with the intent of treating
the cancer) is allowed in the Adjuvant Phase, irrespective of the pCR outcome of the surgery.
The selected ET may be rotated, changed, or switched to another ET (ie, from tamoxifen to an AI, 
from an AI to tamoxifen, from AI to another AI) during the study at the discretion of the 
Investigator. Ovarian function suppression (chemical or surgical) is allowed to be used with ET. 
The respective change should be clearly recorded in the source documents.
5.1.3
Follow-up Period
5.1.3.1
Safety Follow-up Visits
There will be 2 in-person safety follow-up visits. Follow-up visit 1 (FU1) will occur 
30 days (± 7 days) from the last dose of the study treatment. Follow-up visit 2 (FU2) will occur 
approximately 100 days (± 7 days) from the last dose of study treatment. Study treatments are 
defined in Table 7-1.
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5.1.3.2
Long-term Follow-up Visit
As of Protocol Amendment 03, there will be a single Long-term Follow-up Visit at 12 months
post-surgery (± 2 months). For participants in follow-up at the time that Protocol Amendment 03
is approved, the final study visit will happen at the time of the next previously scheduled study 
visit and should consist of the study procedures outlined in the Long-term Follow-up Visit (see
Table 2-5). If a participant requests to be withdrawn from follow-up, this request must be 
documented in the source documents and signed by the Investigator. If the participant withdraws 
from study, the study staff may use a public information source (eg, county records) to obtain 
information about survival status only.
5.1.4
External Committees
5.1.4.1
Independent Data Monitoring Committee
An IDMC will provide oversight of safety and efficacy considerations in protocol CA2097FL and 
provide advice to the Sponsor regarding actions the committee deems necessary for the continued 
protection of participants enrolled in the study. The IDMC will be charged with assessing such 
actions in light of an acceptable benefit-risk profile.
The IDMC will act in an advisory capacity to the Sponsor, monitor participant safety, and evaluate 
the available efficacy data for the study. The oncology therapeutic area of the Sponsor has primary 
responsibility and decision-making authority for the design and conduct of the study, as well as 
any protocol-related aspects.
The IDMC will hold regular meetings to evaluate the ongoing benefit-risk of the trial, including 
data internal and external to the trial. The IDMC will meet to review all available data (safety and 
efficacy) at each meeting, to be held approximately every 6 months, or more frequently, as needed. 
At the conclusion of each IDMC meeting, the committee will provide the Sponsor with a 
recommendation to continue, modify, or terminate the study protocol based upon their review. 
Ultimately, decisions regarding the study protocol will be made by the Sponsor in conjunction 
with feedback from the Investigators and IDMC.
When required, adjudicated events will be submitted to the IDMC and Health Authorities for 
review on a specified timeframe, in accordance with the adjudication documentation.
Additional details concerning IDMC oversight are provided in the IDMC charter.
5.1.4.2
Study Steering Committee
A SSC, consisting of Investigators and personnel members representing the Sponsor of the study,
will be established to obtain scientific guidance and advice for the protocol and conduct of the 
study. The SSC will meet at least annually and on an ad hoc basis, as necessary. Detailed 
information can be found in the SSC Charter.
5.2
Number of Participants
As of 07-Apr-2022, enrollment for new participants was closed. As of 16-May-2022, the number 
of participants screened was 831 and the number of participants randomized was 521.
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5.3
End of Study Definition
The start of the trial is defined as the first participant screened. The end of the trial is defined as
the last participant’s last study visit. Study completion is defined as the final date on which data 
for the primary endpoint was or is expected to be collected, if this is not the same.
5.4
Scientific Rationale for Study Design
5.4.1
Rationale for Choice of Patient Population
Participants with newly diagnosed, treatment-naive, high-risk, histologically proven ER+, HER2-
primary BC, who are eligible for neoadjuvant chemotherapy, will be included in this study 
population. Despite the availability of cytotoxic chemotherapy, as well as ET in this setting, 
relapses occur for a not insignificant proportion of patients with high-risk ER+, HER2- BC. 
Furthermore, due to the lower pCR typically achieved compared with other BC subtypes, there 
remains an unmet medical need in this patient population.
ER+, HER2- disease is the most common BC subtype occurring in ~70% of BC cases and most 
BC deaths occur in ER+ patients.22,23,24 ER+ cancer is emerging as a continuing challenge to 
balance outcomes with treatment options. This BC subtype is generally associated with lower 
recurrence rates than other BC subtypes within the first 5 years after diagnosis and is associated 
with a good prognosis when diagnosed early and appropriately treated. However, despite the 
availability of both chemotherapy and ET options, the risk of recurrence persists over time within 
this patient population, arguing for additional treatment strategies for an unmet need in this 
population.24
The ER+, HER2- population is a heterogeneous BC subtype. There is a subgroup of patients with 
high-risk clinicopathologic features and a poorer prognosis that is characteristic of the so-called
Luminal B molecular subtype, which was identified by GEP analysis studies.87,88 ER+, HER2-
tumors that are high-grade have higher measures of proliferation and lower levels of ER and PgR 
expression tend to be less sensitive to ET and more likely to benefit from chemotherapy, compared 
to their counterparts falling under the so-called Luminal A subtype,7 but patients still recur despite 
treatment.
The 
current 
study 
will 
assess 
the 
combination 
of 
nivolumab 
and 
anthracycline-taxane-based chemotherapy and nivolumab combined with SOC ET in this patient 
population.
Patients with newly diagnosed, non-metastatic, high-risk ER+, HER2- BC represent an important 
unmet need. Their risk of disease relapse is high, especially in those who do not obtain a pCR after 
their neoadjuvant chemotherapy. In contrast, those who do achieve pCR have a better prognosis 
concerning disease relapse. There are preclinical as well as emerging clinical data available to 
suggest the potential of PD-1 inhibition to improve clinical outcomes in early BC.
5.4.2
Rationale for Choice of Endpoints
Neoadjuvant therapy is increasingly used in patients with early BC to improve the likelihood of 
local tumor control, assess the treatment sensitivity of the disease in vivo, and increase the potential 
for curable disease by targeting the micrometastatic disease burden.1 Robust individual 
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patient-level data meta-analyses from well-conducted clinical trials suggest that achieving a pCR 
is positively associated with improvement in EFS and OS; these associations are more robust
within populations with high-risk BC subtypes.2,3,4 Further, use of the neoadjuvant platform 
permits rapid assessment of drug efficacy and may expedite clinical development of new agents 
in this setting. Agents that positively and substantially impact pCR rate may have a reasonable 
expectation of meaningful improvement in EFS.5,6
5.4.3
Rationale for Chemotherapy Plus PD-1 Inhibition
Immunotherapy in combination with chemotherapy has been shown to improve response and OS, 
when compared to these agents used individually, in BC and other tumor types in the metastatic 
setting. It is hypothesized that chemotherapy may modify the immune response to tumors by 
influencing multiple mechanisms, including inducing immunogenic cell death, stimulating release 
of tumor antigens and/or depleting immuno-suppressive Tregs.
Current SOC, consisting of anthracycline-taxane-based chemotherapy administered in the 
neoadjuvant setting, is effective and tolerable among most patients with early BC.7,8,9
Chemotherapy is effective in high-risk, primary ER+, HER2- disease and pCR rates range from 
7-16%, which are lower than those achieved in other BC subtypes (30-50%).2
PD-1 pathway inhibition has demonstrated clinical activity across multiple tumor types, including 
BC.10,11,12,13,14,15,16 There is strong rationale for combining checkpoint blockade with 
chemotherapy in patients with newly diagnosed ER+, HER2- BC. An accumulating body of 
preclinical17 and clinical data10,11,12,16 supports the combination of anti-PD-1 agents and 
chemotherapy to improve clinical outcomes in early and advanced settings across BC subtypes; 
such data culminated recently in the first approval of a PD-L1 inhibitor coupled with single-agent 
chemotherapy for patients with newly diagnosed, PD-L1+ (assessed in the immune-cell 
component of the disease) metastatic TNBC.11
Increasing understanding of the immunobiology of BC indicates that PD-1 inhibition could exert 
potent antitumor activity across all BC subtypes, including cases with ER+, HER2- disease. 
A recently reported study employed single-cell proteomics-based analysis, based on a panel of 
73 antibodies, tailored to interrogate the different (immune-)phenotypes of BC.89 A total number 
of 144 tumor samples were analyzed, exceeding a total of 26 million single cells phenotypically 
characterized. High frequencies of PD-L1+ tumor-associated macrophages and exhausted T cells 
were found in high-grade ER+ and ER- tumors, thus indicating that PD-1 inhibition may be a 
viable therapeutic strategy to reactivate the exhausted immune system. Furthermore, lymphocytic 
infiltration of ER+, HER2- BC tumors has been reported frequently, with a positive correlation 
with lower ER expression and/or high grade.90,91
Preliminary clinical data from a Phase 2 adaptive design neoadjuvant trial (I-SP) in participants 
with HER2- BC (ER+, HER2-, and TNBC cohorts) assessed an anti-PD-1 agent added to standard 
paclitaxel chemotherapy, and demonstrated clinically meaningful improvements in pCR rates
relative to historical controls.12 An absolute increase in the estimated pCR of 21% was observed 
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(34% with pembrolizumab 200 mg Q3W plus standard therapy compared to 13% with standard 
therapy alone) in participants with HR+, HER2- BC. The safety profile of pembrolizumab was 
consistent with that observed in previously reported studies across tumors.12 Similar results in the 
TNBC subtype from Phase 2 trials, indicating increased pCR rates (~60-80%) with either 
pembrolizumab or durvalumab plus taxane and anthracycline-based neoadjuvant chemotherapy 
with or without carboplatin in participants with TNBC, suggest potential clinical activity with 
tolerable safety, while maintaining a full dose of chemotherapy.10,16
Data are available for nivolumab in participants with BC. Nivolumab was evaluated after a short 
induction with 1 of 3 low-dose chemotherapy treatments, irradiation, or no induction, in 
50 participants with metastatic TNBC in a Phase 2 trial. After a 2-week induction period,
participants received nivolumab 3 mg/kg Q2W until progression. With a median 4-month 
follow-up, the ORR was 22%, with 2 complete responses (4%) and 9 partial responses (18%). 
Median duration of response was 10.9 months. These findings suggest that administering 
nivolumab after priming the tumor microenvironment (TME) with either low-dose chemotherapy 
or irradiation is feasible and may render the TME more sensitive to anti-PD-1 agents, which may 
help to improve clinical response rates.35
Nivolumab was evaluated in 39 participants with metastatic TNBC in the CheckMate 32 
(CA209032) study, which demonstrated a favorable safety profile for nivolumab monotherapy and 
nivolumab in combination with ipilimumab. The safety profile of nivolumab is well characterized 
from a large safety database at different doses and schedules, as monotherapy or in combination. 
Consistent with the mechanism of action of nivolumab, the most frequently reported drug-related 
AEs observed in clinical trials are those associated with activation of the immune system. The 
most common types of IMAEs include endocrinopathies, diarrhea/colitis, hepatitis, pneumonitis, 
nephritis, and rash.
A number of ongoing studies are evaluating different chemotherapeutic agents in combination with 
checkpoint inhibitors in patients with BC.
5.4.4
Rationale for Endocrine Therapy Plus PD-1 Inhibition
The safety profile of nivolumab is well characterized and manageable when administered alone or 
in combination with chemotherapy, targeted agents, as well as additional IO products. No data are 
available evaluating the combination of nivolumab and ET (eg, tamoxifen, AIs).
However, checkpoint inhibition via a different immune pathway (CTLA-4) has been reported in 
combination with endocrine therapy in patients with breast cancer.79 In cancer patients, CTLA-4 
appears to regulate immune responses early in T-cell activation, whereas PD-1 inhibits the effector 
phase of T-cell activity in the tumor microenvironment. Based on current understanding, 
checkpoint inhibitors all act to attenuate T-cell activity, and it is thought that anti-CTLA-4 
(eg, ipilimumab and tremelimumab) and anti-PD-1 (eg, nivolumab) primarily act at different 
stages of the cancer immunity cycle.92,93
One of the initial BC studies assessing checkpoint inhibitors was a Phase 1 study of tremelimumab, 
an anti-CTLA-4 antibody, combined with exemestane in 26 women with heavily pretreated ER+ 
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metastatic BC.79 No objective responses were noted; however 11 of 26 participants experienced 
stable disease, including 4 participants who previously progressed on exemestane. Evidence of 
T-cell activation was reported in the periphery, as measured by ICOS expression. Treatment was
associated with T-cell activation, as revealed by an increase in ICOS-expressing T cells in blood
and a marked increase in the ratio of ICOS-positive T cells to FoxP3-positive Tregs.79,80 Most
treatment-related AEs were mild to moderate (Grade 1 or 2) in nature. The most common events
included diarrhea (46%), pruritus (42%), constipation (23%), and fatigue (23%).
Rationale for combining immunotherapy with ET comes from several sources. In a pooled 
assessment of stromal TIL concentrations in participants with BC treated in 6 randomized trials of 
neoadjuvant chemotherapy, pCR had a strong positive correlation with TIL concentrations in all 
BC subtypes. Of note, there was a negative survival effect with higher TIL concentration in 
participants with ER+, HER2- BC, unlike the positive survival effect observed with TNBC and 
HER2+ BC subtypes. In the ER+, HER2- BC cohort, tumor-infiltrating lymphocytes (TILs) were 
not prognostic for DFS and low TIL concentrations were associated with improved survival. 
Therefore, the effect of TILs on OS had the opposite effect for ER+, HER2- BC tumors, as 
compared with TNBC and HER2+ BC subtypes. The negative effect of higher TILs on survival in 
participants with ER+, HER2- tumors was most pronounced in the large group of participants not 
achieving a pCR and was stronger for OS than for DFS.90,94
The negative impact of higher TILs may be explained by increasing resistance to ET in 
ER+, HER2- BC. Poor response to AI treatment has been associated with increased immune 
activity, TILs, and immune-related genes.95,96 Pretreatment expression of an inflammatory 
signature correlated with antiproliferative response to anastrozole in 112 postmenopausal women 
receiving 2-week treatment. Higher expression of immune-related genes, such as signaling 
lymphocytic activation molecule family member 8 (SLAMF8) and tumor necrosis factor (TNF),
as well as lymphocytic infiltration were associated with poorer response (p < 0.001) to neoadjuvant 
anastrozole.95 Similar findings suggest that the presence of immune-related genes were highly 
predictive of poor antiproliferative response to AIs.96 These data suggest that patients with 
evidence of high immune-related gene expression and/or lymphocytic infiltration may be 
candidates for immune-modulators in combination with ET.
These findings suggest a rationale for further evaluation of checkpoint inhibitors, such as 
nivolumab, in combination with ET.
See Section 3.3.5 (Nivolumab and Endocrine Therapy Combination Safety Profile) for additional 
details.
Several ongoing studies are evaluating different ET agents in combination with checkpoint 
inhibitors.81,82
5.4.5
Rationale for Stratification Factors
Randomized participants in the study will be stratified by the following factors:
1) PD-L1 on immune cells (≥1% or < 1%);
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2) Tumor grade (2 or 3, with maximum number of participants with tumor grade 2 BC not
exceeding 20% of the ITT population);
3) Axillary nodal status (pathologic review positive versus radiographic and/or pathologic review
negative, with maximum number of participants with node-negative BC not exceeding 20% of
the ITT population); and
4) AC dose-frequency chemotherapy regimen (Q3W or Q2W).
PD-L1 status, used for stratification, is determined by qualitative immunohistochemical assay 
using rabbit monoclonal anti-PD-L1 clone SP142 on the proportion of tumor area occupied by 
PD-L1-expressing tumor-infiltrating immune cells (% IC) of any intensity.
5.4.5.1
PD-L1 Status
PD-L1 expression has previously been evaluated as a potential predictive marker for treatment 
outcome in patients receiving anti-PD-L1 therapy for advanced TNBC. In a Phase 1 study 
evaluating 116 participants with metastatic TNBC who were treated with atezolizumab, those with 
PD-L1 expression in ≥ 1% of tumor-infiltrating immune cells had higher ORRs and longer OS 
(12% [11 of 91] and 10.1 [95% CI, 7.0-13.8] months, respectively) than those with PD-L1 
expression in < 1% of tumor-infiltrating immune cells (0% [0 of 21] and 6.0 [95% CI, 2.6-12.6] 
months, respectively), while no major differences in ORR were seen between participants with 
PD-L1 expression on ≥1% of tumor cells (12% [95% CI, 2.5%-31.2%]) and those with PD-L1 
expression on < 1% of tumor cells (9.2% [95%CI, 4.1%-17.3%]).13 Similar findings in a Phase 1b 
study of avelumab in heavily pretreated participants with metastatic BC (TNBC and ER+, HER2-
cohorts) demonstrated a trend toward a higher ORR in participants with PD-L1+ vs 
PD-L1-negative (PD-L1-) tumors associated immune cells in the overall population (16.7% vs
1.6%) and in the TNBC cohort (22.2% vs 2.6%).15In participants with untreated metastatic TNBC, 
atezolizumab and nab-paclitaxel combination therapy reduced the risk of disease worsening or 
death by 20% in all participants and 38% in the subgroup expressing PD-L1, as reported from the 
IMpassion 130 study.11 In the IMpassion 130 study, PD-L1 positivity was defined as expression 
on tumor-infiltrating immune cells in ≥ 1% of the tumor area.
Similar findings suggesting PD-L1 positivity on immune cells is associated with response was 
reported in the Phase 2 KATE2 study in 200 participants with previously treated advanced HER2+ 
BC. This placebo-controlled study evaluated trastuzumab emtansine (T-DM1) plus atezolizumab 
vs T-DM1. The primary endpoint of progression-free survival (PFS) in the ITT population was not 
met; however, in participants expressing PD-L1 ≥1% on immune cells, PFS was 8.5 months with 
T-DM1 plus atezolizumab vs 4.1 months with T-DM1 alone. Response rates were 54% vs 33%,
respectively. Similarly, in participants with high levels of TILs, the median PFS was higher with
atezolizumab (8.5 vs 5.3 months, respectively). In the PD-L1- group, atezolizumab added no
benefit, 
nor 
did 
it 
add 
benefit 
for 
participants 
with 
higher 
HER2 
expression
(immunohistochemistry [IHC] 3+ vs 1+ or 2+).97
In a Phase 1b study, pembrolizumab and abemaciclib demonstrated a confirmed ORR of 28.6% in 
heavily pretreated participants with metastatic HR+, HER2- BC, without association to PD-L1 
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positivity.98 In this case, PD-L1 positivity was defined as the CPS of PD-L1 expression on both 
tumor and immune cells, relative to the total tumor cells, of ≥ 1%.
More recent data in the neoadjuvant breast cancer setting have suggested that PD-L1 expression 
may be prognostic and not predictive of treatment benefit from anti-PD-L1.99,100,101
To evaluate PD-L1 status on efficacy analyses, PD-L1 expression on tumor-infiltrating immune 
cells of ≥ 1% based on PD-L1 SP142 was selected as a stratification factor for this study and used 
for secondary endpoint analysis. In addition, for exploratory analysis PD-L1 expression 
determined by PD-L1 IHC 28-8 CPS will also be explored to assess its potential impact on 
efficacy.
5.4.5.2
Tumor Grade
Pathologic characteristics of the tumor are recognized as having prognostic significance.102 Tumor 
grade is a known prognostic factor in patients with early BC.103
Multiple grading systems are available, with the most widely accepted being the 
Scarff-Bloom-Richardson 
(SBR) 
classification.102
Mitotic 
index, 
differentiation, 
and 
pleomorphism are scored from 1 to 3 and the scores from each category are totaled. Tumors with 
scores from 3 to 5 are well differentiated (Grade 1), while scores from 6 to 7 are moderately 
differentiated (Grade 2), and scores from 8 to 9 are poorly differentiated (Grade 3).
Robust studies and meta-analyses have reported a correlation between histologic grade and EFS 
and/or DFS, such that higher grade or low ER expression portends a poorer long-term survival.2,104
In a large meta-analysis in early BC, the pCR rate was positively associated with EFS (HR, 0.49
[95% CI, 0.33-0.71]) and OS (HR, 0·43 [95% CI, 0.23-0.71]) in the ER+/HER2- population. The 
association between pCR and long-term outcome was stronger in patients with higher-grade 
tumors than in those with lower-grade tumors.2 Similarly, pCR rates appear higher in patients 
having lower ER expression compared with those having higher ER expression after neoadjuvant 
chemotherapy.105 Patients with low ER expression appear to behave similarly to ER-negative 
(ER-) disease, and this may translate to improved longer-term outcome106,107 in those having a 
pCR. Thus, tumor grade was selected as a stratification factor for this study.
5.4.5.3
Axillary Nodal Status
A significant prognostic factor for patients with primary BC is the presence or absence of axillary 
lymph node involvement. There is a direct relationship between the number of involved axillary 
nodes and the risk for distant recurrence. Nodal groups were characterized based on the National 
Surgical Adjuvant Breast and Bowel Project (NSABP) data: negative nodes (0 nodes), 1-3 positive 
nodes, 4-9 positive nodes, and 10 or more positive nodes. The 5-year survival for patients with 
node-negative disease is 82.8% compared with 73% for 1-3 positive nodes, 45.7% for 4-12 positive 
nodes, and 28.4% for ≥13 positive nodes.108
A recent retrospective review with long-term follow-up demonstrated an increased risk of 
recurrence and BC-related death in women who had occult or micrometastatic tumor deposits in 
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their axillary lymph nodes.109 Similar results were observed in the International Breast Cancer 
Study Group Trial V of 1,275 node-negative women randomly assigned to a single cycle of 
perioperative cyclophosphamide, methotrexate, and 5-flourouracil (CMF) vs no chemotherapy.110
These micrometastases, detected by either method, were associated with a higher risk of 
recurrence.
Axillary nodal status (confirmed pathologically) is the most consistent prognostic factor used in 
therapy decision making and was selected as a stratification factor for enrollment in this study.
5.4.5.4
Anthracycline-Cyclophosphamide Dose Frequency
Increasing the dose intensity of adjuvant chemotherapy by shortening the interval between 
treatment cycles, or by giving individual drugs sequentially rather than giving the same drugs 
concurrently, moderately reduces the 10-year risk of recurrence and death from BC without 
increasing mortality from other causes.111
An individual patient-level meta-analysis of trials comparing 2-weekly vs standard 3-weekly 
schedules, and of trials comparing sequential vs concurrent administration of anthracycline and 
taxane chemotherapy was conducted by the Oxford group. Individual patient data were provided 
for 26 of 33 relevant trials identified, comprising 37,298 (93%) of 40,070 women randomized. 
Most women were aged younger than 70 years and had node-positive disease.
Combined data showed fewer BC recurrences with dose-intense than with standard-schedule 
chemotherapy (10-year recurrence risk, 28.0% vs 31.4%; relative risk 0.86 [95% CI, 0.82-0.89]; 
p < 0.0001). Ten-year BC mortality was similarly reduced (18.9% vs 21.3%; relative risk, 0.87
[95% CI, 0.83-0.92]; p < 0.0001), as was all-cause mortality (22.1% vs 24.8%; relative risk, 0.87
[95% CI, 0.83-0.91]; p < 0.0001). Death without recurrence was, if anything, lower with 
dose-intense than with standard-schedule chemotherapy (10-year risk, 4.1% vs 4.6%; relative risk,
0.88 [95% CI, 0.78-0.99]; p = 0.034). Recurrence reductions were similar in the 7 trials 
(n = 10,004) that compared 2-weekly chemotherapy with the same chemotherapy given 3-weekly 
(10-year risk, 24.0% vs 28.3%; relative risk, 0.83 [95% CI, 0.76-0.91]; p < 0·0001), in the 6 trials 
(n = 11,028) of sequential vs concurrent anthracycline plus taxane chemotherapy (28.1% vs 31.3%; 
relative risk, 0.87 [95% CI, 0.80-0.94]; p = 0.0006), and in the 6 trials (n = 6532) testing both 
shorter intervals and sequential administration (30.4% vs
35.0%; relative risk,
0.82
[95% CI, 0.74-0.90]; p < 0.0001). The proportional reductions in recurrence with dose-intense 
chemotherapy were similar and highly significant (p < 0.0001) in ER+ and ER- disease and did 
not differ significantly by other patient or tumor characteristics.111
To evaluate AC dose intensity on efficacy analyses, AC frequency was selected as a stratification 
factor for this study.
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5.5
Justification for Dose
5.5.1
Justification for Dose of Nivolumab
5.5.1.1
Nivolumab 240-mg Every-2-Week Dosing Regimen
Nivolumab 240 mg Q2W infused over 30 minutes is approved by FDA and European Medicines
Agency (EMA) for all nivolumab approved indications as monotherapy.56,65 Nivolumab 240 mg 
Q2W infused over approximately 30 minutes will be examined in combination with neoadjuvant 
chemotherapy in this study.
5.5.1.2
Nivolumab 360-mg Every-3-Week Dosing Regimen
Nivolumab monotherapy has been extensively studied in multiple tumor types, including 
melanoma, 
NSCLC, 
RCC,
cHL, 
SCCHN, 
and 
urothelial 
carcinoma, 
using 
body 
weight-normalized dosing (mg/kg), and has been safely administered at doses up to 10 mg/kg 
Q2W. Nivolumab is currently approved for the treatment of various tumors, including melanoma, 
NSCLC, RCC, cHL, SCCHN, and urothelial carcinoma, using a regimen of either nivolumab 
240 mg Q2W, nivolumab 3 mg/kg Q2W, or nivolumab 480 mg Q4W.
Nivolumab has been shown to be safe and well tolerated up to a dose level of nivolumab 10 mg/kg 
Q2W. Population PK (PPK) analyses have shown that the PK of nivolumab is linear, with 
proportional exposures over a dose range of 0.1 to 10 mg/kg; no differences in PK across 
ethnicities and tumor types were observed. Using the PPK model, the exposures following 
administration of several dosing regimens of nivolumab administered as a flat dose were 
simulated, including nivolumab 360 mg Q3W. The simulated steady-state average concentration 
(Cavgss) following administration of nivolumab 360 mg Q3W are expected to be similar to those 
following administration of nivolumab 240 mg Q2W and nivolumab 3 mg/kg Q2W administered 
to participants weighing 80 kg, the approximate median weight of participants with NSCLC, 
melanoma, and RCC used in the PPK analyses. Given that the Cavgss estimates for nivolumab 
360 mg Q3W are predicted to be similar to those for nivolumab 240 mg Q2W and 
nivolumab 3 mg/kg Q2W, the efficacy is predicted to be similar for these regimens. It should be 
noted 
that 
the 
maximum-observed 
concentrations
at 
steady 
state
following 
nivolumab 360 mg Q3W are predicted to be less than those following the administration of 
nivolumab 10 mg/kg Q2W,
providing sufficient safety margins. Further details on 
nivolumab 360 mg Q3W dosing can be found in the IB.34
Finally, nivolumab 360 mg Q3W is currently being investigated in combination with a number of 
other agents, including platinum-doublet chemotherapy dosing, with no new or increased safety 
events observed to date. By using nivolumab 360 mg Q3W in this study, it allows for aligning 
doses of nivolumab at the same dosing frequency of the experimental agent.
Nivolumab 360 mg
Q3W infused over approximately 30 minutes will be examined
in 
combination with neoadjuvant chemotherapy in this study.
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Nivolumab 480-mg Every-4-Week Dosing Regimen
Nivolumab 480 mg Q4W infused over 30 minutes was approved by FDA in Mar-2018 for the
majority of indications approved for nivolumab. The EMA has also approved inclusion of this
dosing schedule in the label for nivolumab for the treatment of patients with advanced melanoma
and previously treated RCC.
Nivolumab 480 mg
Q4W infused over approximately 30 minutes will be examined
in 
combination with Investigator’s choice of ET in this study.
5.5.2
Justification for Dose of Chemotherapy Agents
Chemotherapy regimens used in the neoadjuvant setting are the same as those used in the adjuvant 
setting. An anthracycline-cyclophosphamide-taxane-containing regimen is the most widely 
recommended chemotherapy regimen in the neoadjuvant setting for patients with ER+, HER2- BC
in national and international guidelines.7,8,9 The doses of the individual chemotherapy agents in 
this study are consistent with the national and international guidelines.
The choice among various anthracycline-taxane-based regimens is often a matter of toxicity and 
duration. Within sequential regimens, weekly paclitaxel (80 mg/m2) was shown to have improved 
DFS and OS compared with 3-weekly paclitaxel.112,113 In addition, more frequent administration 
of the AC component (ie, dose-dense approach) was shown to be more effective in minimizing 
residual tumor burden than dose-escalation.114 In a meta-analysis of 10 randomized controlled 
trials, dose-dense chemotherapy improved OS by 16% [hazard ratio (HR),
0.84
[95% CI, 0.72-0.98]; p = 0.03] and DFS by 17% (HR, 0.83 [95% CI, 0.73-0.94]; p = 0.005).115
The superiority of dose-dense chemotherapy, in terms of improved long-term clinical outcome for 
patients with primary BC, has been recently demonstrated by an individual patient-level data 
meta-analysis, pooling data from more than 37,000 individual patients. Importantly, the 
proportional reductions in recurrence with dose-intense chemotherapy were similar and highly 
significant (p < 0.0001) in both ER+ and ER- disease and did not differ significantly by other 
patient or tumor characteristics.47
Nivolumab 360 mg
Q3W infused over approximately 30 minutes will be examined
in 
combination with paclitaxel 80 mg/m2 QW for a maximum 4 cycles (1 cycle = 3 weeks), followed 
by either:
•
Nivolumab 360 mg Q3W infused over approximately 30 minutes in combination with either
doxorubicin 60 mg/m2 or epirubicin 90 mg/m2 and cyclophosphamide 600 mg/m2 Q3W for a
maximum of 4 cycles (1 cycle = 3 weeks); or
•
Nivolumab 240 mg Q2W infused over approximately 30 minutes in combination with either
doxorubicin 60 mg/m2 or epirubicin 90 mg/m2 and cyclophosphamide 600 mg/m2 Q2W for a
maximum of 4 cycles (1 cycle = 2 weeks).
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5.5.3
Justification for Dose of Endocrine Therapy
Adjuvant ET is the cornerstone of treatment for patients with primary ER+, HER2- BC. Use of 
tamoxifen and/or an AI (anastrozole, letrozole, or exemestane) are recommended agents for 
patients with ER+, HER2- BC in national and international guidelines.7,8,9,52 The doses of the 
individual ET agents in this study are consistent with the national and international guidelines. 
Investigator’s choice of ET is permitted from the following options:
•
Tamoxifen 20 mg per os (by mouth; PO) quaque die (once daily; QD)
•
Anastrozole 1 mg PO QD
•
Letrozole 2.5 mg PO QD
•
Exemestane 25 mg PO QD
Investigator’s choice of the above ET options will be examined in combination with nivolumab 
480 mg Q4W in this study.
6
STUDY POPULATION
For entry into the study, the following criteria MUST be met. As of 07-Apr-2022, new participant 
enrollment to this study is closed.
6.1
Inclusion Criteria
1) Signed Written Informed Consent
a) Participants must have signed and dated an Institutional Review Board (IRB)/Independent 
Ethics Committee (IEC)-approved written ICF, in accordance with regulatory and 
institutional guidelines. This must be obtained before the performance of any 
protocol-related procedures that are not part of normal patient care.
b) Participants must be willing and able to comply with scheduled visits, treatment schedules, 
laboratory tests, tumor biopsies, and other requirements of the study.
2) Type of Participant and Target Disease Characteristics
a) Participants must have histologically confirmed unilateral invasive breast carcinoma, with 
documentation of the following characteristics:
i)
Localized invasive breast ductal carcinoma, confirmed by the local pathologist, that 
includes the following combined primary tumor and node (N) categories:
(1) T1c (tumor size = 2 cm)-T2 (tumor size > 2 cm), N1-N2
OR
(2) T3-T4, N0-N2
Note: Axillary lymph node status must be assessed by fine needle biopsy or core 
biopsy. This procedure at screening will be omitted if there is no suspicion for 
positive axillary lymph node(s) radiographically or if a pathological report of 
suspicious lymph nodes of the results of a fine needle biopsy or core biopsy is 
available prior to the screening period. Participants with tumors classified as 
T1c-T2 without nodal involvement are not eligible.
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ii) In the case of a multifocal tumor (defined as the presence of 2 or more foci of cancer
within the same breast quadrant), the largest lesion must be ≥2 cm and designated as
the “target” lesion for all subsequent tumor evaluations.
(1) In participants where there may be a reasonable suspicion of advanced disease
(eg, large tumors, clinically positive axillary lymph nodes, signs and symptoms),
documentation confirming the absence of distant metastasis (M0) as determined by
institutional practice is required.
iii) Documentation of T1c-T2 (tumor size > 2 cm), clinical node stage (cN)1-cN2 or T3-T4,
cN0-cN2.
(1) In participants where there may be a reasonable suspicion of advanced disease (eg,
large tumors, clinically positive axillary lymph nodes, signs and symptoms),
documentation confirming the absence of distant metastasis (M0) as determined by
institutional practice is required.
iv) Not applicable per Revised Protocol 01-Participants must have measurable disease
based on Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 (refer to
Appendix 8), as determined by local radiology review.
v) Participants must have measurable disease based on modified Respond Evaluation
Criteria in Solid Tumors (RECIST) v 1.1 (refer to Appendix 8), as determined by local
radiology review.
b) Participants must have ER+, HER2- BC meeting below characteristics:
i)
ER+ BC and with or without PgR expression (determined on the most recently
analyzed tissue sample, tested locally, and confirmed by the central laboratory), as
defined in the relevant American Society of Clinical Oncology [ASCO]-College of
American Pathologists [CAP] Guidelines).116
ii) HER2- BC tested in the local laboratory, defined as a negative in situ hybridization
test or an immunohistochemistry (IHC) status of 0, 1+, or 2+. If IHC is 2+, a negative
in situ hybridization (fluorescence in situ hybridization [FISH], chromogenic in situ
hybridization [CISH], or silver in situ hybridization [SISH] test, as defined in the
relevant ASCO-CAP Guidelines, is required from the local laboratory.117
iii) Participant must have either:
(1) Grade 3 BC of ductal histology
or
(2) Grade 2 BC of ductal histology having an ER expression level percentage between
1-10%, (tested locally and confirmed by central laboratory) according to the most
recent ASCO-CAP Guidelines.117
c) Participants must be deemed eligible for neoadjuvant chemotherapy.
d) Participants must be deemed eligible for surgery.
e) Participants must have an Eastern Cooperative Oncology
Group (ECOG) scale
performance status of 0 or 1 (refer to Appendix 5).
f)
Participants must have the ability to swallow oral medication.
g) Participants must agree to provide primary breast tumor tissue at baseline (collected
≤90 days prior to enrollment if FFPE block is submitted or prepared ≤60 days prior to
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enrollment from a tissue sample collected ≤ 90 days prior to enrollment) and at Surgery. 
The tumor tissue must be in the format of either one FFPE tissue block (containing 20 mm3
of tissue) or unstained tumor tissue sections (22 slides) from the primary breast tumor 
lesion.
Note: At least 15 slides must be submitted for a participant to be eligible. If < 15 slides are 
available, the participant is not eligible. If a recent tumor specimen is not available, a fresh 
tumor biopsy collection is required. 
 
h) Re-enrollment: This study permits the re-enrollment of a participant that has discontinued 
the study as a pretreatment failure (ie, participant has not been randomized). If re-enrolled, 
the participant must be re-consented and inclusion/exclusion criteria reassessed.
i)
Randomized participants: PD-L1 status, ER status, and ER expression level percentage
from the central laboratory must be provided to IRT prior to randomization. Participants 
with PD-L1, ER, or HER2 unknown/not evaluable status are not eligible.
3) Age and Reproductive Status
a) Males and females, aged at least 18 years or age of majority.
b) Women of childbearing potential (WOCBP) must have a negative serum or urine 
pregnancy test (minimum sensitivity of 25 IU/L or equivalent units of human chorionic 
gonadotropin [HCG]) within 24 hours prior to the start of study treatment. An extension 
up to 72 hours prior to the start of study treatment is permissible in situations where results 
cannot be obtained within the standard 24-hour window.
c) Not applicable per Revised Protocol 01 - Female participants must agree to use effective 
contraception during the Treatment Period and for at least 12 months for participants who 
receive cyclophosphamide, or 6 months for participants who do not receive 
cyclophosphamide, after the last dose of study treatment with nivolumab or nivolumab 
placebo, whichever is longer.
d) WOCBP must agree to follow instructions for method(s) of contraception for the duration 
of treatment with study treatment(s) and for 12 months for participants who receive 
cyclophosphamide, or 6 months for participants who do not receive cyclophosphamide,
after the last dose of study treatment with nivolumab or nivolumab placebo, whichever is 
longer.
e) Males who are sexually active with WOCBP must agree to follow instructions for 
method(s) of contraception and fetal protection (Appendix 4) for the duration of
neoadjuvant (pre-surgery) treatment phase and 12 months after the last dose of 
cyclophosphamide OR 6 months after the last dose of paclitaxel, whichever is the last dose.
f)
Not applicable per Revised Protocol 01 - Male participants must agree to use contraception 
during the Treatment Period and for at least 6 months after the last dose of study 
treatment(s).
g) Azoospermic males are exempt from contraceptive requirements, unless the potential 
exists for fetal toxicity due to study drug being present in seminal fluid, even if the 
participant has undergone a successful vasectomy or if the partner is pregnant. WOCBP 
who are continuously not heterosexually active are also exempt from contraceptive 
requirements and must still undergo pregnancy testing as described in this section.
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Investigators shall counsel WOCBP, and male participants who are sexually active with WOCBP, 
on the importance of pregnancy prevention and the implications of an unexpected pregnancy and, 
when applicable, the potential of fetal toxicity occurring due to transmission of study drug, present 
in seminal fluid, to a developing fetus, even if the participant has undergone a successful 
vasectomy or if the partner is pregnant. Investigators shall advise on the use of highly effective 
methods of contraception (refer to Appendix 4) which have a failure rate of < 1% when used 
consistently and correctly. 
6.2
Exclusion Criteria
1) Medical Conditions
a) Women who are breastfeeding.
b) Participants who are pregnant or expecting to conceive or father children within the
projected duration of the study, starting with the screening visit through 12 months for
participants who receive cyclophosphamide, or 6 months for participants who do not
receive cyclophosphamide, after the last dose of study treatment.
c) The following BC characteristics:
i)
History of ipsilateral invasive BC, regardless of treatment, ipsilateral ductal carcinoma
in situ treated with radiation, or contralateral invasive BC, at any time.
ii) Definitive clinical or radiologic evidence of metastatic disease.
iii) Not applicable per Revised Protocol 01 - Inoperable BC.
iv) Multicentric BC (the presence of > 1 tumor in different quadrants of the breast).
v) Bilateral invasive BC.
vi) Any of the following clinical lymph node staging based on radiological and/or clinical
assessment: cN3, cN3a, cN3b, or cN3c.
vii)History of DCIS, unless a complete remission was achieved at least 2 years prior to
study start and no additional therapy is required or anticipated to be required during the
study.
viii)
History of pleomorphic lobular carcinoma in situ (LCIS), except for participants
surgically managed > 5 years prior to diagnosis of the current BC.
ix) Evidence of ER- BC, regardless of PgR status.
x) Undergone excisional biopsy of the primary tumor and/or axillary lymph nodes or has
undergone sentinel lymph node biopsy prior to study treatment.
d) Participants with > Grade 1 peripheral neuropathy.
e) Participants with an active, known, or suspected autoimmune disease. Participants with
type I diabetes mellitus, hypothyroidism only requiring hormone replacement, skin
disorders (such as vitiligo, psoriasis, or alopecia) not requiring systemic treatment, or
conditions not expected to recur in the absence of an external trigger are permitted to enroll.
f)
Participants with a condition requiring systemic treatment with either corticosteroids
(> 10 mg daily prednisone equivalent) within 14 days or other immunosuppressive
medications within 30 days of randomization. Inhaled or topical steroids, and adrenal
replacement steroid doses > 10 mg daily prednisone equivalent, are permitted in the
absence of active autoimmune disease.
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g) Not Applicable per Protocol Amendment 02 - Known human immunodeficiency virus 
(HIV) positive with an acquired immunodeficiency syndrome (AIDS)
defining 
opportunistic infection within the last year, or a current CD4 count of <350 cells/μL. 
Participants enrolled with known HIV need monitoring of CD4 counts and viral load during 
the study and antiretroviral therapy administered as clinically indicated.
Note: Testing for HIV must be performed at sites where mandated locally (refer to 
Appendix 9).
h) Not Applicable per Protocol Amendment 02 - Prior malignancy active within the previous 
3 years, except for locally curable cancers that have been apparently cured, such as basal 
or squamous cell skin cancer, superficial bladder cancer, or carcinoma in situ of the 
prostate, cervix, or breast.
i)
Participants with serious or uncontrolled medical disorders.
i)
Additionally, in the case of prior SARS-CoV-2 infection within 4 weeks prior to 
screening, participant may be enrolled if acute symptoms have resolved and based on 
Investigator assessment in consultation with the Medical Monitor, there are no sequelae 
that would place the participant at a higher risk of receiving investigational treatment 
(see Section 6.4.1).
j)
Other nonmalignant systemic disease that would preclude the participant from receiving 
study treatment or would prevent required follow-up, such as:
i)
Active infection or chronic infection requiring chronic suppressive antibiotics.
ii) Malabsorption syndrome, ulcerative colitis, inflammatory bowel disease, resection of 
the stomach or small bowel, or other disease or condition significantly affecting 
gastrointestinal (GI) function.
k) Any psychological, familial, sociological, or geographical condition potentially hampering 
compliance with the study protocol and follow-up schedule.
l)
Concurrent malignancy (present during screening) requiring treatment or history of prior 
malignancy active within 2 years prior to randomization (ie, participants with a history of 
prior malignancy are eligible if treatment was completed at least 2 years before 
randomization and the participants has no evidence of disease). Participants with history 
of prior early stage basal/squamous cell skin cancer or noninvasive or in situ cancer that 
have undergone definitive treatment at any time are also eligible, except for ipsilateral 
ductal carcinoma in situ treated with radiation.
m) Known human immunodeficiency virus (HIV) positive with an AIDS defining 
opportunistic infection within the 12 months or a current CD4 count < 350 cells/μL,
participants with HIV are eligible if:
i)
They have received antiretroviral therapy (ART) for at least 4 weeks prior to 
randomization, as clinically indicated.
ii) They continue on ART as clinically indicated while on study treatment.
iii) CD4 counts and viral load are monitored per standard of care by a local health care 
provider while on study treatment.
NOTE: Testing for HIV must be performed at sites where mandated locally. HIV positive 
participants must be excluded where mandated locally (refer to Appendix 9).
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2) Prior/Concomitant Therapy
a) Prior treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2, or anti-CTLA-4 antibody, or
any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint
pathways.
b) Any treatment, local or systemic, including prior chemotherapy, ET, targeted therapy,
and/or radiation therapy for the currently diagnosed BC prior to enrollment.
c) Concurrent use of hormone replacement therapy, hormonal contraception, or any other
estrogen-containing medication, including vaginal estrogens. Participant is eligible if the
therapy is discontinued prior to randomization (refer to Appendix 4).
d) Surgical axillary staging procedure prior to enrollment (with the exception of fine-needle
aspiration or core biopsy).
e) Surgical excisional biopsy of primary tumor.
f)
Participants for whom upfront ET alone is judged clinically appropriate as optimal
neoadjuvant therapy.
g) Not applicable per Protocol Amendment 02 - Treatment with botanical preparations (eg,
herbal supplements, traditional Chinese medicines) to treat the disease under study within
2 weeks prior to start of study treatment. See Section 7.7.1 (Prohibited and/or Restricted
Treatments for Nivolumab) for prohibited therapies.
h) Participants who have received a live/attenuated vaccine within 30 days before the first
treatment.
i)
Any complementary medications (eg, herbal supplements or traditional Chinese
medicines) intended to treat the disease under study within 2 weeks prior to first study
treatment. Such medications are permitted if they are used as supportive care. Refer to
Section 7.7.1.1 (Prohibited and/or Restricted Treatments for Nivolumab) for prohibited
therapies.
j)
Participants currently in other interventional trials, including those for coronavirus disease
2019 (COVID-19), may not participate in Bristol-Myers Squibb (BMS) clinical trials until the
protocol-specific washout period is achieved. COVID-19 vaccines that are NOT live may be
administered during the study, including during IP treatment and after the last administration
of investigational product (IP). If a study participant has received a live COVID-19 vaccine
prior to screening, enrollment should be delayed until the impact of the vaccine is stabilized as
per the asset level standard, unless a delay would compromise patient health, as determined by
discussion between the Investigator and the Medical Monitor. No data are available on the
response to COVID-19 vaccines. The efficacy and safety of vaccination in subjects who are
receiving IP are unknown.
3) Physical and Laboratory Test Findings
a) White blood cells < 2,000/μL.
b) Neutrophils < 1500/μL.
c) Platelets < 100 × 103/μL.
d) Hemoglobin < 9.0 g/dL.
e) Serum creatinine > 1.5 × upper limit of normal (ULN), unless creatinine clearance
≥40 mL/min (measured or calculated using the Cockroft-Gault formula).
f)
Aspartate aminotransferase (AST)/ALT: > 3.0 × ULN.
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g) Total bilirubin > 1.5 × ULN (except participants with Gilbert Syndrome who must have a 
total bilirubin level of < 3.0 × ULN).
h) Not applicable per Revised Protocol 01 - Any positive test result for hepatitis B virus or 
hepatitis C virus indicating presence of virus (eg, hepatitis B surface antigen [HBsAg, 
Australia antigen] positive, or hepatitis C antibody [anti-HCV] positive [except if HCV-
ribonucleic acid (RNA) negative]).
i)
Has significant cardiovascular disease, such as:
i)
LVEF < 50% at baseline as assessed by ECHO (preferred) or MUGA scan;
ii) Class III or Class IV myocardial disease as described by the New York Heart 
Association (refer to Appendix 10);
iii) Recent history (within 6 months prior to enrollment) of myocardial infarction; or
iv) Symptomatic arrhythmia at the time of randomization.
j)
Evidence of interstitial lung disease, active pneumonitis, myocarditis, or a history of 
myocarditis.
k) Not Applicable per Protocol Amendment 02 - Serologic evidence of chronic HBV 
infection with an HBV viral load above the limit of quantification. Patients with chronic 
HBV infection must be on concurrent viral suppressive therapy.
l)
Not Applicable per Protocol Amendment 02 - Serologic evidence of current HCV 
infection with an HCV viral load above the limit of quantification.
m) Any positive test result for hepatitis C virus (HCV) indicating presence of active viral 
replication (detectable HCV-RNA). Note: participants with positive HCV antibody and an 
undetectable HCV RNA are eligible to enroll.
n) Any positive test result for hepatitis B virus (HBV) indicating presence of virus (eg, 
Hepatitis B surface antigen [HBsAg, Australian antigen] positive).
4) Allergies and Adverse Drug Reaction
a) History of allergy or severe hypersensitivity (≥Grade 3) to study drug components.
5) Other Exclusion Criteria
a) Prisoners or participants who are involuntarily incarcerated. (Note: Under certain specific 
circumstances, and only in countries where local regulations permit, a person who has been 
imprisoned may be included or permitted to continue as a participant. Strict conditions 
apply and BMS approval is required.)
b) Participants who are compulsorily detained for treatment of either a psychiatric or physical 
(eg, infectious disease) illness.
Eligibility criteria for this study have been carefully considered to ensure the safety of the study 
participants and that the results of the study can be used. It is imperative that participants fully 
meet all eligibility criteria.
6.3
Lifestyle Restrictions
Not applicable. No restrictions are required.
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6.4
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study but who 
are not subsequently randomized in the study/included in the analysis population. A minimal set 
of screen failure information is required to ensure transparent reporting of screen failure 
participants, to meet the Consolidated Standards of Reporting Trials (CONSORT) publishing 
requirements, as applicable, and to respond to queries from regulatory authorities. Minimal 
information includes date of consent, demography, screen failure details, eligibility criteria, and 
any serious AEs.
6.4.1
Retesting During Screening
Participant Re-enrollment: This study permits the re-enrollment of a participant that has 
discontinued the study as a pretreatment failure (ie, participant has not been randomized/has not 
been treated). If re-enrolled, the participant must be re-consented.
Retesting of laboratory parameters and/or other assessments within any single Screening will be 
permitted (in addition to any parameters that require a confirmatory value).
The most current result prior to randomization is the value by which study inclusion will be 
assessed, as it represents the participant’s most current, clinical state.
Laboratory parameters and/or assessments that are included in Table 2-1 (Screening Procedural 
Outline) may be repeated in an effort to find all possible well-qualified participants. Consultation 
with the Medical Monitor (or designee) may be needed to identify whether repeat testing of any 
particular parameter is clinically relevant.
Testing for asymptomatic COVID-19 (eg, by reverse transcription polymerase chain reaction 
[RT-PCR] or viral antigen) is not required. However, some participants may develop suspected or 
confirmed symptomatic COVID-19 or be discovered to have asymptomatic COVID-19 during the 
screening period. In such cases, participants may be considered eligible for the study after meeting 
all inclusion/exclusion criteria related to active infection and after meeting the following criteria:
•
At least 10 days (20 days for severe/critical illness) have passed since symptoms first appeared
or positive RT-PCR or viral antigen test result.
•
At least 24 hours have passed since last fever without the use of fever-reducing medications.
•
Acute symptoms (eg, cough, shortness of breath) have resolved.
•
In the opinion of the Investigator and in consultation with the Medical Monitor or Study
Director, there are no COVID-19-related sequelae (eg, cardiovascular) that may place the
participant at a higher risk of receiving investigational treatment.
•
Negative follow-up SARS-CoV-2 RT-PCR or viral antigen test based on institutional, local,
or regional guidelines.
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7
TREATMENT
Study treatment is defined as any investigational treatment(s), marketed product(s), placebo or 
medical device intended to be administered to a study participant according to the study 
randomization or treatment allocation.
Study 
treatment
includes 
both 
Investigational 
[Medicinal] 
Product 
(IP/IMP) 
and 
Non-investigational [Medicinal] Product (Non-IP/Non-IMP) and can consist of the following:
•
Nivolumab (BMS-936558)
•
Nivolumab placebo
•
Chemotherapy
−
Paclitaxel
−
Anthracycline
♦Doxorubicin
♦Epirubicin
−
Cyclophosphamide
•
Growth Factors
−
Granulocyte colony-stimulating factor
−
Granulocyte-macrophage colony-stimulating factor
•
Endocrine Therapy
−
Anastrozole
−
Exemestane
−
Letrozole
−
Tamoxifen
An IP, also known as an IMP in some regions, is defined as a pharmaceutical form of an active 
substance or placebo being tested or used as a reference in a clinical study, including products 
already with a marketing authorization but used or assembled (formulated or packaged) differently 
than the authorized form, or used for an unauthorized indication, or when used to gain further 
information about the authorized form.
Consider, if possible, avoiding overlap of administration of vaccine and protocol therapy (eg, at 
least 2 days, preferably 7 days, apart).
Other medications used as support or escape medication for preventative, diagnostic, or therapeutic 
reasons, as components of the SOC for a given diagnosis, may be considered as non-IPs.
Premedications or medications used to treat infusion-related reactions should be sourced by the 
investigative sites, if available and permitted by local regulations.
Solutions used as diluent or placebo (ie, 0.9% sodium chloride injection, 5% dextrose injection) 
should also be sourced by investigative sites, if available and permitted by local regulations.
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Table 7-1:
Study Treatments for CA2097FL
Product Description/
Class and Dosage Form
Potency
IP/
Non-IP
Blinded or
Open Labela
Packaging/
Appearance
Storage Conditions
(per label)
Nivolumab Injectionb
10 mg/mL;
100-mg fill volume
and
10 mg/mL;
40-mg fill volume
IP
Open Label
Vials
Refer to the label or container 
and/or Pharmacy Manual.
Paclitaxel Solution for Injectionc
6 mg/mL; 
100-mg fill volume
IP
Open Label
Vials
Refer to the label or container 
and/or Pharmacy Manual .
Doxorubicin Hydrochloride Injectionc
2 mg/mL;
200-mg fill volume
IP
Open Label
Vials
Refer to the label or container 
and/or Pharmacy Manual.
Epirubicin Solution for Injectionc
2 mg/mL;
200-mg fill volume
IP
Open Label
Vials
Refer to the label or container 
and/or Pharmacy Manual.
Cyclophosphamide Injectionc
1-g vial
IP
Open Label
Vials
Refer to the label or container 
and/or Pharmacy Manual.
0.9% Sodium Chloride for Injection
NA
IP
Open Label
Various (local 
commercial product)
Refer to the label or container 
and/or Pharmacy Manual.
5% Dextrose for Injection
NA
IP
Open Label
Various (local 
commercial product)
Per active IP.
Tamoxifen Tabletsc
Various strengths
IP
Open Label
Various packing 
configurations
Refer to the label or container 
and/or Pharmacy Manual.
Letrozole Tabletsc
2.5 mg
IP
Open Label
Various packing 
configurations
Refer to the label or container 
and/or Pharmacy Manual.
Anastrozole Tabletsc
1 mg
IP
Open Label
Various packing 
configurations
Refer to the label or container 
and/or Pharmacy Manual.
Exemestane Tabletsc
25 mg
IP
Open Label
Various packing 
configurations
Refer to the label or container 
and/or Pharmacy Manual.
Granulocyte colony-stimulating factor 
(G-CSF)d
Various strengths
Non-IP
Open Label
Various (local 
commercial product)
Refer to the label
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BMS-936558
nivolumab
Table 7-1:
Study Treatments for CA2097FL
Product Description/
Class and Dosage Form
Potency
IP/
Non-IP
Blinded or
Open Labela
Packaging/
Appearance
Storage Conditions
(per label)
Granulocyte-macrophage colony-
stimulating factor (GM-CSF)d
Various strengths
Non-IP
Open Label
Various (local 
commercial product)
Refer to the label
Abbreviations: g, gram; IMP, investigational medicinal product. IP, investigational product; mg, milligram; mL, milliliter; NA, not applicable; SmPC, summary 
of product characteristics.
a The term “open label” refers to the medication as it is upon receipt at the pharmacy. The trial will be conducted in a double-blinded fashion. As of Protocol 
Amendment 03, participants will be unblinded in the Adjuvant phase.
b May be labeled as either “BMS-936558-01” or “Nivolumab.”
c These products may be obtained by the investigational sites as local commercial product in certain countries if allowed by local regulations. In these cases, 
products may be a different pack size/potency than listed in the table. These products should be prepared/stored/administered in accordance with the package 
insert or SmPC or according to local standards.
d To be sourced locally by investigational sites. These products should be prepared/stored/administered in accordance with their package insert or SmPC or 
according to local standards.
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nivolumab
7.1
Treatments Administered
The selection and timing of dose for each participant is provided in Table 7.1-1, Table 7.1-2, and
Table 7.1-3.
Table 7.1-1:
Selection and Timing of Dose - Neoadjuvant (Pre-surgery) Phase -
PTX
Arm
Study Treatment
Dosage Level
Frequency of 
Administration
Start and Duration 
of Treatment
Route of 
Administration
A
Nivolumab
360 mg
Q3W
PTX Cycles 1-4
IV
Paclitaxel
80 mg/m2
QW
PTX Cycles 1-4
IV
B
Nivolumab 
Placebo
NA
Q3W
PTX Cycles 1-4 
IV
Paclitaxel
80 mg/m2
QW
PTX Cycles 1-4
IV
Abbreviations: IV, intravenous; m2, square meter; mg, milligram; NA, not applicable; PTX, paclitaxel; QW, every
week; Q3W, every 3 weeks.
Table 7.1-2:
Selection and Timing of Dose - Neoadjuvant (Pre-surgery) Phase -
AC
Arm
Study Treatment
Dosage Level
Frequency of 
Administration
Start and 
Duration of 
Treatment
Route of 
Administration
A
Nivolumab
360 mg
Q3W
AC Cycles 1-4
IV
ORa
240 mg
Q2W
Doxorubicinb
60 mg/m2
Q3W or Q2Wa,c
AC Cycles 1-4
IV
Epirubicinb
90 mg/m2
Q3W or Q2Wa,c
AC Cycles 1-4
IV
Cyclophosphamide
600 mg/m2
Q3W or Q2Wa,c
AC Cycles 1-4
IV
B
Nivolumab 
Placebo
NA
Q3W or Q2Wa
AC Cycles 1-4
IV
Doxorubicinb
60 mg/m2
Q3W or Q2Wa,c
AC Cycles 1-4
IV
Epirubicinb
90 mg/m2
Q3W or Q2Wa,c
AC Cycles 1-4
IV
Cyclophosphamide
600 mg/m2
Q3W or Q2Wa,c
AC Cycles 1-4
IV
Abbreviations: AC, anthracycline + cyclophosphamide; IV, intravenous; m2, square meter; mg, milligram; NA, not
applicable; Q2W, every 2 weeks; Q3W, every 3 weeks.
a Dosing frequency of Q2W or Q3W for AC cycles to be determined by the Investigator.
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b Choice of anthracycline, either doxorubicin or epirubicin, to be determined by the Investigator.
c Prophylaxis  with growth factors is required for the AC 2QW schedule.
Table 7.1-3:
Selection and Timing of Dose - Adjuvant (Post-surgery) Phase
Arm
Study Treatment
Dosage Level
Frequency of 
Administration
Start and Duration 
of Treatment
Route of 
Administration
A
Nivolumab
480 mg
Q4W
Cycles 1-7
IV
Investigator’s 
Choice ET
See Notea
See Notea
Cycles 1-7
See Notea
B
Investigator’s 
Choice ET
See Notea
See Notea
Cycles 1-7
See Notea
Abbreviations: ET, endocrine therapy; IV, intravenous; mg, milligram; NA, not applicable; Q4W, every 4 weeks.
a May include tamoxifen, letrozole, anastrozole, or exemestane, to be administered per the respective package inserts.
All participants should begin study treatment within 3 days of randomization.
7.1.1
Nivolumab/Nivolumab Placebo Dosing
The study design requires a total of 8 cycles of neoadjuvant treatment with nivolumab or 
nivolumab placebo in combination with anthracycline-taxane-based chemotherapy, followed by 
7 cycles of adjuvant treatment with nivolumab + Investigator’s choice of ET or Investigator’s 
choice of ET alone (per Protocol Amendment 03).
There will be no dose escalations or reductions of nivolumab or nivolumab placebo allowed. If at 
a particular cycle, nivolumab or nivolumab placebo cannot be administered within a ± 3-day 
window from the scheduled chemotherapy dose, nivolumab or nivolumab placebo administration 
must be omitted for that cycle.
•
Participants may be dosed no less than 12 days from the previous dose during Q2W cycles.
•
Participants may be dosed no less than 18 days from the previous dose during Q3W cycles.
•
Participants may be dosed no less than 25 days from the previous dose during Q4W cycles.
Premedications are not recommended for the first dose of nivolumab or nivolumab placebo. 
Premedication with corticosteroids should be avoided. However, if considered clinically 
necessary, premedication with corticosteroids can be used in accordance with the local treatment 
guidelines.
Participants should be carefully monitored for infusion reactions during nivolumab or nivolumab 
placebo administration. If an acute infusion reaction is noted, participants should be managed 
according to Section 7.4.1.3 (Treatment of Nivolumab Infusion Reaction).
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BMS-936558
nivolumab
Doses of nivolumab or nivolumab placebo may be interrupted, delayed, omitted, or discontinued,
depending on how well the participant tolerates the treatment. For additional information, please 
see Sections 7.4.1 (Dose Modifications for Nivolumab), Section 7.4.1.2 (Criteria to Resume 
Treatment with Nivolumab) and Section 8.1.1 (Nivolumab Dose Discontinuation). Instructions for 
dilution and infusion of nivolumab or nivolumab placebo injection may be provided in the clinical 
protocol, pharmacy manual, or pharmacy reference sheet. Care must be taken to assure sterility of 
the prepared solution, as the product does not contain any antimicrobial preservative or 
bacteriostatic agent.
7.1.2
Neoadjuvant (Pre-surgery) Phase
During the Neoadjuvant (Pre-surgery) Phase, when given in combination with chemotherapy,
nivolumab or nivolumab placebo is to be given first. Nivolumab or nivolumab placebo must be 
given on the same day as the assigned chemotherapy. Nivolumab or nivolumab placebo infusion 
must be promptly followed by a saline flush to clear the line per local standards. Separate infusion 
bags and filters should be used when administering nivolumab or nivolumab placebo and assigned
chemotherapy as per local standards. Do not co-administer other drugs through the same 
intravenous line. Chemotherapy starts after the infusion line has been flushed, filters changed, and 
the participant has been observed for approximately 30 minutes, to ensure no infusion reaction has 
occurred.
Participants should receive neoadjuvant nivolumab or nivolumab placebo at a dose of 360 mg 
infusion given over approximately 30 minutes on Day 1 of each treatment cycle (Q3W), for a 
maximum of 8 cycles, until disease worsening or disease progression, unacceptable toxicity, 
withdrawal of consent, neoadjuvant treatment is completed, death, the study ends, or Q4W dosing 
begins, whichever occurs first. If needed, flush the intravenous line with an appropriate amount of 
diluent (eg, 0.9% sodium chloride or 5% dextrose in water to ensure that the complete dose is 
administered over approximately 30 minutes).
In cases where a dose-dense regimen of AC is administered Q2W, nivolumab or nivolumab 
placebo will also be administered on a Q2W schedule. Participants should receive nivolumab or 
nivolumab placebo at a dose of 240 mg infusion given over approximately 30 minutes on Day 1 
of each treatment cycle, until disease worsening or disease progression, unacceptable toxicity, 
withdrawal of consent, neoadjuvant treatment is completed, death, the study ends, or Q4W dosing 
begins, whichever occurs first.
7.1.3
Adjuvant (Post-surgery) Phase
As of Protocol Amendment 03, treatment in the Adjuvant phase will be open label. Participants 
who are randomized to Arm B will not receive adjuvant nivolumab placebo infusions, only 
Investigator’s choice of ET (per Protocol Amendment 03). 
Participants will follow previous randomization and will receive nivolumab with Investigator’s 
choice of ET or Investigator’s choice of ET alone (per Protocol Amendment 03) as adjuvant 
treatment.
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BMS-936558
nivolumab
During the Adjuvant (Post-surgery) Phase of treatment, when nivolumab is scheduled to be 
administered on the same day with Investigator’s choice of ET, nivolumab dosing should be started 
> 1 hour after the ET (ie, tamoxifen or AI) administration.
Participants should receive adjuvant nivolumab at a dose of 480 mg infusion given over
approximately 30 minutes on Day 1 of each treatment cycle (Q4W) (± 3 days), for a maximum of 
7 cycles, until disease recurrence or progression, unacceptable toxicity, withdrawal of consent, 
adjuvant treatment is completed, death, or the study ends, whichever occurs first.
7.1.4
Chemotherapy Dosing
7.1.4.1
Paclitaxel
Participants will receive paclitaxel at a dose of 80 mg/m2 over a minimum of 60 minutes as an
intravenous (IV) infusion or per institutional policy on Day 1, Day 8, and Day 15 of each 3-week 
treatment cycle. Paclitaxel will be administered for PTX Cycles 1-4 until disease worsening or 
disease progression, unacceptable toxicity, withdrawal of consent, PTX Cycles 1-4 are completed, 
death, or the study ends, whichever occurs first.
Dosing calculations should be based on the body surface area calculation. The dose should remain 
the same if the participant’s weight is within 10% of the weight used to calculate the previous 
dose. All doses should be rounded to the nearest milligram or per institutional standards. 
All participants should be carefully monitored for infusion reactions during the paclitaxel 
administration.
Participants should be treated in a facility with the necessary medical-resuscitation equipment and 
medications on hand to manage serious acute infusion reactions.
Paclitaxel premedication with corticosteroids should be avoided, if clinically justifiable. However, 
if considered clinically necessary or in accordance with the local treatment guidelines, 
premedication with corticosteroids can be used. Corticosteroids can be administered after the 
observation period of approximately 30 minutes following nivolumab.
Doses of paclitaxel may be interrupted, delayed, reduced, or discontinued, depending on how well 
the participant tolerates the treatment. For additional information, please see Section 7.4.2.1 (Dose 
Delay for Paclitaxel Therapy), Section 7.4.2.2 (Dose Reductions for Paclitaxel Chemotherapy), 
Section 7.4.2.3 (Criteria to Resume Treatment with Paclitaxel Chemotherapy), and Section 8.1.2
(Chemotherapy Dose Discontinuation). Participants may be dosed no less than 6 days from the 
previous dose of paclitaxel.
Every effort should be made to administer a total of 4 cycles of paclitaxel chemotherapy in 
combination with nivolumab or nivolumab placebo.
7.1.4.2
Anthracycline and Cyclophosphamide
The first dose of AC should be administered at the completion of 4 cycles (PTX Cycles 4D1 + 3 
weeks) of paclitaxel, unless the participant meets criteria for a treatment delay.
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nivolumab
Participants will receive doxorubicin at a dose of 60 mg/m2 as an IV bolus over 3-5 minutes or as 
an infusion over approximately 15-30 minutes, or per institutional-standard IV infusion, followed 
by cyclophosphamide as an IV infusion at a dose of 600 mg/m2 over approximately 60 minutes, 
or per institutional-standard IV infusion, on Day 1 of each cycle.
If per SOC, epirubicin 90 mg/m2 can be administered in place of doxorubicin. Epirubicin may be 
given as an IV bolus over 3-5 minutes or as an infusion over approximately 15-30 minutes, or per 
institutional-standard IV infusion followed by cyclophosphamide as an IV infusion at a dose of 
600 mg/m2 over approximately 60 minutes, or per institutional-standard IV infusion, on Day 1 of 
each cycle.
AC will be administered for AC Cycles 1-4 until disease worsening or disease progression, 
unacceptable toxicity, withdrawal of consent, AC Cycles 1-4 are completed, death, or the study 
ends, whichever occurs first.
Participants may receive the AC treatment on a Q3W or Q2W schedule. See Section 7.1
(Treatments Administered) for more details regarding nivolumab or nivolumab placebo dosing 
with AC treatment schedules.
Dosing calculations should be based on the body surface area calculation. The dose should remain 
the same if the participant’s weight is within 10% of the weight used to calculate the previous 
dose. All doses should be rounded to the nearest milligram or per institutional standards.
AC premedication with corticosteroids should be avoided. However, if considered clinically 
necessary, or in accordance with the local treatment guidelines, premedication with corticosteroids 
can be used.
Doses of anthracycline or cyclophosphamide may be interrupted, delayed, reduced, or 
discontinued, depending on how well the participants tolerates the treatment. For additional 
information, please see Section 7.4.2.4 (Dose Delay for Anthracycline and Cyclophosphamide 
Chemotherapy), Section 7.4.2.5
(Dose Reductions for Anthracycline-Cyclophosphamide 
Chemotherapy), 
Section 
7.4.2.6
(Criteria 
to 
Resume 
Treatment 
with 
for 
Anthracycline-Cyclophosphamide Chemotherapy), and Section 8.1.2 (Chemotherapy Dose 
Discontinuation).
Every effort should be made to administer a total of 4 cycles of AC chemotherapy in combination 
with nivolumab or nivolumab placebo. 
7.1.5
Endocrine Therapy Dosing
Following definitive surgery, the Investigator can decide which ET (tamoxifen, anastrozole, 
letrozole, or exemestane) will be administered to a particular participant. The decision must be
recorded in the source documents. The selected ET may be rotated, changed, or switched to another 
ET during the study. The respective change should be clearly recorded in the source documents.
ET may be given for a maximum of 10 years, per local standards. ET will be documented as study 
treatment up to the last dose of adjuvant treatment and documented as concomitant medication 
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after the last dose of adjuvant treatment. Participants will be required to complete a drug diary to 
assess compliance during the Adjuvant (Post-surgery) Phase.
No dose reductions are permitted for the ET (ie, tamoxifen, anastrozole, letrozole, or exemestane). 
ET may be interrupted, delayed, or discontinued, depending on how well the participant tolerates 
treatment. For additional information, please see Section 7.4.3 (Dose Modifications for 
Investigator’s Choice Endocrine Therapy) and Section 8.1.3 (Endocrine Therapy Dose 
Discontinuation).
More detailed information about administration, known and expected benefits and risks, and 
reasonably anticipated AEs of the study treatments may be found in the respective Patient 
Information Leaflets, Package Inserts,61,62,63,64 Development Safety Update Reports, or 
SmPCs.70,71,72,73
7.2
Method of Treatment Assignment
Before the study is initiated, each user will receive log-in information and directions on how to 
access the IRT. Each participant will be assigned a unique participant number after signing the 
ICF. Participant numbers will be used on all participants’ study information. Participant numbers 
will not be reassigned. An IRT will be employed to manage participant randomization. The 
Investigator or designee will register the participant for enrollment by following the enrollment 
procedures established by the Sponsor.
The following information is required for enrollment:
•
Date that informed consent was obtained
•
Year of birth
•
Gender at birth
Once enrolled in IRT, enrolled participants who have met all eligibility criteria will be ready to be 
randomized through the IRT. The following information is required for participant randomization:
•
Participant number
•
Year of birth
•
Gender at birth (female or male)
•
ER status/expression levels tumor type
•
PD-L1 on immune cells (≥ 1% or < 1%)
•
Tumor grade (2 or 3)
•
Axillary nodal status (pathological review positive versus radiographic and/or pathologic 
review negative)
•
AC dose-frequency regimen (Q3W or Q2W)
The exact procedures for using the IRT will be detailed in the IRT manual.
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BMS-936558
nivolumab
7.3
Blinding
This is a randomized, double-blinded study. Access to treatment codes will be restricted from all 
participants and site and Sponsor personnel prior to each interim and final database lock, with 
exceptions as specified below.
Each investigative site must assign an unblinded pharmacist or designee, and an unblinded site 
monitor will be assigned by the Sponsor to provide oversight of drug supply and other unblinded 
study documentation.
Blinding of treatment assignment is critical to the integrity of this clinical study. However, in the 
event of a medical emergency or pregnancy in an individual participant, in which knowledge of 
the IP is critical to the participant's management, the blind for that participant may be broken by 
the Investigator. The participant’s safety takes priority over any other considerations in 
determining if a treatment assignment should be unblinded.
Before breaking the blind of an individual participant's treatment, the Investigator should 
determine that the unblinded information is necessary (ie, that it will alter the participant's 
immediate management). In many cases, particularly when the emergency is clearly not related to 
the IP, the problem may be properly managed by assuming that the participant is receiving active 
product. It is highly desirable that the decision to unblind treatment assignment be discussed with 
the Medical Monitor (or designee), but the Investigator always has the ultimate authority for the 
decision to unblind. The Principal Investigator or appointed designee should only call in for 
emergency unblinding AFTER the decision to unblind the participant has been documented.
For this study, the method of unblinding for emergency purposes is through the IRT. Refer to the 
IRT manual for details.
In the case of an emergency, the Investigator(s) has unrestricted access to randomization 
information via the IRT and is capable of breaking the blind through the IRT system without prior 
approval from the Sponsor. Following the unblinding, the Investigator shall notify the Medical 
Monitor and/or Study Director (or designee). After emergency unblinding through the IRT, 
participant will be discontinued from study treatment and move to safety follow-up phase.
In cases of accidental unblinding, contact the Medical Monitor (or designee) and ensure that every 
attempt is made to preserve the blind.
Any request to unblind a participant for non-emergency purposes should be discussed with the 
Medical Monitor (or designee). Non-emergency unblinding will be requested by the Principal 
Investigator or appointed designee upon approval by the Medical Monitor. The latter will start 
internal process (outside of IRT system) to unblind the participants’ treatment. The unblinded 
participant continues to receive the randomized study treatment.
With Protocol Amendment 03, treatment assignment remains blinded through the Neoadjuvant
and Surgical phases. When participants enter the Adjuvant phase, treatment assignment will be 
open label to both the Sponsor and the study sites. For participants entering the Adjuvant phase or 
already in the Adjuvant or Follow-up phases at the time Protocol Amendment 03 is approved, 
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treatment assignment will be provided. Treatment assignment will only be provided after the 
pathological response information is entered in the CRF.
Designated staff of BMS Research & Development (R&D) may be unblinded (obtain the 
randomization codes) prior to database lock to facilitate the bioanalytical analysis of PK samples 
and immunogenicity. A bioanalytical scientist in the Bioanalytical Sciences department of 
BMS R&D (or a designee in the external central bioanalytical laboratory) will be unblinded to 
(may obtain) the randomized treatment assignments in order to minimize unnecessary 
bioanalytical analysis of samples from control group participants.
The pharmacist at the site and/or designee will be unblinded to the randomized treatment 
assignments in order to prepare blinded study treatment from bulk supplies, as needed. This (these) 
individual(s) will be unblinded to study drug identification but will not be involved in any other 
aspect of study conduct.
7.4
Dosage Modification
When assessing AEs, the Investigator must assign drug causality to each study drug for each AE. 
If a reasonable determination cannot be made, then the AE should be considered related to each of 
the study drugs. IO agents are associated with AEs that can differ in severity and duration from 
AEs caused by other therapeutic classes.
Recommendations for dose reduction, delay, interruption, or discontinuation of individual study 
drugs in the management of study drug-related adverse reactions are summarized below. For 
additional information, please refer to individual drug labels. Clinical judgment of the treating 
physician should guide the management plan of each participant based on individual benefit-risk 
assessment. However, for events requiring a discontinuation, treatment must be discontinued. Any 
changes to the dose must be recorded on the appropriate electronic case report form (eCRF).
7.4.1
Dose Modifications for Nivolumab
Participants who require a dose delay for nivolumab or nivolumab placebo should be re-evaluated 
and resume treatment at the next cycle or within ± 3 days from scheduled chemotherapy dose when 
retreatment criteria are met. AE criteria for delaying, resuming, and discontinuing of study treatment 
is provided in Table 7.4.1-1.
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Table 7.4.1-1:
Adverse Event Criteria for Delay, Resume, and Discontinue of Nivolumab
Drug-related AE per
CTCAE v5.0
Severity
Action Takena
Clarifications, Exceptions, and Resume Criteriaa
Gastrointestinal
Colitis or Diarrhea
Grade 2
Delay dose
Dosing mayresume when AE resolves to baseline
Grade 3
Delay dose
Dosing mayresume when AE resolves to baseline
Grade 4
Permanently discontinue
Renal
Serum Creatinine
Increased
Grade 2 or 3
Delay dose
Dosing mayresume when AE resolves to Grade ≤1 or
baseline value
Grade 4
Permanently discontinue
Pulmonary
Pneumonitis
Grade 2
Delay dose
Dosing mayresume after pneumonitis has resolved to 
≤Grade 1
Grade 3 or 4
Permanently discontinue
Hepatic
AST, ALT, or T.bili
Increased
AST or ALT >3x and ≤5x ULN or T.Bili 
>1.5x and ≤3x ULN, regardless of baseline
value
Delay dose
Dosing mayresume when laboratory values return to 
baseline after discussion with the Medical Monitor.
AST or ALT >5x ULN or T.Bili >3x ULN, 
regardless of baseline value
Permanently discontinue
Concurrent AST or ALT >3x ULN and 
T.Bili >2x ULN, regardless of baseline value
Permanently discontinue
Endocrinopathy
Adrenal Insufficiency
Grade 2 adrenal insufficiency
Delay dose
Dosing mayresume after adequately controlled with
hormone replacement
Grade 3 or 4 adrenal insufficiency or adrenal
crisis
Delay dose or perman
ently discontinue
Mandatory discussion with and approval from the
Medical Monitor needed prior to resuming therapy. If
adrenal insufficiency resolves or is adequately
controlled with physiologic hormone replacement,
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Table 7.4.1-1:
Adverse Event Criteria for Delay, Resume, and Discontinue of Nivolumab
Drug-related AE per
CTCAE v5.0
Severity
Action Takena
Clarifications, Exceptions, and Resume Criteriaa
participant maynot require discontinuation of study
drug
Hyperglycemia
Hyperglycemia requiring initiation or change
in daily management (Grade 2 or 3)
Delay dose
Dosing mayresume if hyperglycemia resolves to
Grade ≤1 or baseline value, or is adequately
controlled with glucose-controlling agents
Grade 4
Delay dose or perman
ently discontinue
Mandatory discussion with and approval from the
Medical Monitor needed prior to resuming therapy. If
hyperglycemia resolves or is adequately controlled
with glucose-controlling agents, participant maynot
require discontinuation of study drug
Hypophysitis/ 
Hypopituitarism
Symptomatic Grade 1-3 that is also
associated with corresponding abnormal lab
and/or pituitary scan
Delay dose
Dosing mayresume if endocrinopathyresolves to be
asymptomatic or is adequately controlled with only
physiologic hormone replacement
Grade 4
Delay dose or
permanently discontinue
Mandatory discussion with and approval from the
Medical Monitor needed prior to resuming therapy. If
endocrinopathy resolves or is adequately controlled
with physiologic hormone replacement, participant
maynot require discontinuation of study drug
Hyperthyroidism or
Hypothyroidism
Grade 2 or 3
Delay dose
Dosing mayresume if endocrinopathyresolves to be
asymptomatic, or is adequately controlled with only
physiologic hormone replacement or other medical
management
Grade 4
Delay dose or
permanently discontinue
Mandatory discussion with and approval from the
Medical Monitor needed prior to resuming therapy. If
endocrinopathy resolves or is adequately controlled
with physiologic hormone replacement or other
medical management, participant may not require
discontinuation of study drug
Skin
Rash
Grade 2 rash covering > 30% body surface
area or Grade 3 rash
Delay dose
Dosing mayresume when rash reduces to ≤10% body
surface area
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Table 7.4.1-1:
Adverse Event Criteria for Delay, Resume, and Discontinue of Nivolumab
Drug-related AE per
CTCAE v5.0
Severity
Action Takena
Clarifications, Exceptions, and Resume Criteriaa
SJS, TEN or DRESS
Delay dose
Dosing mayresume if SJS, TEN, or DRESS is  ruled
out and rash reduces to ≤10% body surface area
Grade 4 rash or confirmed SJS, TEN, or
DRESS
Permanently discontinue
Neurological
GBS
Any Grade
Permanently discontinue
MG
Any Grade
Permanently discontinue
Encephalitis
Any Grade encephalitis
Delay dose
After workup for differential diagnosis
(ie, infection, tumor-related), if encephalitis is not
drug-related, then dosing mayresume when AE
resolves
Any Grade drug-related encephalitis
Permanently discontinue
Myelitis
Any Grade myelitis
Delay dose
After workup for differential diagnosis
(ie, infection, tumor-related), if myelitis is not drug-
related, then dosing mayresume when AE resolves
Any Grade drug-related myelitis
Permanently discontinue
Neurological (other than
GBS, MG, encephalitis,
or myelitis)
Grade 2
Delay dose
Dosing mayresume when AE resolves to baseline
Grade 3 or 4
Permanently discontinue
Cardiovascular
Myocarditis
Symptoms induced from mild to moderate
activity or exertion
Delay dose
Dosing mayresume after myocarditis has resolved
Severe or life threatening, with symptoms at
rest or with minimal activity or exertion,
and/or where intervention indicated
Permanently discontinue
Cardiac Troponin I or
Troponin T Increased
Asymptomatic
Delay dose
All troponin elevations (including asymptomatic
elevations) will require a dose delay in order for the 
participant to undergo a cardiac evaluation (via prompt 
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Table 7.4.1-1:
Adverse Event Criteria for Delay, Resume, and Discontinue of Nivolumab
Drug-related AE per
CTCAE v5.0
Severity
Action Takena
Clarifications, Exceptions, and Resume Criteriaa
cardiology consult) and a confirmatory repeat within 24 
hours. If troponin elevation is not confirmed within 24 
hours in an asymptomatic participant, the dose delay
may not be needed provided that the cardiac evaluation 
is completed, and a cardiologist has made the 
recommendation to proceed with treatment.
Otherwise, if troponin elevation is confirmed, dosing 
mayresume when AE resolves to baseline
Other Clinical AEs
Pancreatitis:
Amylase or Lipase
Increased
Grade 3 with symptoms
Delay dose
Note: Grade 3 increased amylase or lipase without
signs or symptoms of pancreatitis does not require
dose delay
Dosing mayresume when participant becomes
asymptomatic
Grade 4
Permanently discontinue
Uveitis
Grade 2 uveitis
Delay dose
Dosing mayresume if uveitis responds to topical
therapy (eye drops) and after uveitis resolves to  Grade
≤1 or baseline. If participant requires oral steroids for
uveitis, then permanently discontinue study drug
Grade 3 or 4 uveitis
Permanently discontinue
Other Drug-related AE
(not listed above)
Grade 2 non-skin AE, except fatigue
Delay dose
Dosing mayresume when AE resolves to Grade ≤1 or
baseline value
Grade 3 AE - First occurrence lasting ≤7 
days
Delay dose
Dosing mayresume when AE resolves to Grade ≤1 or
baseline value
Grade 3 AE- First occurrence lasting > 7 
days
Permanently discontinue
Recurrence of Grade 3 AE of any duration
Permanently discontinue
Grade 4 or Life-threatening adverse reaction
Permanently discontinue
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Table 7.4.1-1:
Adverse Event Criteria for Delay, Resume, and Discontinue of Nivolumab
Drug-related AE per
CTCAE v5.0
Severity
Action Takena
Clarifications, Exceptions, and Resume Criteriaa
Other Laboratory Abnormalities
Other Drug-related
Laboratory Abnormality
(not listed above)
Grade 3
Delay dose
Exceptions:
No delayrequired for: Grade 3 lymphopenia
Permanent Discontinuation for: Grade 3
thrombocytopenia > 7 days or associated with
bleeding
Grade 4
Permanently discontinue
Exceptions: The following events do not require
discontinuation of study drug:
•
Grade 4 neutropenia ≤7 days
•
Grade 4 lymphopenia or leukopenia
Grade 4 isolated electrolyte imbalances/abnormalities
that are not associated with clinical sequelae and are
responding to supplementation/appropriate
management within 72 hours of their onset
Infusion Reactions
(manifested by fever, chills, rigors, headache, rash, pruritus, arthralgia, hypotension, hypertension, bronchospasm, or other allergic-like reactions)
Hypersensitivity reaction
or infusion reaction
Grade 3 or 4
Permanently discontinue
See Section 7.4.1.3 (Treatment of Nivolumab Infusion
Reaction)
Abbreviations: AE, adverse event; ALT, alanine aminotransferase; AST, aspartate aminotransferase; CTCAE, Common Terminology Criteria for Adverse Events;
DRESS, drug reaction with eosinophilia and systemic symptoms; GBS, Guillain-Barre Syndrome; MG, Myasthenia Gravis; SJS, Stevens-Johnson syndrome;
T.bili, total bilirubin; TEN, toxic epidermal necrolysis; ULN, upper limit of normal.
a All actions taken, clarifications, exceptions, and resume criteria apply to nivolumab.
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7.4.1.1
Dose Delay Criteria for Nivolumab
Nivolumab administration should be delayed for the following:
•
For participants receiving nivolumab, dose delay criteria apply for all drug-related AEs
(regardless of) whether the event is attributed to nivolumab. Delay administration of nivolumab
if any of the delay criteria in Table 7.4.1-1 are met. Delay nivolumab dosing for any AE,
laboratory abnormality, or intercurrent illness which, in the judgment of the investigator,
warrants delaying the dose of study medication.
•
Study treatment must also be delayed for SARS-CoV-2 infections, either confirmed or
suspected.
•
For participants who require delay of nivolumab reevaluate weekly, or more frequently if
clinically indicated, and resume nivolumab dosing when the retreatment criteria are met (see
Table 7.4.1-1). Continue tumor assessment per protocol, even if dosing is delayed.
The other study treatments may still be administered.
7.4.1.2
Criteria to Resume Treatment with Nivolumab
•
Participants may resume treatment with study treatment following Table 7.4.1-1.
•
Participants with SARS-CoV-2 infection (either confirmed or suspected) may resume
treatment after all of the following:
•
At least 10 days (20 days for severe/critical illness) have passed since symptoms first appeared
or positive test result (eg, RT-PCR or viral antigen); and
•
Resolution of acute symptoms (including at least 24 hours has passed since last fever without
fever reducing medications); and
•
Evaluation by the Investigator with confirmation that there are no sequelae that would place
the participant at a higher risk of receiving investigational treatment; and
•
Consultation with the Medical Monitor. For suspected cases, treatment may also resume if
SARS-CoV-2 infection is ruled out and other criteria to resume treatment are met.
Participants with drug-related endocrinopathies adequately controlled with only physiologic 
hormone replacement may resume treatment after consultation with the Medical Monitor 
(or designee). Adrenal insufficiency requires discontinuation, regardless of control with hormone 
replacement.
7.4.1.3
Treatment of Nivolumab Infusion Reaction
Since nivolumab contains only human immunoglobulin protein sequences, it is unlikely to be 
immunogenic and induce infusion or hypersensitivity reactions. However, if such a reaction were 
to occur, it might manifest with fever, chills, rigors, headache, rash, pruritus, arthralgia, 
hypotension, hypertension, bronchospasm, or other allergic-like reactions. All Grade 3 or 4 
infusion reactions should be reported within 24 hours to the study Medical Monitor (or designee)
and reported as an SAE, if it meets the criteria. Infusion reactions should be graded according to 
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National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v5.0 
guidelines.
Treatment recommendations are provided below based on CTCAE v5.0 and may be modified 
based on local treatment standards and guidelines, as appropriate:
For Grade 1 symptoms (mild reaction; infusion interruption not indicated; intervention not 
indicated):
•
Remain at bedside and monitor participant until recovery from symptoms. The following
prophylactic premedications are recommended for future infusions: diphenhydramine 50 mg
(or equivalent) and/or acetaminophen/paracetamol 325 to 1000 mg, at least 30 minutes before
subsequent nivolumab/nivolumab placebo administrations.
For Grade 2 symptoms (moderate reaction required therapy or infusion interruption but responds 
promptly to symptomatic treatment [eg, antihistamines, non-steroidal anti-inflammatory drugs, 
narcotics, corticosteroids, bronchodilators, IV fluids]; prophylactic medications indicated for 
≤24 hours):
•
Stop the study drug infusion, begin an IV infusion of normal saline, and treat the participant
with diphenhydramine 50 mg IV (or equivalent) and/or acetaminophen/paracetamol
325 to 1000 mg; remain at bedside and monitor participant until resolution of symptoms.
Corticosteroid and/or bronchodilator therapy may also be administered, as appropriate. If the
infusion is interrupted, then restart the infusion at 50% of the original infusion rate when
symptoms resolve; if no further complications ensue after approximately 30 minutes, the rate
may be increased to 100% of the original infusion rate. Monitor the participant closely. If
symptoms recur, then no further study medication will be administered at that visit.
•
For future infusions, the following prophylactic premedications are recommended:
diphenhydramine 50 mg (or equivalent) and/or acetaminophen/paracetamol 325 to 1000 mg
should be administered at least 30 minutes before nivolumab/nivolumab placebo infusions.
If necessary, corticosteroids (up to 25 mg of hydrocortisone or equivalent) may be used.
For Grade 3 or 4 symptoms (severe reaction, Grade 3: prolonged [ie, not rapidly responsive to 
symptomatic medication and/or brief interruption of infusion]; recurrence of symptoms following 
initial improvement; hospitalization indicated for other clinical sequelae [eg, renal impairment, 
pulmonary infiltrates]; Grade 4: Life threatening; pressor or ventilatory support indicated):
•
Immediately discontinue infusion of study drug. Begin an IV infusion of normal saline and
treat the participant as follows: Recommend bronchodilators, epinephrine 0.2 to 1 mg of a
1:1000 solution for subcutaneous administration or 0.1 to 0.25 mg of a 1:10,000 solution
injected slowly for IV administration, and/or diphenhydramine 50 mg IV with
methylprednisolone 100 mg IV (or equivalent), as needed. Participant should be monitored
until the Investigator is comfortable that the symptoms will not recur. Study drug will be
permanently discontinued. Investigators should follow their institutional guidelines for the
treatment of anaphylaxis. Remain at bedside and monitor the participant until recovery of the
symptoms.
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In the case of late-occurring hypersensitivity symptoms (eg, appearance of a localized or 
generalized pruritus within 1 week after treatment), symptomatic treatment may be given (eg, oral 
antihistamine or corticosteroids).
7.4.2
Dose Modifications for Chemotherapy
Recommendations for dose reduction, delay, interruption, or discontinuation of individual study 
drugs in the management of study drug-related adverse reactions are summarized below.
Participants who require a dose delay for chemotherapy should be re-evaluated and resume 
treatment at the next cycle, when retreatment criteria are met. 
For participants who meet criteria to delay chemotherapy (paclitaxel, doxorubicin or epirubicin, 
or cyclophosphamide), the corresponding drug will be delayed and nivolumab or nivolumab 
placebo will also be delayed in an effort to maintain synchronization of the combination regimen.
Efforts to maintain dose intensity and the intended treatment schedule are recommended.
7.4.2.1
Dose Delay for Paclitaxel Therapy
It is permissible, in cases of a dose held due to AEs, to omit the dose in the cycle in order to 
re-synchronize the participant with the next cycle visit.
Chemotherapy delay should not exceed 6 weeks. In the event that treatment with chemotherapy 
needs to be delayed beyond 6 weeks due to toxicity, a participant may continue on study to receive 
neoadjuvant AC study treatment at an earlier timepoint, or may transition to the Adjuvant (Post-
surgery) Phase at an earlier timepoint. Such treatment decisions will be at the discretion of the 
Investigator and participant, and upon consultation with the Medical Monitor (or designee).
Paclitaxel should be delayed for the following:
•
Presence of febrile neutropenia or neutropenia < 1000 cells/mm3 for > 1 week, despite the use
of growth factors.
•
Platelets < 100,000/mm3.
•
Any Grade ≥2 neuropathy (sensory or motor).
•
Any Grade ≥2 non-skin, chemotherapy-related AE, except for alopecia, fatigue, or laboratory
abnormalities.
•
Any Grade 3 skin chemotherapy-related AE.
•
Any Grade 3 chemotherapy-related laboratory abnormality, with the following exceptions:
−
Grade 3 lymphopenia does not require a dose delay.
−
Delay if total bilirubin > 1 × ULN or if AST and/or ALT > 1.5 × ULN occurs concomitant
with alkaline phosphatase (ALP) > 2.5 × ULN.
•
Any AE, laboratory abnormality, or inter-current illness which, in the judgment of the
Investigator, warrants omitting the dose of study medication.
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Subsequent dose reductions may be required, per Section 7.4.2.2 (Dose Reductions for Paclitaxel 
Chemotherapy). Granulocyte colony-stimulating factor (G-CSF; ie, filgrastim or pegfilgrastim) or 
human granulocyte-macrophage colony-stimulating factor (GM-CSF) treatment is permitted for 
participants receiving chemotherapy and is required during the AC portion of chemotherapy if 
given as Q2W dose-dense regimen.9,118 Such primary prophylaxis should be administered per the 
ASCO, European Organisation for the Research and Treatment of Cancer (EORTC) or European 
Society for Medical Oncology (ESMO) guidelines, or per local standard practice for all 
participants receiving ddAC chemotherapy. Participants may receive growth factors (including 
G[M]-CSF and erythropoietin) at the discretion of the Investigator, in accordance with institutional 
and/or current ASCO guidelines for secondary prophylaxis.
A dose given more than 3 days after the intended dose date will be considered a dose delay. Longer 
delays may be allowed following discussion with the Medical Monitor (or designee).
7.4.2.2
Dose Reductions for Paclitaxel Chemotherapy
The full dose of paclitaxel is 80 mg/m2. This dose may be reduced by 1 dose level to 65 mg/m2
and subsequently by 1 more dose level to 52 mg/m2. In the case of any toxicity requiring more 
than 2 dose reductions, paclitaxel must be discontinued, unless the participant is benefitting from 
therapy.
Any participant experiencing the following toxicities described below (see Table 7.4.2.2-1) may 
have the paclitaxel dose reduced by 1 dose level for all subsequent cycles.
Table 7.4.2.2-1:
Dose Modifications for Paclitaxel Chemotherapy
Toxicity
Paclitaxel Dose 
Neutrophils ≥1000/mm3 and
platelets ≥100,000/mm3
Maintain dose
Neutrophils 500-999/mm3 and
platelets ≥100,000/mm3
Hold therapy until ANC ≥1000/mm3and resume at same
dose/ may use prophylactic G-CSF or GM-CSF
Grade 4 neutropenia lasting ≥7 days
Prophylactic G-CSF or GM-CSF and/or decrease 1 dose 
level
Febrile neutropenia (≥38.5°C) associated with 
ANC < 1000/mm3
Prophylactic G-CSF or GM-CSF and/or decrease 1 dose 
level
Platelets < 100,000/mm3
Decrease 1 dose level
Neuropathy (sensory or motor), Grade 2 lasting 
≥7 days OR Grade 3 lasting < 7 days
Decrease 1 dose level
Grade 3 neuropathy (sensory or motor) lasting 
≥7 days OR Grade 4 neuropathy (sensory or motor)
Discontinue paclitaxel
≥Grade 3 stomatitis, vomiting, diarrhea
Decrease 1 dose level
Other Grade ≥3 non-hematologic toxicitiesa
Decrease 1 dose level or discontinue therapy as medically 
indicated
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Abbreviations: ANC, absolute neutrophil count; C, Celsius; G-CSF, granulocyte colony-stimulating factor; GM-CSF,  
human granulocyte-macrophage colony-stimulating factor; mm3, cubic millimeters.
a Despite adequate/maximal medical intervention and/or prophylaxis. Except Grade 3 transient fatigue or joint or 
muscle pain, for which no dose modifications are required.
A maximum of 2 dose reductions per chemotherapy are permitted, unless otherwise noted; if
additional reductions are required, that particular study drug must be discontinued. Once a dose
has been decreased, it should remain reduced for all subsequent dosing unless the dose is further
reduced. No dose escalations will be allowed.
7.4.2.3
Criteria to Resume Treatment with Paclitaxel Chemotherapy
Participants may resume treatment with paclitaxel when the drug-related AE(s) resolve(s) to 
Grade ≤ 1 or baseline, with the following exceptions:
•
Participants may resume treatment in the presence of Grade 2 fatigue.
•
Participants who have not experienced a Grade 3 drug-related skin AE may resume treatment 
in the presence of Grade 2 skin toxicity.
•
Participants with decreased neutrophil counts, or with elevations in total bilirubin, AST, or 
ALT must meet criteria for resuming treatment, according to the boxed warning contained 
within the paclitaxel prescribing information.
•
Participants with combined Grade 2 AST/ALT AND total bilirubin values meeting 
discontinuation parameters (Section 8.1.2 [Chemotherapy Dose Discontinuation]) should have 
treatment permanently discontinued.
Participants that meet retreatment criteria for the chemotherapy, but have not yet met retreatment 
criteria for nivolumab or nivolumab placebo, are to receive the chemotherapy alone and delay 
nivolumab or nivolumab placebo (Section 7.4.1.1 Dose Delay Criteria for Nivolumab).
7.4.2.4
Dose Delay for Anthracycline and Cyclophosphamide Chemotherapy
Chemotherapy delay should not exceed 6 weeks. In the event that treatment with chemotherapy 
needs to be delayed beyond 6 weeks due to toxicity, a participant may transition to the Adjuvant 
(Post-surgery) Phase at an earlier timepoint. Such treatment decisions will be at the discretion of 
the Investigator and participant, and upon consultation with the Medical Monitor (or designee).
Participants may only receive a cycle of anthracycline (doxorubicin or epirubicin) and 
cyclophosphamide 
if 
absolute 
neutrophil 
count 
(ANC)
is 
≥
1000/mm3, 
platelets 
are ≥100,000/mm3, and treatment-related non-hematologic toxicity has resolved to baseline or 
Grade 1 (except for Grade 2 alopecia, myalgia, arthralgia, and fatigue, for which resolution is not 
required). Once the dose at the start of a new treatment cycle has been reduced, no re-escalation is 
permitted.
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7.4.2.5
Dose Reductions for Anthracycline-Cyclophosphamide Chemotherapy
The full dose of doxorubicin is 60 mg/m2 and that of cyclophosphamide is 600 mg/m2. Doses of 
anthracycline and cyclophosphamide may be reduced jointly or stopped, depending on the toxicity 
(Table 7.4.2.5-1). Growth factors, such as G-CSF or GM-CSF, may be used at the discretion of 
the Investigators, in accordance with institutional and/or current ASCO guidelines; per such 
guidelines, G-CSF or GM-CSF support is considered SOC for patients undergoing ddAC 
chemotherapy, as primary prophylaxis. However, recurrence of neutropenia despite adequate 
growth factor support would allow dose reduction in addition to growth factor support.
A maximum of 2 AC dose reductions are permitted; if additional reductions are required, that 
particular study drug must be discontinued. Once a dose has been decreased, it should remain 
reduced for all subsequent dosing, unless the dose is further reduced. No dose escalations will be 
allowed.
Participants will receive a maximum of 4 cycles of AC chemotherapy.
Table 7.4.2.5-1:
Dose Levels of AC Chemotherapy
Dose Level
Doxorubicin/Cyclophosphamide
Epirubicin/Cyclophosphamide
1 (full dose)
60/600 mg/m2
90/600 mg/m2
-1
45/450 mg/m2
75/450 mg/m2
-2
33/330 mg/m2
56/330 mg/m2
Abbreviations: m2, squared meter; mg, milligram.
Participants experiencing toxicities described in Table 7.4.2.5-2 during the previous cycle may 
receive colony-stimulating growth factors and/or have the AC doses reduced by 
approximately 20% of the previous dose or discontinue AC, depending on the toxicity.
Table 7.4.2.5-2:
Dose Modifications for AC Chemotherapy
Toxicity
AC
Grade 4 neutropenia lasting ≥7 days
Prophylactic G-CSF or GM-CSF and/or decrease 1 dose 
level
Febrile neutropenia (≥38,3°C) associated with 
ANC < 1000/mm3
Prophylactic G-CSF or GM-CSF and/or decrease 1 dose 
level
Infection with neutropenia ANC < 1000/mm3
Prophylactic G-CSF or GM-CSF and/or decrease 1 dose 
level
Failure of platelets to recover to ≥100,000/mm3 
at next scheduled retreatment
Decrease 1 dose level
Platelets < 50, 000/mm3 with significant bleeding
or requiring blood transfusion
Decrease 1 dose level
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Table 7.4.2.5-2:
Dose Modifications for AC Chemotherapy
Toxicity
AC
Platelets < 25, 000/mm3
Decrease 1 dose level
≥Grade 3 stomatitis, vomiting, diarrhea
Decrease 1 dose level
≥Grade 3 cardiovascular toxicity (eg,
arrhythmias, CHF or Grade ≥3 LVEF)
Discontinue AC and manage the cardiac condition
Other Grade ≥3 non-hematologic toxicitiesa
The treating physician may adjust dose or discontinue 
therapy as medically indicated
Abbreviations: °C, degrees Celsius; AC, anthracycline and cyclophosphamide; ANC, absolute neutrophil count; CHF,
congestive heart failure; G-CSF, granulocyte colony-stimulating factor; GM-CSF, human granulocyte-macrophage 
colony-stimulating factor; LVEF, left ventricular ejection fraction; mm3, cubic millimeters.
a Despite adequate/maximal medical intervention and/or prophylaxis, except Grade 3 transient fatigue or joint or 
muscle pain, for which no dose modifications are required.
If 1 of the study drugs is delayed due to drug-related toxicities during a treatment cycle, the other 
study drugs in the regimen may be administered at the discretion of the Investigator; when dosing 
is resumed, dose reduction should only be applied to the study drug that was withheld.
7.4.2.6
Criteria to Resume Treatment with Anthracycline-Cyclophosphamide
Chemotherapy
Participants may resume treatment with study treatment when the drug-related AE(s) resolve as 
follows:
•
Participants may resume treatment with an anthracycline when the ANC returns to 
≥1000/mm3, the platelet count returns to ≥100,000/mm3, and all other drug-related toxicities 
have returned to baseline or Grade ≤1 (or Grade ≤2 for alopecia and fatigue).
−
If a participant fails to meet criteria for reinitiating treatment, then treatment should be 
delayed, and the participant should be re-evaluated weekly or more frequently, as clinically 
indicated.
•
Participants may resume treatment with cyclophosphamide when the ANC returns to 
≥1500/mm3, the platelet count returns to ≥50,000/mm3, severe infections have improved to 
≤Grade 1, and all other drug-related toxicities have returned to baseline or Grade ≤1 
(or Grade ≤2 for alopecia and fatigue).
−
If a participant fails to meet criteria for reinitiating treatment, then the treatment should be 
delayed and the participant should be re-evaluated weekly or more frequently, as clinically 
indicated.
−
Participants that meet retreatment criteria for the chemotherapy, but have not yet met 
retreatment criteria for nivolumab or nivolumab placebo, are to receive the chemotherapy 
alone and delay nivolumab or nivolumab placebo until the subsequent chemotherapy 
treatment.
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7.4.3
Dose Modifications for Investigator’s Choice Endocrine Therapy
No dose reductions are permitted for the ET (ie, tamoxifen, anastrozole, letrozole, or exemestane). 
Dose delay or interruption may be considered.
Participants who require a dose delay or interruption for ET should be re-evaluated and resume 
treatment when retreatment criteria are met. 
For participants who meet criteria to delay ET (ie, tamoxifen, anastrozole, letrozole, or 
exemestane), the corresponding drug will be delayed but nivolumab may be continued as 
scheduled.
Efforts to maintain the intended treatment schedule are recommended.
7.4.3.1
Dose Delay for Investigator’s Choice Endocrine Therapy
Dose delay or interruption for a period of up to 3 consecutive weeks for ET-related AEs are 
permitted at the discretion of the Investigator.
All possible efforts should be made to maintain the participant on ET during study treatment,
through the use of dose delay, interruption (ie, drug holiday), or rotation to another ET agent.
7.4.3.2
Criteria to Resume Treatment with Investigator’s Choice Endocrine 
Therapy
More detailed information regarding resuming treatment following AEs resulting in dose delay or 
interruption of the individual ET agents may be found in the respective Patient Information 
Leaflets, Package Inserts,61,62,63,64 and SmPCs.70,71,72,73
7.5
Preparation/Handling/Storage/Accountability
The IP should be stored in a secure area according to local regulations. It is the responsibility of 
the Investigator to ensure that IP is only dispensed to study participants. The IP must be dispensed 
only from official study sites by authorized personnel, according to local regulations.
The product storage manager should ensure that the study treatment is stored in accordance with 
the environmental conditions (temperature, light, and humidity) as determined by BMS. 
If concerns regarding the quality or appearance of the study treatment arise, the study treatment
should not be dispensed and BMS should be contacted immediately.
Study treatment not supplied by BMS will be stored in accordance with the package insert.
IP documentation (whether supplied by BMS or not) must be maintained that includes all processes 
required to ensure drug is accurately administered. This includes documentation of drug storage, 
administration, and, as applicable, storage temperatures, reconstitution, and use of required 
processes (eg, required diluents, administration sets).
Further guidance and information for final disposition of unused study treatment are provided in 
Appendix 2.
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7.6
Treatment Compliance
Study treatment compliance will be periodically monitored by drug accountability, as well as the 
ET dosing diary, participant’s medical records and eCRF. Study drug will be administered in the 
clinic by trained personnel. Drug accountability should be reviewed by the site study staff at each 
visit. Sites should discuss discrepancies with the participant at each scheduled visit.
7.7
Concomitant Therapy
Concomitant medications, all forms of premedications, and supportive care are recorded at 
baseline and throughout study Treatment Period and Follow-up Period in the appropriate section 
of the eCRF at each visit.
All medications (prescription and over-the-counter [OTC]), vitamin and mineral supplements, 
and/or herbs taken by the participant, from the Screening Period through the Follow-up Period,
will be documented and recorded, including start and stop date, dose and route of administration, 
frequency, and indication. Medications taken for a procedure (eg, biopsy) should also be included.
ET therapy taken after completion of the Adjuvant (Post-surgery) Phase, will be collected as 
concomitant medication.
Prior anti-cancer treatments will be recorded during the Screening Period and documented on the 
appropriate eCRF. Any subsequent anti-cancer therapy will be recorded until end of study or death, 
in the appropriate section of the eCRF.
7.7.1
Prohibited and/or Restricted Treatments
7.7.1.1
Prohibited and/or Restricted Treatments for Nivolumab
The following medications are prohibited during study treatment (unless utilized to treat a drug-
related AE):
•
Any live/attenuated vaccine (eg, varicella, zoster, yellow fever, rotavirus, oral polio, and
measles, mumps, rubella [MMR]) within 30 days prior to first dose, during treatment and until
100 days after the last dose.
•
Immunosuppressive agents.
•
Immunosuppressive doses of systemic corticosteroids (except as stated in Section 6.2
[Exclusion Criteria]).
•
Any concurrent anti-neoplastic therapy (ie, chemotherapy, CDK4/6 inhibitors, hormonal
therapy, immunotherapy, extensive, non-palliative radiation therapy, or standard or
investigational agents for treatment of BC) not already specified in the protocol.
•
Treatment with complementary medications (eg, herbal supplements, traditional Chinese
medicines) intended to treat the disease under study. Such medications are permitted if they
are used as supportive care.
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7.7.1.2
Prohibited and/or Restricted Treatments for Chemotherapy and 
Endocrine Therapy
The following medications not already specified in the protocol are prohibited and/or restricted 
during the study treatment. Medications taken within 4 weeks prior to study drug administration 
must be recorded on the eCRF.
•
Anticancer agents:
No additional investigational or commercial anticancer agents 
(ie, chemotherapy, CDK4/6 inhibitors, hormonal therapy, immunotherapy, extensive, non-
palliative radiation therapy, radiation therapy in the neoadjuvant setting, or standard or 
investigational agents for treatment of BC) other than those specified in the protocol will be 
permitted during the study treatment. In general, any drugs containing “for the treatment of 
breast cancer” on the product insert are not permitted during the study treatment. Use of 
megestrol acetate as an appetite stimulant is not permitted.
•
Investigational agents: Exposure to any investigational drug or placebo within 4 weeks of 
prior study drug administration or during the study treatment.
•
Hormonal agents: Concurrent use of an oral, injectable, or implantable hormonal 
contraceptive agent.
•
OTC Agents: No concomitant medications (prescription, OTC, or herbal) are to be 
administered during the study treatment, unless they are prescribed for treatment of specific 
clinical events. Any concomitant therapies must be recorded on the eCRF.
•
Other prohibited and/or restricted treatments:
−
Co-administration of letrozole, anastrozole, or exemestane with other anti-estrogens or 
estrogens should be avoided.
−
Co-administration of tamoxifen with potent cytochrome p-450 (CYP)2D6 inhibitors 
(eg, paroxetine, fluoxetine, quinidine, cinacalcet, bupropion) should be avoided.
−
Co-administration of paclitaxel with known inducers of either CYP2C8 or CYP3A4 
(eg, rifampicin, carbamazepine, phenytoin, efavirenz, nevirapine) is not recommended.
−
Stop cimetidine during treatment with epirubicin.
−
Neither doxorubicin nor epirubicin should be administered with other cardiotoxic agents 
or other cardioactive compounds (eg, calcium channel blockers), unless the participant’s
cardiac function is closely monitored.
−
Cyclophosphamide is inactive, but is metabolised in the liver, mainly by CYP2A6, 2B6, 
2C9, 2C19 and 3A4, into two active metabolites. Planned co-administration or sequential 
administration of other substances or treatments with cyclophosphamide that could 
increase the likelihood or severity of toxic effects (by means of pharmacodynamic or 
pharmacokinetic interactions) requires careful individual assessment of the expected 
benefit and the risks (eg, CYP2B6 inducers such as rifampicin, efavirenz and nevirapine; 
CYP2C9 inducers such as carbamazepine, and rifampicin, and CYP3A4 inhibitors such as 
ketoconazole, clarithromycin, itraconazole, ritonavir, nelfinavir, and saquinavir).
−
Vaccination with a live vaccine should be avoided in participants receiving doxorubicin or 
epirubicin.
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Additional information regarding prohibited and/or restricted medications may be found in the 
respective Patient Information Leaflets, Package Inserts,56,57,58,59,60 Development Safety Update 
Report, or SmPCs.65,66,67,68,69
7.7.2
Other Restrictions and Precautions
Participants with a condition requiring systemic treatment with either corticosteroids (> 10 mg 
daily prednisone equivalent) or other immunosuppressive medications within 14 days of 
randomization/study treatment are excluded. Inhaled or topical steroids, and adrenal replacement 
steroid doses > 10 mg daily prednisone equivalent, are permitted in the absence of active 
autoimmune disease.
Additional information about the known restrictions, precautions, and/or contraindications of 
study treatments may be found in the respective IBs, Patient Information Leaflets, Package 
Inserts,56,57,58,59,60 Development Safety Update Report, or SmPCs.65,66,67,68,69
7.7.2.1
Imaging Restriction and Precautions
It is the local imaging facility’s responsibility to determine, based on participant attributes 
(eg, allergy history, diabetic history, and renal status), the appropriate imaging modality and 
contrast regimen per imaging study. Imaging contraindications and contrast risks are to be 
considered in this assessment. Participants with renal insufficiency are to be assessed as to whether 
or not they should receive contrast and, if so, which contrast agent and dose is appropriate. Specific 
to magnetic resonance imaging (MRI), participants with severe renal insufficiency (ie, estimated 
glomerular filtration rate [eGFR] < 30 mL/min/1.73 m2) are at increased risk of nephrogenic 
systemic fibrosis; therefore, MRI contrast is contraindicated. In addition, participants may be 
excluded from MRI if they have tattoos, metallic implants, pacemakers, etc. This will be outlined 
in the Imaging Manual.
Gentle hydration before and after IV contrast should follow local SOC. The ultimate decision to 
perform MRI in an individual participant in this study rests with the site radiologist, the 
Investigator, and standards set by the local IEC.
7.7.3
Permitted Therapy
Participants are permitted the use of topical, ocular, intra-articular, intranasal, and inhalational 
corticosteroids (with minimal systemic absorption). Adrenal replacement steroid doses > 10 mg 
daily prednisone are permitted. A brief (less-than-3-weeks) course of corticosteroids for 
prophylaxis (eg, contrast dye allergy) or for treatment of non-autoimmune conditions 
(eg, delayed-type hypersensitivity reaction caused by a contact allergen) is permitted.
Participants receiving the dose-dense administration of AC must receive G-CSF or GM-CSF
prophylaxis per international guidelines. In addition, men and premenopausal women may receive 
concurrent luteinizing hormone-releasing hormone (LHRH) agonist using an approved dose or as 
per local standard for these agents. Participants may receive a bisphosphonate using an approved 
dose or as per local standard for these agents.119,120
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7.8
Treatment After the End of the Study
At the end of the study, BMS will not continue to provide BMS-supplied study treatment to 
participants/Investigators, unless BMS chooses to extend the study. The Investigator should ensure 
that the participant receives appropriate SOC to treat the condition under study.
BMS reserves the right to terminate access to BMS-supplied study treatment if any of the following 
occur:
•
The study is terminated due to safety concerns.
•
The development of nivolumab is terminated for other reasons, including, but not limited to,
lack of efficacy and/or not meeting the study objectives.
•
The participant can obtain medication from a government-sponsored or private health program.
In all cases, BMS will follow local regulations.
8
DISCONTINUATION CRITERIA
Reasons for discontinuation of treatment or from the study are given below. Participants are 
expected to complete 8 cycles of neoadjuvant therapy, undergo definitive surgery, and complete 
7 cycles of adjuvant therapy, except in the event of disease progression that precludes definitive 
surgery, local or distant recurrence, second primary malignancy, death, unacceptable toxicity,
symptomatic deterioration, Investigator’s decision to discontinue treatment, start of subsequent 
cancer treatment, the participant’s decision to discontinue treatment or withdraw consent, the 
participant being lost to follow-up, or if the Sponsor terminates the study.
8.1
Discontinuation from Study Treatment
Participants MUST discontinue IP (and non-IP at the discretion of the Investigator) for any of the 
following reasons:
•
Participant’s request to stop study treatment. Participants who request to discontinue study
treatment will remain in the study and must continue to be followed for protocol-specified
follow-up procedures. The only exception to this is when a participant specifically withdraws
consent for any further contact with him/her or persons previously authorized by the participant
to provide this information (see Section 8.2 [Discontinuation from the Study]).
•
Any clinical AE, laboratory abnormality, or intercurrent illness which, in the opinion of the
Investigator, indicates that continued participation in the study is not in the best interest of the
participant.
•
Termination of the study by BMS.
•
Loss of ability to freely provide consent through imprisonment or involuntarily incarceration
for treatment of either a psychiatric or physical (eg, infectious disease) illness. (Note: Under
specific circumstances, and only in countries where local regulations permit, a participant who
has been imprisoned may be permitted to continue as a participant. Strict conditions apply and
BMS approval is required.)
•
In the case of pregnancy, the Investigator must immediately, within 24 hours of awareness of
the pregnancy, notify the Medical Monitor (or designee) of this event. In most cases, the study
treatment will be permanently discontinued in an appropriate manner (eg, dose tapering if
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necessary for participant safety). See Section 9.2.6 (Pregnancy). For additional details on 
country specific requirements, refer to Appendix 9. 
•
Occurrence of an EFS event. See Section 9.1.2 (Definition of Event-free Survival) for details.
•
Disease progression. See Section 9.1.2 (Definition of Event-free Survival) for details.
•
See Section 8.1.1 for Nivolumab Discontinuation criteria.
•
Start of subsequent cancer treatment, including abemaciclib, during the Adjuvant phase.
•
Emergency unblinding prior to the Adjuvant phase.
All participants who discontinue study treatment should comply with protocol-specified
procedures, as outlined in Section 2 (Schedule of Activities) and Section 7 (Treatment). The only 
exception to this requirement is when a participant withdraws consent for all study procedures (see 
Section 8.2 [Discontinuation from the Study]), including post-treatment study follow-up, or loses 
the ability to consent freely (ie, is imprisoned or involuntarily incarcerated for the treatment of 
either a psychiatric or physical illness).
If study treatment is discontinued prior to the participant’s completion of the study, the reason for 
the discontinuation must be documented in the participant’s medical records and entered on the 
appropriate eCRF page.
8.1.1
Nivolumab Dose Discontinuation
Nivolumab treatment should be permanently discontinued if meets criteria for discontinuation in 
Table 7.4.1-1.
•
Any event that leads to delay in dosing lasting > 8 weeks with the Q3W schedule or > 6 weeks 
with the Q2W schedule in the Neoadjuvant (Pre-surgery) Phase, or > 10 weeks with the Q4W 
schedule
in the Adjuvant (Post-surgery) Phase,
from the previous dose requires 
discontinuation, with the following exceptions:
−
Dosing delays to allow for prolonged steroid tapers to manage drug-related AEs are 
allowed.
−
Dosing delays lasting > 8 weeks with the Q3W schedule, > 6 weeks with the Q2W 
schedule, or > 10 weeks with the Q4W schedule from the previous dose that occur for 
non-drug-related reasons may be allowed if approved by the Medical Monitor 
(or designee).
♦Prior to re-initiating treatment in a participant with a dosing delay lasting > 8 weeks
with the Q3W schedule, > 6 weeks with the Q2W schedule, or > 10 weeks with the 
Q4W schedule, the Medical Monitor (or designee) must be consulted.
♦Tumor assessments should continue per protocol, even if dosing is delayed. Periodic 
study visits to assess safety and laboratory studies should also continue every 6 weeks,
or more frequently if clinically indicated during such dosing delays.
•
Any AE, laboratory abnormality, or intercurrent illness that, in the judgment of the 
Investigator, presents a substantial clinical risk to the participant with continued nivolumab 
dosing.
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•
The underlying reason(s) for any instance of study treatment discontinuation should be
documented in the eCRF.
8.1.2
Chemotherapy Dose Discontinuation
If unacceptable toxicities related to paclitaxel occur, as determined by Investigator judgment and 
in accordance with the prescribing information, paclitaxel may be discontinued, but other study 
treatments may be continued. For example, a participant may continue on study to receive 
neoadjuvant AC study treatment at an earlier timepoint, or may transition to the Adjuvant 
(Post-surgery) Phase at an earlier timepoint. Such treatment decisions will be at the discretion of 
the Investigator and participant, and upon consultation with the Sponsor’s Medical Monitor 
(or designee).
If unacceptable toxicities related to doxorubicin or epirubicin and/or cyclophosphamide occur, as 
determined by Investigator judgment and in accordance with the prescribing information, 
doxorubicin or epirubicin and/or cyclophosphamide may be discontinued, but other study 
treatments may be continued. For example, a participant may transition to the Adjuvant 
(Post-surgery) Phase at an earlier timepoint. Such treatment decisions will be at the discretion of 
the Investigator and participant, and upon consultation with the Sponsor’s Medical Monitor 
(or designee).
The underlying reason(s) for any instance of study treatment discontinuation should be 
documented in the eCRF.
8.1.3
Endocrine Therapy Dose Discontinuation
If unacceptable toxicities related to the Investigator’s choice of ET occur, as determined by 
Investigator judgment and in accordance with the prescribing information, the Investigator’s 
choice of ET may be discontinued, but the other study treatments may be continued.
The underlying reason(s) for any instance of study treatment discontinuation should be 
documented in the eCRF.
8.1.4
Post-study Treatment Study Follow-up
In this study, pCR is a key endpoint of the study. Post-study follow-up is of critical importance 
and is essential to preserving participant safety and the integrity of the study. Participants who 
discontinue study treatment must continue to be followed (in this study or a rollover study) for 
collection of outcome and/or survival follow-up data, as required and in line with Section 5 (Study 
Design) and Section 8.1 (Discontinuation from Study Treatment), until death or the conclusion of 
the study.
8.2
Discontinuation from the Study
Participants who request to discontinue study treatment will remain in the study and must continue 
to be followed for protocol-specified follow-up procedures. The only exception to this is when a 
participant specifically withdraws consent for any further contact with him/her or persons 
previously authorized by participant to provide this information.
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•
Participants should notify the Investigator of the decision to withdraw consent from future
follow-up in writing, whenever possible.
•
The withdrawal of consent should be explained in detail in the medical records by the
Investigator, as to whether the withdrawal is from further treatment with study treatment only
or also from study procedures and/or post treatment study follow-up, and entered on the
appropriate eCRF page.
•
In the event that vital status (whether the participant is alive or dead) is being measured,
publicly available information should be used to determine vital status only as appropriately
directed in accordance with local law.
•
If the participant withdraws consent for disclosure of future information, the Sponsor may
retain and continue to use any data collected before such a withdrawal of consent.
8.3
Lost to Follow-up
•
All reasonable efforts must be made to locate participants to determine and report their ongoing
status. This includes follow-up with persons authorized by the participant.
•
Lost to follow-up is defined by the inability to reach the participant after a minimum of three
documented phone calls, faxes, or emails, as well as lack of response by the participant to one
registered mail letter. All attempts should be documented in the participant’s medical records.
•
If it is determined that the participant has died, the site will use permissible local methods to
obtain the date and cause of death.
•
If the Investigator’s use of third-party representative to assist in the follow-up portion of the
study has been included in the participant’s informed consent, then the Investigator may use a
Sponsor-retained third-party representative to assist site staff with obtaining the participant’s
contact information or other public vital status data necessary to complete the follow-up
portion of the study.
•
The site staff and representative will consult publicly available sources, such as public health
registries and databases, in order to obtain updated contact information.
•
If after all attempts, the participant remains lost to follow-up, then the last known alive date as
determined by the Investigator should be reported and documented in the participant’s medical
records.
9
STUDY ASSESSMENTS AND PROCEDURES
•
Study procedures and timing are summarized in the Schedule of Activities (Section 2).
•
Protocol waivers or exemptions are not allowed.
•
All immediate safety concerns must be discussed with the Sponsor immediately upon
occurrence or awareness to determine if the participant should continue or discontinue
treatment.
•
Adherence to the study design requirements, including those specified in the Schedule of
Activities (Section 2), is essential and required for study conduct.
•
All screening evaluations must be completed and reviewed to confirm that potential
participants meet all eligibility criteria before randomization. The Investigator will maintain a
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screening log to record details of all participants screened and to confirm eligibility or record 
reasons for screening failure, as applicable.
•
Procedures conducted as part of a participant’s routine clinical management (eg, blood count)
and obtained before signing of informed consent may be utilized for screening or baseline
purposes, provided the procedure meets the protocol-defined criteria and has been performed
within the timeframe defined in the Schedule of Activities (Section 2).
Additional measures, including non-study-required laboratory tests, should be performed as 
clinically indicated or to comply with local regulations. Laboratory toxicities (eg, suspected 
drug-induced liver enzyme evaluations) will be monitored during the Follow-up Period via 
on-site/local laboratories, until all study drug-related toxicities resolve, return to baseline, or are 
deemed irreversible.
If a participant shows cardiac or pulmonary-related signs (hypoxia, abnormal heart rate or changes 
from baseline) or symptoms (eg, dyspnea, cough, chest pain, fatigue, palpitations), the participant 
should be immediately evaluated to rule out cardiac or pulmonary toxicity.
Some of the assessments referred to in this section may not be captured as data on the eCRF. They 
are intended to be used as safety monitoring by the treating physician. Additional testing or 
assessments may be performed as clinically necessary or where required by institutional or local 
regulations.
9.1
Efficacy Assessments
9.1.1
Pathological Assessment of Effect
9.1.1.1
Pathological Complete Response Determination
The determination of pCR will be performed by the local pathologist following examination of 
tissue (breast and nodes) removed at the time of surgery.
Criteria for evaluation of pCR includes the following:
•
pCR in breast and axillary lymph nodes as well as non-axillary sentinel node (pCR breast and
nodes).
•
No histologic evidence of invasive tumor cells in the surgical breast specimen or axillary nodes
after neoadjuvant treatment.
•
pCR in the breast (pCR breast).
Tumor and lymph node collection from definitive surgical resection is mandatory on the day of 
surgery. Tumor sample acquisition guidelines and submission process will be outlined in the study 
Laboratory Manual. Additional details are provided in the Pathology Manual.
9.1.1.2
Residual Cancer Burden Determination
Residual cancer burden (RCB) is estimated from routine pathologic sections of the primary breast 
tumor site and the regional lymph nodes after the completion of neoadjuvant therapy.121
Six variables are included in a calculation formula.
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Local RCB will be assessed from routine pathologic sections of the primary breast tumor site and 
the regional lymph nodes right after surgery 
. Five variables are included in a 
calculation formula, which include the following:
•
The primary tumor bed area in its 2 dimensions. For multifocal tumors (defined as the presence
of 2 or more foci of cancer within the same breast quadrant), the largest lesion must be ≥ 2 cm
and designated as the “target” lesion for the RCB determination.
•
The overall cancer cellularity (percentage of area).
•
The proportion of in situ disease (percentage of area).
•
The number of positive lymph nodes.
•
The diameter of the largest lymph node metastasis.
The calculated RCB index value can also be categorized as 1 of 4 RCB classes. The calculation 
formula 
and 
detailed 
description 
can 
be 
found 
at 
a 
dedicated 
website: 
http://www.mdanderson.org/breastcancer_RCB. The 4 RCB classes are the following:
1) RCB-0: no residual disease
2) RCB-I: minimal residual disease
3) RCB-II: moderate residual disease
4) RCB-III: extensive residual disease
Detailed procedures are provided in the Pathology Manual.
9.1.2
Definition of Event-free Survival
EFS is defined as the time from randomization to disease progression that precludes definitive 
surgery, results in a local or distant recurrence, results in a second primary malignancy, or results 
in death due to any cause.
The diagnosis of a BC recurrence or second primary tumor should be confirmed histologically 
whenever clinically feasible. In cases where confirmation is not feasible, efforts should be made 
to obtain an autopsy report.
With respect to timing of an EFS event, the earliest date of diagnosis of recurrent disease should 
be used and recorded. This date should be based on objective clinical, radiological, histological, 
or cytological evidence. The recurrence of disease should correspond to the date of the first 
diagnosis of lesion (ie, an objective finding), and not to the date of occurrence of the first symptom
(eg, a participant presenting with shortness of breath is found to have possible lesions in the lungs 
on thorax CT scan of uncertain significance). If a subsequent CT scan confirms disease 
progression, the date of the first diagnostic CT scan should be taken as the date of recurrence, and 
not the date of presentation with shortness of breath. The date of disease relapse is the time of first 
appearance of a suspicious lesion (in a radiological procedure in this example), later proven to be 
a definitive recurrence or metastasis.
Details on EFS events are provided below:
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•
Worsening of disease that precludes surgery (as determined by the Investigator).
•
If surgery is possible but not performed for other reasons (eg, participant refuses, worsening
of medical condition), then the participant may continue on study treatment and will be
considered to have an EFS event if and when there is defined progression or biopsy confirmed
local recurrence.
•
If surgery is attempted but gross resection is abandoned, due to unresectable tumor or
worsening of disease, then that will be considered an EFS event.
•
If surgery is completed with no or only microscopic residual disease (positive margins, not
visible on imaging), then the participant will continue on study and will be considered to have
an EFS event if and when radiographically visible recurrence occurs.
•
If surgery is completed after the development of distant disease (visible on imaging) or
in-transit disease, it will be considered as an EFS event.
•
Local recurrence
−
Local relapse: Defined as the area bound by the midline of the sternum, extending
superiorly to the clavicle and inferiorly to the costal margin. Soft tissue recurrences in this
area extending into the bony chest wall or extending across the midline will be considered
as evidence of local recurrence. Provide histologic or cytological confirmation if clinically
feasible.
−
Regional relapse: Defined as evidence of tumor in the axillary scar, ipsilateral nodal areas
(axillary, internal mammary, supraclavicular), extra-nodal soft tissue of the ipsilateral
axilla, as well as skin or soft tissues within the regional area. Provide histologic,
cytological, or radiologic confirmation if clinically feasible.
−
Contralateral BC: Defined as invasive tumor in the contralateral breast.
•
Distant recurrence
−
Distant relapse: Defined as evidence of tumor beyond the local-regional level, as
previously defined. This includes the following: lymph nodes not included in the areas
defined above (ie, contralateral supraclavicular, contralateral axilla, paratracheal); skin not
included in the areas defined above; liver; lung; bone; central nervous system; other sites
not defined above. Provide histologic or cytological confirmation if clinically feasible.
•
Development of a second non-breast primary cancer
−
Defined as any other histopathologically proven invasive cancer. Excluded are
non-melanoma skin cancer, in situ carcinoma of the cervix, in situ carcinoma of the breast
(LCIS/DCIS), and ipsilateral invasive primary BC with the same histologic features of the
first tumor. Provide histologic or cytological confirmation if clinically feasible.
•
Death due to any cause.
9.1.3
Definition of Disease-free Survival
DFS is defined as the time after surgery to disease progression that results in a local or distant 
recurrence, results in a second primary malignancy, or results in death due to any cause. Details 
on DFS events are provided below:
•
Local recurrence
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−
Local relapse: Defined as the area bound by the midline of the sternum, extending 
superiorly to the clavicle and inferiorly to the costal margin. Soft tissue recurrences in this 
area extending into the bony chest wall or extending across the midline will be considered 
as evidence of local recurrence. Provide histologic or cytological confirmation if clinically 
feasible.
−
Regional relapse: Defined as evidence of tumor in the axillary scar, ipsilateral nodal areas 
(axillary, internal mammary, supraclavicular), extra-nodal soft tissue of the ipsilateral 
axilla, as well as skin or soft tissues within the regional area. Provide histologic,
cytological, or radiologic confirmation if clinically feasible.
−
Contralateral BC: Defined as invasive tumor in the contralateral breast.
•
Distant recurrence
−
Distant relapse: Defined as evidence of tumor beyond the local-regional level, as 
previously defined. This includes the following: lymph nodes not included in the areas 
defined above (ie, contralateral supraclavicular, contralateral axilla, paratracheal); skin not 
included in the areas defined above; liver; lung; bone; central nervous system; other sites 
not defined above. Provide histologic or cytological confirmation if clinically feasible.
•
Development of a second non-breast primary cancer
−
Defined as any other histopathologically proven invasive cancer. Excluded are 
non-melanoma skin cancer, in situ carcinoma of the cervix, in situ carcinoma of the breast 
(LCIS/DCIS), and ipsilateral invasive primary BC with the same histologic features of the 
first tumor.
•
Death due to any cause.
9.1.4
Definition of Distant Metastasis-free Survival
Distant metastasis-free survival (DMFS) is defined as the time from randomization to disease 
progression that results in a distant recurrence. Details on DMFS events are provided below:
•
Distant recurrence
−
Distant relapse: Defined as evidence of tumor beyond the local-regional level as previously 
defined. This includes the following: lymph nodes not included in the areas defined above 
(ie, contralateral supraclavicular, contralateral axilla, paratracheal); skin not included in the 
areas defined above; liver; lung; bone; central nervous system; other sites not defined 
above. Provide histologic or cytological confirmation if clinically feasible.
9.1.5
Imaging Assessment for the Study
Screening and on-study images should be acquired as outlined in Section 2 (Schedule of 
Activities)
Radiological response for progression or local or distant recurrence will be assessed by the 
Investigator.
Images will also be submitted to a central imaging vendor and may undergo blinded independent 
central review (BICR) at any time during the study until the EFS event is documented. Prior to 
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scanning the first participant, sites should be qualified and understand the image acquisition 
guidelines and submission process, as outlined in the Imaging Manual provided by the central 
imaging vendor.
Tumor assessments at other timepoints may be performed if clinically indicated, and should be 
submitted to the central imaging vendor as soon as possible. X-rays that clearly demonstrate 
interval progression of disease (eg, most commonly as unequivocal lesions that are unmistakably 
new) should be submitted to the central imaging vendor; otherwise, radiographs do not need to be 
submitted centrally. Any additional imaging that may demonstrate tumor response or disease 
recurrence or disease progression (including scans performed at unscheduled timepoints and/or at 
an outside institution) should be submitted to the central imaging vendor.
Every attempt should be made to image each participant using an identical acquisition protocol on 
the same scanner for all imaging timepoints. Tumor assessments for all participants should 
continue per protocol, even if dosing is delayed or discontinued. Tumor measurements should be 
made by the same Investigator or radiologist for each assessment, whenever possible. Change in 
tumor measurements and tumor response to guide ongoing study treatment decisions will be 
assessed by the Investigator using the modified RECIST v1.1 criteria (refer to Appendix 8).
9.1.5.1
Objective Response Rate
ORR will be assessed by imaging at the end of the neoadjuvant treatment prior to Surgery.
For the purposes of this study, tumor response assessments will be performed by bilateral 
ultrasound or mammogram of breast and axilla or breast MRI. Changes in tumor measurements 
and tumor responses will be assessed by the same Investigator or designee. The timepoint of tumor 
assessments will be reported on the eCRF based on the Investigator’s assessment.
Assessments of partial response and complete response do not require confirmation. A best 
objective response of stable disease requires a minimum of 42 days on study from randomization 
to the date of the follow-up imaging assessment.
9.1.6
Clinical Response by Physical Examination
Clinical response by physical examination (PE; palpation) will be assessed throughout study visits
as outlined in Section 2 (Schedule of Activities).
Target lesions should be followed clinically and their clinical size recorded at baseline. 
Measurements are required at the completion of the PTX neoadjuvant cycles and at the completion 
of the Neoadjuvant Phase prior to Surgery. In situ carcinoma does not represent a non-target lesion 
and should not be recorded or followed.
9.1.7
Breast-conserving Surgery Rate
BCS rate is defined as the number of participants who undergo BCS after completing the study 
treatments divided by the number of randomized participants for each treatment group.
For this study, planned surgery (mastectomy or BCS) at the time of diagnosis or baseline and the 
actual surgery the participants undergo after completion of the study treatment will be captured on 
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the eCRF, to assess BCS rate with neoadjuvant chemotherapy with or without nivolumab in 
participants with untreated high-risk ER+, HER2- primary BC.
9.1.8
Clinical Outcomes Assessments
The evaluation of COAs is an increasingly important aspect of clinical efficacy in oncology trials. 
Such data provide an understanding of the impact of treatment from the participant’s perspective 
and offer insights into patient experience that may not be captured through physician reporting. 
Additionally, generic health-related quality of life (HRQOL) measures provide data needed for 
calculating utility values to inform health economic models.
Participants will be asked to complete the EORTC Quality of Life Questionnaire–Core 30 
(QLQ-C30), EORTC Quality of Life Questionnaire-Breast Cancer-specific Module (QLQ-BR23), 
5-level EQ-5D (EQ-5D-5L) questionnaires and selected items Functional Assessment of Chronic
Illness Therapy General Physical Item 5 (FACIT GP5) as indicated in Section 2 (Schedule of
Activities). The questionnaires will be provided in the participant’s preferred language, if
available, and may be administered using electronic devices or a web-based platform. At sites,
where the electronic device is not available at study start or where the language is not yet available
in the device, paper administration of questionnaires will be permitted. When the electronic device
and/or language becomes available at those sites, paper administration of the questionnaires will
no longer be allowed. If exceptional circumstances preclude the continued administration of
measures using planned modalities, then alternative administration methods may be required after
consultation with Sponsor or the Sponsor’s representative.
The questionnaires should be administered during the Neoadjuvant (Pre-surgery) Phase, at the pre-
surgery visit, at the post-surgery visit, during the Adjuvant (Post-surgery) Phase, and at the end of 
adjuvant therapy at the start of any visit before the participant sees the physician and before any 
study-related procedures are performed (with the exception of procedures completed 72 hours 
prior to a visit). Section 2 (Schedule of Activities) provides information regarding the timing of 
COAs.
9.1.8.1
EORTC QLQ-C30
The EORTC QLQ-C30 will be used to assess the effects of disease symptoms on functioning and 
well-being. The EORTC QLQ-C30122 is the most commonly used QOL instrument in oncology 
trials. The instrument’s 30 items are divided among 5 functional scales (physical, role, cognitive, 
emotional, and social), 9 symptom scales (fatigue, pain, nausea/vomiting, dyspnea, insomnia, 
appetite loss, constipation, diarrhea, and financial difficulties), and a global health/QOL scale. 
With the exception of 2 items included in the global health/QOL scale, for which responses range 
from 1 (very poor) to 7 (excellent), item responses range from 1 (not at all) to 4 (very much). 
Raw scores for the EORTC QLQ-C30 are transformed to a 0-100 metric, such that higher values 
indicate better functioning or QOL or a higher level of symptoms. A score difference of 10 will be 
used as an estimate of a clinically meaningful difference for the subscales of the 
EORTC QLQ-C30.123
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9.1.8.2
EORTC QLQ-BR23
The EORTC QLQ-BR23124 will be used to assess symptoms and QOL domains specific to a BC
patient population. It is a valid and reliable measure of concerns and symptoms specific to BC and 
its treatment. The questionnaire’s 23 items are divided among multi-item scales measuring 
systemic therapy side effects (7 items), bodily image (4 items), breast symptoms (4 items), arm 
symptoms (3 items), and sexual functioning (2 items), as well as single-item measures of sexual 
enjoyment, future perspective, and bother due to hair loss. The questionnaire’s items use a 4-point 
response scale ranging from 1 (Not at all) to 4 (Very much). Similar to the EORTC QLQ-C30, 
raw scores for the EORTC QLQ-BR23 are transformed to a 0-100 metric, such that higher values 
indicate better functioning or QOL or a higher level of symptoms. A score difference of 10 will be 
used as an estimate of a clinically meaningful difference
for the subscales of the 
EORTC QLQ-BR23.
9.1.8.3
FACIT GP5
A single item drawn from the FACIT measurement system, item GP5, will be administered to 
assess the overall extent of perceived bother due to symptomatic AEs. Evidence exists for the 
validity of this item and its usefulness as an overall summary measure of burden due to 
symptomatic treatment toxicities.125
9.1.8.4
EQ-5D-5L
Participants’ reports of general health status will be assessed using the 5-level EQ-5D (EQ-5D-
5L) questionnaire. The EQ-5D-5L has 2 components: a descriptive system and a visual analogue 
scale (VAS). The instrument’s descriptive system consists of 5 dimensions: mobility, self-care, 
usual activities, pain/discomfort, and anxiety/depression. Each dimension describes 5 levels of 
problems, including “no,” “slight,” “moderate,” “severe,” and “extreme” or “unable to.” A 
dimension for which there are no problems is said to be at level 1, while a dimension for which 
there are extreme problems is said to be at level 5. Thus, the numbers 11111 and 55555 represent 
the best health state and the worst health state, respectively, described by the EQ-5D-5L. 
Altogether, the instrument describes 55 = 3,125 health states. Empirically derived weights can be 
applied to an individual’s responses to the EQ-5D-5L to generate a utility index measuring the 
value to society of his or her current health. In addition, the EQ-5D-5L a VAS allows respondents 
to rate their own current health on a 101-point scale ranging from 0 = ”worst imaginable” to 
100 = “best imaginable.” In oncology applications, post-baseline score changes 7 for the VAS are 
considered to be clinically meaningful.
9.2
Adverse Events
The definitions of an AE or SAE can be found in Appendix 3.
AEs will be reported by the participant (or, when appropriate, by a caregiver, surrogate, or the 
participant's legally authorized representative).
The Investigator and any designees are responsible for detecting, documenting, and reporting 
events that meet the definition of an AE or SAE and remain responsible for following up AEs that 
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are serious, considered related to the study treatment or the study, or that caused the participant to 
discontinue before completing the study.
Contacts for SAE reporting specified in Appendix 3.
9.2.1
Immune-mediated Adverse Events
IMAEs are AEs consistent with an immune-mediated mechanism or immune-mediated component 
for which non-inflammatory etiologies (eg, infection, tumor progression) have been ruled out. 
IMAEs can include events with an alternate etiology that were exacerbated by the induction of 
autoimmunity. Information supporting the assessment will be collected on the participant’s eCRF.
9.2.2
Time Period and Frequency for Collecting AE and SAE Information
All non-serious AEs (not only those deemed to be treatment-related) should be collected 
continuously during the treatment period and for a minimum of 100 days following discontinuation 
of study treatment.
Sections 5.6.1 and 5.6.2 in the IB represent the Reference Safety Information to determine 
expectedness of SAEs for expedited reporting.
All SAEs must be collected from the time of signing the consent, including those thought to be 
associated with protocol-specified procedures and for a minimum of 100 days of discontinuation 
of dosing. For participants randomized/assigned to treatment and never treated with study drug, 
SAEs should be collected for 30 days from the date of randomization.
All AEs of special interest (SAE or nonserious AE) as described in Section 9.2.1
(Immune-mediated Adverse Events) must be collected throughout the Long-term Follow-up (until
the end of the study).
All AEs (SAE or non-serious AE) related to the protocol-specified definitive breast cancer surgery 
should be collected continuously during the treatment period and for a minimum of 100 days 
following discontinuation of study treatment.
The Investigator must report any SAE that occurs after these time periods and that is believed to 
be related to study drug or protocol-specified procedure (eg, a follow-up skin biopsy).
•
Medical occurrences that begin before the start of study treatment but after obtaining informed 
consent will be recorded on the appropriate section of the CRF module.
•
All SAEs will be recorded and reported to the Sponsor or designee within 24 hours, as indicated 
in Appendix 3.
•
The Investigator will submit any updated SAE data to the Sponsor or designee within 24 hours
of the updated information being available.
All SAEs, and all AEs (SAEs and non-serious AEs) associated with confirmed or suspected SARS-
CoV-2 infection must be collected from the date of the participant’s written consent until 100 days 
following discontinuation of dosing.
Investigators are not obligated to actively seek AEs or SAEs in former study participants. 
However, if the Investigator learns of any SAE, including a death, at any time after a participant 
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has been discharged from the study, and he/she considers the event reasonably related to the study 
treatment or study participation, the Investigator must promptly notify the Sponsor.
The method of evaluating and assessing causality of AEs and SAEs and the procedures for 
completing and reporting/transmitting SAE reports are provided in Appendix 3.
9.2.3
Method of Detecting AEs and SAEs
AEs can be spontaneously reported or elicited during open-ended questioning, examination, or 
evaluation of a participant. Care should be taken not to introduce bias when collecting AEs and/or 
SAEs. Inquiry about specific AEs should be guided by clinical judgement in the context of known 
AEs, when appropriate for the program or protocol.
Every AE must be assessed by the Investigator with regard to whether it is considered 
immune-mediated. For events that are potentially immune-mediated, additional information will 
be collected on the participant’s eCRF.
9.2.4
Follow-up of AEs and SAEs
•
Nonserious AEs should be followed to resolution or stabilization, or reported as SAEs if they
become serious (see Appendix 3).
•
Follow-up is also required for nonserious AEs that cause interruption or discontinuation of
study treatment and for those present at the end of study treatment, as appropriate.
•
All identified nonserious AEs must be recorded and described on the nonserious AE page of
the case report form (CRF; paper or electronic). Completion of supplemental CRFs may be
requested for AEs and/or laboratory abnormalities that are reported/identified during the course
of the study.
After the initial AE/SAE report, the Investigator is required to proactively follow each participant 
at subsequent visits/contacts. All SAEs and nonserious AEs of special interest (as defined in 
Section 9.2.1 [Immune-mediated Adverse Events]) and AEs (SAEs and non-serious AEs) associated 
with confirmed or suspected SARS-CoV-2 infection will be followed until resolution, the condition 
stabilizes, the event is otherwise explained, the event is deemed irreversible, or the participant is 
lost to follow-up (as defined in Section 8.3 [Lost to Follow-up]) or for suspected cases, until SARS-
CoV-2 infection is ruled out.
Further information on follow-up procedures is given in Appendix 3.
9.2.5
Regulatory Reporting Requirements for SAEs
•
Prompt notification by the Investigator to the Sponsor of SAEs is essential so that legal
obligations and ethical responsibilities towards the safety of participants and the safety of a
product under clinical investigation are met.
•
An Investigator who receives an Investigator safety report describing SAEs or other specific
safety information (eg, summary or listing of SAEs) from the Sponsor will file it along with
the IB and will notify the IRB/IEC, if appropriate according to local requirements.
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The Sponsor or designee will be reporting AEs to regulatory authorities and IECs, according to 
local applicable laws including European Directive 2001/20/EC and FDA Code of Federal 
Regulations 21 CFR Parts 312 and 320. A suspected, unexpected serious adverse reaction
(SUSAR) is a subset of SAEs and will be reported to the appropriate regulatory authorities and 
Investigators, following local and global guidelines and requirements.
9.2.6
Pregnancy
If, following initiation of the study treatment, it is subsequently discovered that a participant is 
pregnant or may have been pregnant at the time of study exposure, including during at least 
5 half-lives after product administration, the Investigator must immediately notify the BMS 
Medical Monitor/designee of this event and complete and forward a Pregnancy Surveillance Form 
to the BMS designee within 24 hours of awareness of the event and in accordance with SAE 
reporting procedures described in Appendix 3.
If the Investigator determines a possible favorable benefit-risk ratio that warrants continuation of 
study treatment or re-initiation of study treatment, a discussion between the Investigator and the 
BMS Medical Monitor/designee must occur. If, for whatever reason, the pregnancy has ended, 
confirmed by negative serum pregnancy test, treatment may be resumed (at least 3 weeks and not 
greater than 6 weeks after the
pregnancy
has ended), 
following approvals of 
participant/Sponsor/IRB/IEC, as applicable.
Follow-up information regarding the course of the pregnancy, including perinatal and neonatal 
outcome and, where applicable, offspring information must be reported on the Pregnancy 
Surveillance Form.
Any pregnancy that occurs in a female partner of a male study participant should be reported to 
the Sponsor or designee. In order for the Sponsor or designee to collect any pregnancy surveillance
information from the female partner, the female partner must sign an ICF for disclosure of this 
information. Information on this pregnancy will be collected on the Pregnancy Surveillance Form.
In cases where a study drug can be present in seminal fluid, at exposures sufficient to potentially 
cause fetal toxicity, and if any sexual activity (eg, vaginal, anal, oral) has occurred between a male 
participant and a pregnant WOCBP partner(s), the information should be reported to the Sponsor 
or designee, even if the male participant has undergone a successful vasectomy. In order for the 
Sponsor or designee to collect any pregnancy surveillance information from the female partner, 
the female partner(s) must sign an ICF for disclosure of this information. Information on the 
pregnancy will be collected on the Pregnancy Surveillance Form. For additional details on country 
specific requirements, refer to Appendix 9. 
9.2.7
Laboratory Test Result Abnormalities
The following laboratory test result abnormalities should be captured on the nonserious AE eCRF 
page or SAE Report Form electronic, as appropriate. Paper forms are only intended as a back-up 
option when the electronic system is not functioning.
•
Any laboratory test result that is clinically significant or meets the definition of an SAE.
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•
Any laboratory test result abnormality that required the participant to have study treatment
discontinued or interrupted.
•
Any laboratory test result abnormality that required the participant to receive specific 
corrective therapy.
It is expected that wherever possible, the clinical, rather than laboratory, term would be used by 
the reporting Investigator (eg, anemia vs low hemoglobin value).
9.2.8
Potential Drug Induced Liver Injury
Wherever possible, timely confirmation of initial liver-related laboratory abnormalities should 
occur prior to the reporting of a potential DILI (p-DILI) event. All occurrences of p-DILIs meeting 
the defined criteria must be reported as SAEs (see Section 9.2.5 and Appendix 3 for reporting 
details).
p-DILI is defined as:
1) Aminotransaminase (AT; ALT or AST) elevation > 3× ULN
AND
2) Total bilirubin > 2× ULN, without initial findings of cholestasis (elevated serum ALP)
AND
3) No other immediately apparent possible causes of AT elevation and hyperbilirubinemia, 
including, but not limited to, viral hepatitis, pre-existing chronic or acute liver disease, or the 
administration of other drug(s) known to be hepatotoxic.
9.2.9
Other Safety Considerations
Any significant worsening noted during interim or final PEs, ECG, X-ray filming, radiation, and 
any other potential safety assessment required or not required by protocol should also be recorded 
as a nonserious or serious AE, as appropriate, and reported accordingly.
9.2.10
Management Algorithms for Nivolumab
IO agents are associated with IMAEs that can differ in severity and duration from AEs caused by 
other therapeutic classes. Nivolumab is considered an IO agent in this protocol. Early recognition 
and management of IMAEs associated with IO agents may mitigate severe toxicity. Management 
algorithms have been developed from extensive experience with nivolumab to assist Investigators 
in assessing and managing the following groups of IMAEs:
•
GI
•
Renal
•
Pulmonary
•
Hepatic
•
Endocrinopathies
•
Skin
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Neurological
•
Myocarditis
The algorithms recommended for the management of IMAEs in this protocol are in Appendix 6.
9.3
Overdose
An overdose is defined as the accidental or intentional administration of any dose of a product that 
is considered both excessive and medically important. Overdoses that meet the regulatory 
definition of an SAE will be reported as an SAE (refer to Appendix 3).
All instances of accidental overdose and/or dosing errors should be reported on the Record of 
Study Medication eCRF.
There is no available information concerning overdose with nivolumab. Depending on the 
symptoms and/or signs leading to the suspicion of overdose, supportive medical management 
should be provided. There is no specific antidote.
More detailed information regarding overdose for the study treatments may be found in the 
respective IBs, Patient Information Leaflets, Package Inserts,56,57,58,59,60 Development Safety 
Update Report, or SmPCs.65,66,67,68,69
9.4
Safety
Planned timepoints for all safety assessments are listed in Section 2 (Schedule of Activities).
9.4.1
Physical Examinations
Physical examinations are to be performed as outlined in the Schedule of Activities (refer to 
Section 2) and as clinically indicated. If there are any new or worsening clinically significant 
changes since the last exam, report changes on the appropriate non-serious or SAE page.
9.4.2
Vital Signs
See the Schedule of Activities (Section 2).
9.4.3
Electrocardiograms and ECHO or MUGA
See the Schedule of Activities (Section 2).
9.4.4
Clinical Safety Laboratory Assessments
Investigators must document their review of each laboratory safety report.
Results of clinical laboratory tests must be available within 3 calendar days prior to dosing.
•
A list of the clinical laboratory analyses to be tested is provided in Table 9.4.4-1. Please see
Section 2 (Schedule of Activities) for additional information on timing of assessments.
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Table 9.4.4-1:
Clinical Safety Laboratory Assessments
Hematology
Hemoglobin
Hematocrit
Total leukocyte count, including differential
Platelet count
Chemistry
Aspartate aminotransferase (AST)
Alanine aminotransferase (ALT)
Total bilirubin
Alkaline phosphatase (ALP)
Lactate dehydrogenase (LDH)
Creatinine
Blood Urea Nitrogen (BUN) or serum urea
Fasting glucose
Albumin - screening only
Sodium
Potassium
Chloride
Calcium
Phosphorus
TSH with reflexive fT3 and fT4 at screening, TSH, 
with reflexive fT3 and fT4 if TSH abnormal on 
treatment
Serology
Hepatitis B/C (HBV sAG, HCV antibody or HCV RNA) - screening only
HIV testing where locally mandated. Refer to Appendix 9.
Other Analyses
Pregnancy test (WOCBP only: minimum sensitivity 25 IU/L or equivalent units of HCG)
FSH screening - only required to confirm menopause in women < age 55
Cortisol
Estradiol
Abbreviations: CBC, complete blood count; FSH, follicle stimulating hormone; HBV sAG, hepatitis B surface 
antigen; HCG, human chorionic gonadotropin; HCV, hepatitis C virus; HIV, human immunodeficiency virus; IU,
international unit; L, liter; RNA, ribonucleic acid; TSH, thyroid-stimulating hormone; WOCBP, women of 
childbearing potential.
9.4.5
Imaging Safety Assessment
Any incidental findings of potential clinical relevance that are not directly associated with the 
objectives of the protocol should be evaluated and handled by the Investigator per standard 
medical/clinical judgment.
9.5
Pharmacokinetics and Immunogenicity
Samples for PK and immunogenicity assessments will be collected for study participants in both 
the Neoadjuvant (Pre-surgery) Phase and the Adjuvant (Post-surgery) Phase at prespecified 
timepoints, as described in Table 9.5-1. All timepoints are relative to the start of nivolumab or 
nivolumab placebo administration. All timepoints during the Treatment Period are intended to 
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align with days on which nivolumab or nivolumab placebo is administered. If it is known that a 
nivolumab dose is going to be delayed/omitted, then the predose sample should be collected just 
prior to the next scheduled dose. However, if a predose sample is collected but the dose is 
subsequently delayed/omitted, an additional predose sample should not be collected. During the 
Adjuvant phase, when the treatment assignment is unblinded, PK and immunogenicity samples 
should no longer be collected in the placebo cohort for participants randomized to Arm B. Further 
details of sample collection, processing, and shipment will be provided in the Laboratory 
Procedures Manual. In addition, bioanalytics staff will be unblinded to the randomized treatment 
assignment in order to permit PK/IMG assays on samples from investigational arm only.
Serum PK samples will be analyzed for nivolumab concentrations by a validated ligand binding 
immunoassay method, and immunogenicity serum samples will be analyzed for anti-nivolumab 
antibodies by a validated immunoassay method. Immunogenicity serum samples may also be 
analyzed for nivolumab-neutralizing antibodies by a validated cell-based method. In addition, 
selected serum samples may be analyzed by an exploratory method that measures nivolumab, or 
detects anti-nivolumab antibodies for technology exploration purposes; exploratory results will 
not be reported. The corresponding serum samples designated for either PK, immunogenicity, or 
biomarker assessments may also be used for any of those analyses, if required (eg, insufficient 
sample volume to complete testing or to follow up on a suspected immunogenicity-related AE).
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Table 9.5-1:
Pharmacokinetic and Anti-drug Antibody Sampling Schedule for 
All Participants (CA2097FL)
Study Day of 
Sample Collection
Event
Time
(Relative To 
Nivolumab/Placebo
Dose)
Hour:Min
Nivolumab PK 
Sample
Nivolumab IMG
Sample
Neoadjuvant (Pre-surgery) PTX Treatment (Cycles 1-4, 1 cycle = 3 weeks)
C1D1
Predosea
0:00
X
X
EOIb
0:30
X
C2D1
Predosea
0:00
X
X
C3D1
Predosea
0:00
X
X
Neoadjuvant (Pre-surgery) AC Treatment (Cycles 1-4, 1 cycle = 2 or 3 weeks)
C1D1
Predosea
0:00
X
X
C2D1
Predosea
0:00
X
X
C3D1
Predosea
0:00
X
X
Adjuvant (Post-surgery)Treatment (Cycles 1-7, 1 cycle = 4 weeks) c
C1D1
Predosea
0:00
X
X
EOIb
0:30
X
C2D1
Predosea
0:00
X
X
C3D1
Predosea
0:00
X
X
C7D1
Predosea
0:00
X
X
Abbreviations: AC, anthracycline + cyclophosphamide; C, cycle; D, day; EOI, end of infusion; IMG, immunogenicity; 
IV, intravenous; PK, pharmacokinetic; PTX, paclitaxel.
a All predose samples for nivolumab must be taken prior to the start of nivolumab infusion (within approximately
30 minutes prior to infusion).
b Since the EOI-PK sample is drawn with the intent of accurately estimating the maximum  concentration of the drug,
draw the EOI-PK when all the study drug has been infused. If the site infuses drug without a flush, then collect the 
EOI-PK sample within approximately 5 minutes after the EOI. If a flush is administered to clear the IV lines of the 
drug and to ensure the delivery of the entire drug dose, then draw the EOI-PK sample within approximately 5 
minutes after end of the flush. Do not draw EOI samples from the same IV access that the drug was administered.
c When the treatment assignment is unblinded, and the participant is assigned to Arm B, PK and IMG samples should
no longer be collected.
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Biomarkers
 
 
 
 
 
 
 
 
 
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9.8.2
Tumor-based Biomarkers
9.8.2.1
PD-L1 Expression
The PD-L1 status in the study is primarily determined by an analytically validated qualitative IHC 
assay, PD-L1 SP142, using rabbit monoclonal anti-PD-L1 clone SP142 on the proportion of tumor 
area occupied by PD-L1-expressing tumor-infiltrating immune cells (% IC) of any intensity. The 
PD-L1 status must be confirmed from a designated central laboratory prior to randomization. 
Participants with PD-L1 expression (% IC) higher than the defined cutoff (eg, 1%) will be 
considered as the PD-L1+ population. Several secondary and exploratory endpoints of the study 
will be conducted in the PD-L1+ population. Participants with a PD-L1 status of unknown/not 
evaluable are not eligible.
In addition, PD-L1 expression determined by another quantitative IHC assay, PD-L1 28-8, using 
Combined Positive Score (CPS) will also be explored, in which the PD-L1 status in all PD-L1 
staining cells including tumor cells, lymphocytes, and macrophages would be reported. 
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9.8.4
Additional Research Collection
This protocol will include residual sample storage for additional research (AR).
1TAny remaining 
tissue collected for this study will be used for AR. Residual blood (or blood derivatives, such as 
serum, plasma, plasma ctDNA, PBMCs, and extracted RNA/DNA), tumor tissue (archival or fresh 
biopsy and extracted RNA/DNA) from tumor biopsy, and stool collections (Table 9.8.4-1) will 
also be retained for AR purposes.
For All US sites:
AR is required for all study participants, except where prohibited by IRBs/IECs, or 
academic/institutional requirements. Where 1 or more of these exceptions occurs, participation in 
the AR should be encouraged but will not be a condition of overall study participation.
•
If the IRB/IEC and site agree to the mandatory AR retention and/or collection, then the study 
participant must agree to the mandatory AR as a requirement for inclusion in the study.
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If optional participation is permitted and approved, then the study participants may opt out of
the additional AR and/or collection.
For non-US Sites
AR is optional for all study participants, except where retention and/or collection is prohibited by 
local laws or regulations, IECs, or institutional requirements.
This collection for AR is intended to expand the translational R&D capability at BMS, and will 
support as-yet-undefined research aims that will advance our understanding of disease and options 
for treatment. It may also be used to support health authority requests for analysis, and 
advancement of pharmacodiagnostic development to better target drugs to the right patients. 
This may also include genetic/genomic exploration aimed at exploring disease pathways, 
progression, response to treatment, etc.
Sample Collection and Storage
All requests for access to samples or data for AR will be vetted through a diverse committee of the 
study Sponsor’s senior leaders in R&D (or designee) to ensure that the research supports 
appropriate and well-defined scientific research activities.
Samples kept for future research will be stored at the BMS Biorepository 
 or 
an independent, BMS-approved storage vendor.
The manager of these samples will ensure that they are properly used throughout their usable life 
and will destroy the samples at the end of the scheduled storage period, no longer than fifteen (15) 
years after the end of the study or the maximum allowed by applicable law.
Transfers of samples by the research Sponsor to third parties will be subject to the recipient’s 
agreement to establish similar storage procedures.
Samples will be stored in a coded fashion, and no researcher will have access to the key. The key 
is securely held by the Investigator at the clinical site, so there is no direct ability for a researcher 
to connect a sample to a specific individual.
Further details of sample collection and processing will be provided to the site in the procedure 
manual.
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9.9
Health Economics OR Medical Resource Utilization and Health 
Economics
Healthcare resource utilization (HCRU) data will be collected for all randomized participants using 
an internal measure developed for use in previous trials. The questionnaire records information 
about medical care encounters, including hospital admissions and their duration, outpatient visits, 
diagnostic tests and procedures, concomitant medications, and reasons for encounters.
HCRU data associated with medical encounters will be collected on the eCRF by the Investigator
and study-site personnel for all participants throughout the study. Protocol-mandated procedures, 
tests, and encounters are excluded.
The data collected may be used to conduct exploratory economic analyses and will include:
•
Number and duration of medical care encounters, including surgeries, and other selected 
procedures (inpatient and outpatient).
•
Duration of hospitalization (total days length of stay, including duration by wards [eg, intensive 
care unit]).
•
Number and character of diagnostic and therapeutic tests and procedures.
•
Outpatient medical encounters and treatments (including physician or emergency room visits, 
tests and procedures, and medications).
10
STATISTICAL CONSIDERATIONS
10.1
Sample Size Determination 
The primary objective of this study is to compare the pCR rates between treatment groups in all 
randomized participants. The pCR rates will be compared at the 0.05 alpha level. 
As of 16-May-2022, a total of 521 participants were randomized in a 1:1 ratio to Arm A and Arm 
B. See Table 10.1-1 for a summary of the power assumptions.
Given a 2-sided alpha of 0.05, 521 participants will provide approximately 87% power to detect a 
10% pCR difference between Arm A and Arm B, assuming a pCR of 22% and 12% for all 
randomized participants in Arm A and Arm B, respectively.
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The final analysis for pCR will be conducted at approximately 37 months from the first 
participant’s randomization date.
Power calculation of pCR analysis was estimated using EAST 6.4.1.
Table 10.1-1:
Power Assumptions
Population
ITT
Sample Size
521
Accrual Duration, months
29
Endpoint
pCR
Hypothesized Rates Control vs Experimental, %
12 vs 22
Alpha 2-sided
0.05
Power, %
87
Timing of pCR Final Analysis (from 
randomization of first participant), months
37
Abbreviations: ITT, intent to treat; pCR, pathological complete response; vs, versus.
10.2
Populations for Analyses
For purposes of analysis, the following populations are defined in Table 10.2-1.
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Table 10.2-1:
Populations for Analyses
Population
Description
All Enrolled
All participants who signed an ICF and were registered into the IRT.
All Randomized (ITT 
Population)
All participants who were randomized to any treatment arm in the study. Participants 
are grouped within the all randomized population by the treatment to which they 
were randomized.
This is the primary analysis set for demography, protocol deviations, baseline 
characteristics, and efficacy analyses.
All Treated
All enrolled participants who received at least 1 dose of study drug. Participants are 
grouped within the all treated population according to the treatment they actually 
received. This is the analysis set for all safety analyses and study drug administration.
All Randomized PD-L1+
All participants with PD-L1 expression on immune cells ≥1% who were 
randomized to any treatment arm in the study. Participants are grouped within the all
randomized PD-L1+ population by the treatment to which they were randomized.
All Treated PD-L1+
All enrolled participants with PD-L1 expression on immune cells ≥1% who receive 
at least 1 dose of study drug. Participants are grouped within the all treated PD-L1+
population according to the treatment they actually received.
PK
All treated participants with available serum concentration data for nivolumab.
Immunogenicity
All treated participants with baseline and at least 1 pre-infusion immunogenicity 
assessment.
Abbreviations: ICF, informed consent form; IRT, interactive response technology; PD-L1, programmed death-ligand 
1; PK, pharmacokinetic.
10.3
Statistical Analyses
The statistical analysis plan (SAP) will be developed and finalized before database lock and will 
describe the selection of participants to be included in the analyses, and procedures for accounting 
for missing, unused, and spurious data. Below is a summary of planned statistical analyses of the 
primary, secondary, and key exploratory endpoints.
A description of the participant population will be included in a statistical output report, including 
subgroups of age, gender, race, and other baseline characteristics.
10.3.1
Efficacy Analyses
Statistical analyses for efficacy are shown in Table 10.3.1-1. Primary efficacy endpoint will be 
explored in the ITT population.100,126,127
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Table 10.3.1-1:
Efficacy - Statistical Analyses
Endpoint
Statistical Analysis Methods
Primary
•
pCR, defined as no invasive residual disease in 
breast and lymph nodes (eg, ypT0/is, ypN0) by 
a local pathologist (ITT population).
•
pCR rates and corresponding 95% exact CIs will be 
calculated using the Clopper-Pearson method for each 
treatment arm in the all randomized participants (ITT). 
Participants who do not undertake surgery will be 
counted as non-pCR and will be included in the 
denominator.
•
The pCR rates in all randomized participants will be 
compared using a 2-sided stratified CMH test with 
alpha = 0.05. Associated odds ratios with 2-sided 95% 
CIs will be calculated.
Secondary
•
pCR, defined as no invasive residual disease in 
breast and lymph nodes (eg, ypT0/is, ypN0) by 
a local pathologist (PD-L1+ population).
•
Rates and exact 95% CI will be calculated using the 
same method as the primary analysis.
•
RCB class (0, I, II, III) frequency, for RCB 
assessed by a local pathologist in ITT and PD-
L1+ populations.
•
Rates and exact 95% CI will be calculated using the 
same method as the primary analysis.
Exploratory
•
pCR, defined as no invasive or in situ residual 
disease in breast and lymph nodes (ie, ypT0 
ypN0) by a local pathologist in ITT and PD-L1+
populations.
•
pCR, defined as no invasive residual disease in 
the breast irrespective of in situ or nodal
involvement (ypT0/is) by a local pathologist in 
ITT and PD-L1+ populations.
•
ORR, defined as investigator-assessed tumor 
response rate per radiologic-based assessment 
(RECIST v1.1) in the Neoadjuvant (pre-
surgery) phase in ITT and PD-L1+ populations.
•
Response rates and corresponding 95% exact CIs will 
be calculated using the Clopper-Pearson method for 
each treatment arm in the all randomized (ITT)
participants and all randomized PD-L1+ participants.
•
EFS in ITT population.
•
OS in ITT population.
•
DFS in ITT population.
•
DMFS in ITT population.
•
The
EFS, OS, DFS, and DMFS curves for each 
randomized arm will be estimated using the KM 
product-limit method. A 2-sided 95% CI for median 
survival time in each randomized arm will be computed 
via the log-log transformation.
•
EFS, OS, DFS, and DMFS rates at 1 year will be 
estimated and associated 2-sided 95% CIs will be 
calculated. These estimates will be derived from the 
KM estimates, and corresponding CIs will be derived 
based on Greenwood formula for variance derivation 
and on log-log transformation applied on the survival 
function.
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Table 10.3.1-1:
Efficacy - Statistical Analyses
Endpoint
Statistical Analysis Methods
•
Clinical efficacy endpoints (eg, pCR, RCB,
ORR) by PD-L1 expression using PD-L1 IHC
28-8 CPS.
•
Rates and corresponding 95% exact CIs will be
calculated using the Clopper-Pearson method for a
specific population.
Abbreviations: BCS,
breast-conserving surgery; CI,
confidence interval; CPS, combined positive
score; 
DFS, disease-free survival; DMFS, distant metastasis-free survival; EFS, event-free survival; ER+, estrogen receptor 
positive; IHC, immunohistochemistry assay; ITT, intent to treat; KM, Kaplan-Meier; ORR, objective response rate; 
OS, overall survival; pCR,
pathological complete response; PD-L1+, programmed death-ligand 1-positive; 
RCB, residual cancer burden; SARS-CoV-2, severe acute respiratory syndrome-coronavirus-2.
10.3.2
Safety Analyses
Statistical analyses for Safety are shown in Table 10.3.2-1.
Table 10.3.2-1:
Safety - Statistical Analyses
Endpoint
Statistical Analysis Methods
Secondary
•
Incidence
of AEs, drug-related
AEs, 
AEs 
leading 
to
discontinuation, 
and 
SAEs
as 
defined by NCI CTCAE v5.0.
•
Incidence of deaths.
AEs will be graded according to NCI CTCAE v5.0. Frequency 
distribution of treated participants with AEs will use the worst CTC 
grade. Participants will only be counted: (1) once at the PT level; 
(2) once at the system organ class level; and (3) once in the “total
participant” row at their worst CTC grade, regardless of system organ
class or PT.
Laboratory values will be graded according to NCI CTCAE v5.0.
Abbreviations: AE, adverse event; CTC, common toxicity criteria; CTCAE, Common Terminology Criteria for 
Adverse Events; NCI, National Cancer Institute; PT, preferred term; SAE, serious adverse event.
10.3.3
Clinical Outcomes Assessments
Change from baseline in the EORTC QLQ-C30 Global Health Status and Physical Functioning 
subscale are secondary endpoints. Summary statistics and 95% CIs at each assessment point for 
both these PRO secondary endpoints will be provided for each treatment arm (as randomized) in 
the treatment period. All remaining subscales of the EORTC QLQ-C30 and all other PROs are 
exploratory endpoints. Summary statistics for other COA measures at each assessment point will 
be provided for each treatment arm (as randomized) in the Treatment Period.
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10.3.3.1
EORTC QLQ-C30 and EORTC QLQ-BR23
Change from baseline scores in EORTC QLQ-C30 global health/QOL and physical functioning 
subscale scores will be assessed. Change in baseline scores in all other EORTC QLQ-C30 domains 
and individual items and QLQ-BR23 subscales will be assessed. These analyses will use all 
available data from randomized participants.
Additional analyses for all other domains of the EORTC QLQ-C30 and EORTC QLQ-BR23 will 
be described in the SAP.
10.3.3.2
EQ-5D-5L
The EQ-5D will be described in the following 3 ways:
1) Participant’s overall health state on a visual analog scale (EQ-VAS) at each assessment 
timepoint will be summarized using descriptive statistics, as randomized.
2) Proportion of participants reporting problems for the 5 EQ-5D dimensions at each assessment 
timepoint will be summarized by level of problem, as randomized for all randomized 
participants.
3) Percentages will be based on number of participants assessed at assessment timepoint.
A by-participant listing of EQ-5D with the problem levels for each of the 5 dimensions (mobility, 
self-care, usual activities, pain/discomfort, and anxiety/depression), health state (5 dimensions 
digits combined in a 5-digit number), and EQ-5D VAS will be provided.
10.3.3.3
FACIT GP5
FACIT GP5 responses will be analysed using mean and post-mean baseline changes for each 
treatment group at each assessment timepoint. Additional analyses will include the proportion of 
participants who endorse each response category at each timepoint.
10.3.4
Other Analyses
PK,
 analyses will be described in the SAP, which 
will be finalized before database lock. The PPK analysis 
 will be 
presented separately from the main clinical study report.
10.3.4.1
Pharmacokinetic Analyses
The nivolumab concentration vs time data obtained in this study may be combined with data from 
other studies in the clinical development program to develop a PPK model. This model may be 
used to evaluate the effects of intrinsic and extrinsic covariates on the PK of nivolumab to 
determine measures of individual exposure. Model-determined exposures may be used for 
exposure-response analyses of selected efficacy and safety endpoints, if the data permit. The PPK 
and exposure-response analyses will be presented separately from the main clinical study report, 
if conducted.
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10.3.4.2
Immunogenicity Analyses
Immunogenicity will be reported for positive status of anti-drug antibodies (ADAs) for nivolumab 
and ADA-negative status, relative to baseline. In addition, presence of neutralizing antibody may 
be reported, if applicable. Effect of immunogenicity on safety, efficacy, and PK may be explored.
 
 
 
 
 
 
10.3.5
Interim Analyses
The SAP will further describe the planned interim analysis.
10.3.5.1
Futility Analysis Based on pCR
An interim futility analysis of pCR will be conducted when approximately 260 ITT participants 
are randomized and have the opportunity to be evaluated for pCR (approximately 29 months from 
the first participant randomization date). At the time of the analysis, IDMC will evaluate whether
the following futility stopping criterion is met and notify the Sponsor. The futility analysis is 
non-binding and the decision of whether to continue the trial will be made by the study team based 
on the analysis results. The study will remain blinded at the futility analysis.
Consider stopping the trial when both ΔpCR in PD-L1+ participants ≤ 4% and ΔpCR in ITT 
participants ≤ 2%, where ΔpCR = estimated pCR in Arm A - estimated pCR in Arm B.
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11
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23 Yersal O, Barutca S. Biological Subtypes of Breast Cancer: Prognostic and Therapeutic 
Implications. World Journal of Clinical Oncology 2014;5(3):412-24.
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63 Anastrozole (Arimidex) Tablets Package Insert. AstraZeneca Pharmaceuticals, LP; Revised 
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75 Medicines.org.uk. Leuprorelin acetate Depot 3.75 mg Powder and Solvent for 
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12
APPENDICES
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APPENDIX 1
ABBREVIATIONS AND TRADEMARKS
Term
Definition
°C
degrees Celsius
μL
microliter
%CA
proportion of cancer
%CIS
proportion of in situ component
AC
anthracycline + cyclophosphamide
ADA
anti-drug antibody
AE
adverse event
AI
aromatase inhibitor
AIDS
acquired immunodeficiency syndrome
AJCC
American Joint Committee on Cancer
ALP
alkaline phosphatase
ALT
alanine aminotransferase
ANC
absolute neutrophil count
AR
additional research
ART
antiretroviral therapy
ASCO
American Society of Clinical Oncology
ASCO-CAP
American Society of Clinical Oncology- College of American 
Pathologists
AST
aspartate aminotransferase
AT
aminotransaminases
AUC
area under the curve
BC
breast cancer
Bcl-xL
B-cell lymphoma-extra large
BCS
breast-conserving surgery
BICR
blinded independent central review
BID
bis in die, twice daily
BMS
Bristol-Myers Squibb
BP
blood pressure
BRCA1/2
breast cancer gene 1/2
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Term
Definition
BTLA
B- and T-lymphocyte attenuator
BUN
blood urea nitrogen
C
cycle
Cavgss
steady state average concentration
CBC
complete blood count
CD28
cluster of differentiation 28
CFR
Code of Federal Regulations 
CHF
congestive heart failure
cHL
classical Hodgkin lymphoma
CI
confidence interval
CIOMS
Council for International Organizations of Medical Sciences
CISH
chromogenic in situ hybridization
Cm
centimeter
CMF
cyclophosphamide, methotrexate, and 5-flourouracil
CMH
Cochran Mantel Haenszel
CMV
cytomegalovirus
COA
clinical outcomes assessment
CONSORT
Consolidated Standards of Reporting Trials
COVID-19
coronavirus disease 2019
CPS
combined positive score
CR
complete response
CRC
colorectal cancer
CRF
case report form
CRO
contract research organization
CSR
clinical study report
CT
computed tomography
CTAg
clinical trial agreement
CTC
common toxicity criteria
CTCAE
Common Terminology Criteria for Adverse Events
ctDNA
circulating tumor DNA
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Term
Definition
CTLA-4
cytotoxic T-lymphocyte-associated protein-4
CYP
cytochrome p-450
D
day
DCIS
ductal carcinoma in situ
DD
dose-dense
ddAC
dose-dense anthracycline + cyclophosphamid
DFS
disease-free survival
DILI
drug-induced liver injury
dL
deciliter
DLT
dose-limiting toxicity
DMFS
distant metastasis-free survival
DNA
deoxyribonucleic acid
DRESS
Drug Rash with Eosinophilia and Systemic Symptoms
EC
epirubicin and cyclophosphamide
EC
ethics committee
EC50
half-maximal effective concentration
ECG
electrocardiogram
ECHO
echocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic case report form
EDC
electronic data capture
EFS
event-free survival
eg
exempli gratia (for example)
eGFR
estimated glomerular filtration rate
EHR
electronic health record
ELISA
enzyme-linked immunosorbent assay
EMA
European Medicines Agency
EMR
electronic medical record
EOI
end of infusion
EORTC
European Organisation for the Research and Treatment of Cancer
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Term
Definition
EOT
end of treatment
EQ-5D-5L
EuroQol-5 Dimensions-5 Levels
ER
estrogen receptor
ER-
estrogen receptor-negative
ER+
estrogen receptor-positive
ESMO
European Society for Medical Oncology
ET
endocrine therapy
etc
et cetera
EU
Europe
FACIT GP5
Functional Assessment of Chronic Illness Treatment General Physical 
Item 5
FDA
Food and Drug Administration
FDG-PET
Fluorodeoxyglucose-positron emission tomography
FFPE
formalin-fixed, paraffin-embedded
FISH
fluorescence in situ hybridization
FSH
follicle-stimulating hormone
FU
follow-up
FU1
follow-up visit 1
FU2
follow-up visit 2
g
gram
GBS
Guillian Barre Syndrome
GCP
Good Clinical Practice
G-CSF
granulocyte-colony stimulating factor
GEP
gene expression profiling
GI
gastrointestinal
GM-CSF
granulocyte-macrophage colony-stimulating factor
HBsAg
hepatitis B surface antigen
HBV
hepatitis B virus
HCC
hepatocellular carcinoma
HCG
human chorionic gonadotropin
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Term
Definition
HCRU
healthcare resource utilization
HCV
hepatitis C virus
HER2
human epidermal growth factor receptor 2
HER2+
human epidermal growth factor receptor 2-positive
HER2-
human epidermal growth factor receptor 2-negative
HIPAA
Health Insurance Portability and Accountability Act
HIV
human immunodeficiency virus
HR
hazard ratio
HR+
hormone receptor-positive
HRQOL
health-related quality of life
IB
Investigator’s Brochure
IC
immune cells
IC50
half-maximal inhibitory concentration
ICF
informed consent form
ICH
International Conference on Harmonisation
ICMJE
International Committee of Medical Journal Editors
ICOS
inducible T cell co-stimulator
IDMC
Independent Data Monitoring Committee
ie
id est (that is)
IEC
Independent Ethics Committee
IFN-γ
interferon-γ
IgG
immunoglobulin G
IHC
immunohistochemistry
IL
interleukin
IMAE
immune-mediated adverse event
IMG
immunogenicity
IMP
investigational medicinal product
IND
Investigational New Drug
IO
immuno-oncologic
IP
investigational product
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Term
Definition
IRB
Institutional Review Board
IRT
interactive response technology
ISH
in situ hybridzation
ITT
intent to treat
IU
international unit
IUD
intrauterine device
IUS
intrauterine hormone-releasing system
IV
intravenous
kg
kilogram
KM
Kaplan-Meier
L
liter
LAM
lactation amenorrhea method
LCIS
lobular carcinoma in situ
LD
longest diameter
LDH
lactate dehydrogenase
LHRH
luteinizing hormone-releasing hormone
LN
lymph node
m2
meters squared
mm3
cubic millimeters
M
distant metastasis
MD
medical doctor
MDSC
myeloid-derived suppressor cells
MG
Myasthenia Gravis
mg
milligram
min
minute
miRNA
micro ribonucleic acid
mL
milliliter
MLR
mixed lymphocyte reaction
mm3
cubic millimeters
MMR
measles, mumps, rubella
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Term
Definition
MRI
magnetic resonance imaging
mRNA
messenger ribonucleic acid
MTD
maximum tolerated dose
MUGA
multiple-gated acquisition
N
number of subjects or observations
NA
not applicable
NCCN
National Cancer Care Network
NCI
National Cancer Institute
Nivo
nivolumab
NE
not evaluable; inevaluable
nM
nanomolar
NSABP
National Surgical Adjuvant Breast and Bowel Project
NSCLC
non-small cell lung cancer
NYHA
New York Heart Association
OR
odds ratio
ORR
objective response rate
OS
overall survival
OTC
over-the-counter
PALB2
partner and localizer of BRCA2
PBMC
peripheral blood mononuclear cells
Pbo
placebo
pCR
pathological complete response
PD
progressive disease
PD-1
programmed cell death-1
p-DILI
potential drug-induced liver injury
PD-L1
programmed death-ligand 1
PD-L1+
programmed death-ligand 1-positive
PD-L1-
programmed death-ligand 1-negative
PD-L2
programmed death-ligand 2
PE
physical examination
PET
positron emission tomography
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Term
Definition
PFS
progression-free survival
PgR
progesterone receptor
PIK3CA
phosphatidylinositol 3-kinase catalytic alpha polypeptide
PK
pharmacokinetic
PO
per os (by mouth route of administration)
PPK
population pharmacokinetics
PR
partial response
PRO-CTCAE
Patient-Reported Outcome-Common Terminology Criteria for Adverse 
Events
PS
performance status
PT
preferred term
PTX
paclitaxel
Q2W
every 2 weeks
Q3W
every 3 weeks
Q4W
every 4 weeks
QD, qd
quaque die, once daily
QLQ-BR23
Quality of Life Questionnaire-Breast Cancer-specific Module
QLQ-C30
Quality of Life Questionnaire-Core 30
QOL
quality of life
QW
every week
R&D
research and development
Rand
randomized
RCB
residual cancer burden
RCC
renal cell carcinoma
RECIST
Response Evaluation Criteria in Solid Tumors
RNA
ribonucleic acid
RT
radiotherapy
RT-PCR
reverse transcription polymerase chain reaction
SAE
serious adverse event
SAP
statistical analysis plan
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Term
Definition
SARS-CoV-2
severe acute respiratory syndrome-coronavirus-2
SCCHN
squamous cell carcinoma of the head and neck
SD
stable disease
SISH
silver in situ hybridization
SJS
Steven Johnson Syndrome
SLAMF8
signaling lymphocytic activation molecule family member 8
SmPC
summary of product characteristics
SOC
standard of care
SOP
standard operating procedures
SSC
study steering committee
SUSAR
suspected, unexpected serious adverse reaction
T
tumor
T.bili
total bilirubin
TCR
T-cell receptor
T-DM1
trastuzumab emtansine
TEN
toxic epidermal necrolysis
TIL
tumor-infiltrating lymphocyte
TMB
tumor mutational burden
TME
tumor microenvironment
TNBC
triple-negative breast cancer
TNF
tumor necrosis factor
TNM
tumor node metastasis
Tregs
regulatory T cells
TSH
thyroid-stimulating hormone
UK
United Kingdom
ULN
upper limit of normal
US
United States
USP
United States Pharmacopeia
VAS
visual analog scale
vs
versus
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Term
Definition
WOCBP
women of childbearing potential
WNOCBP
women not of childbearing potential
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APPENDIX 2
STUDY GOVERNANCE CONSIDERATIONS
The terms “participant” and “subject” refer to a person who has consented to participate in the 
clinical research study. Typically, the term “participant” is used in the protocol and the term 
“subject” is used in the Case Report Form (CRF).
REGULATORY AND ETHICAL CONSIDERATIONS
GOOD CLINICAL PRACTICE
This study will be conducted in accordance with:
•
Consensus ethical principles derived from international guidelines, including the Declaration
of Helsinki and Council for International Organizations of Medical Sciences (CIOMS)
International Ethical Guidelines
•
Applicable International Council for Harmonisation (ICH) Good Clinical Practice (GCP)
Guidelines
•
Applicable laws, regulations, and requirements
The study will be conducted in compliance with the protocol. The protocol,
any 
revisions/amendments,
and the participant
informed consent form (ICF) will receive 
approval/favorable 
opinion 
by 
Institutional 
Review 
Board/Independent 
Ethics 
Committee (IRB/IEC), and regulatory authorities according to applicable regulations prior to 
initiation of the study.
All potential serious breaches must be reported to the Sponsor or designee immediately. A 
potential serious breach is defined as a Quality Issue (eg, protocol deviation) that is likely to affect, 
to a significant degree, one or more of the following: (1) the rights, physical safety or mental 
integrity of one or more participants; (2) the scientific value of the clinical trial (eg, reliability and 
robustness of generated data). Items (1) or (2) can be associated with either GCP regulation(s) or 
trial protocol(s).
Personnel involved in conducting this study will be qualified by education, training, and 
experience to perform their respective tasks.
This study will not use the services of study personnel where sanctions have been invoked or where 
there has been scientific misconduct or fraud (eg, loss of medical licensure, debarment). 
INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS COMMITTEE
Before study initiation, the investigator must have written and dated approval/favorable opinion 
from the IRB/IEC for the protocol, Investigator’s Brochure, product labeling information, ICF, 
participant recruitment materials (eg, advertisements), and any other written information to be 
provided to participants.
The investigator, Sponsor, or designee should provide the IRB/IEC with reports, updates, and other 
information (eg, expedited safety reports, amendments, administrative letters) annually, or more 
frequently, in accordance with regulatory requirements or institution procedures.
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The investigator is responsible for providing oversight of the conduct of the study at the site and 
adherence to requirements of the following where applicable:
•
ICH guidelines,
•
United States Code of Federal Regulations, Title 21, Part 50 (21CFR50)
•
European Union Directive 2001/20/EC; or
•
European Regulation 536/2014 for clinical studies (if applicable),
•
European Medical Device Regulation 2017/745 for clinical device research (if applicable),
•
the IRB/IEC
•
and all other applicable local regulations.
COMPLIANCE WITH THE PROTOCOL AND PROTOCOL REVISIONS
The investigator should not implement any deviation or change to the protocol without prior 
review and documented approval/favorable opinion of an amendment from the IRB/IEC (and, if 
applicable, also by the local Health Authority), except where necessary to eliminate an immediate 
hazard(s) to study participants. 
If a deviation or change to a protocol is implemented to eliminate an immediate hazard(s) prior to 
obtaining relevant approval/favorable opinion(s), the deviation or change will be submitted as soon 
as possible to:
•
IRB/IEC
•
Regulatory authority(ies), if applicable by local regulations (per national requirements)
Documentation of approval/favorable opinion signed by the chairperson or designee of the 
IRB(s)/IEC(s) and, if applicable, also by the local Health Authority, must be sent to Bristol-Myers 
Squibb (BMS).
If an amendment substantially alters the study design or increases the potential risk to the 
participant: (1) the ICF must be revised and submitted to the IRB(s)/IEC(s) for review and 
approval/favorable opinion; (2) the revised form must be used to obtain consent from participants 
currently enrolled in the study if they are affected by the amendment; and (3) the new form must 
be used to obtain consent from new participants prior to enrollment.
FINANCIAL DISCLOSURE
Investigators and sub-investigators will provide the Sponsor with sufficient, accurate financial 
information, in accordance with regulations, to allow the Sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate Health Authorities. Investigators 
are responsible for providing information on financial interests during the course of the study and 
for 1 year after completion of the study.
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INFORMED CONSENT PROCESS
Investigators must ensure that participants are clearly and fully informed about the purpose, 
potential risks, and other critical issues regarding clinical studies in which they volunteer to 
participate. 
The Sponsor or designee will provide the investigator with an appropriate sample ICF, which will 
include all elements required by the ICH GCP, and applicable regulatory requirements. The sample 
ICF will adhere to the ethical principles that have their origin in the Declaration of Helsinki.
The investigator or his/her representative must:
•
Obtain IRB/IEC written approval/favorable opinion of the written ICF and any other 
information to be provided to the participant prior to the beginning of the study and after any 
revisions are completed for new information.
•
Provide a copy of the ICF and written information about the study in the language in which 
the participant is proficient prior to clinical study participation. The language must be 
nontechnical and easily understood. 
•
Explain the nature of the study to the participant or his/her legally acceptable representative
and answer all questions regarding the study.
•
Inform participant that his/her participation is voluntary. Participant or his/her legally 
acceptable representative will be required to sign a statement of informed consent that meets 
the requirements of 21 CFR 50, local regulations, ICH guidelines, Health Insurance Portability 
and Accountability Act (HIPAA) requirements, where applicable, and the IRB/IEC or study 
center.
•
Allow time necessary for participant or his/her legally acceptable representative to inquire 
about the details of the study.
•
Obtain an ICF signed and personally dated by participant or his/her legally acceptable 
representative and by the person who conducted the informed consent discussion. 
•
Include a statement in participant’s medical record that written informed consent was obtained 
before participant was enrolled in the study and the date the written consent was obtained. The 
authorized person obtaining the informed consent must also sign the ICF.
•
Re-consent participant to the most current version of the ICF(s) during his/her participation in 
the study, as applicable.
Revise the ICF whenever important new information becomes available that is relevant to the 
participant’s consent. The investigator, or a person designated by the investigator, should fully 
inform the participant or his/her legally acceptable representative of all pertinent aspects of the 
study and of any new information relevant to the participant’s willingness to continue participation 
in the study. This communication should be documented.
The confidentiality of records that could identify participants must be protected, respecting the 
privacy and confidentiality rules applicable to regulatory requirements, the participant’s signed 
ICF, and, in the US, the participant’s signed HIPAA Authorization.
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The ICF must also include a statement that BMS and local and foreign regulatory authorities have 
direct access to participant records.
In situations where consent cannot be given by participants, their legally acceptable representatives 
(as per country regulation) are clearly and fully informed about the purpose, potential risks, and 
other critical issues regarding clinical studies in which the participant volunteers to participate. 
If informed consent is initially given by a participant’s legally acceptable representative or legal 
guardian and the participant subsequently becomes capable of making and communicating his or 
her informed consent during the study, consent must additionally be obtained from the participant.
The rights, safety, and well-being of the study participants are the most important considerations 
and should prevail over interests of science and society.
SOURCE DOCUMENTS
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. Source documents are filed at the investigator’s site.
Data reported on the CRF or entered in the electronic CRF (eCRF) that are transcribed from source 
documents must be consistent with the source documents or the discrepancies must be explained. 
•
The investigator may need to request previous medical records or transfer records, depending 
on the study. Also, current medical records must be available.
•
Definitions of what constitutes source data can be found in the Source document location map 
(or equivalent) and Site Process Source Document.
The investigator is responsible for ensuring that the source data are accurate, legible, 
contemporaneous, original, and attributable, whether the data are handwritten on paper or entered 
electronically. If source data are created (first entered), modified, maintained, archived, retrieved, 
or transmitted electronically via computerized systems (and/or any other kind of electronic 
devices) as part of regulated clinical trial activities, such systems must be compliant with all 
applicable laws and regulations governing use of electronic records and/or electronic signatures. 
Such systems may include, but are not limited to, electronic medical records/electronic health 
records, adverse event (AE) tracking/reporting, protocol-required assessments, and/or drug 
accountability records.
When paper records from such systems are used in place of an electronic format to perform 
regulated activities, such paper records should be certified copies. A certified copy consists of a 
copy of original information that has been verified, as indicated by a dated signature, as an exact 
copy having all of the same attributes and information as the original. 
STUDY TREATMENT RECORDS
Records for study intervention (whether supplied by BMS, its vendors, or the site) must 
substantiate study intervention integrity and traceability from receipt, preparation, administration, 
and through destruction or return. Records must be made available for review at the request of 
BMS/designee or a Health Authority.
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If
Then
Supplied by BMS (or its vendors):
Records or logs must comply with applicable 
regulations and guidelines and should include:
•
amount received and placed in storage area
•
amount currently in storage area
•
label identification number or batch number
•
amount dispensed to and returned by each 
participant, including unique participant
identifiers
•
amount transferred to another area/site for 
dispensing or storage
•
nonstudy disposition (eg, lost, wasted) 
•
amount destroyed at study site, if applicable
•
amount returned to BMS
•
retain samples for 
bioavailability/bioequivalence/biocomparability, 
if applicable 
•
dates and initials of person responsible for 
Investigational Product 
dispensing/accountability, as per the Delegation 
of Authority Form
Sourced by site and not supplied by BMS 
or its vendors (examples include IP 
sourced 
from 
the 
sites 
stock or 
commercial supply or a specialty 
pharmacy)
The investigator or designee accepts responsibility 
for documenting traceability and study treatment
integrity in accordance with requirements applicable 
under 
law 
and 
the 
standard 
operating 
procedures/standards of the sourcing pharmacy
BMS or its designee will provide forms to facilitate inventory control if the investigational site 
does not have an established system that meets these requirements.
CASE REPORT FORMS
An investigator is required to prepare and maintain adequate and accurate case histories designed 
to record all observations and other data pertinent to the investigation on each individual treated 
or entered as a control in the investigation. Data that are derived from source documents and 
reported on the CRF must be consistent with the source documents, or the discrepancies must be 
explained. Additional clinical information may be collected and analyzed in an effort to enhance 
understanding of product safety. CRFs may be requested for AEs and/or laboratory abnormalities 
that are reported or identified during the course of the study.
For sites using the Sponsor or designee electronic data capture (EDC) tool, eCRFs will be prepared 
for all data collection fields except for fields specific to SAEs and pregnancy, which will be 
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reported on the electronic SAE form and Pregnancy Surveillance Form, respectively. If the 
electronic SAE form is not available, a paper SAE form can be used. Spaces may be left blank 
only in those circumstances permitted by study-specific CRF completion guidelines provided by
the Sponsor or designee.
The confidentiality of records that could identify participants must be protected, respecting the 
privacy and confidentiality rules in accordance with the applicable regulatory requirement(s).
The investigator will maintain a signature sheet to document signatures and initials of all persons 
authorized to make entries and/or corrections on CRFs. 
The completed CRF and SAE/pregnancy CRFs must be promptly reviewed, signed, and dated by 
the investigator or qualified physician who is a sub-investigator and who is delegated this task on 
the Delegation of Authority Form. Sub-investigators in Japan may not be delegated the CRF 
approval task. For eCRFs, review and approval/signature is completed electronically through the 
BMS EDC tool. The investigator must retain a copy of the CRFs, including records of the changes 
and corrections.
Each individual electronically signing eCRFs must meet Sponsor or designee training 
requirements and must only access the BMS EDC tool using the unique user account provided by 
the Sponsor or designee. User accounts are not to be shared or reassigned to other individuals.
MONITORING
Sponsor or designee representatives will review data centrally to identify potential issues to 
determine a schedule of on-site visits for targeted review of study records.
Representatives of BMS must be allowed to visit all study site locations periodically to assess the 
data quality and study integrity. On site, they will review study records and directly compare them 
with source documents, discuss the conduct of the study with the investigator, and verify that the 
facilities remain acceptable.
Certain CRF pages and/or electronic files may serve as the source documents.
In addition, the study may be evaluated by the Sponsor or designee internal auditors and 
government inspectors who must be allowed access to CRFs, source documents, other study files, 
and study facilities. BMS audit reports will be kept confidential.
The investigator must notify BMS promptly of any inspections scheduled by regulatory authorities 
and promptly forward copies of inspection reports to the Sponsor or designee.
RECORDS RETENTION
The investigator (or head of the study site in Japan) must retain all study records and source 
documents for the maximum period required by applicable regulations and guidelines, or 
institution procedures, or for the period specified by BMS or its designee, whichever is longer. 
The investigator (or head of the study site in Japan) must contact BMS prior to destroying any 
records associated with the study.
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BMS or its designee will notify the investigator (or head of the study site in Japan) when the study 
records are no longer needed.
If the investigator withdraws from the study (eg, relocation, retirement), the records shall be 
transferred to a mutually agreed-upon designee (eg, another investigator, study site, IRB). Notice 
of such transfer will be given in writing to BMS or its designee. 
RETURN OF STUDY TREATMENT
For this study, study treatments (those supplied by BMS or a vendor or sourced by the 
investigator), such as partially used study treatment containers, vials, and syringes, may be 
destroyed on site. 
If
Then
Study treatments supplied by BMS (including 
its vendors)
Any unused study interventions supplied by 
BMS can only be destroyed after being 
inspected and reconciled by the responsible 
Study Monitor, unless study treatments 
containers must be immediately destroyed as 
required for safety, or to meet local regulations 
(eg, cytotoxics or biologics).
Partially used study interventions and/or 
empty containers may be destroyed after 
proper reconciliation and documentation. But 
unused IMP must be reconciled by site 
monitor/Clinical Research Associate prior to 
destruction.
If study treatments will be returned, the return 
will be arranged by the responsible Study 
Monitor.
Study treatments sourced by site, not supplied 
by BMS (or its vendors; eg, study treatments 
sourced from the site’s stock or commercial 
supply or a specialty pharmacy)
It 
is 
the 
investigator’s 
or 
designee’s
responsibility to dispose of all containers 
according to the institutional guidelines and 
procedures.
It is the investigator’s or designee’s responsibility to arrange for disposal of study interventions, 
provided that procedures for proper disposal have been established according to applicable federal, 
state, local, and institutional guidelines and procedures, and provided that appropriate records of 
disposal are kept. The following minimal standards must be met:
•
On-site disposal practices must not expose humans to risks from the drug.
•
On-site disposal practices and procedures are in agreement with applicable laws and 
regulations, including any special requirements for controlled or hazardous substances.
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•
Written procedures for on-site disposal are available and followed. The procedures must be 
filed with the site’s standard operating procedures and a copy provided to BMS upon request.
•
Records are maintained that allow for traceability of each container, including the date 
disposed of, quantity disposed, and identification of the person disposing the containers. The 
method of disposal (eg, incinerator, licensed sanitary landfill, or licensed waste-disposal 
vendor) must be documented.
•
Accountability and disposal records are complete, up-to-date, and available for the Study 
Monitor to review throughout the clinical trial period.
It is the investigator’s or designee’s responsibility to arrange for disposal of all empty containers.
If conditions for destruction cannot be met, the responsible Study Monitor will make arrangements 
for return of study treatments provided by BMS (or its vendors). Destruction of non-study 
treatments sourced by the site, not supplied by BMS, is solely the responsibility of the investigator 
or designee.
STUDY AND SITE START AND CLOSURE
The Sponsor/designee reserves the right to close the study site or to terminate the study at any time 
for any reason at the sole discretion of the Sponsor. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study supplies have 
been collected and a study-site closure visit has been performed.
The investigator may initiate study-site closure at any time, provided there is reasonable cause and 
sufficient notice is given in advance of the intended termination.
Reasons for the early closure of a study site by the Sponsor or investigator may include, but are 
not limited to:
•
Failure of the investigator to comply with the protocol, the requirements of the IRB/IEC or 
local Health Authorities, the Sponsor’s procedures, or GCP guidelines
•
Inadequate recruitment of participants by the investigator
•
Discontinuation of further study intervention development
If the study is prematurely terminated or suspended, the Sponsor shall promptly inform the 
investigators, the IECs/IRBs, the regulatory authorities, and any contract research organization(s) 
used in the study of the reason for termination or suspension, as specified by the applicable 
regulatory requirements. The investigator shall promptly inform the participant and should assure 
appropriate participant therapy and/or follow-up.
DISSEMINATION OF CLINICAL STUDY DATA
In the European Union (EU), the summary of results and summary for laypersons will be submitted 
within 1 year of the end of trial in EU/European Economic Area and third countries.
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CLINICAL STUDY REPORT
A Signatory Investigator must be selected to sign the Clinical Study Report (CSR).
For each CSR related to this protocol, the following criteria will be used to select the Signatory 
Investigator:
•
External Principal Investigator designated at protocol development
•
National Coordinating Investigator
•
Participant recruitment (eg, among the top quartile of enrollers)
SCIENTIFIC PUBLICATIONS
The data collected during this study are confidential and proprietary to the Sponsor or designee. 
Any publications or abstracts arising from this study must adhere to the publication requirements 
set forth in the Clinical Trial Agreement (CTAg) governing [study site or investigator] 
participation in the study. These requirements include, but are not limited to, submitting proposed 
publications to the Sponsor or designee at the earliest practicable time prior to submission or 
presentation and otherwise within the time period set forth in the CTAg.
Scientific publications (such as abstracts, congress podium presentations and posters, and 
manuscripts) of the study results will be a collaborative effort between the study Sponsor and the 
external authors. No public presentation or publication of any interim results may be made by any 
Principal Investigator, sub-investigator, or any other member of the study staff without the prior 
written consent of the Sponsor.
Authorship of publications at BMS is aligned with the criteria of the International Committee of 
Medical Journal Editors (ICMJE, www.icmje.org). Authorship selection is based upon significant 
contributions to the study (ie, ICMJE criterion #1). Authors must meet all 4 ICMJE criteria for 
authorship:
1) Substantial intellectual contribution to the conception or design of the work; or the acquisition 
of data (ie, evaluable participants with quality data), analysis, or interpretation of data for the 
work (eg, problem solving, advice, evaluation, insights and conclusion); AND
2) Drafting the work or revising it critically for important intellectual content; AND
3) Final approval of the version to be published; AND
4) Agreement to be accountable for all aspects of the work in ensuring that questions related to 
the accuracy or integrity of any part of the work are appropriately investigated and resolved.
Those who make the most significant contributions, as defined above, will be considered by BMS 
for authorship of the primary publication. Sub-investigators will generally not be considered for 
authorship in the primary publication. Geographic representation will also be considered.
Authors will be listed by order of significant contributions (highest to lowest), with the exception 
of the last author. Authors in first and last position have provided the most significant contributions 
to the work. 
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For secondary analyses and related publications, author list and author order may vary from 
primary to reflect additional contributions.
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APPENDIX 3
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS: 
DEFINITIONS AND PROCEDURES FOR RECORDING, 
EVALUATING, FOLLOW UP AND REPORTING
ADVERSE EVENTS
Adverse Event Definition:
An adverse event (AE) is defined as any new untoward medical occurrence or worsening of a 
pre-existing medical condition in a clinical investigation participant administered study 
treatment that does not necessarily have a causal relationship with this treatment. 
An AE can therefore be any unfavorable and unintended sign (such as an abnormal laboratory 
finding), symptom, or disease temporally associated with the use of study treatment, whether or 
not considered related to the study treatment.
Events Meeting the AE Definition
•
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or
results from other safety assessments (eg, electrocardiograms, radiological scans, vital signs
measurements), including those that worsen from baseline, considered clinically significant
in the medical and scientific judgment of the investigator. Note that abnormal lab tests or
other safety assessments should only be reported as AEs if the final diagnosis is not
available. Once the final diagnosis is known, the reported term should be updated to be the
diagnosis.
•
Exacerbation of a chronic or intermittent pre-existing condition, including either an increase
in frequency and/or intensity of the condition.
•
New conditions detected or diagnosed after study intervention administration, even though
it may have been present before the start of the study.
•
Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.
•
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study intervention
or a concomitant medication. Overdose, as a verbatim term (as reported by the investigator),
should not be reported as an AE/serious adverse event (SAE) unless it is an intentional
overdose taken with possible suicidal/self-harming intent. Such overdoses should be
reported regardless of sequelae and should specify “intentional overdose” as the verbatim
term.
Events NOT Meeting the AE Definition
•
Medical or surgical procedure (eg, endoscopy, appendectomy); the condition that leads to
the procedure is the AE.
•
Situations in which an untoward medical occurrence did not occur (social and/or
convenience admission to a hospital).
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DEFINITION OF SAE
If an event is not an AE per definition above, then it cannot be an SAE, even if serious conditions 
are met.
SERIOUS ADVERSE EVENTS
A serious adverse event (SAE) is defined as any untoward medical occurrence that, at any 
dose:
Results in death.
Is life-threatening (defined as an event in which the participant was at risk of death at the time 
of the event; it does not refer to an event which hypothetically might have caused death if it were 
more severe).
Requires inpatient hospitalization or causes prolongation of existing hospitalization (see NOTE 
below).
NOTE: 
The following hospitalizations are not considered SAEs in Bristol-Myers Squibb (BMS) clinical 
studies: 
•
A visit to the emergency room or other hospital department < 24 hours that does not result
in admission (unless considered an important medical or life-threatening event).
•
Elective surgery, planned prior to signing consent.
•
Admissions as per protocol for a planned medical/surgical procedure.
•
Routine health assessment requiring admission for baseline/trending of health
status (eg, routine colonoscopy).
•
Medical/surgical admission other than to remedy ill health and planned prior to entry into
the study. Appropriate documentation is required in these cases.
•
Admission encountered for another life circumstance that carries no bearing on health status
and requires no medical/surgical intervention (eg, lack of housing, economic inadequacy,
caregiver respite, family circumstances, administrative reason).
•
Admission for administration of anticancer therapy in the absence of any other
SAEs (applies to oncology protocols).
Results in persistent or significant disability/incapacity.
Is a congenital anomaly/birth defect.
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Is an important medical event (defined as a medical event[s] that may not be immediately 
life-threatening or result in death or hospitalization but, based upon appropriate medical and 
scientific judgment, may jeopardize the participant or may require intervention [eg, medical, 
surgical] to prevent one of the other serious outcomes listed in the definition above). Examples 
of such events include, but are not limited to, intensive treatment in an emergency room or at 
home for allergic bronchospasm and blood dyscrasias or convulsions that do not result in 
hospitalization. Potential drug-induced liver injury (DILI) is also considered an important 
medical event. (See Section 9.2.7 for the definition of potential DILI.) 
Pregnancy and DILI must follow the same transmission timing and processes to BMS as used for 
SAEs. (See Section 9.2.5 for reporting pregnancies.)
Any component of a study endpoint that is considered related to study therapy should be reported 
as an SAE (eg, death is an endpoint; if death occurred due to anaphylaxis, anaphylaxis must be 
reported).
EVALUATING AES AND SAES
Assessment of Causality
•
The investigator is obligated to assess the relationship between study intervention and each 
occurrence of each AE/SAE.
•
A “reasonable possibility” of a relationship conveys that there are facts, evidence, and/or 
arguments to suggest a causal relationship, rather than a relationship cannot be ruled out.
•
The investigator will use clinical judgment to determine the relationship.
•
Alternative causes, such as underlying disease(s), concomitant therapy, and other risk 
factors, as well as the temporal relationship of the event to study intervention administration, 
will be considered and investigated.
•
The investigator will also consult the Investigator’s Brochure and/or product information for 
marketed products in his/her assessment.
•
For each AE/SAE, the investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality.
•
There may be situations in which an SAE has occurred and the investigator has minimal 
information to include in the initial report to the Sponsor. However, it is very important that 
the investigator always make an assessment of causality for every event before the initial 
transmission of the SAE data to the Sponsor.
•
The investigator may change his/her opinion of causality in light of follow-up information 
and send an SAE follow-up report with the updated causality assessment.
•
The causality assessment is one of the criteria used when determining regulatory reporting 
requirements.
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Assessment of Intensity
The investigator will make an assessment of intensity for each AE and SAE reported during the 
study and assign it to 1 of the following categories: 
•
Mild: An event that is easily tolerated by the participant, causing minimal discomfort and
not interfering with everyday activities.
•
Moderate: An event that causes sufficient discomfort and interferes with normal everyday
activities.
•
Severe: An event that prevents normal everyday activities. An AE that is assessed as severe
should not be confused with an SAE. Severe is a category utilized for rating the intensity of
an event, and both AEs and SAEs can be assessed as severe.
An event is defined as “serious” when it meets at least 1 of the predefined outcomes as described 
in the definition of an SAE, NOT when it is rated as severe.
Follow-up of AEs and SAEs
If only limited information is initially available, follow-up reports are required. (Note: Follow-
up SAE reports must include the same investigator term(s) initially reported.)
If an ongoing SAE changes in its intensity or relationship to study treatment or if new 
information becomes available, the SAE report must be updated and submitted within 24 hours 
to BMS (or designee) using the same procedure used for transmitting the initial SAE report.
All SAEs must be followed to resolution or stabilization.
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REPORTING OF SAES TO SPONSOR OR DESIGNEE
•
SAEs, whether related or not related to study treatment, and pregnancies must be reported
to BMS (or designee) immediately within 24 hours of awareness of the event.
•
SAEs must be recorded on the SAE Report Form.
−
The required method for SAE data reporting is through the electronic case report
form (eCRF).
−
The paper SAE Report Form is intended only as a back-up option when the electronic
data capture system is unavailable/not functioning for transmission of the eCRF to BMS
(or designee).
♦In this case, the paper form is transmitted via email or confirmed facsimile
transmission.
♦When paper forms are used, the original paper forms are to remain on site.
•
Pregnancies must be recorded on paper Pregnancy Surveillance Forms and transmitted via
email or confirmed facsimile transmission.
SAE Email Address: 
SAE Facsimile Number: Will be provided by local site monitor.
SAE Telephone Contact (required for SAE and pregnancy reporting): Will be provided by local 
site monitor.
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APPENDIX 4
WOMEN OF CHILDBEARING POTENTIAL DEFINITIONS AND 
METHODS OF CONTRACEPTION
Appendix 4 provides general information and definitions related to Woman of Childbearing 
Potential and methods of contraception that can be applied to most clinical trials. For information 
specific to this study regarding acceptable contraception requirements for female and male 
participants, refer to Section 6.1 of the protocol. Only the contraception methods as described in 
Section 6.1 are acceptable for this study.
DEFINITIONS
Woman of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming postmenopausal unless 
permanently sterile. Permanent sterilization methods include hysterectomy, bilateral 
salpingectomy, and bilateral oophorectomy.
Women in the following categories are not considered WOCBP:
•
Premenarchal
•
Premenopausal female with 1 of the following:
−
Documented hysterectomy
−
Documented bilateral salpingectomy
−
Documented bilateral oophorectomy
Note: Documentation can come from the site personnel’s review of the participant’s medical 
records, medical examination, or medical history interview.
•
Postmenopausal female
−
A postmenopausal state is defined as 12 months of amenorrhea in a woman over age
45 years in the absence of other biological or physiological causes. In addition, females
under the age of 55 years must have a serum follicle-stimulating hormone (FSH) level
> 40 mIU/mL to confirm menopause.
Note: Females treated with hormone replacement therapy (HRT) are likely to have artificially 
suppressed FSH levels and may require a washout period in order to obtain a physiologic FSH 
level. The duration of the washout period is a function of the type of HRT used. Suggested 
guidelines for the duration of the washout periods for HRT types are presented below. Investigators 
should use their judgement in checking serum FSH levels. 
•
1-week minimum for vaginal hormonal products (rings, creams, gels)
•
4-week minimum for transdermal products
•
8-week minimum for oral products
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Other parenteral products may require washout periods as long as 6 months. If the serum FSH 
level is > 40 mIU/mL at any time during the washout period, the woman can be considered 
postmenopausal.
End of Relevant Systemic Exposure
End of relevant systemic exposure is the timepoint where the Investigational Medicinal Product 
(IMP) or any active major metabolites have decreased to a concentration that is no longer 
considered to be relevant for human teratogenicity or fetotoxicity. This should be evaluated in 
context of safety margins from the no-observed-adverse-effect level or the time required for 5 half-
lives of the IMP to pass.
CONTRACEPTION GUIDANCE FOR FEMALE PARTICIPANTS OF CHILD BEARING 
POTENTIAL
One of the highly effective methods of contraception listed below is required during study duration 
and until the end of relevant systemic exposure, defined as 12 months after the end of study 
treatment, for participants who receive cyclophosphamide, or for 6 months for participants who 
do not receive cyclophosphamide, after the last dose of study treatment with nivolumab or 
nivolumab placebo, whichever is longer.
Local laws and regulations may require use of alternative and/or additional contraception methods.
In the CA209-7FL study, use of hormonal methods of contraception is prohibited in 
WOCBP.
Highly Effective Contraceptive Methods That Are User Dependent 
Failure rate of < 1% per year when used consistently and correctly.a
•
Combined (estrogen- and progestogen-containing) hormonal contraception associated with 
inhibition of ovulation and/or implantation (These methods of contraception cannot be used 
by WOCBP participants in studies where hormonal contraception is prohibited)b
−
oral (birth control pills)
−
intravaginal (vaginal birth control suppositories, rings, creams, gels)
−
transdermal
•
Progestogen-only hormonal contraception associated with inhibition of ovulation (These 
methods of contraception cannot be used by WOCBP participants in studies where hormonal 
contraception is prohibited)b
−
oral
−
injectable
Highly Effective Methods That Are User Independent
•
Implantable progestogen-only hormonal contraception associated with inhibition of 
ovulation and/or implantation (This method of contraception cannot be used by WOCBP 
participants in studies where hormonal contraception is prohibited)b
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Intrauterine device (IUD)c
•
Intrauterine hormone-releasing system (IUS) (This method of contraception cannot be used
by WOCBP participants in studies where hormonal contraception is prohibited)b,c
•
Bilateral tubal occlusion
•
Vasectomized partner
A vasectomized partner is a highly effective contraception method provided that the partner
is the sole male sexual partner of the WOCBP and the absence of sperm has been confirmed.
If not, an additional highly effective method of contraception should be used.
•
Sexual abstinence
Sexual abstinence is considered a highly effective method only if defined as refraining from
heterosexual intercourse during the entire period of risk associated with the study treatment.
The reliability of sexual abstinence needs to be evaluated in relation to the duration of the
study and the preferred and usual lifestyle of the participant.
•
It is not necessary to use any other method of contraception when complete abstinence is
elected.
•
WOCBP participants who choose complete abstinence must continue to have pregnancy
tests, as specified in Section 2.
•
Acceptable alternate methods of highly effective contraception must be discussed in the
event that the WOCBP participants chooses to forego complete abstinence.
NOTES:
a Typical use failure rates may differ from those when used consistently and correctly. Use should be consistent
with local regulations regarding the use of contraceptive methods for participants participating in clinical studies.
b Hormonal contraception may be susceptible to interaction with the study treatment, which may reduce the
efficacy of the contraceptive method. Hormonal contraception is permissible only when there is sufficient 
evidence that the IMP and other study medications will not alter hormonal exposures such that contraception 
would be ineffective or result in increased exposures that could be potentially hazardous. In this case, alternative 
methods of contraception should be utilized.
c Intrauterine devices and intrauterine hormone releasing systems are acceptable methods of contraception in the
absence of definitive drug interaction studies when hormone exposures from intrauterine devices do not alter 
contraception effectiveness.
Less Than Highly Effective Contraceptive Methods That Are User Dependent 
Failure rate of >1% per year when used consistently and correctly.
•
Male or female condom with or without spermicide. Male and female condoms cannot be
used simultaneously
•
Diaphragm with spermicide
•
Cervical cap with spermicide
•
Vaginal Sponge with spermicide
•
Progestogen-only oral hormonal contraception, where inhibition of ovulation is not the
primary mechanism of action (This method of contraception cannot be used by WOCBP
participants in studies where hormonal contraception is prohibited)
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Unacceptable Methods of Contraception*
•
Periodic abstinence (calendar, symptothermal, post-ovulation methods)
•
Withdrawal(coitus interruptus)
•
Spermicide only
•
LAM
CONTRACEPTION GUIDANCE FOR MALE PARTICIPANTS WITH PARTNER(S) OF 
CHILD BEARING POTENTIAL.
Male participants with female partners of childbearing potential are eligible to participate if they 
agree to the following during the treatment and until the end of relevant systemic exposure.
Inform any and all partner(s) of their participation in a clinical drug study and the need to comply 
with contraception instructions as directed by the investigator.
•
Male who are sexually active with WOCBP must agree to follow instructions for method(s) of
contraception and fetal protection for the duration of neoadjuvant (pre-surgery) treatment
phase, and 12 months after the last dose of cyclophosphamide OR 6 months after last dose of
paclitaxel, whichever is the last dose.
•
Female partners of males participating in the study to consider use of effective methods of
contraception until the end of relevant systemic exposure, defined as 12 months after the last
dose of cyclophosphamide OR 6 months after the last dose of paclitaxel, whichever is the last
dose.
COLLECTION OF PREGNANCY INFORMATION
Guidance for collection of pregnancy information and outcome of pregnancy on the Pregnancy 
Surveillance Form is provided in Section 9.2.6 and Appendix 3.
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APPENDIX 5
ECOG PERFORMANCE STATUS
ECOG PERFORMANCE STATUSa
0
Fully active, able to carry on all pre-disease performance without restriction
1
Restricted in physically strenuous activity but ambulatory and able to carry out work of a 
light or sedentary nature, eg, light house work, office work
2
Ambulatory and capable of all selfcare but unable to carry out any work activities. Up and 
about more than 50% of waking hours
3
Capable of only limited selfcare, confined to bed or chair more than 50% of waking hours
4
Completely disabled. Cannot carry on any selfcare. Totally confined to bed or chair
5
Dead
a Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, and Carbone PP. Toxicity and Response 
Criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol 1982; 5: 649-655.
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APPENDIX 6
MANAGEMENT ALGORITHMS
These general guidelines constitute guidance to the Investigator and may be supplemented by 
discussions with the Medical Monitor representing the Sponsor. The guidance applies to all 
immuno-oncology agents and regimens.
A general principle is that differential diagnoses should be diligently evaluated according to 
standard medical practice. Non-inflammatory etiologies should be considered and appropriately 
treated.
Corticosteroids are a primary therapy for immuno-oncology drug-related adverse events. The oral 
equivalent of the recommended IV doses may be considered for ambulatory patients with low 
grade toxicity. The lower bioavailability of oral corticosteroids should be taken into account when 
switching to the equivalent dose of oral corticosteroids.
Consultation with a medical or surgical specialist, especially prior to an invasive diagnostic or 
procedure, is recommended.
The frequency and severity of the related adverse events covered by these algorithms will depend 
on the immuno-oncology agent or regimen being used.
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APPENDIX 7
RADIOTHERAPY GUIDELINES
1
RADIOTHERAPY POST-BREAST CONSERVING THERAPY
Breast radiotherapy (RT) after complete local excision is mandatory.
Breast RT may be contraindicated in participants with significant comorbidity (eg, scleroderma 
and systemic lupus erythematosus). Reasons for not delivering breast RT after complete local 
excision of the primary breast cancer should be documented in the eCRF.
1.1
Target Volume
Whole breast including the primary tumor bed.
Primary tumor bed boost in conjunction with whole breast RT may be used per local policy, 
declared by the center prior to local activation.
Partial breast RT may be used per local policy, declared by the center prior to local activation.
Regional nodal RT: Refer to Item 3 below.
1.2
Dose Fractionation
Whole breast - recommended schedules:
1) 50 Gy in 25 fractions, 5 fractions per week, or
2) 42.5 Gy in 16 fractions, 5 fractions per week, or
3) 40 Gy in 15 fractions, 5 fractions per week.
Other schedules may be used per local policy, declared by the center prior to local activation.
Primary tumor bed boost in conjunction with whole breast RT: Per local policy, declared by the 
center prior to local activation.
Partial breast RT: Per local policy declared by the center prior to local activation.
1.3
Treatment Planning
Computer tomography (CT)-based treatment planning is strongly recommended for whole breast 
RT and tumor bed boost.
CT-based treatment planning is mandatory for partial breast irradiation delivered using 
external-beam RT.
2
RADIOTHERAPY POST-MASTECTOMY
Breast RT after mastectomy is mandatory under the following conditions:
1) 4 or more positive axillary nodes or,
2) Pathologic T4 disease, or
3) ‘Non-resectable’ microscopic positive deep margin.
Breast RT after mastectomy is optional under the following conditions:
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1) 1-3 positive axillary nodes, or
2) Higher-risk node-negative disease (eg, T3 primary in the presence of high histologic grade 
and/or lymphovascular invasion).
2.1
Target Volume
Whole breast including the primary tumor bed.
Primary tumor bed boost in conjunction with whole breast RT may be used per local policy,
declared by the center prior to local activation.
Regional nodal RT: Refer to Item 3 below.
2.2
Dose Fractionation
Whole breast: Recommended schedule is 50 Gy in 25 fractions, 5 fractions per week. Other 
schedules may be used per local policy, declared by the center prior to local activation.
Primary tumor bed boost in conjunction with chest wall RT: Per local policy, declared by the center 
prior to local activation.
2.3
Treatment Planning
CT-based treatment planning is strongly recommended for chest wall RT.
3
REGIONAL NODAL RT
Regional nodal RT is recommended under the following conditions:
1) Any breast surgery, 4 or more positive axillary nodes.
Regional nodal radiotherapy is optional under the following conditions:
1) Any breast surgery, 0-3 positive axillary nodes, pathological T4 (pT4) disease.
3.1
Target Volume
If required:
•
Supraclavicular fossa if there are 4 or more positive axillary nodes;
•
Internal mammary nodes if tumor involvement is biopsy confirmed.
If optional:
•
Supraclavicular fossa if there are 0-3 positive axillary nodes;
•
Axilla as per local policy declared by the center prior to local activation (eg, known or high 
risk of residual axillary disease post surgery);
•
Internal mammary nodes if there is a high risk of tumor involvement, per local policy, declared 
by the center prior to local activation.
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3.2
Dose Fractionation
Recommended schedule: 50 Gy in 25 fractions, 5 fractions per week. Other schedules may be used 
per local policy, declared by the center prior to local activation. Hypofractionated schedules are 
not recommended.
3.3
Treatment Planning
CT-based treatment planning is strongly recommended for supraclavicular fossa and/or axillary 
RT.
CT-based treatment planning is mandatory for internal mammary nodal RT.
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APPENDIX 8
RESPONSE EVALUATION CRITERIA IN SOLID TUMORS 
GUIDELINES (VERSION 1.1) WITH BMS MODIFICATIONS FOR 
NEOADJUVANT BREAST CANCER
HIGH LEVEL SUMMARY OF THE MODIFICATIONS
•
Up to two lesions in the breast may be identified as target lesions.
•
Lymph nodes are not to be designated as target or non-target lesions.
•
Target and Non-Target lesions can be selected from mammography, ultrasound, or MRI.
•
Removal of fluid  (ascites, pleural and pericardial effusions) from response  assessment as non-
target or new lesion due to potential unconfirmed etiology and volume changes resulting from
interventional procedures unrelated to treatment response (thoracentesis).
•
Best Overall Response of CR or PR does not require confirmation. SD must meet minimum
time on study requirement as defined in protocol.
1
EVALUATION OF LESIONS
Solid tumors will be evaluated using Response Evaluation Criteria In Solid Tumors version 1.1 
(RECIST v1.1) guideline1 with BMS modifications for neoadjuvant breast cancer.
At baseline, breast tumor lesions will be categorized as measurable or non-measurable as follows:
1.1
Measurable
Tumor lesions must be accurately measured in at least one dimension (longest diameter in the 
plane of measurement is to be recorded).
•
Measurable lesions may be measured by mammography, ultrasound, or MRI.
1.2
Non-measurable
All other breast lesions are considered non-measurable, including small lesions.
1.3
Baseline Documentation Of ‘Target’ And ‘Non-target’ Lesions
Up to two lesions in the breast may be identified as target lesions. Per this protocol, first target 
lesion must be at least 20 mm and, if selected, second target lesion must be at least 10 mm. 
Lymph nodes are not to be designated as target or non-target lesions at baseline.
Target lesions should be selected on the basis of their size (lesions with the longest diameter) but 
in addition should be those that lend themselves to reproducible repeated measurements. A sum of 
the longest diameters for all target lesions will be calculated and reported as the baseline sum 
diameters. The baseline sum diameters will be used as reference to further characterize any 
objective tumor regression in the measurable dimension of the disease.
All other breast lesions should be identified as non-target lesions and should also be recorded at 
baseline. Measurements are not required and these lesions should be followed as ‘present’, 
‘absent’, or in rare cases ‘unequivocal progression’ (more details to follow). In addition, it is 
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possible to record multiple non-target lesions involving the same organ as a single item on the case 
record form.
2
RESPONSE CRITERIA
2.1
Evaluation of Target Lesions
•
Complete Response (CR): Disappearance of all target lesions.
•
Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, 
taking as reference the baseline sum diameters.
•
Progressive Disease (PD): At least a 20% increase in the sum of diameters of target lesions, 
taking as reference the smallest sum on study (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. Appearance of one or more new lesions is also considered 
progression.
•
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest sum diameters while on study.
•
Not Evaluable (NE): If one or more target lesions cannot be measured or adequately assessed 
as either fully resolved or too small to measure (due to missing or poor quality images), and 
the sum of diameters of the remaining measured target lesions (if any) has not increased 
sufficiently to meet Progressive Disease as defined above. 
2.1.1
Special Notes on the Assessment of Target Lesions
2.1.1.1
Target Lesions That Become ‘Too Small to Measure’
While on study, all lesions recorded at baseline should have their actual measurements recorded 
at each subsequent evaluation, even when very small (eg, 2 mm). However, sometimes lesions or 
lymph nodes which are recorded as target lesions at baseline become so faint on imaging that the 
radiologist may not feel comfortable assigning an exact measure and may report them as being 
‘too small to measure’. When this occurs it is important that a value be recorded on the case report 
form. If it is the opinion of the radiologist that the lesion has likely disappeared, the measurement 
should be recorded as 0 mm. If the lesion is believed to be present and is faintly seen but too small 
to measure, a default value of 5 mm should be assigned as the reference diameter. The 
measurement of these lesions is potentially non-reproducible, therefore providing this default 
value will prevent false responses or progressions based upon measurement error. To reiterate, 
however, if the radiologist is able to provide an actual measure, that should be recorded, even if it 
is below 5 mm.
2.1.1.2
Lesions That Split or Coalesce on Treatment
When non-nodal lesions ‘fragment’, the longest diameters of the fragmented portions should be 
added together to calculate the target lesion sum. Similarly, as lesions coalesce, a plane between 
them may be maintained that would aid in obtaining maximal diameter measurements of each 
individual lesion. If the lesions have truly coalesced such that they are no longer separable, the 
vector of the longest diameter in this instance should be the maximal longest diameter for the 
‘coalesced lesion’.
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2.2
Evaluation of Non-target Lesions
This section provides the definitions of the criteria used to determine the tumor response for the 
group of non-target lesions. While some non-target lesions may actually be measurable, they need 
not be measured and instead should be assessed only qualitatively at the time points specified in 
the protocol.
•
Complete Response (CR): Disappearance of all non-target lesions.
•
Non-CR/Non-PD: Persistence of one or more non-target lesion(s).
•
Progressive Disease (PD): Unequivocal progression of existing non-target lesions.
2.2.1
Special Notes on Assessment of Progression of Non-target Disease
The concept of progression of non-target disease requires additional explanation as follows:
2.2.1.1
When the Patient also has Measurable Disease
In this setting, to achieve ‘unequivocal progression’ on the basis of the non-target disease, there 
must be an overall level of substantial worsening in non-target disease such that, even in presence 
of SD or PR in target disease, the overall tumor burden has increased sufficiently to merit 
discontinuation of therapy A modest ‘increase’ in the size of one or more non-target lesions is 
usually not sufficient to qualify for unequivocal progression status. Pleural effusions, pericardial 
effusions and ascites will not be followed as target or non-target lesions and will not contribute to 
response or progression. The designation of overall progression solely on the basis of change in 
non-target disease in the face of SD or PR of target disease will therefore be extremely rare.
2.2.1.2
When the Patient has Only Non-measurable Disease
This circumstance arises in some trials when it is not a criterion of study entry to have measurable 
disease. The same general concepts apply here as noted above, however, in this instance there is 
no measurable disease assessment to factor into the interpretation of an increase in non-measurable 
disease burden. Because worsening in non-target disease cannot be easily quantified (by definition: 
if all lesions are truly non-measurable) a useful test that can be applied when assessing patients for 
unequivocal progression is to consider if the increase in overall disease burden based on the change 
in non-measurable disease is comparable in magnitude to the increase that would be required to 
declare PD for measurable disease: ie, an increase in tumor burden representing an additional 73% 
increase in ‘volume’ (which is equivalent to a 20% increase diameter in a measurable lesion). 
Examples include, an increase in lymphangitic disease from localized to widespread, or may be 
described as ‘sufficient to require a change in therapy’. If ‘unequivocal progression’ is seen, the 
patient should be considered to have had overall PD at that point. While it would be ideal to have 
objective criteria to apply to non-measurable disease, the very nature of that disease makes it 
impossible to do so; therefore the increase must be substantial.
2.2.2
New Lesions
The appearance of new malignant lesions denotes disease progression; therefore, some comments 
on detection of new lesions are important. There are no specific criteria for the identification of 
new radiographic lesions; however, the finding of a new lesion should be unequivocal: ie, not 
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attributable to differences in scanning technique, change in imaging modality or findings thought 
to represent something other than tumor (for example, some ‘new’ bone lesions may be simply 
healing or flare of pre-existing lesions). This is particularly important when the patient’s baseline 
lesions show partial or complete response. For example, necrosis of a liver lesion may be reported 
on a CT scan report as a ‘new’ cystic lesion, which it is not.
NOTE: Fluid collections (pleural effusions, pericardial effusions, and ascites) will not be 
considered new lesions and will not contribute to response or progression. In the event a new fluid 
collection is seen on a post-baseline imaging exam, a comment may be made, but the appearance 
of a new fluid collection alone should not result in an assessment of Progressive Disease (PD). A 
lesion identified on a follow-up study in an anatomical location that was not scanned at baseline 
is considered a new lesion and will indicate disease progression. An example of this is the patient 
who has visceral disease at baseline and while on study has a CT or MRI brain ordered which 
reveals metastases. The patient’s brain metastases are considered to be evidence of PD even if 
he/she did not have brain imaging at baseline. A lesion identified on Chest X-Ray that was not 
present in prior CT can be considered a new lesion and will result in Progressive Disease (PD).
If a new lesion is equivocal, for example because of its small size, continued follow-up evaluation 
will clarify if it represents truly new disease. If repeat scans confirm there is definitely a new 
lesion, then progression should be declared using the date of the initial scan. While FDG-PET 
response assessments need additional study, it is sometimes reasonable to incorporate the use of 
FDG-PET scanning to complement CT scanning in assessment of progression (particularly 
possible ‘new’ disease). New lesions on the basis of FDG-PET imaging can be identified according 
to the following algorithm:
1) Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of PD based
on a new lesion.
2) No FDG-PET at baseline and a positive FDG-PET at follow-up: If the positive FDG-PET at
follow-up corresponds to a new site of disease confirmed by CT, this is PD. If the positive
FDG-PET at follow-up is not confirmed as a new site of disease on CT, additional follow-up
CT scans are needed to determine if there is truly progression occurring at that site (if so, the
date of PD will be the date of the initial abnormal FDG-PET scan). If the positive FDG-PET
at follow-up corresponds to a pre-existing site of disease on CT that is not progressing on the
basis of the anatomic images, this is not PD.
2.3
Response Assessment
2.3.1
Evaluation of Best Overall Response
The best overall response is the best response recorded from the start of the study treatment in the 
Neoadjuvant (Pre-surgery) Phase.
The patient’s best overall response assignment will depend on the findings of both target and non-
target disease and will also take into consideration the appearance of new lesions. Assessments of 
partial response and complete response do not require confirmation.
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2.3.2
Time Point Response
At each protocol specified time point, a response assessment occurs. Table 2.3.2-1 provides a 
summary of the overall response status calculation at each time point for patients who have 
measurable disease at baseline. When patients have non-measurable (therefore non-target) disease 
only, Table 2.3.2-2 is to be used. 
Table 2.3.2-1:
Time Point Response
Target Lesions
Non-Target Lesions
New Lesions
Overall Response
CR
CR
No
CR
CR
Non-CR/non-PD
No
PR
CR
Not evaluated
No
PR
PR
Non-PD or not all 
evaluated
No
PR
SD
Non-PD or not all 
evaluated
No
SD
Not all evaluated
Non-PD
No
NE
PD
Any
Yes or No
PD
Any
PD
Yes or No
PD
Any
Any
Yes
PD
Abbreviations: CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease; NE, 
inevaluable.
Table 2.3.2-2:
Time Point Response
Non-Target Lesions
New Lesions
Overall Response
CR
No
CR
Non-CR/non-PD
No
Non-CR/non-PDa
Not all evaluated
No
NE
Unequivocal PD
Yes or No
PD
Any
Yes
PD
Abbreviations: CR, complete response; PD, progressive disease; NE, inevaluable; SD, stable disease.
a Non-CR/non-PD is preferred over SD for non-target disease since SD is increasingly used as endpoint for
assessment of efficacy in some trials so to assign this category when no lesions can be measured is not advised.
2.3.3
Best Overall Response
Best response determination of complete or partial response does not require confirmation. When 
SD is believed to be best response, it must meet the protocol specified minimum time from the 
date of first treatment or randomization date.
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For example, if the first scheduled follow-up imaging visit is Week 6 (± 7 days) for a particular 
protocol, a Best Response of SD can only be made after the subject is on-study for a minimum of 
6 weeks (42 days) minus 7 days, for an absolute minimum time on-study of 35 days from the 
reference start date (reference date is considered Day 1 on study). If the subject is not on-study for 
at least this amount of time, any tumor assessment indicating stable disease before this time period 
will have a Best Response of NE unless PD is identified.
2.3.4
Confirmation Scans
Verification of Progression: Progression of disease should be verified in cases where progression 
is equivocal. If repeat scans confirm PD, then progression should be declared using the date of the 
initial scan. If repeat scans do not confirm PD, then the subject is considered to not have 
progressive disease.
REFERENCES
1.
Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid 
tumors: revised RECIST guideline (version 1.1). Eur J Cancer 2009; 45: 228-47.
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APPENDIX 9
COUNTRY-SPECIFIC REQUIREMENTS/DIFFERENCES
Country
Section Number & Title
Original Language
Country-specific Language or 
Differences
Argentina, 
Czech Republic, 
Germany, Romania,
and 
Any Other Countries 
Where Exclusion of 
HIV Positive 
Participants is Locally 
Mandated
2: Schedule of Activities,
Table 2-1: Screening Assessments 
- LaboratoryTests
Add “HIV” to the list of laboratory tests.
Argentina, 
Czech Republic, 
Germany, 
and 
Any Other Countries 
Where Exclusion of 
HIV Positive 
Participants is Locally 
Mandated
6.2: Exclusion Criteria,
Exclusion Criterion 1) g)
Known history of testing positive for
human immunodeficiency virus (HIV) or
known
acquired
immunodeficiency
syndrome (AIDS).
Positive test for HIV.
Czech Republic
8.1: Discontinuation from Study 
Treatment
In the case of pregnancy, the Investigator 
must immediately, within 24 hours of 
awareness of the pregnancy, notify the 
Medical Monitor (or designee) of this 
event. In most cases, the study treatment 
will be permanently discontinued in an 
appropriate manner (eg, dose tapering if 
necessary for participant safety). See 
Section 9.2.6 (Pregnancy).
In the case of pregnancy, the Investigator 
must immediately, within 24 hours of 
awareness of the pregnancy, notify the 
Medical Monitor (or designee) of this 
event. In all cases, the study treatment will 
be 
permanently 
discontinued 
in 
an 
appropriate manner (eg, dose tapering if 
necessary for participant safety). See 
Section 9.2.6 (Pregnancy).
Czech Republic
9.2.6: Pregnancy
If, following initiation of the study 
treatment, it is subsequently discovered 
that a participant is pregnant or may have 
been pregnant at the time of study 
If, following initiation of the study 
treatment, it is subsequently discovered 
that a participant is pregnant or may have 
been pregnant at the time of study 
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Country-specific Language or 
Differences
exposure, including during at least 5 half-
lives after product administration, the 
Investigator must immediately notify the 
BMS Medical Monitor/designee of this 
event and complete and forward a 
Pregnancy Surveillance Form to the BMS 
designee within 24 hours of awareness of 
the event and in accordance with SAE 
reporting 
procedures 
described 
in 
Appendix 3.
If the Investigator determines a possible 
favorable benefit-risk ratio that warrants 
continuation of study treatment or re-
initiation of study treatment, a discussion 
between the Investigator and the BMS 
Medical Monitor/designee must occur. If, 
for whatever reason, the pregnancy has 
ended, confirmed by negative serum 
pregnancy test, treatment may be resumed 
(at least 3 weeks and not greater than 6 
weeks after the pregnancy has ended), 
following 
approvals 
of 
participant/Sponsor/IRB/IEC, 
as 
applicable.
Any pregnancy that occurs in a female 
partner of a male study participant should 
be reported to the Sponsor or designee. In 
order for the Sponsor or designee to 
collect 
any 
pregnancy 
surveillance 
information from the female partner, the 
female partner must sign an ICF for 
disclosure of this information. Information 
on this pregnancy will be collected on the 
Pregnancy Surveillance Form.
In cases where a study drug can be present 
in seminal fluid, at exposures sufficient to 
exposure, including during at least 5 half-
lives after product administration, the 
Investigator must immediately notify the 
BMS Medical Monitor/designee of this 
event and complete and forward a 
Pregnancy Surveillance Form to the BMS 
designee within 24 hours of awareness of 
the event and in accordance with SAE 
reporting 
procedures 
described 
in 
Appendix 3.
Any pregnancy that occurs in a female 
partner of a male study participant should 
be reported to the Sponsor or designee. In 
order for the Sponsor or designee to collect 
any pregnancy surveillance information 
from the female partner, the female partner 
must sign an ICF for disclosure of this 
information. 
Information 
on 
this 
pregnancy will be collected on the 
Pregnancy Surveillance Form.
In cases where a study drug can be present 
in seminal fluid, at exposures sufficient to 
potentially cause fetal toxicity, and if any 
sexual activity (eg, vaginal, anal, oral) has 
occurred between a male participant and a 
pregnant 
WOCBP 
partner(s), 
the 
information should be reported to the 
Sponsor or designee, even if the male 
participant has undergone a successful 
vasectomy. In order for the Sponsor or 
designee 
to 
collect 
any 
pregnancy 
surveillance information from the female 
partner, the female partner(s) must sign an 
ICF for disclosure of this information. 
Information on the pregnancy will be 
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Section Number & Title
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potentially cause fetal toxicity, and if any 
sexual activity (eg, vaginal, anal, oral) has 
occurred between a male participant and a 
pregnant 
WOCBP 
partner(s), 
the 
information should be reported to the 
Sponsor or designee, even if the male 
participant has undergone a successful 
vasectomy. In order for the Sponsor or 
designee 
to 
collect 
any 
pregnancy 
surveillance information from the female 
partner, the female partner(s) must sign an 
ICF for disclosure of this information. 
Information on the pregnancy will be 
collected on the Pregnancy Surveillance 
Form.
collected on the Pregnancy Surveillance 
Form.
 
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Section Number & Title
Original Language
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Differences
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Section Number & Title
Original Language
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Differences
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APPENDIX 10
NYHA FUNCTIONAL CLASSIFICATION
Heart failure is usually classified according to the severity of the patient’s symptoms. The table 
below describes the most commonly used classification system, the New York Heart Association 
(NYHA) functional classification. It places patients in 1 of 4 categories based on how much they 
are limited during physical activity.
Class
Patient Symptoms
I
No limitation of physical activity. Ordinary physical activity does 
not cause undue fatigue, palpitation, or dyspnea (shortness of 
breath).
II
Slight limitation of physical activity. Comfortable at rest. Ordinary 
physical activity results in fatigue, palpitation, or dyspnea 
(shortness of breath).
III
Marked limitation of physical activity. Comfortable at rest. Less 
than ordinary activity causes fatigue, palpitation, or dyspnea.
IV
Unable to carry on any physical activity without discomfort. 
Symptoms of heart failure at rest. If any physical activity is 
undertaken, discomfort increases.
Class
Objective Assessment
A
No objective evidence of cardiovascular disease. No symptoms 
and no limitation in ordinary physical activity.
B
Objective evidence of minimal cardiovascular disease. Mild 
symptoms and slight limitation during ordinary activity. 
Comfortable at rest.
C
Objective evidence of moderately severe cardiovascular disease. 
Marked limitation in activity due to symptoms, even during 
less-than-ordinary activity. Comfortable only at rest.
D
Objective evidence of severe cardiovascular disease. Severe 
limitations. Experiences symptoms even while at rest.
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APPENDIX 11
PROTOCOL AMENDMENT SUMMARY OF CHANGE HISTORY
Overall Rationale for the Protocol Amendment 02, 21-May-2021
The primary reasons for these changes are to align with current clinical practice, 
 
 provide clarification for study conduct, and ensure that the protocol is 
consistent with program level guidance, internal BMS policies and operating procedures. 
Additional revisions including to sections of the Synopsis have been made to align the protocol 
with respect to these changes.
The key updates include the following:
•
Updated BMS study contact information.
•
Aligned dose modification criteria and IO management algorithms with CTCAE v5.
•
•
Incorporated additional revisions to improve alignment across protocol sections and/or clarify
expectations for eligibility, assessments, sample collection, and treatment administration.
Summary of key changes for Protocol Amendment 02
Section Number & Title
Description of Change
Brief Rationale
2: Schedule of Activities
Table 2-1 (Screening Procedural 
Outline)
•
PE, Measurements, Vital
Signs, and ECOG PS
•
Table 2-1 Pregnancy Test
(WOCBP only)
Table 2-2 (On-treatment 
Neoadjuvant Procedural Outline 
with PTX and AC Q2W)
Table 2-3 (On-treatment 
Neoadjuvant Procedural Outline 
with PTX and AC Q3W)
Table 2-4 (On-treatment 
Adjuvant Procedural Outline)
Table 2-5 (Follow-up Procedural 
Outline)
•
Targeted PE, Measurements,
Vital Signs, and ECOG PS
9.4.1: Physical Examination
Removed external ocular 
examination.
Serum or urine pregnancy test 
(minimum sensitivity of 25 IU/L or 
equivalent units of HCG) to be done 
at screening and repeated within 24 
hours prior to the first dose of study 
therapy. An extension up to 72 
hours prior to the start of study 
treatment is permissible in situations 
where results cannot be obtained 
within the standard 24-hour 
window.
Updated safety assessment, removed 
external ocular examination to align 
with updated Nivolumab guidance.
Physical examination are to be 
performed if there are any new or 
worsening clinically significant 
changes since the last exam report 
changes on appropriate non-serious or 
SAE page. 
2: Schedule of Activities
Table 2-1 (Screening Procedural  
Outline)
Table 2-2 (On-treatment 
Neoadjuvant Procedural Outline 
with PTX and AC Q2W)
Correction: Bilateral Breast and 
Axilla Ultrasound, Mammogram or 
Breast MRI.
Clarification: either Bilateral 
Ultrasound or Mammogram of Breast 
and Axilla or Breast MRI should be 
done.
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Summary of key changes for Protocol Amendment 02
Section Number & Title
Description of Change
Brief Rationale
Table 2-3 (On-Treatment 
Neoadjuvant Procedural Outline 
with PTX and AC Q3W)
•
Bilateral Ultrasound or
Mammogram of Breast and
Axilla or Breast MRI
2: Schedule of Activities
Table 2-1 (Screening Procedural  
Outline)
•
Pretreatment Tumor Sample
Submission
Added: For participant with planned 
BCS, surgical clip(s) should be 
placed prior to starting neoadjuvant 
treatment but no later than PTX 
C2D1. For participant with planned 
mastectomy, placement of surgical 
clip(s) is strongly recommended. 
Placement of surgical clip(s) marks 
the tumor bed to ensure its 
appropriate localization at the time 
of the surgery and to enable 
accurate sampling of the specimen 
by the pathologist. (Refer to 
pathology manual for additional 
details).
Placement of clip(s) will facilitate 
localization of the tumor bed at time 
of the breast cancer surgery.
2: Schedule of Activities
Table 2-1 (Screening Procedural 
Outline)
•
ECG
Updated ECG must be performed 
within 14 days prior to 
randomization.
Updated ECG safety assessment 
timelines to schedule of activities.
2: Schedule of Activities
Table 2-1 (Screening Procedural 
Outline)
Table 2-2 (On-treatment 
Neoadjuvant Procedural Outline 
with PTX and AC Q2W)
Table 2-3 (On-treatment 
Neoadjuvant Procedural Outline 
with PTX and AC Q3W)
Table 2-4 (On-treatment 
Adjuvant Procedural Outline)
•
Pregnancy Test (WOCBP
only)
6.1: Inclusion Criteria
Updated schedule of activities and 
inclusion criterion 3) b) to add an 
extension up to 72 hours prior to the 
start of study treatment is 
permissible in situations where 
results cannot be obtained within 
the standard 24-hour window.
Updated pregnancy language to align 
with the current nivolumab program 
standard.
2: Schedule of Activities
Table 2-1 (Screening Procedural 
Outline)
•
SAE Assessment
•
•
Serum and AE/SAE collection in
the context of SARS-CoV-2 was
added in the event that
coronavirus disease 2019
(COVID-19) sequelae may
increase toxicity or impact
interpretation of study
events/results.
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Summary of key changes for Protocol Amendment 02
Section Number & Title
Description of Change
Brief Rationale
Table 2-2 (On-treatment 
Neoadjuvant Procedural Outline 
with PTX and AC Q2W)
Table 2-3 (On-treatment 
Neoadjuvant Procedural Outline 
with PTX and AC Q3W)
Table 2-4 (On-treatment 
Adjuvant Procedural Outline)
Table 2-5 (Follow-up Procedural 
Outline)
•
AEs Assessment (Including 
SAEs)
•
3.3.1: Nivolumab Safety Profile
4-1: Objectives and Endpoints
6.2: Exclusion Criteria
6.4.1: Retesting During 
Screening
7.4.1.1: Dose Delay Criteria for 
Nivolumab
7.4.1.2: Criteria to Resume 
Treatment with Nivolumab
9.2.2: Time Period and 
Frequency for Collecting AE and 
SAE Information
9.2.4: Follow up of AEs and 
SAEs
9.8.3.6: Other Assessments
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Summary of key changes for Protocol Amendment 02
Section Number & Title
Description of Change
Brief Rationale
2: Schedule of Activities
Table 2-1 (Screening Procedural 
Outline)
Table 2-2 (On-treatment 
Neoadjuvant Procedural Outline 
with PTX and AC Q2W)
Table 2-3 (On-treatment 
Neoadjuvant Procedural Outline 
with PTX and AC Q3W)
•
Bilateral Ultrasound or 
Mammogram of Breast 
Axilla or Breast MRI
Table 2-4 (On-treatment 
Adjuvant Procedural Outline)
Table 2-5 (Follow-up Procedural 
Outline)
•
Mammogram or Breast MRI 
for Participants with 
Remaining Breast Tissue 
Post-surgery
The following modifications were 
made:
•
Added ‘bilateral’ to procedure.
•
Regarding breast 
reconstruction, clarified if the 
other breast remains, this needs 
to be imaged on an annual 
basis.
•
Clarified the need to perform 
bilateral breast imaging and align 
with the requirement described for 
objective response rate 
assessment in Section 9.1.5.1 
Objective Response Rate.
•
Clarified post-surgery breast 
imaging requirements.
2: Schedule of Activities
Table 2-2 (On-treatment 
Neoadjuvant Procedural Outline 
with PTX and AC Q2W)
Table 2-3 (On-treatment 
Neoadjuvant Procedural Outline 
with PTX and AC Q3W)
•
Cortisol-Notes
Changed to:
Cortisol must be collected at AC 
C1D1 (predose) and prior to 
surgery. Result is not required prior 
to dosing.
Clarified that the cortisol result is not 
required prior to the first dose of 
anthracycline and cyclophosphamide, 
but the cortisol testing sample must be 
collected prior to the first dose.
2: Schedule of Activities
Table 2-2 (On-treatment 
Neoadjuvant Procedural Outline 
with PTX and AC Q2W)
Table 2-3 (On-treatment 
Neoadjuvant Procedural Outline 
with PTX and AC Q3W)
•
Surgery (SOC)
Clarified pathologic TNM staging is 
performed after tumor resection.
Clarified surgery timelines.
Clarified that TNM staging is done on 
the breast surgical sample after 
surgery.
2: Schedule of Activities
Table 2-2 (On-treatment 
Neoadjuvant Procedural Outline 
with PTX and AC Q2W)
Added footnote to define end of 
PTX as 3 weeks after PTX C4D1 or 
Clarified timing of the End of PTX 
visit which is expected 3 weeks after 
PTX Cycle 4 D1 or sooner if 
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Summary of key changes for Protocol Amendment 02
Section Number & Title
Description of Change
Brief Rationale
Table 2-3 (On-treatment 
Neoadjuvant Procedural Outline 
with PTX and AC Q3W)
•
End of PTX visit
sooner if participant discontinues 
prior to completion of the 4 cycles.
participant discontinues prior to 
completion of the 4 PTX cycles.
2: Schedule of Activities
Table 2-4 On-treatment 
Adjuvant Procedural Outline
 
 
Added a footnote to clarify the end 
of adjuvant therapy time point.
Clarified the end of adjuvant therapy 
time point to be 4 weeks after 
Adjuvant Cycle 7 Day 1, or sooner if 
the participant discontinues the 
adjuvant phase sooner.
Figure 5.1-1 Study design 
Schematic
Added T1c-T2, cN1-cN2 or T3-T4, 
cN0-cN2 as key inclusion criterion.
Clarified key TNM staging eligibility 
criterion.
5.1: Overall Design
5.4.5: Rationale for Stratification 
Factors
Clarified the need to confirm 
suspicious positive lymph node 
pathologically prior randomization.
Suspicious positive axillary lymph
node after clinical/radiographic 
assessment must be confirmed 
pathologically prior randomization.
5.1.2.1: Neoadjuvant (Pre-
surgery) Phase
5.1.2.2: Surgery
5.2: Number of Participants
Deleted 3rd paragraph:
For participants to proceed to the 
Adjuvant (Post-surgery) Phase of 
the study, definitive surgery must 
occur and be recorded in the source 
document as such. If definitive 
surgery does not occur, the 
participant will move to the 
Follow-up Period.
Clarified timeline for surgery.
Updated that it is anticipated that 
approximately 1,870 participants 
will be screened to treat 1,200 
eligible participants with nivolumab 
(Arm A; n = 600) or nivolumab 
placebo (Arm B; n = 600) in 
combination with neoadjuvant 
chemotherapy and adjuvant ET.
Corrected an inconsistency between 
Section 5.1.2.1 Neoadjuvant 
(Pre-surgery) Phase and Section 9.1.2 
Definition of event-free survival on 
how to manage participants who may 
not proceed to definitive surgery. 
Those participants may continue in the 
study treatment phase (adjuvant 
phase).
Clarified timeline for surgery.
Updated number of participants.
6.1: Inclusion Criteria
The following modifications were 
made:
•
Inclusion criterion 2) a) i)
Localized invasive breast ductal
carcinoma, confirmed by the
local pathologist, that includes
the following combined
primary tumor and clinical node
(cN) categories with subcriteria
detailed below.
•
Inclusion criterion 2) d)
removed must agree to undergo
These changes were made for the 
following reasons:
•
Clarified nodal status pathological
assessment.
•
Clarified inclusive tumor size
with nodal status.
•
Updated inclusion criteria 2) d)
with the protocol.
•
Updated contraceptive
requirements for male participants
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Summary of key changes for Protocol Amendment 02
Section Number & Title
Description of Change
Brief Rationale
surgery after the completion of 
neoadjuvant therapy.
•
Updated male contraception 
criteria 3) e) and f).
•
Inclusion criterion 2) a) v) 
added to the protocol as: 
Participants must have 
measurable disease based on 
modified Response Evaluation 
Criteria in Solid Tumors 
(RECIST) v1.1 (Refer to 
Appendix 8), as determined by 
local radiology review. 
based on current safety 
information.
•
Protocol has ORR as a secondary 
endpoint, which requires imaging 
evaluation of tumor size changes 
after systemic treatment.
6.2: Exclusion Criteria
The following modifications were 
made:
•
Replaced criterion 1) g) with 
new criterion 1) m) related to 
human immunodeficiency 
virus.
•
Replaced criterion 1) h) with 
new criterion 1) l) related to 
concurrent or prior malignancy.
•
Replaced criterion 2) g) with 
new criterion 2) i) related to 
complementary medications.
•
Added new criterion 3) m) 
related to hepatitis C.
•
Added new criterion 3) n) 
related to hepatitis B.
•
Removed criteria 3) k) and l) 
related to chronic HBV and 
HCV infection, respectively.
These changes were made to include 
new clinical approaches for eligibility 
related to viral infections, and 
concurrent or prior malignancies, prior 
anticancer therapy AEs, supportive 
care, and eligibility criteria for 
participants in interventional trials.
Table 7.1-2 Selection and 
Timing of Dose - Neoadjuvant 
(Pre-surgery) Phase - AC
Updated footnote ‘c’ by clarifying 
prophylaxis medication with growth 
factors required for AC 2QW 
schedule.
Clarified the administration of 
prophylaxis growth factor.
7.1.2: Neoadjuvant (Pre-surgery) 
Phase
The following modifications were 
made:
•
Added ‘approximately’ in front 
of 30 minutes and ‘flush 
language’ for clarity.
•
Chemotherapy starts after the 
infusion line has been flushed, 
filter changes, and the 
participant has been observed 
for 30 minutes, to ensure no 
infusion reaction has occurred.
Clarified treatment administration 
window and flush language.
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Date: 27-Jun-2022
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Summary of key changes for Protocol Amendment 02
Section Number & Title
Description of Change
Brief Rationale
7.1.4.1: Paclitaxel
Added that corticosteroids can be 
administered after the observation 
period of 30 minutes following 
nivolumab.
Clarified timings of the administration 
of premedication with corticosteroids 
before paclitaxel.
7.1.4.2: Anthracycline and 
Cyclophosphamide
Clarified the first dose of AC should 
be administered at the completion of 
4 cycles (PTX C4D1 + 3 weeks) of 
paclitaxel, unless the participant 
meets criteria for a treatment delay.
Clarified initiation of the AC cycles in 
Section 7.1.4.2. Anthracycline and 
Cyclophosphamide. The first dose of 
AC should be administered at the 
completion of 4 cycles (3 weeks 
cycle) of paclitaxel, unless the 
participants meet criteria for treatment 
delay.
7.2:Method of Treatment 
Assignment:  Axillary nodal 
status (pathological review 
positive versus radiographic 
and/or pathologic review 
negative)
7.4.1: Dosage Modification for 
Nivolumab
7.4.1.3: Treatment of Nivolumab 
Infusion Reaction
8.1.1: Nivolumab Dose 
Discontinuation
The following modifications were 
made:
Added axillary nodal status 
clarification.
•
Added Table 7.4.1-1 for AE
criteria for delaying, resuming,
and discontinuation of
nivolumab.
•
Clarified treatment
recommendations are based on
CTCAE v5.
•
Updated Section 8.1.1 to refer
reader to Table 7.4.1-1 for
nivolumab dose discontinuation
criteria.
Reorganized dose delay, resume, and 
discontinuation criteria for improved 
readability and to align with CTCAE 
v5.
7.7.1.1: Prohibited and/or 
Restricted Treatments for 
Nivolumab
Updated language related to herbal 
supplements and traditional Chinese 
medicines for supportive care.
Aligned section with new exclusion 
criteria 2) i) in Section 6.2.
8.1: Discontinuation from Study 
Treatment
9.2.6: Pregnancy
 
Referred the reader to Appendix 9 
for additional details on country-
specific requirements.
 
 
 
 
Added reference to appendix based on 
health authority feedback.
Clarification of end adjuvant therapy.
9.1.5: Imaging Assessment for 
the Study
Clarified text with imaging 
timelines.
Clarified image collection timelines.
9.2.6: Pregnancy
Added follow-up information must 
be reported on the Pregnancy 
Surveillance Form.
Clarified reporting requirements.
9.4.4: Clinical Safety Laboratory 
Assessments
Clarified TSH testing, TSH with 
reflexive fT3 and fT4 at screening, 
Clarified TSH testing requirements.
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Summary of key changes for Protocol Amendment 02
Section Number & Title
Description of Change
Brief Rationale
TSH, with reflexive fT3 and fT4 if 
TSH abnormal on treatment.
Table 9.5-1 (Pharmacokinetic 
and Anti-drug Antibody 
Sampling Schedule for All 
Participants)
Updated footnote b in Table 9.5-1, 
instructions for end of infusion 
samples.
Changes were made to clarify timing 
and expectations for PK sample 
collection and provide additional 
flexibility for end-of-infusion samples.
 
 
 
 
 
 
 
 
Appendix 4: Women of 
Childbearing Potential 
Definitions and Methods of 
Contraception
Updated the text regarding male 
participant contraception.
Aligned methods of contraception 
with updates made to male 
contraceptive requirements in Section 
6.1.
Appendix 6: Management 
Algorithms
Updated management algorithms.
Updated algorithms.
All
Minor formatting and typographical 
corrections.
Minor, therefore have not been 
summarized.
Overall Rationale for the Revised Protocol 01, 24-Mar-2020
The primary reasons for these changes are to align with current clinical practice, align with recent 
updated international guidelines for assessing hormone receptor status in breast cancer, enhance 
exploratory objectives, enhance capture of relevant biomarkers at baseline, provide clarifications 
for study conduct, reduce participant burden, and ensure that the protocol is consistent with internal 
BMS policies and operating procedures. Additional amendments, including to sections of the 
Synopsis, have been made to align the protocol with respect to these changes.
The key updates include the following:
•
Updated tumor assessment criteria to reflect modified RECIST v1.1 criteria relevant for
the neoadjuvant setting.
•
Updated the histologic Grade 2 low ER expression subgroup to be defined as Grade 2 with
an ER expression level 1-10% to align with recently updated ASCO-CAP guidance on
hormone receptor testing in breast cancer.
•
Allow flexibility for use of breast MRI as an alternate method of tumor assessment during
study conduct if it is the local standard instead of breast ultrasound and mammogram.
•
Updated window for primary breast lesion tumor sample to be ≤90 days prior to enrollment
for FFPE blocks or ≤ 60 days for cut unstained slides submitted at baseline.
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•
Removed requirement for mammography at the post-surgery visit.
•
Allowed flexibility to accommodate sequential or concomitant administration of adjuvant 
systemic endocrine therapy and adjuvant radiotherapy per local standards.
•
Included exploratory objectives related to efficacy assessments and PD-L1 expression 
using a combined positive score (CPS) algorithm.
Summary of key changes for Revised Protocol 01
Section Number & Title
Description of Change
Brief Rationale
2: Schedule of Activities
Table 2-1 (Screening Procedural 
Outline)
The following modifications were 
made to Table 2-1 (screening 
procedural outline):
•
Added disease biomarkers.
•
Clarified menopausal status is 
for women only.
•
Removed body surface area.
•
Added cortisol.
•
Increased imaging window to 
45 days prior to randomization.
Tables were modified to add clarity on 
expectation and timing of assessments 
and to reduce participant burden.
2: Schedule of Activities
Table 2-1 (Screening Procedural 
Outline)
Table 2-2 (On-treatment 
Neoadjuvant Procedural Outline 
with PTX and AC Q2W)
Table 2-3 (On-treatment 
Neoadjuvant Procedural Outline 
with PTX and AC Q3W)
Table 2-4 (On-treatment 
Adjuvant Procedural Outline)
Table 2-5 (Follow-up Procedural 
Outline)
Added option for breast MRI.
Allowed flexibility for use of this 
method instead of breast ultrasound 
and mammogram to be used for tumor 
assessment per local standards.
2: Schedule of Activities
Table 2-1 (Screening Procedural 
Outline)
 
 
 
Updated window for primary breast 
lesion tumor sample to be ≤90 days 
prior to enrollment for FFPE blocks 
or ≤60 days for cut unstained slides 
submitted at baseline.
Aligned with similar trials and 
increased flexibility without 
compromising sample quality.
2: Schedule of Activities
Table 2-2 (On-treatment 
Neoadjuvant Procedural Outline 
with PTX and AC Q2W)
The following modifications were 
made:
•
Added a column for end of 
PTX assessments.
•
Clarified pre-surgery window.
Tables were modified to add clarity on 
expectation and timing of assessments 
and to reduce participant burden.
Protocol Amendment No.: 03
Date: 27-Jun-2022
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Clinical Protocol
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nivolumab
Summary of key changes for Revised Protocol 01
Section Number & Title
Description of Change
Brief Rationale
Table 2-3 (On-treatment 
Neoadjuvant Procedural Outline 
with PTX and AC Q3W)
•
Removed FACIT-GP5 on
Days 8 and 15.
•
Added pathologic TNM staging
at surgery.
2: Schedule of Activities
Table 2-4 (On-treatment 
Adjuvant Procedural Outline)
The following modifications were 
made to Table 2-4 (on-treatment 
adjuvant procedural outline):
•
Added a column for end of
adjuvant assessments.
•
Clarified menopausal status is
for women only.
•
Removed FACIT-GP5
collection on Days 8, 15, and
22.
•
Removed requirement for
mammogram at the post-
surgery visit.
•
Allowed for either annual
mammogram or breast MRI for
annual follow-up.
Table was modified to add clarity on 
expectation and timing of assessments 
and to reduce participant burden.
Table 2-4 (On Treatment 
Adjuvant Procedural Outline)
Table 2-5 (Follow-up Procedural 
Outline)
9.2.2: Time Period and 
Frequency for collecting AE and 
SAE information
Added the need to collect 
AEs/SAEs related to breast surgery 
until 100 days after last dose of 
study treatment.
Added as part of the safety analysis.
2: Schedule of Activities
Table 2-5 (Follow-up Procedural 
Outline)
The following modifications were 
made to Table 2-5 (follow-up 
procedural outline):
•
Clarified concomitant
medication use includes
endocrine therapy.
•
Added cortisol.
Table was modified to add clarity on 
expectation and timing of assessments.
Table 2-5 (Follow-up Procedural 
Outline)
5.1.3.1: Safety Follow-up Visits
5.1.3.2: Long-term Follow-up 
Visits
Updated the window for safety 
follow-up 2 to be approximately 
100 days from last dose of study 
treatment instead of nivolumab and 
added a window for long-term 
follow-up visits ± 28 days.
Aligned requirement with similar 
trials.
3.2.4: Neoadjuvant 
Chemotherapy
Changed dose-dense anthracyclines 
from ‘twice weekly’ to ‘Q2W.’
Clarified dose frequency of dose-
dense anthracyclines.
3.3.3: Endocrine Therapy Safety 
Profile
Removed luteinizing hormone 
releasing hormone (LHRH) 
agonists.
LHRH are not considered 
investigational product but may be 
used as concomitant medication.
Protocol Amendment No.: 03
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Summary of key changes for Revised Protocol 01
Section Number & Title
Description of Change
Brief Rationale
5.5.3: Justification for Dose of 
Endocrine Therapy
7: Treatment
Table 7-1 (Study Treatments)
Table 7.1-3 (Selection and 
Timing of Dose - Adjuvant 
Phase)
3.3.4: Nivolumab and 
Anthracycline-Taxane-Based 
Chemotherapy Combination 
Safety Profile
Included summary of the 
KEYNOTE-522 study results.
Provided additional information 
regarding IO agents in the neoadjuvant 
and adjuvant setting in patients with 
early stage TNBC.
Table 4-1 (Objectives and 
Endpoints)
5.4.5.1: PD-L1 Status
Included exploratory objectives 
related to assessments of efficacy 
using a combined positive score 
(CPS) algorithm.
Updated to reflect new knowledge in 
the breast cancer field for potential use 
of CPS as a biomarker of response 
with checkpoint inhibitors.
5.1: Overall Design
Figure 5.1-1 (Study Design 
Schematic)
6.1: Inclusion Criteria
Updated the histologic Grade 2 low 
ER expression subgroup to be 
defined as Grade 2 with an ER 
expression level 1-10%.
Aligned with recent ASCO-CAP 
Guidelines for estrogen and 
progesterone testing in breast cancer 
(Allison et al., J Clin Oncol January 
2020).
5.1.1: Screening Period
The following changes were made:
•
Updated sequence of events to
enroll a participant in IRT.
•
Updated post-menopausal
status definition.
•
Removed specific details
surrounding a pretreatment
tumor tissue sample and
referred the reader to Section
6.1 (inclusion criteria) for
details.
•
Added ER status and ER
expression level to central
laboratory readout.
These changes were made for the 
following reasons:
•
Corrected inconsistency.
•
Aligned with post-menopausal
definition in Appendix 4.
•
Reduced redundancy in text.
•
Clarified inclusion of ER testing
at central laboratory.
5.1.2.1: Neoadjuvant (Pre-
surgery) Phase
The following changes were made:
•
Updated patients to
participants.
•
Clarified expectation with study
conduct if participant
discontinues chemotherapy or if
chemotherapy is delayed.
These changes were made to correct 
inconsistency and to clarify study 
conduct requirement.
5.1.2.1: Neoadjuvant (Pre-
surgery) Phase
7.1.2: Neoadjuvant (Pre-surgery) 
Phase
Updated disease recurrence to 
worsening of disease.
Clarified terminology.
Protocol Amendment No.: 03
Date: 27-Jun-2022
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Clinical Protocol
CA2097FL
BMS-936558
nivolumab
Summary of key changes for Revised Protocol 01
Section Number & Title
Description of Change
Brief Rationale
7.1.4.1: Paclitaxel
7.1.4.2: Anthracyclines and 
Cyclophosphamide
5.1: Overall Design
Table 2-2 (On-treatment 
Neoadjuvant Procedural Outline 
with PTX and AC Q2W)
Table 2-3 (On-treatment
Neoadjuvant Procedural Outline 
with PTX and AC Q3W)
5.1.2.2: Surgery
Clarified timing for surgery and 
expectation if not performed within 
the requested window or if actual 
surgery performed is different from 
the planned surgery at baseline.
Added reference to the pathology 
manual.
Allowed for flexibility for countries 
with national health system standards 
greater than the optimal window.
5.1: Overall Design
5.1.2.3: Radiotherapy
5.1.2.4: Adjuvant (Post-surgery) 
Phase
Allowed adjuvant treatment with 
nivolumab/nivolumab placebo plus 
endocrine therapy to start at same 
time of radiotherapy for participant 
requiring radiotherapy.
Allowed increased flexibility to 
accommodate sequential or 
concomitant administration of 
adjuvant endocrine therapy and 
radiotherapy per local standards of 
care.
5.1.2.3: Radiotherapy
Removed the international 
guidelines for administration of 
breast RT in this section as 
recommendations are described in 
Appendix 7 (Radiotherapy 
Guidelines).
Increased window for initiation of 
adjuvant systemic therapy from 
1 week to 1-2 weeks after 
completion of RT in participants 
receiving sequential RT and 
adjuvant systemic therapy.
Removed redundancy.
This change was made to reduce 
patient burden and to allow flexibility 
to accommodate local standards of 
care.
5.1: Overall Design
5.1.2.4: Adjuvant (Post-surgery) 
Phase
The following changes were made:
•
Option to group the post-
surgery visit and the first cycle 
of adjuvant treatment if 
adjuvant treatment is started 
within 7-14 days after surgery.
•
Increased the window to begin 
adjuvant systemic therapy from 
‘3’ to ‘4-6’ weeks following 
surgery.
These changes were made to reduce 
patient burden and to allow flexibility 
and consistency with local standards 
of care.
5.5.3: Justification for Dose of 
Endocrine Therapy
Updated anastrozole use from ‘BID’ 
to ‘QD.’
Updated incorrect information in the 
frequency of anastrozole 
administration per package insert, 
SmPC.
5.1.3.2: Long-term Follow-up 
Visits
Included a window around each 
assessment of ±28 days.
Reduced participant burden.
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Summary of key changes for Revised Protocol 01
Section Number & Title
Description of Change
Brief Rationale
5.4.5: Rationale for Stratification 
Factors
Included description of the 
maximum number of participants 
allotted for each strata.
Added to increase awareness.
5.5.1.1: Nivolumab 240-mg 
every-2-week Dosing Regimen
5.5.1.2: Nivolumab 360-mg 
Every-3-Week Dosing Regimen
5.5.1.3: Nivolumab 480-mg 
every-4-week Dosing Regimen
5.5.1: Justification for Dose of 
Chemotherapy Agents
5.5.2: Justification for Dose of 
Chemotherapy Agents
7.1.3: Adjuvant (Post-surgery) 
Phase
7.4.1.3: Treatment of Nivolumab 
Infusion Reaction
Added window for nivolumab 
administration.
Allowed flexibility in study drug 
administration.
6.1: Inclusion Criteria
The following modifications were 
made:
•
Updated criterion 2) a) iii)
removing the word ‘operable.’
•
Removed the criterion 2) a) iv)
requiring measurable disease
per RECIST v1.1.
•
Removed female participant
effective contraception criterion
3) c).
•
Extended window for male
contraception criterion 3) e).
•
Removed male contraception
criterion 3) f).
This change was made for the 
following reasons:
•
Removed redundancy with
inclusion criterion 2) d).
•
RECIST 1.1 is not used in our
study and the criterion for
measurable disease criterion is
already included in inclusion
criterion 2) a).
•
Inclusion criterion 3) c) was
duplicating inclusion criterion
3) d).
•
Aligned with Appendix 4.
•
Inclusion criterion 3) f) was
duplicating inclusion criterion
3) e).
6.2: Exclusion Criteria
The following modifications were 
made:
•
Removed criterion 1) c) iii).
•
Updated criterion 1) d)
excluding participant with
> Grade 1 peripheral
neuropathy.
•
Updated criterion 1) f) to
increase immunosuppressive
medication use window.
•
Clarified criterion 1) h)
excluding participant with
known HIV/AIDS within last
These changes were made for the 
following reasons: 
•
Removed redundancy with
inclusion criterion 2) d).
•
Included a window for exclusion
in case of HIV/AIDS infection.
•
Corrected typographical error.
•
Aligned with Appendix 4 and
consistent with standard practice
in this setting.
•
Updated criteria to align with the
nivolumab program standards.
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BMS-936558
nivolumab
Summary of key changes for Revised Protocol 01
Section Number & Title
Description of Change
Brief Rationale
year or a current CD4 count 
< 350 cells/μL.
•
Clarified criterion 2) c) 
excluding concurrent use of 
hormone replacement therapy 
or any other estrogen-
containing medication.
•
Updated criterion 2) g) to 
clarify use of botanical 
preparations.
•
Added criteria 3) k) and 3) l) to 
clarify exclusion related to 
HCV and HBV infection.
7: Treatment
Table 7.1 (Study Treatments)
Added growth factors (G-CSF and 
GM-CSF) as Non-IMP.
Growth factors are required as 
premedication prior administration of 
anthracyclines at a dose dense 
schedule (Q2W).
7.1.1: Nivolumab/Nivolumab 
Placebo Dosing
7.1.4.1: Paclitaxel
7.1.4.2: Anthracycline and 
Cyclophosphamide
Updated guidance regarding 
corticosteroid premedication.
Clarified use of corticosteroid 
premedication.
7.1.2: Neoadjuvant (Pre-surgery) 
Phase)
Provided additional details for study 
treatment administration.
Clarified study treatment 
administration procedures.
7.1.4.2: Anthracycline and 
Cyclophosphamide
Added window for anthracycline 
and cyclophosphamide 
administration and clarified when 
administration will end.
Allowed flexibility in study drug 
administration and clarify timing.
7.1.5: Endocrine Therapy 
Dosing
Removed mention of LHRH 
agonists.
LHRH agonists removed as IMP. 
LHRH agonist permitted as 
concomitant medication.
7.4.1: Dose Modifications for 
Nivolumab
Clarified nivolumab/nivolumab 
placebo may be given within ±3 
days from a scheduled 
chemotherapy dose in the event of 
chemotherapy delay.
Clarified study treatment 
administration procedures.
7.4.1.1: Dose Delay Criteria for 
Nivolumab
The following changes were made:
•
Added 
criterion 
to 
delay 
nivolumab 
or 
nivolumab 
placebo for Grade 3 drug-related 
diarrhea or colitis.
•
Clarified 
that 
other 
study 
treatment may continue to be 
administered.
Aligned with the nivolumab 
Investigator Brochure and clarified 
study treatment recommendations.
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Summary of key changes for Revised Protocol 01
Section Number & Title
Description of Change
Brief Rationale
7.4.2: Dose Modifications for 
Chemotherapy
The following changes were made:
•
Clarified that the dose
modifications are
recommendations for
investigators.
•
Clarified expectations with
regards nivolumab or
nivolumab placebo in cases
there is a delay of
chemotherapy administration.
Clarified study treatment 
recommendations.
7.4.2.1: Dose Delay for 
Paclitaxel Therapy
Removed second sentence.
Redundant with clarification made in 
Section 7.4.2.
7.4.2.2: Dose Reductions for 
Paclitaxel Chemotherapy
Removed last paragraph.
Redundant with clarification made in 
Section 7.4.2.
7.4.2.4: Dose Delay for 
Anthracycline and 
Cyclophosphamide 
Chemotherapy
The following changes were made:
•
Removed first sentence.
•
Updated criterion to resume
treatment with anthracycline-
cyclophosphamide
chemotherapy for ANC count
from ≥1500 mm3 to ≥1000
mm3.
Aligned with clinical practice and 
remove redundancy.
7.4.2.6: Criteria to Resume 
Treatment with Anthracycline-
cyclophosphamide 
Chemotherapy
Updated unit of measure for ANC 
count from uL to mm3.
Aligned with criterion for ANC unit of 
measure.
7.4.3: Dose Modifications for 
Investigator’s Choice Endocrine 
Therapy
Clarified that nivolumab or 
nivolumab placebo may be 
continued as scheduled in case of 
delay in endocrine therapy 
administration.
Clarified study treatment 
administration procedures.
7.5.1: Retained Samples for 
Bioavailability/Bioequivalence/
Biocomparability
Removed section.
Not applicable for registrational 
studies.
7.7.1.1: Prohibited and/or 
restricted Treatments for 
Nivolumab
7.7.1.2: Prohibited and/or 
Restricted Treatments for 
Chemotherapy and Endocrine 
Therapy
Updated period of 
prohibition/restriction of concurrent 
treatment.
Medications are no longer prohibited 
after participant completed study 
treatment.
7.7.1.2: Prohibited and/or 
Restricted Treatments for 
The following changes were made: 
Clarified the treatments which can be 
taken after completion of the study 
treatment (ie, during the follow-up 
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BMS-936558
nivolumab
Summary of key changes for Revised Protocol 01
Section Number & Title
Description of Change
Brief Rationale
Chemotherapy and Endocrine 
Therapy
•
Clarified use of hormonal
agents is prohibited during
study treatment.
•
Added restriction for
cyclophosphamide.
•
Added restriction for live
vaccine if doxorubicin is
received.
phase) and to add restrictions to 
answer health authority requests.
7.7.3: Permitted Therapy
The following modifications were 
made:
•
Clarified that participants
receiving anthracycline dose
dense regimen must receive
G-CSF or GM-CSF.
•
Allowed use of
bisphosphonates.
•
Allowed use of LHRH agonists.
Aligned with local standard practice, 
prescribing information, and/or 
SmPCs.
8.1: Discontinuation from Study 
Treatment
Added occurrence of an EFS event 
to the criterion.
Clarified the need to discontinue study 
treatment in case of an EFS events as 
described in Section 9.1.2.
9: Study Assessments and 
Procedures
Added the need to evaluate 
participant to rule out cardiac 
toxicity in case of cardiac 
signs/events.
Aligned with nivolumab program 
standards.
9.1.5: Imaging Assessment for 
the Study
The following changes were made:
•
Added requirements to submit
additional images
demonstrating disease
recurrence to vendor.
•
Clarified expectations with
tumor measurement
assessments which must be
made using a modified RECIST
v1.1 for neaoadjuvant breast
setting.
Clarified expectations and procedures 
for tumor measurement assessments 
aligning with standard practice.
9.1.5.1: Objective Response 
Rate
Removed the need to perform 
imaging assessment as the end of 
paclitaxel treatment.
Clarified expectation with regards to 
assessment of radiographic tumor 
response in this setting.
9.1.6: Clinical Response by 
Physical Examination
Added when target lesions should 
be measured.
Clarified expectation with regards to 
assessment of clinical response by 
physical examination in this setting. 
9.1.8: Clinical Outcomes 
Assessments
Changed section title and clarified 
that paper questionnaires are 
permitted when electronic devices 
are not available at study start.
This change was made to allow 
flexibility in case of operational 
challenge with the electronic device 
used to complete the questionnaires.
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Date: 27-Jun-2022
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Clinical Protocol
CA2097FL
BMS-936558
nivolumab
Summary of key changes for Revised Protocol 01
Section Number & Title
Description of Change
Brief Rationale
9.2.10: Management Algorithms 
for Nivolumab
Updated the list of IMAEs adding 
myocarditis event.
Updated per nivolumab Investigator 
Brochure.
9.3: Overdose
Updated text with additional 
information referring reader to 
additional sources of information.
Provided additional details and 
clarification of available information 
for study treatments.
2: Schedule of Activities
Table 2-1 (Screening Procedural 
Outline), footnote b
Table 2-2 (On-treatment 
Neoadjuvant Procedural Outline 
with PTX and AC Q2W), 
footnote e
Table 2-3 (On-treatment 
Neoadjuvant Procedural Outline 
with PTX and AC Q3W), 
footnote e
Table 2-4 (On-treatment 
Adjuvant Procedural Outline), 
footnote e
9.4.1: Physical Examination
Clarified ocular examination 
included in target physical 
examination.
Ocular examination is included with 
the regular physical examination. If 
there are any abnormalities, 
participant can be referred to an 
ophthalmologist.
9.4.4: Clinical Safety Laboratory 
Assessments
Moved cortisol and estradiol to 
Other Analyses.
Incorrect categorization.
Table 9.5-1 (Pharmacokinetic 
and Anti-drug Antibody 
Sampling Schedule for All 
Participants)
Updated footnote a) to clarify 
window for PK collection to be 
preferably within 30 minutes prior 
to the infusion.
This change was made to allow 
flexibility in sample collection prior to 
the infusion.
 
 
 
 
 
 
 
 
 
10.1: Sample Size Determination
Corrected typographical error to 
clarify that PD-L1 negative 
participants will be capped to be 
within 40% of the total number of 
randomized participants.
Clarified which PD-L1 status will be 
capped within the randomized 
participants.
Appendix 4: Women of 
Childbearing Potential 
Updated text to include 
contraception guidance to address 
all study treatments.
Improved consistency between 
protocol text and Appendix 4.
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Clinical Protocol
CA2097FL
BMS-936558
nivolumab
Summary of key changes for Revised Protocol 01
Section Number & Title
Description of Change
Brief Rationale
Definitions and Methods of 
Contraception
Restated the use of hormonal 
methods of contraception were not 
permitted in the study.
Appendix 6: Nivolumab 
Management Algorithm
Updated the nivolumab 
management algorithms and 
includes neurological and 
myocarditis AEs.
Aligned with latest nivolumab 
Investigator Brochure.
Appendix 8: Response 
Evaluation Criteria in Solid 
Tumors Guidelines (version 1.1) 
with BMS Modifications
Updated Appendix 8 to include 
modifications applicable for 
neoadjuvant breast studies.
Aligned with standard practice.
Appendix 9: Staging Criteria
Removed Appendix 9 and 
subsequent appendices were 
renumbered thereafter.
TNM status is being used for 
eligibility, not staging criteria which is 
specific to TNBC.
Appendix 12: Detailed 
Pathology Methods for Using 
Residual Cancer Burden
Removed Appendix 12 and 
subsequent appendices were 
renumbered thereafter.
Removed as information is included in 
the Pathology Manual.
Appendix 9: Country-specific 
Requirements/Differences
Appendix was renumbered.
Revised presentation format of 
country–specific information to be 
more clear and concise.
Removed France and Italy from the 
list of countries where HIV testing 
at baseline and exclusion of HIV-
positive participants is locally 
mandated.
Added or updated country-specific 
language revisions for the protocol 
for the following countries:
•
Czech Republic
•
Denmark
Renumbering required due to revision 
of Appendices.
France and Italy no longer require 
HIV testing at baseline nor exclusion 
of HIV-positive participants at 
baseline per health authority feedback.
Provide specific country-specific 
protocol language requirements based 
on local health authority standards or 
specific health authority feedback.
All
Minor formatting and typographical 
corrections.
Minor, therefore have not been 
summarized.
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