Conditions: Breast Cancer Cancer
Keywords: Nivolumab Breast Cancer Cancer ER+ HER2- Neoadjuvant
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 23
Healthy volunteers: no

Brief summary:
A randomized multi-arm study evaluating the safety and efficacy of palbociclib and anastrozole with or without nivolumab in participants with ER+/HER2- breast cancer

Detailed description:

Arms:
arm 1: None arm 2: None arm 3: None

Interventions: intervention 1: Nivolumab intervention 2: Anastrozole intervention 3: Palbociclib
Intervention descriptions: intervention 1: Specified Dose on Specified Days intervention 2: Specified Dose on Specified Days intervention 3: Specified Dose on Specified Days

Protocol document:
Prot_000.pdf: 
Official Title of Study: 
Randomized, Non-comparative Neoadjuvant Phase II Study in Patients with ER+/HER2- Breast Cancer ≥ 2 
cm with Safety Run-in, Assessing Nivolumab + Palbociclib + Anastrozole  
(CheckMate 7A8: CHECKpoint pathway and nivoluMAb clinical Trial Evaluation 7A8) 
 
 
PROTOCOL(S) CA209-7A8 
 
NCT Number: NCT04075604 
  
Document Date (Date in which document was last revised): March 13, 2020 


Page:
1
Protocol Number:
CA2097A8
IND Number:
136,843
EX-US
Non-IND
EUDRACT Number:
2019-001334-34
Date:
02-May-2019
Revised Date:
13-Mar-2020
CLINICAL PROTOCOL CA2097A8
Randomized, Non-comparative Neoadjuvant Phase II Study in Patients with ER+/HER2- Breast 
Cancer ≥2 cm with Safety Run-in, Assessing Nivolumab + Palbociclib + Anastrozole
(CheckMate 7A8: CHECKpoint pathway and nivoluMAb clinical Trial Evaluation 7A8)
Short Title:
Nivolumab with Palbociclib, plus Anastrozole in Patients with ER+/HER2- Breast Cancer ≥2 cm
Revised Protocol 03
24-hr Emergency Telephone Number
USA: 
International: 
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 
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). 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 
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Clinical Protocol
CA2097A8
BMS-936558
nivolumab
Revised Protocol No.: 03
Date: 13-Mar-2020
2
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).
Replace all previous version(s) of the protocol with this revised protocol and please provide a copy 
of this revised protocol to all study personnel under your supervision, and archive the previous 
versions.
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Clinical Protocol
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BMS-936558
nivolumab
Revised Protocol No.: 03
Date: 13-Mar-2020
3
DOCUMENT HISTORY
Document
Date of Issue
Summary of Change
Revised 
Protocol 03
13-Mar-2020
Closed the abemaciclib safety run-in Cohort 1 and removed the 
abemaciclib-containing combinations from the randomization phase.
Removed eligibility criteria based on RECIST 1.1 as it has been covered by 
inclusion criteria 2.a.i. Added further instructions on unidimensional 
measurement for response assessment using ultrasound and mammogram as 
modifications.
Incorporated Administrative Letter 01 and Germany specific amendment.
Revised 
Protocol 02
24-Jul-2019
Added men, additional dose-limiting toxicity (DLT) criteria, and early 
study termination criteria. Updated definition of DLT, inclusion/exclusion 
criteria, and dose modifications.
Revised 
Protocol 01
12-Jun-2019
Decreased and clarified the frequency of assessments and sample 
collections, clarified participant eligibility and stratification, and reduced 
the dose-limiting toxicity period. These changes were made to reduce 
participant burden and increase overall feasibility of the study.
Original 
Protocol
02-May-2019
Not applicable
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CA2097A8
BMS-936558
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OVERALL RATIONALE FOR REVISED PROTOCOL 03:
On 6-Mar-2020, Bristol Myers Squibb (BMS) decided to permanently discontinue enrollment and 
dosing in the nivolumab + abemaciclib + anastrozole cohorts of the CA2097A8 study. 
 
 
 
 
 
 
The study 
is currently in the Safety Run-In Phase. At implementation of Revised Protocol 03, the study will 
only evaluate whether the combination of nivolumab, with palbociclib, plus anastrozole is a safe 
and effective neoadjuvant treatment for men and postmenopausal women with primary BC ≥2 cm 
that is ER+ and HER2- subtype who are suitable to receive NET and willing to undergo SOC 
breast surgery after completion of the study treatment. Participants must have histologically 
confirmed invasive breast carcinoma meeting the characteristics described in the Inclusion 
Criteria. Participants in screening and not yet treated were offered the option to join the safety
lead-in of the nivolumab + palbociclib + anastrozole arm. Participants on treatment with 
nivolumab + abemaciclib + anastrozole were to be re-consented and continue on anastrozole alone, 
or taken off study. Safety monitoring for ILD/pneumonitis (baseline chest X-ray, periodic pulse 
oximetry) as risk mitigation measures have also been included. 
Additional changes were made to include the updates from Administrative Letter 01 and 
clarifications.
SUMMARY OF KEY CHANGES FOR REVISED PROTOCOL 03
Section Number & Title
Description of Change
Brief Rationale
All
Removed references where 
applicable to abemaciclib-containing 
treatment in the randomization phase
As of 6-March-2020, cohort 1 is 
closed for enrollment and study will 
not move forward with 
abemaciclib-containing treatment in 
the randomization phase as an 
urgent safety measure
Section 2 Schedule Of Activities, 
Table 2-1: Screening Procedural 
Outline (Safety Run-in Phase and 
Randomized Phase; CA2097A8)
Section 5.1.1 Screening Period
Section 6.1 Inclusion Criteria
 
 
Updated Pretreatment Tumor Sample 
Submission sample collection 
timing.
Clarity
Revised Protocol No.: 03
Date: 13-Mar-2020
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SUMMARY OF KEY CHANGES FOR REVISED PROTOCOL 03
Section Number & Title
Description of Change
Brief Rationale
Section 2 Schedule Of Activities, 
Table 2-1: Screening Procedural 
Outline (Safety Run-in Phase and 
Randomized Phase; CA2097A8)
Section 5.1 Overall Design
Added Chest X-ray procedure
Safety monitoring for 
ILD/pneumonitis
Section 2 Schedule Of Activities, 
Table 2-1: Screening Procedural 
Outline (Safety Run-in Phase and 
Randomized Phase; CA2097A8)
Added Estradiol to the required 
laboratory testing for women ≤55
Updated per the Administrative 
Letter 01 to align with the inclusion 
criteria
Table 2-2 On-treatment Pre-surgery 
(Neoadjuvant) Procedural Outline 
(Safety Run-in Phase and 
Randomized Phase; CA2097A8)
•
Updated footnote b in indicate 
that participants will undergo 
surgical treatment within 4 
weeks of last dose instead of 1 
week.
•
Footnote e added to table.
•
Clarifying inconsistency within 
the protocol. 
•
Cohort 1 is now closed for 
enrollment and samples will no 
longer be collected or analyzed 
for existing Cohort 1 
participants to alleviate patient 
burdens.
Table 2-2 On-treatment Pre-surgery 
(Neoadjuvant) Procedural Outline 
(Safety Run-in Phase and 
Randomized Phase; CA2097A8)
Section 5.1 Overall Design
Pulse Oximetry has been added to 
Day 1 of the On-treatment Pre-
surgery (Neoadjuvant) Procedural 
Outline
Safety monitoring for 
ILD/pneumonitis
Table 2-2 On-treatment Pre-surgery 
(Neoadjuvant) Procedural Outline 
(Safety Run-in Phase and 
Randomized Phase; CA2097A8)
Section 5.1.2.1 Safety Run-in Phase
Section 7.1 Treatments Administered
Section 7.1.1 Nivolumab Dosing 
(Safety Run-in Cohorts and 
Randomized Phase Arms A, B, D, 
and E)
Section 7.1.2 CDK4/6 Inhibitors and 
Anastrozole Dosing
Language has been removed 
regarding first dose of nivolumab 
being administered following 
treatment assignment for participants 
in the Safety Run in Phase
Clarity
Section 3.3 Benefit/Risk Assessment
Added following sentence: As of 
Protocol Revision 03, the benefit-risk  
profile of the abemaciclib-containing 
combination is no longer considered 
favorable; thus BMS will not move 
forward with randomization to 
nivolumab in combination with 
abemaciclib and anastrozole (see 
Section 5.1).
As of 6-March-2020, cohort 1 is 
closed for enrollment and study will 
not move forward with 
abemaciclib-containing treatment in 
the randomization phase as an 
urgent safety measure
Revised Protocol No.: 03
Date: 13-Mar-2020
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SUMMARY OF KEY CHANGES FOR REVISED PROTOCOL 03
Section Number & Title
Description of Change
Brief Rationale
Section 3.3.3 CDK4/6 Inhibitor and 
Nivolumab Combination Safety 
Profile
Added the following paragraph:
In a Phase 2 study of 
pembrolizumab, palbociclib and 
letrozole (AI) in patients with 
metastatic ER+, HER2- BC 
(NCT02778685), of 20 patients 
treated with the triple combination, 
Grade 3 pneumonitis was reported in 
1 patient during the DLT assessment 
period. The median follow up for this 
study was 13.7 months (95% CI 6.4-
16.9) and progression-free survival 
(PFS) has not been reached.  Also in 
a phase 1 study exploring safety and 
efficacy of avelumab, palbociclib 
and axitinib (tyrosine kinase 
inhibitor) in patients with advanced 
non-small cell lung cancer 
(NCT03386929), of 13 patients 
treated at 3 dose levels, 1 patient 
with baseline chronic obstructive 
pulmonary disease at dose level 3 
developed a respiratory failure event 
possibly related to study treatment 
and died. No Grade 3 or above 
ILD/pneumonitis events were 
reported.  A randomized Phase 2 trial 
assessing a triple combination 
regimen of palbociclib + avelumab 
(anti-PD-L1 inhibitor) + fulvestrant 
(estrogen receptor antagonist) for 
patients with pre-treated metastatic 
ER+/HER2- BC has been ongoing 
since Aug-2017; no clinical data 
have been reported to date. 
(NCT03147287). Thus, the potential 
benefit of the palbociclib 
combination therapy appears to 
outweigh the known risks and 
warrants clinical investigation.
Additional supporting information.
Section 4 Objectives and Endpoints
For pCR secondary 
 
endpoints the definitions of pCR 
were expanded
Consistency across program 
protocols.
Section 5.1 Overall Design
Added the following paragraphs and 
removed reference to equal 
distribution of participants in both 
safety run-in cohorts: 
On 6-Mar-2020, Bristol Myers 
Squibb (BMS) decided to 
permanently discontinue enrollment 
Cohort 1 is now closed for 
enrollment.
Revised Protocol No.: 03
Date: 13-Mar-2020
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BMS-936558
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SUMMARY OF KEY CHANGES FOR REVISED PROTOCOL 03
Section Number & Title
Description of Change
Brief Rationale
and dosing in the nivolumab + 
abemaciclib + anastrozole cohorts of 
the CA2097A8 study during the 
Safety Run-in Phase. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
At implementation of Revised 
Protocol 03, the study will only 
evaluate whether the combination of 
nivolumab, with palbociclib, plus 
anastrozole is a safe and effective 
neoadjuvant treatment for men and 
postmenopausal women with 
primary BC ≥2 cm that is ER+ and 
HER2- subtype who are suitable to 
receive NET and willing to undergo 
SOC breast surgery after completion 
of the study treatment. Participants 
must have histologically confirmed 
invasive breast carcinoma meeting 
the characteristics described in 
Section 6.1 (Inclusion Criteria). 
Participants in screening and not yet 
treated were offered the option to 
join the safety lead-in of the 
nivolumab + palbociclib + 
anastrozole arm. Participants on 
treatment with nivolumab + 
abemaciclib + anastrozole were to be 
re-consented and continue on 
anastrozole alone, OR taken off 
study. In addition, baseline chest X-
ray and periodic pulse oximetry are 
implemented to monitor 
ILD/pneumonitis in patients who 
Revised Protocol No.: 03
Date: 13-Mar-2020
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BMS-936558
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SUMMARY OF KEY CHANGES FOR REVISED PROTOCOL 03
Section Number & Title
Description of Change
Brief Rationale
will be treated with nivolumab + 
palbociclib + anastrozole.
Figure 5.1-1: Study Design 
Schematic
Updated study design schematic to 
remove abemaciclib-containing
treatment in the randomization phase
and updated study numbers. Added 
two footnotes to clarify the closing 
of Cohort 1 to enrollment and the 
removal of abemaciclib-containing
treatment in the randomization 
phase.
Study will not move forward with 
abemaciclib-containing treatment in 
the randomization phase
Section 5.1.2.1 Safety Run-in Phase
Added the following paragraph:  As 
of Revised Protocol 03, Cohort 1 will 
be discontinued. Participants in 
screening and not yet treated were 
offered the option to join the 
nivolumab + palbociclib + 
anastrozole arm. Participants on 
treatment were to be re-consented 
and continue on anastrozole alone, 
OR taken off study.
Removed references to abemaciclib, 
and to equal distribution of 
participants in both safety run-in 
cohorts.
Deleted the following text: At the 
end of the Safety Run-in Phase, the 
Sponsor will evaluate the safety 
profile of the 2 cohorts. In the case 
that the treatment regimen for 1 of 
the 2 cohorts is not deemed to be 
tolerable for use in the 
Randomization Phase, then the 
treatment regimen for the other 
cohort will advance to the 
Randomization Phase, with the 
statistical assumptions remaining 
unchanged for this part, as captured 
in Section 10 (Statistical 
Considerations).
Cohort 1 is now closed for 
enrollment.
Section 5.1.2.1 Safety Run-in Phase
Updated to include additional DLTs
 
 Integrated all the AEs 
that require discontinuation of 
nivolumab per approved label into 
the list of DLTs.
Section 5.1.2.2 Randomized Phase
Updated randomization and text to 
reflect removal of Arms A-C
Study will not move forward with 
Arms A, B, and C.
Revised Protocol No.: 03
Date: 13-Mar-2020
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BMS-936558
nivolumab
SUMMARY OF KEY CHANGES FOR REVISED PROTOCOL 03
Section Number & Title
Description of Change
Brief Rationale
Section 5.2 Number of Patients
Section 10.1 Sample Size 
Determination
Updated participant numbers to 
reflect the closing of enrollment for 
Cohort 1 and removal of 
abemaciclib-containing treatment in
the randomization phase
Cohort 1 is now closed for 
enrollment and study will not move 
forward with abemaciclib-
containing treatment in the 
randomization phase.
Section 6.1 Inclusion Criteria
Removed the criterion requiring 
measurable disease per RECIST 
v1.1.
RECIST 1.1 is not used in this
study and the criterion for
measurable disease criterion is 
already included in inclusion 
criterion.
Section 6.2. Exclusion Criteria
Removed the following exclusion 
criterion from Medical Conditions:
C) Active hepatitis B or hepatitis C 
with abnormal liver function tests.
Redundant to another criterion.
Section 6.2. Exclusion Criteria
Added the following qualifier to a 
prior/concomitant therapy exclusion 
criteria:
e)
Prior ET or CDK4/6 inhibitors 
for BC within 5 years
Clarity
Section 6.2. Exclusion Criteria
Updated criterion 1, e.
Criterion 3, i no longer applicable
Added criterion 3, l
Added crterion 3, m
updated language, criterion 3, l and 
m replace criterion 3, i
Table 7.1-1 Selection and Timing of 
Dose - Safety Run-in Phase and 
Table 7.1-2 Selection and Timing of 
Dose - Randomized Phase
Ddded the following footnote:
Note: At the time of Revised 
Protocol 03, 2 participants had been 
treated in Cohort 1 (nivolumab + 
abemaciclib + anastrozole), which 
was subsequently closed for 
enrollment.
Cohort 1 is now closed for 
enrollment and study will not move 
forward with abemaciclib-
containing treatment in the 
randomization phase.
Section 7.1.2 CDK4/6 Inhibitors and 
Anastrozole Dosing
Added the following text: The 
selected CDK4/6 inhibitor cannot be 
changed or switched to another one 
once the study treatment has been 
initiated. At implementation of 
Revised Protocol 03, the study will 
only evaluate the combination of 
nivolumab with palbociclib plus 
anastrozole. Patients in screening and 
not yet treated were offered the 
option to join the nivolumab + 
palbociclib + anastrozole arm. 
Patients on treatment were to be re-
consented and continue on 
anastrozole alone, OR taken off 
study.
Cohort 1 is now closed for 
enrollment and study will not move 
forward with abemaciclib-
containing treatment in the 
randomization phase.
Revised Protocol No.: 03
Date: 13-Mar-2020
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CA2097A8
BMS-936558
nivolumab
SUMMARY OF KEY CHANGES FOR REVISED PROTOCOL 03
Section Number & Title
Description of Change
Brief Rationale
Removed text about equal 
distribution between cohorts.
Section 7.4 Dosage Modification
Section 7.4.1. Dose Modifications 
for Abemaciclib
Section 7.4.2 Dose Modifications for 
Palbociclib
Removed summary tables of dose 
reduction, interruption or 
discontinuation of individual study 
drugs in the management of study 
drug-related adverse reactions and 
added language to consult the 
individual drug labels
Specifically removed Table 7.4.1-1, 
Table 7.4.1-2, Table 7.4.1-3, Table 
7.4.1-4, Table 7.4.1-5, Table 7.4.2-2, 
and Table 7.4.2-3
Referenced the approved package 
inserts instead
.
Section 7.7.3.1 Imaging Restriction 
and Precautions
Removed reference to the image 
acquisition manual
Per imaging lead.
Section 8.1.2 Abemaciclib Dose 
Discontinuation
Changed text to read: At the 
implementation of Revised Protocol 
03, abemaciclib dosing will be 
discontinued in all patients.
No longer studying abemaciclib-
containg combination.
Section 9.1.3. Clinical Response 
Assessments
Removed reference to RECIST
v1.1.Added language regarding 
reporting the longest diameter of the 
initial lesion as the baseline 
measurement and used to 
characterize the objective tumor 
response.
Clarified expectations and 
procedures for tumor measurement 
assessments.
Section 9.1.3.1 Objective Response 
Rate
Added new section
To define radiographic response 
assessments
Section 9 Study Assessments And 
Procedures, 
Table 9.4.4-1: Clinical Safety 
Laboratory Assessments, Other 
Analyses
Added the following text regarding 
Estradiol levels
“Estradiol level - only required to 
confirm menopause in women ≤age 
55”
Updated per the Administrative 
Letter 01 to align with the inclusion 
criteria 
Section 10.3.4 Interim Analysis
Removed interim analysis
No longer applicable.
APPENDIX 9 Concomitant 
Medications
Removed Category and Drug Name 
for Strong CYP2D6 Inhibitors or 
Inducers (for participants receiving 
tamoxifen)
Not applicable for the current 
treatment regimen. 
All
Minor formatting and typographical 
corrections.
Incorporate corrections for clarity 
and consistency within the 
document. These changes were 
minor, and therefore have not been 
summarized.
Revised Protocol No.: 03
Date: 13-Mar-2020
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3.2.1 ER+/HER2- Breast Cancer ..................................................................... 
3.2.2 Neoadjuvant Endocrine Treatment .......................................................... 
3.2.3 Nivolumab Mechanism of Action ............................................................. 
3.2.4 CDK 4/6 Inhibitors and Mechanism of Action ........................................ 
3.2.5 Clinical Experience with Nivolumab ....................................................... 
3.2.6 Clinical Experience with CDK 4/6 Inhibitors and Endocrine Therapy ... 
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3.3.1 Nivolumab Safety Profile ......................................................................... 
3.3.2 CDK 4/6 Inhibitor and Endocrine Therapy Combination Safety Profile  
3.3.3 CDK4/6 Inhibitor and Nivolumab Combination Safety Profile ............... 
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5.1.1 Screening Period ...................................................................................... 
5.1.2 On-treatment Pre-surgery (neoadjuvant) Period .................................... 
5.1.2.1 Safety Run-in Phase ........................................................................ 
5.1.2.2 Randomized Phase .......................................................................... 
5.1.3 Safety Follow-up Period .......................................................................... 
5.1.4 External Committees ................................................................................ 
5.1.4.1 Study Steering Committee ............................................................... 
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5.5.1 Rationale for the Choice of Patient Population ....................................... 
5.5.2 Rationale for Choice of Endpoint (Residual Cancer Burden 0-I Rate) ... 
5.5.3 Rationale for CDK 4/6 Plus PD-1 Inhibition .......................................... 
5.5.4 Rationale for Phased Therapy (Arm B) ................................................... 
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5.6.1 Justification for Dose of Nivolumab ........................................................ 
5.6.2 Justification for Dose of CDK4/6 Inhibitors ............................................ 
5.6.3 Justification for Dose of Anastrozole ....................................................... 
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6.3.1 Meals and Dietary Restrictions for CDK 4/6 Inhibitor ........................... 
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6.4.1 Retesting During Screening or Lead-In Phase ........................................ 
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7.1.1 Nivolumab Dosing (Safety Run-in Cohorts and Randomized Phase Arms 
A and B) ...................................................................................................... 
7.1.2 CDK4/6 Inhibitors and Anastrozole Dosing ............................................ 
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7.4.1 Dose Modifications for Abemaciclib ....................................................... 
7.4.2 Dose Modifications for Palbociclib ......................................................... 
7.4.3 Dose Modification for Anastrozole .......................................................... 
7.4.4 Dose Modifications for Nivolumab .......................................................... 
7.4.4.1 Dose Omission Criteria for Nivolumab .......................................... 
7.4.4.2 Criteria to Resume Treatment with Nivolumab .............................. 
7.4.4.3 Treatment of Nivolumab Infusion Reaction .................................... 
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7.7.3.1 Imaging Restriction and Precautions ............................................. 
7.7.4 Permitted Therapy ................................................................................... 
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8.1.1 Nivolumab Dose Discontinuation ............................................................ 
8.1.2 Abemaciclib Dose Discontinuation .......................................................... 
8.1.3 Palbociclib Dose Discontinuation ........................................................... 
8.1.4 Anastrozole Dose Discontinuation .......................................................... 
8.1.5 Post-study Treatment Study Follow-up .................................................... 
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9.1.1 Blinded Independent Pathology Review .................................................. 
9.1.2 Pathologic Assessment of Effect .............................................................. 
9.1.2.1 RCB Determination ......................................................................... 
9.1.2.2 Pathological Complete Response Determination ........................... 
9.1.3 Clinical Response Assessments ................................................................ 
9.1.3.1 Objective Response Rate Assessed by Imaging .............................. 
9.1.4 Breast Conserving Surgery Rate .............................................................. 
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9.2.1 Time Period and Frequency for Collecting AE and SAE Information .... 
9.2.2 Method of Detecting AEs and SAEs ......................................................... 
9.2.3 Follow-up of AEs and SAEs ..................................................................... 
9.2.4 Regulatory Reporting Requirements for SAEs ......................................... 
9.2.5 Pregnancy ................................................................................................ 
9.2.6 Laboratory Test Result Abnormalities ..................................................... 
9.2.7 Potential Drug-Induced Liver Injury ....................................................... 
9.2.8 Other Safety Considerations .................................................................... 
9.2.9 Management Algorithms for Nivolumab .................................................. 
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9.4.1 Physical Examinations ............................................................................. 
9.4.2 Vital Signs ................................................................................................ 
9.4.3 Electrocardiograms/ECHO (preferred) or MUGA ................................. 
9.4.4 Clinical Safety Laboratory Assessments .................................................. 
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10.3.1 Efficacy Analyses ................................................................................... 
10.3.2 Safety Analyses....................................................................................... 
10.3.4 Interim Analysis ..................................................................................... 
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Clinical Protocol
CA2097A8
BMS-936558
nivolumab
1
SYNOPSIS
Protocol Title: Randomized, Non-comparative Neoadjuvant Phase II Study in Patients with 
ER+/HER2- Breast Cancer ≥2 cm with Safety Run-in, Assessing Nivolumab + Palbociclib + 
Anastrozole
Short Title: Nivolumab with Palbociclib plus Anastrozole in Patients with ER+/HER2- Breast 
Cancer ≥2 cm
Study Phase: 2
Rationale:
Blockade of the programmed cell death-1 (PD-1) pathway has demonstrated clinical activity across 
multiple tumor types, including breast cancer (BC). An accumulating body of evidence supports 
PD-1/cyclin-dependent kinases (CDK)4/6 blockade potential synergy, as it has become more 
apparent that CDK4/6 inhibitors affect the tumor immune microenvironment (ie, increases 
expression of programmed death-ligand 1 [PD-L1], enhances antigen presentation and secretion 
of cytokines from both tumor and CD8+ T cells, and suppresses proliferation of 
immunosuppressive regulatory T cells [Tregs]). Preliminary clinical data supporting synergistic 
activity of the combination of pembrolizumab and abemaciclib has been demonstrated in a Phase 
1b study of heavily pretreated participants with metastatic hormone receptor-positive (HR+), 
human epidermal growth factor receptor 2-negative (HER2-) BC. Clinical data on combinations 
of other CDK4/6 inhibitors coupled with PD-(L)1 inhibition are being generated in multiple 
clinical trials spanning from the neoadjuvant to metastatic setting (ClinicalTrials.gov: 
NCT03573648, NCT02778685, NCT03294694).
The aim of CA2097A8 is to assess the potential synergistic activity of nivolumab with palbociclib 
and anastrozole in participants with newly diagnosed, previously untreated primary estrogen 
receptor-positive (ER+), HER2- BC ≥2 cm, defined by significantly improved residual cancer
burden (RCB; 0-I) rate. 
 
 
Additional objectives of the 
study include characterization of safety and tolerability of this combination
 
 
. 
Study Population:
Participants will include men and postmenopausal women with ER+ and HER2- primary 
BC ≥2 cm.
Revised Protocol No.: 03
Date: 13-Mar-2020
15
Approved
5.0
v
Approved
1.0
v


Clinical Protocol
CA2097A8
BMS-936558
nivolumab
Objectives and Endpoints:
Objectives
Endpoints
Primary
•
Safety 
Run-in 
Phase: 
Number 
of 
participants with occurrence of DLT.
•
DLT is defined as TEAE (graded according to the NCI 
CTCAE v5.0) that occurs during the first 4 weeks after 
treatment start and that meets specific criteria.
•
Randomized Phase: To assess RCB 0-I rate
by central assessment of palbociclib plus 
anastrozole with or without nivolumab in 
all participants with untreated primary BC 
≥2 cm (ER+, HER2-).
•
RCB 0-I rate assessed by central assessment at the time of 
definitive surgery.
•
RCB is a continuous index combining pathological 
measurements of primary tumor (size and cellularity) and 
nodal metastases (number and size) defined by a point 
system at surgery (refer to Appendix 7).
Secondary
•
To assess the safety and tolerability of 
palbociclib plus anastrozole with or without 
nivolumab.
•
Incidence of AEs, SAEs, AEs leading to discontinuation, 
immune-related AEs, deaths, and laboratory abnormalities 
in all participants.
•
To assess pCR rate by local assessment of 
palbociclib plus anastrozole with or without 
nivolumab in participants with untreated 
primary BC ≥2 cm (ER+, HER2-).
•
pCR rate in all participants assessed by the local pathologist 
at the time of definitive surgery. pCR is defined as the 
absence of residual invasive cancer on hematoxylin and 
eosin evaluation of the complete resected breast specimen 
and all sampled regional lymph nodes following completion 
of neoadjuvant systemic therapy (ie, ypT0/Tis ypN0 in the 
current AJCC staging system).
−
pCR, defined as no invasive residual disease in breast 
or lymph nodes (ie, ypT0/is, ypN0) in the current AJCC 
staging system.
•
To assess ORR (clinical and radiological 
[ultrasound (preferred) or mammography]) 
by Investigator assessment and BCS rate of 
palbociclib plus anastrozole with or without 
nivolumab in participants with untreated 
primary BC ≥2 cm (ER+, HER2-).
•
ORR is defined as the number of participants with a BOR 
of CR or PR divided by the number of randomized 
participants for each treatment group at the end of the study 
treatment period.
•
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.
Revised Protocol No.: 03
Date: 13-Mar-2020
16
Approved
5.0
v
Approved
1.0
v


Clinical Protocol
CA2097A8
BMS-936558
nivolumab
Objectives
Endpoints
Abbreviations: 
 AE = adverse event; AJCC = American Joint Committee on Cancer;
BC = breast cancer; BCS = breast-conserving surgery; BOR = best overall response; CR = complete response; 
CTCAE = Common Terminology Criteria for Adverse Events; DLT = dose-limiting toxicity;
 
 
HER2- = human epidermal growth factor receptor 2-negative; 
 NCI = National Cancer 
Institute; ORR = objective response rate; pCR = pathological complete response; 
 
 PR = partial response; 
RCB = Residual 
Cancer Burden; SAE = serious adverse event; TEAE = treatment-emergent adverse event; TIL = tumor-infiltrating 
lymphocyte; 
.
Overall Design:
This randomized, open-label Phase 2 study was to evaluate whether the combination of nivolumab, 
with palbociclib, plus anastrozole is a safe and effective neoadjuvant treatment for men and
postmenopausal women with primary BC ≥2 cm that is ER+ and HER2- subtype who are suitable 
Revised Protocol No.: 03
Date: 13-Mar-2020
17
Approved
5.0
v
Approved
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CA2097A8
BMS-936558
nivolumab
to receive neoadjuvant endocrine therapy (NET) and willing to undergo standard-of-care (SOC) 
breast surgery after completion of the study treatment. 
On 6-Mar-2020, Bristol Myers Squibb (BMS) decided to permanently discontinue enrollment and 
dosing in the nivolumab + abemaciclib + anastrozole cohorts of the CA209-7A8 study during the 
Safety Run-in phase. 
 
 
 
 
 
 
At implementation of Revised Protocol 03, the study will only evaluate whether the combination 
of nivolumab, with palbociclib plus anastrozole is a safe and effective neoadjuvant treatment for 
men and postmenopausal women with primary BC ≥2 cm that is ER+ and HER2- subtype who 
are suitable to receive NET and willing to undergo SOC breast surgery after completion of the 
study treatment. Participants must have histologically confirmed invasive breast carcinoma 
meeting the characteristics described in the Inclusion Criteria. Participants in screening and not 
yet treated were be offered the option to join the safety lead-in of the nivolumab + palbociclib + 
anastrozole arm. Participants on treatment with nivolumab + abemaciclib + anastrozole were to be 
re-consented and continue on anastrozole alone, OR taken off study. In addition, baseline chest X-
ray and periodic pulse oximetry are implemented to monitor ILD/pneumonitis in patients who will 
be treated with nivolumab + palbociclib + anastrozole.
The study is divided into 3 periods: Screening Period, On-treatment Pre-surgery (neoadjuvant) 
Period (Safety Run-in Phase and Randomized Phase), and Safety Follow-up Period.
The study started with a Safety Run-in Phase for the combination of nivolumab, with abemaciclib 
or palbociclib, plus anastrozole and will begin the Randomized Phase after the regimen is 
determined to be safe. Participants in the Safety Run-in Phase will move to the Safety Follow-up 
Period upon completion of the neoadjuvant treatment or upon discontinuation. Potential needs for 
additional enrollment or for dose de-escalation will be discussed with Investigators and BMS 
during the Safety Run-in Phase. Once a safe dose for the regimen has been determined by BMS in 
collaboration with Investigators, the Randomized Phase of the study will begin.
In the Randomized Phase, participants will be randomly assigned by an IRT system to 3 different 
treatment arms and stratified by the following factors: 
 
 2) evaluation of lymph nodes (cytologically positive vs radiologically or 
cytologically negative); and 3) tumor size (> 3 cm or ≤3 cm).
For both the Safety Run-in Phase and Randomized Phase, participants will be treated for a 
maximum of 5 cycles (1 cycle = 4 weeks). Participants with progressive disease prior to 
completion of the 5-cycle study treatment must discontinue all study drugs and proceed to the 
Safety Follow-up Period. Participants who permanently discontinue the study drugs for any reason 
are considered to have completed the On-treatment Pre-surgery (neoadjuvant) Period, and hence 
Revised Protocol No.: 03
Date: 13-Mar-2020
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CA2097A8
BMS-936558
nivolumab
reach end of treatment (EOT). After Cycle 5 or EOT, participants must continue to receive 
anastrozole (as concomitant medication and not as study treatment) until subsequent SOC breast 
surgery. Following the completion of neoadjuvant treatment, all participants who remain operative 
candidates will undergo definitive surgery for BC within 4 weeks of the last neoadjuvant treatment 
administration. If anastrozole can no longer be administered after EOT, participants will go to 
breast surgery right away. Pre-surgical lymph node biopsy is not allowed. Information on the type 
of the surgery will be collected and recorded in the electronic case report form (eCRF). Surgical
specimens will be collected for the analyses outlined in the protocol. Depending on treatment 
assignment, up to 2 safety follow-up visits will be conducted in person. The first safety follow-up 
visit (FU1) will be completed for all participants within 30 days (± 7 days) from the last study 
treatment (oral or intravenous [IV], whichever occurs later). The second safety follow-up visit 
(FU2) will occur approximately within 100 days (± 7 days) from the last dose of nivolumab and 
will be required for participants in the Safety Run-in Phase and participants randomized to Arms A
or Bin the Randomized Phase. Further planned treatment of participants in the adjuvant setting 
(ie, radiotherapy, endocrine treatment, chemotherapy or any other treatment modality) will be at 
the discretion of the treating physician, following local clinical guidelines, and collected in the 
appropriate eCRF. 
The study design schematic is presented in the Figure below.
Revised Protocol No.: 03
Date: 13-Mar-2020
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CA2097A8
BMS-936558
nivolumab
Study Design Schematic
Abbreviations: Abema = abemaciclib; ANZ = anastrozole; BID = twice daily; cm = centimeter; ECOG = Eastern Cooperative Oncology Group; 
ER+ = estrogen-receptor-positive; FU1 = follow-up visit 1; FU2 = follow-up visit 2; HER2- = human epidermal growth factor receptor 2-negative; mg = milligram; 
IV = intravenous; N = number; Nivo = nivolumab; Palbo = palbociclib; 
 PO = per os (by mouth); PS = performance status; 
Q4W = every 4 weeks; QD = once daily; Rand = randomized; wk = week.
a
FU1 begins at the end of study treatment.
b Cytologically positive vs radiologically or cytologically negative.
Screening Period
Pre-surgery Treatment Period (N = 115~136)
Safety Follow-up Period
Key Inclusion 
Criteria
• Newly diagnosed, 
histologically 
proven ER+, 
HER2- primary 
breast cancer
≥ 2 cm
• Men and 
postmenopausal 
women
• ECOG PS 0-1
Safety Run-in Phase
(3 + 3 Approach)
(n = 3~24)c
Randomized Phase
(n = 110)d
FU1a
(All Participants in he 
Safety Run-in Phase and 
the Randomized Phase)
FU2
(All Participants in the 
Safety Run-in Phase and 
Arms A and B Only in 
the Randomized Phase)
Investigator’s Choice
Cohort 1 (n = 3~24)
Nivo 480 mg Q4W IV
+ Abema 150 mg BID PO 
+ ANZ 1 mg QD PO
x 5 cycles
Cohort 2 (n = 3~24)
Nivo 480 mg Q4W IV
+ Pa bo 125 mg QD PO 
3 wks on 1 wk off
+ ANZ 1 mg QD PO
x 5 cycles
Arm A (n = 40)
Nivo 480 mg Q4W IV + Palbo 125 mg QD PO 3 wks on 
1 wk off + ANZ 1 mg QD PO x 5 cycles
Arm B (n = 40)
Palbo 125 mg QD PO 3 wks on 1 wk off + ANZ 1 mg 
QD PO x 1 cycle THEN Nivo 480 mg Q4W IV + Palbo
125 mg QD PO 3 wks on 1 wk off + ANZ 1 mg QD PO 
x 4 cycles
Arm C (n = 30)
Palbo 125 mg QD PO 3 wks on 1 wk off + ANZ 1 mg 
QD PO x 5 cycles
Rand
4:4:3
30-Day Safety 
Follow-up
100-Day Safety 
Follow-up
(from last Nivo dose)
30-Day Safety 
Follow-up
100-Day Safety 
Follow-up
(from last Nivo dose)
30-Day Safety 
Follow-up
Stratify Randomized 
Phase Participants by:
•
Node (+ or -)b
•
Tumor size
(> 3 cm or ≤ 3 cm)
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BMS-936558
nivolumab
c At the time of Revised Protocol 03, 2 subjects had been treated in Cohort 1 (nivolumab + abemaciclib + anastrozole), which was subsequently closed for 
enrollment.
d At time of Revised Protocol 03, the decision was made to no longer evaluate abemaciclib in combination with nivolumab plus anastrozole; thus, the abemaciclib-
containing combination arms have been removed from the Randomization Phase of the study.
Revised Protocol No.: 03
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CA2097A8
BMS-936558
nivolumab
Number of Participants:
A total of approximately 115~136 participants will be treated in the study. It is anticipated that 
approximately 3~24 participants (up to approximately 30 screened) will be treated in each cohort 
in the Safety Run-in Phase. At the time of Revised Protocol 03, 2 subjects had been treated in 
Cohort 1 (nivolumab + abemaciclib + anastrozole), which was subsequently closed for enrollment. 
Approximately 138 participants will be screened for 110 participants to be treated in the 
Randomized Phase, assuming a screen failure rate of approximately 20%. 
Originally, approximately 3~24 participants will be treated in the Safety Run-in Phase in each 
cohort (Cohort 1: nivolumab + abemaciclib + anastrozole for 5 cycles; n = 3∼6 per dose level of 
abemaciclib; Cohort 2: nivolumab + palbociclib + anastrozole for 5 cycles; n = 3∼6 per dose level 
of palbociclib). At the time of Revised Protocol 03, 2 subjects had been treated in Cohort 1 
(nivolumab + abemaciclib + anastrozole), which was subsequently closed for enrollment.
Approximately 110 participants are planned to be randomized in this study at a 4:4:3 ratio into 
Arm A (nivolumab + palbociclib + anastrozole for 5 cycles; n = 40), Arm B (palbociclib + 
anastrozole for 1 cycle, followed by nivolumab + palbociclib + anastrozole for 4 cycles; n = 40), 
and Arm C (palbociclib + anatrozole for 5 cycles; n = 30), respectively. Participants will be 
stratified by 
 node status, and tumor size.
Treatment Arms and Duration:
The treatment arms and duration for the Safety Run-in Phase and Randomized Phase are provided 
in the tables below.
Selection and Timing of Dose - Safety Run-in Phase
Cohort
Study 
Treatment
Dosage Levela
Frequency of
Administration
Start and Duration 
of Treatment
Route of 
Administration
1
Nivolumab
480 mg
Q4W
Cycle 1-5
IV
Abemaciclib
150 mg
BID
Cycle 1-5
PO (with or 
without food)
Anastrozole
1 mg
QD
Cycle 1-5b
PO (with or 
without food)
2
Nivolumab
480 mg
Q4W
Cycle 1-5
IV
Palbociclib
125 mg
QD × 3 weeks on
(1 week off)
Cycle 1-5
PO (with food)
Anastrozole
1 mg
QD
Cycle 1-5b
PO (with or 
without food)
Abbreviations: BID = twice daily; EOT = end of treatment; IV = intravenous; mg = milligram; PO = per os (by mouth); 
Q4W = every 4 weeks; QD = once daily.
Note: At the time of Revised Protocol 03, 2 subjects had been treated in Cohort 1 (nivolumab + abemaciclib + 
anastrozole), which was subsequently closed for enrollment.
a For abemaciclib and palbociclib, this is the starting dose level. Dose levels may be reduced per Dosage Modification 
guidelines in the main protocol.
b After 5 cycles or EOT, all participants should continue to receive anastrozole until breast surgery. Anastrozole is 
not considered study therapy beyond completion of Cycle 5 or EOT.
Revised Protocol No.: 03
Date: 13-Mar-2020
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CA2097A8
BMS-936558
nivolumab
Selection and Timing of Dose - Randomized Phase
Arm
Study 
Treatment
Dosage Levela
Frequency of
Administration
Start and Duration 
of Treatment
Route of 
Administration
A
Nivolumab
480 mg
Q4W
Cycle 1-5
IV
Palbociclib
125 mg
QD × 3 weeks on
(1 week off)
Cycle 1-5
PO (with food)
Anastrozole
1 mg
QD
Cycle 1-5b
PO (with or 
without food)
B
Palbociclib
125 mg
QD × 3 weeks on
(1 week off)
Cycle 1-5
PO (with food)
Anastrozole
1 mg
QD
Cycle 1-5b
PO (with or 
without food)
Nivolumab
480 mg
Q4W
Cycle 2-5
IV
C
Palbociclib
125 mg
QD × 3 weeks on
(1 week off)
Cycle 1-5
PO (with food)
Anastrozole
1 mg
QD
Cycle 1-5b
PO (with or 
without food)
Abbreviations: BID = twice daily; EOT = end of treatment; IV = intravenous; mg = milligram; PO = per os (by mouth); 
Q4W = every 4 weeks; QD = once daily.
Note: As of Revised Protocol 03, the abemaciclib-containing combination arms have been removed from the 
Randomization Phase of the study.
a For palbociclib, the starting dose level will be the safe dose determined upon completion of the Safety Run-in 
Phase.
b After 5 cycles or EOT, all participants should continue to receive anastrozole until breast surgery. Anastrozole is 
not considered study therapy beyond completion of Cycle 5 or EOT.
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Date: 13-Mar-2020
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CA2097A8
BMS-936558
nivolumab
Study Treatment:
Study Drug for CA2097A8
Medication 
Potency 
IP/Non-IP 
Nivolumab Injection
10 mg/mL; 100 mg fill volume
and
10 mg/mL; 40-mg fill volume
IP
Abemaciclib Tablets
150 mg, 100 mg, and 50 mg
IP
Palbociclib Capsules
125 mg, 100 mg, and 75 mg
IP
Anastrozole Tablets
1 mg
IP
Abbreviations: IP = investigational product; mg = milligram; mL = milliliter.
Data Monitoring Committee: No
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CA2097A8
BMS-936558
nivolumab
2
SCHEDULE OF ACTIVITIES
Table 2-1:
Screening Procedural Outline (Safety Run-in Phase and Randomized Phase; CA2097A8)
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 assessed at screening and must be confirmed prior to: 
•
Safety Run-in participants: first dose
•
Randomized participants: randomization
Medical History
X
All medical history relevant to the disease under study, including tobacco history.
Documentation of Postmenopausal Status
X
Please see inclusion criterion 3) b) in Section 6.1 (Inclusion Criteria) for a definition of 
postmenopausal women.
Pretreatment Tumor Sample Submission
X
A recent archival tumor biopsy (collected within 90 days prior to enrollment) is required in the format 
of FFPE block (strongly preferred) or 22 unstained tumor slides (sectioned within 60 days prior to 
enrollment from a tissue sample collected within 90 days prior to enrollment). If a recent tumor 
specimen is not available, a fresh tumor biopsy collection is required. At least 15 unstained slides 
must be submitted for a participant to be eligible. If < 15 unstained slides are available, the participant 
is not eligible.
•
Safety Run-in participants: Participant can start study treatment before confirmation of receipt of 
the tumor sample by the central laboratory. However, receipt of the tumor sample by the central 
laboratory must occur within 28 days of the first dose.
Safety Assessments
Targeted PE, Measurements, Vital Signs, 
and ECOG PS
X
Height, weight, BP, HR, RR, temperature, and ECOG PS (Appendix 5). Must be collected within 
14 days prior to: 
•
Safety Run-in participants: first dose
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Table 2-1:
Screening Procedural Outline (Safety Run-in Phase and Randomized Phase; CA2097A8)
Procedurea
Screening
Visit
Notes
All windows are based on calendar days.
•
Randomized participants: randomization
•
Targeted PE must include ocular examination.
ECG
X
Must be performed within 28 days prior to: 
•
Safety Run-in participants: first dose
•
Randomized participant: randomization
ECHO (preferred) or MUGA
X
Must be performed within 28 days prior to:  
•
Safety Run-in participants: first dose
•
Randomized participants: randomization
Assessment of Signs and Symptoms
X
Must be performed within 14 days prior to:  
•
Safety Run-in participants: first dose
•
Randomized participants: randomization
Concomitant Medication Use
X
Must be performed within 14 days prior to: 
•
Safety Run-in participants: first dose
•
Randomized participants: randomization
Vaccine use within 30 days prior to first dose.
Chest X-ray
X
Must be performed within 14 days prior to: 
•
Safety Run-in participants: first dose
•
Randomized Phase participants: randomization
SAE Assessment
X
SAE collection from time of consent.
Laboratory Tests
CBC with Differential, Chemistry, 
Endocrine, and Serology
X
Must be performed within 14 days prior to:  
•
Safety Run-in participants: first dose
•
Randomized Phase participants: randomization
FSH and Estradiol are required for women ≤55.
See Section 9.4.4 for a list of laboratory tests to conduct.
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CA2097A8
BMS-936558
nivolumab
Table 2-1:
Screening Procedural Outline (Safety Run-in Phase and Randomized Phase; CA2097A8)
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
Clinical breast examination by palpation of breast and axilla.
Breast and Axilla Ultrasound (Preferred) 
or Mammogram
X
Perform breast and axilla ultrasound (preferred) or a mammogram within 28 days prior to:  
•
Safety-run in participants: first dose
•
Randomized participant: randomization
•
Every attempt should be made to image each participant using an identical imaging modality and 
acquisition protocol for all imaging time points.
Other Imaging (eg, Bone Scan)
X
As clinically indicated per local standards, including pathologic examination of suspected lesions.
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 are available prior to the Screening Period. 
Abbreviations: BC = breast cancer; BCS = breast-conserving surgery; BP = blood pressure; CBC = complete blood count; ECG = electrocardiogram; 
ECHO = echocardiogram; ECOG = Eastern Cooperative Oncology Group; eCRF = electronic case report form; ER = estrogen receptor; FFPE = formalin-fixed, 
paraffin-embedded; FSH = follicle-stimulating hormone; HR = heart rate; IHC = immunohistochemistry; IRT = Interactive Response Technology; 
MUGA = multiple gated acquisition;
 PE = physical examination; PS = performance status; RR = respiratory rate; 
SAE = serious adverse event.
a Some of the assessments referred to in this section may not be captured as data in 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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CA2097A8
BMS-936558
nivolumab
Table 2-2:
On-treatment Pre-surgery (Neoadjuvant) Procedural Outline (Safety Run-in Phase and Randomized 
Phase; CA2097A8)
Procedurea
Neoadjuvant Treatmentb,c
Cycle 1-5 (1 cycle = 4 weeks)
Pre-surgery
(within 7 days 
prior to surgery)
Notesd
Day 1
Day 8
Day 15
Day 22
Safety Assessments
Targeted PE, 
Measurements, Vital Signs, 
and ECOG PS
X
C2D15
(see Notes)
X
Weight, BP, HR, temperature, and ECOG PS 
(Appendix 5) on Day 1 of each cycle.
Targeted PE must also include ocular 
examination at C1D1, C2D15, and as clinically 
indicated.
Pulse Oximetry
X
(predose)
For each testing, two measurements are needed, 
i.e. at rest and immediately post ambulation
ECG
C1D1
(predose)
C1D15
(predose)
Triplicate ECG (collected within ~ 5 minute 
window) at C1D1, C1D15, and as clinically 
indicated.
AEs Assessment 
(including SAEs)
Continuously.
Record at each visit.
Concomitant Medication 
Review
Continuously.
Record at each visit.
Laboratory Tests
CBC with Differential, 
Chemistry Panel, and 
Endocrine Testing
X
X
C1-C2
Must be performed within 3 calendar days prior 
to dosing for all time points, except C1D1,
which does not need to be repeated if performed 
within 7 days prior to the first dose.
See Section 9.4.4 (Clinical Safety Laboratory 
Assessments) for list of laboratory tests.
Efficacy Assessments
Clinical Breast 
Examination
X
Clinical breast examination by palpation of
breast and axilla.
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BMS-936558
nivolumab
Table 2-2:
On-treatment Pre-surgery (Neoadjuvant) Procedural Outline (Safety Run-in Phase and Randomized 
Phase; CA2097A8)
Procedurea
Neoadjuvant Treatmentb,c
Cycle 1-5 (1 cycle = 4 weeks)
Pre-surgery
(within 7 days 
prior to surgery)
Notesd
Day 1
Day 8
Day 15
Day 22
Breast and Axilla 
Ultrasound (Preferred) or 
Mammogram 
C2D22 (as clinically indicated)
X
Breast and axilla ultrasound (preferred) or 
mammogram to be done on C2D22 and within 7 
calendar days prior to surgery. Every attempt 
should be made to image each participant using 
an identical imaging modality and acquisition 
protocol for all imaging time points.
Documentation of Actual 
Breast Surgery
See Notes.
Record actual type of BC surgery (ie, BCS, 
mastectomy) on day of or within 7 days after 
surgery.
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BMS-936558
nivolumab
Table 2-2:
On-treatment Pre-surgery (Neoadjuvant) Procedural Outline (Safety Run-in Phase and Randomized 
Phase; CA2097A8)
Procedurea
Neoadjuvant Treatmentb,c
Cycle 1-5 (1 cycle = 4 weeks)
Pre-surgery
(within 7 days 
prior to surgery)
Notesd
Day 1
Day 8
Day 15
Day 22
Study Drug
Randomization
X
First dose to be administered within 3 calendar 
days following randomization (for Randomized 
Phase ONLY).
IRT Drug Assignment
X
Register the visit in the IRT for study drug 
allocation.
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CA2097A8
BMS-936558
nivolumab
Table 2-2:
On-treatment Pre-surgery (Neoadjuvant) Procedural Outline (Safety Run-in Phase and Randomized 
Phase; CA2097A8)
Procedurea
Neoadjuvant Treatmentb,c
Cycle 1-5 (1 cycle = 4 weeks)
Pre-surgery
(within 7 days 
prior to surgery)
Notesd
Day 1
Day 8
Day 15
Day 22
Administer Nivolumab 
480 mg (Safety Run-in 
Cohorts and Arms A and 
B)
X
To be administered Q4W IV. First dose to be 
administered within 3 calendar days following 
randomization.
•
Randomized Phase:
•
Arm A and Arm B
•
Starting at C2D1 for Arm B 
Dispense Anastrozole 1 mg 
and Provide and Review 
Patient Diary (Safety 
Run-in Cohorts and all 
Arms)
X
To be administered QD PO, with or without food.
Review patient diary at each study visit.
Note: Anastrozole given beyond C5 or beyond 
EOT will not be considered as study treatment 
and must be collected as concomitant medication.
AND
Dispense Abemaciclib and 
Provide/Review Patient 
Diary (Safety Run-in 
Cohort 1)e
X
To be administered BID PO with or without 
food. Review patient diary at each study visit.
OR
Dispense Palbociclib and 
Provide/Review Patient 
Diary (Safety Run-in 
Cohort 2 and Arms A, B, 
and C)
X
To be administered QD PO with food during the 
first 3 weeks of each cycle (1 week off). 
Review patient diary at each study visit.
Abbreviations: AE = adverse event; BC = breast cancer; BCS = breast-conserving surgery; BID = twice daily; BP = blood pressure; C = cycle; CBC = complete 
blood count; D = day; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; eCRF = electronic case report form; EOT = end of treatment; 
; HR = heart rate; 
 IRT = interactive response 
technology; IV = intravenous; mg = milligram; PE = physical examination; 
 PO = per os, (by mouth); 
 
PS = performance status; QD = daily; Q4W = every 4 weeks; SAE = serious adverse event.
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BMS-936558
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a The schedule for each procedure should coincide with actual dosing.
b Participants will undergo surgical treatment within 4 weeks of the last dose of neoadjuvant treatment (IV or oral, whichever comes later).
c On-treatment procedures may generally be performed within a ± 3-day window, unless otherwise specified (eg, breast ultrasound or mammogram, tumor biopsy).
d Some of the assessments referred to in this section may not be captured as data in 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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BMS-936558
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Table 2-3:
Follow-up Procedural Outline (Safety Run-in Phase and Randomized Phase; CA2097A8)
Procedure
30-Day Safety Follow Up
(FU1)a
(± 7 days)
(All Participants in the 
Safety Run-in Phase and 
the Randomized Phase)
100-Day Safety Follow Up
(FU2)a
(± 7 days)
(All Participants in the 
Safety Run-in Phase and 
Arms A and B Only in the 
Randomized Phase)
Notesb
Safety Assessments
Targeted PE, 
Measurements, Vital Signs, 
and ECOG PS
X
X
Weight, BP, HR, temperature, and ECOG PS.
Targeted PE may include ocular examination, if clinically 
indicated.
AE Assessment (including 
SAEs)
X
X
Participants will be followed for treatment-related toxicities 
until these toxicities resolve, return to baseline, or are deemed 
irreversible.
Note: All AEs will be documented for a minimum of 100 days 
after last dose of nivolumab for Safety Run-in Cohorts and 
Arms A and B, and for 30 days from the last dose of study 
treatment for Arm C.
Concomitant Medication 
Review
X
X
Record at each visit.
Subsequent Cancer 
Treatment
X
X
At each visit, record any new surgery, radiotherapy, and 
systemic cancer therapy given for the disease under study.
Laboratory Tests
CBC with Differential, 
Chemistry, and Endocrine
X
X
Must be performed at FU1. If study drug-related toxicities 
persist, must be repeated at FU2.
See Section 9.4.4 (Clinical Safety Laboratory Assessments) for 
list of laboratory tests to conduct.
Abbreviations: AE = adverse event; BP = blood pressure; CBC = complete blood count; ECOG = Eastern Cooperative Oncology Group; eCRF = electronic case 
report form; FU1 = follow-up visit 1; FU2 = follow-up visit 2; HR = heart rate; 
 IV = intravenous; PE = physical examination; 
 PS = performance status; SAE = serious adverse event; SOC = standard of care.
a Participants must be followed for at least 100 days after last dose of nivolumab. FU1 should occur 30 days (± 7 days) from the last dose of any treatment (IV or 
oral whichever comes later). FU2 occurs approximately 100 days (± 7 days) from last dose of nivolumab. Both follow-up visits should be conducted in person.
b Some of the assessments referred to in this section may not be captured as data in 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
CA2097A8 is an open-label, randomized, non-comparative Phase 2 study assessing 
nivolumab, plus palbociclib, and anastrozole as either concurrent or phased neoadjuvant treatment 
for men and postmenopausal women with primary breast cancer (BC) ≥2 cm that are estrogen 
receptor-positive (ER+) and human epidermal growth factor receptor 2-negative (HER2-) with 
safety run-in.
Nivolumab (BMS-936558) is a fully human, IgG4 (kappa) isotype monoclonal antibody (mAb),
an immuno-oncologic (IO) checkpoint inhibitor that binds programmed cell death-1 (PD-1) on 
activated immune cells and disrupts engagement of the receptor with its ligands programmed 
death-ligand 1 (PD-L1; B7-H1/CD274) and programmed death-ligand 2 (PD-L2; B7-DC/CD273), 
thereby abrogating inhibitory signals and augmenting the host anti-tumor response. Palbociclib is
an orally bioavailable and highly selective small-molecule inhibitor against cyclin-dependent
kinases (CDK)4/cyclin-D1 and CDK6/cyclin-D3 enzyme complexes, lead to reactivation of 
retinoblastoma (Rb) protein, binding back of E2F transcription factor and subsequent cell cycle 
arrest, thus abrogating endocrine-resistant cell proliferation. Anastrozole is a reversible, third-
generation, selective nonsteroidal aromatase inhibitor (NSAI) that reduces peripheral estrogen
synthesis by blocking the conversion of androgens to estrogens in non-ovarian tissues. A detailed 
description of the chemistry, pharmacology, efficacy, and safety of the study treatments is 
provided in the Investigator Brochures (IBs) and package inserts.1,2,3,4
The study will assess the efficacy and safety of: i) concurrent therapy with nivolumab in 
combination with palbociclib, and anastrozole (Arm A), ii) phased therapy with one initial priming 
cycle of palbociclib and anastrozole followed by nivolumab in combination with palbociclib, and 
anastrozole (Arm B), and iii) control treatment with palbociclib and anastrozole (Arm C). 
Participants with newly diagnosed, previously untreated primary ER+ and HER2- BC ≥2 cm will 
be subjected to a total 5 cycles (4 weeks per cycle) of neoadjuvant therapy before definitive 
surgery. Efficacy will be measured by significantly improved residual cancer burden (RCB) 0-I 
rate. 
 
 
3.1
Study Rationale
PD-1 pathway inhibition has demonstrated clinical activity across multiple tumor types, including
BC.5 An accumulating body of evidence supports PD-1/CDK4/6 blockade potential synergy, as it 
has become more apparent that CDK4/6 inhibitors modulate the tumor immune 
microenvironment6 (ie, increases expression of PD-L1,7 enhances antigen presentation8 and 
secretion of cytokines from both tumor and CD8+ T cells,9,10 and suppresses proliferation of 
immunosuppressive regulatory T cells [Tregs]8). Preliminary clinical data in support of synergistic 
activity of the combination of pembrolizumab and abemaciclib has been demonstrated in a 
Phase 1b study on heavily pretreated participants with metastatic hormone receptor-positive 
(HR+), HER2- BC.11 Clinical data on combinations of other CDK4/6 inhibitors with PD-(L)1 
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blocking agents are being generated in multiple clinical trials spanning from the neoadjuvant to 
metastatic 
setting 
(ClinicalTrials.gov: 
NCT03573648, 
NCT02778685, 
NCT03294694).
Additional treatment benefit (improved anti-tumor efficacy and complete tumor regression) was 
observed in a syngeneic mouse tumor model by priming the anti-cancer immune response with 
abemaciclib in a phased administration of abemaciclib and an anti-PD-L1 therapy.12 Therefore, an 
additional phased therapy arm has been added for each CDK4/6 inhibitor to explore possible 
treatment benefit in patients.
The aim of the CA2097A8 study is to assess the potential synergistic activity of nivolumab, with 
palbociclib, and anastrozole in participants with newly diagnosed, previously untreated primary 
ER+, HER2- BC ≥2 cm, defined by significantly improved RCB (0-I) rate.
 
 
 
Additional objectives of the study include characterization of safety and 
tolerabilit
 
. 
 
3.1.1
Research Hypothesis
The combination of nivolumab, with palbociclib, and anastrozole is a safe and effective 
neoadjuvant treatment for patients with ER+, HER2- primary BC ≥2 cm.
3.2
Background
3.2.1
ER+/HER2- Breast Cancer
BC ranks second as a cause of cancer death in women after lung cancer.13 An estimated 42,260 
BC deaths (41,760 women) are expected in 2019 in the United States (US). In clinical practice, 
BC tumors are classified by the expression status of estrogen receptor (ER), progesterone receptor 
(PgR), and human epidermal growth factor receptor 2 (HER2). The BC subtypes identified on the 
basis of these receptors have been reported to bear distinct gene expression profiles,14,15 as well 
as different prognoses and treatment vulnerabilities. Seventy percent of invasive BC in 
women > 45 years of age express ER and/or PgR, but not HER2, and are termed hormone 
receptor-positive (HR+), HER2-.16 Seminal studies performed with gene expression profiling 
analysis of primary BC samples indicated that the tumors in the HR+ group are characterized by 
the relatively high expression of genes related to 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, namely: luminal A 
(50-60% of all BC, showing higher dependence on ER signaling, slower proliferation rate and 
overall more indolent clinical course) and luminal B (15-20% of all BC, showing lower 
dependence on ER signaling, higher proliferation rate, and overall, a more aggressive clinical 
course and worse prognosis, as compared to their luminal A counterparts).17
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3.2.2
Neoadjuvant Endocrine Treatment
While, traditionally, neoadjuvant chemotherapy has been used to downstage locally advanced and 
unresectable primary BC, a number of studies have highlighted the role of neoadjuvant endocrine 
treatment (NET) as an alternative option to chemotherapy in patients with HR+, HER2- primary 
tumors,18 particularly for postmenopausal women. Available data suggest that NET is associated 
with similar response rates and rates of breast-conserving surgery (BCS) as neoadjuvant 
chemotherapy, albeit with lower toxicity in postmenopausal women with HR+ BC.18,19,20,21,22 For 
postmenopausal women receiving NET, the administration of an aromatase inhibitor (AI) is 
recommended instead of tamoxifen, based on evidence suggesting improved outcomes for women 
treated with AIs across clinical trials and meta-analyses.21,23,24,25,26,27,28,29 Similar clinical 
outcomes (rate of BCS) in the neoadjuvant setting among the AIs were observed in 
377 postmenopausal women with Stage II or III strongly ER+ BC who were randomly assigned to 
treatment with exemestane, letrozole, or anastrozole for 16-18 weeks before surgery in the 
American College of Surgeons Oncology Group (ACOSOG) Z1031 trial.28
3.2.3
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 immune surveillance 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 immune surveillance and escape effective innate and adaptive immune responses.30,31,32
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).33 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).34 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.35 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 a host 
genetic factors. Thus, PD-1 deficiency or inhibition is not accompanied by a universal loss of 
tolerance to self-antigens.
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In vitro, nivolumab (BMS-936558) binds to PD-1 with high affinity (half-maximal effective 
concentration [EC50] 0.39-2.62 nM), and inhibits the binding of PD-1 to its ligands PD-L1 and 
PD-L2 (half-maximal inhibitory concentration [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 indicates 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 analog of nivolumab enhances the anti-tumor 
immune response and results in tumor rejection in several immunocompetent mouse tumor models 
(MC38, SA1/N, and PAN02).36
3.2.4
CDK 4/6 Inhibitors and Mechanism of Action
Cell cycle progression is regulated by cyclin-dependent serine-threonine protein kinases. 
Extracellular growth and adhesion signals increase the level and function of cyclin D proteins 
within the cell. In turn, the cyclin D proteins associate with and activate CDK4 and CDK6.37 CDK4 
and CDK6 phosphorylation leads to inactivation of the Rb protein and thus releases E2F, which in 
turn leads to the transcription initiation of proteins involved in cell cycle propagation and 
proliferation. 
The luminal A and B subtypes of BC (85% of which are ER+, HER2-) have high rates of 
cyclin D/CDK activation; in the luminal A and B subtypes, cyclin D1 (CCND1) amplifications 
were observed in 29% and 58%, and CDK4 amplifications were observed in 14% and 25%, 
respectively.38,39 Luminal A subtype tumors also have loss of CDKN2A, which encodes 
p16INK4A, a CDK inhibitor.40 The luminal subtypes also maintain expression of Rb, which is 
essential for benefit from treatment with a CDK4/6 inhibitor.41
Dysregulation of cell cycle checkpoints is common in BC, and in all cancers in general, and may 
have clinical and therapeutic significance. For example, patients with HR+ BC exhibiting a gene 
expression signature of Rb loss had a shorter recurrence-free survival following adjuvant 
tamoxifen.42 A tumor gene expression signature of E2F activation is also associated with higher 
residual tumor cell proliferation following neoadjuvant AI therapy. Therefore, activation of the 
CDK4/6-Rb-E2F pathway promotes endocrine resistance, and treatment with a CDK4/6 inhibitor 
or knockdown of CDK4 expression leads to reactivation of Rb, binding back of E2F and 
subsequent cell cycle arrest thus abrogating endocrine-resistant cell proliferation. A seminal 
preclinical study exploring 47 human BC cell lines reported that palbociclib monotherapy was 
active in luminal BC cell lines compared to non-luminal BC cells lines, and that palbociclib 
potentiated tamoxifen and trastuzumab activity in ER+ and human epidermal growth factor 
receptor 2-positive (HER2+) BC cell lines, respectively.43
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3.2.5
Clinical Experience with Nivolumab
The overall clinical safety experience with nivolumab, as either monotherapy or in combination 
with other therapeutics, is based on experience in approximately 17,700 participants.3 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, 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.3
In 39 patients with BC, nivolumab alone or in combination with ipilimumab were tolerable without 
additional safety signal detected in the CheckMate 32 study (unpublished data). In 66 patients with 
metastatic triple negative breast cancer (TNBC), nivolumab with or without various induction 
therapies (radiation therapy, cyclophosphamide, cisplatin, or doxorubicin) demonstrated ORRs
from 17% without induction therapy to 35% with doxorubicin induction therapy (TONIC trial).44
An additional 37 clinical trials of nivolumab alone or in combination treating patients with BC are 
currently ongoing (eg, ClinicalTrials.gov: NCT03414684, NCT03789110, NCT03316586).
Details on the clinical safety and PK profile of nivolumab, including results from other clinical 
studies, are summarized in the nivolumab IB.3
3.2.6
Clinical Experience with CDK 4/6 Inhibitors and Endocrine Therapy
The clinical development of second generation, CDK4/6-selective inhibitors, namely palbociclib, 
abemaciclib, and ribociclib, led to practice-changing results in the setting of advanced HR+, 
HER2- BC. In combination with aromatase inhibitors in the first-line setting and fulvestrant in the 
second-line setting, CDK4/6 inhibitors not only significantly increased ORR and prolonged
progression-free survival (PFS),45 but also achieved clinically meaningful overall survival (OS) 
benefit from treatment combining palbociclib and fulvestrant, albeit not statistically significant.46
In addition, single-agent abemaciclib demonstrated an ORR of 19.7% in heavily pretreated patients 
with refractory HR+, HER2- metastatic BC.47 Selective CDK4/6 inhibitors are currently assessed 
in early-stage HR+, HER2- primary BC (neoadjuvant and adjuvant setting) as well as other BC 
subtypes. In the neoadjuvant setting, the combination of palbociclib and letrozole markedly 
enhanced the suppression of malignant cell proliferation as assessed by Ki67, a marker of cellular 
proliferation, but did not substantially increase the clinical response of primary ER+ BC over a 
14-week period.48,49 Therefore, novel combinations are needed in this setting to optimize efficacy.
Details on the clinical safety and PK profile of palbociclib, including results from other clinical 
studies, are summarized in its respective product label.4
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3.3
Benefit/Risk Assessment
Based on preclinical and clinical data, treatment of nivolumab and palbociclib in combination with 
endocrine therapy (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.
Participants in this study will be carefully monitored for key toxicities. Risks will be further 
minimized by adherence to inclusion/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 9.2.9 [Management Algorithms for 
Nivolumab], 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. 
A Study Steering Committee (SSC; see Section 5.1.4.1 [Study Steering Committee]) will be 
established comprising of Investigators and BMS 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 IB,3 Patient Information 
Leaflet, Package Insert,1,2,4,50 Development Safety Update Report, or Summary of Product 
Characteristics (SmPC).
Due to the need to develop improved therapies to reverse or delay resistance to current ET in ER+, 
HER2- BC, and on the basis of the clinical and nonclinical data in support of the current study, 
BMS feels that the benefit-risk profile of nivolumab in combination with palbociclib and 
anastrozole in men and postmenopausal women with ER+, HER2- early-stage BC is favorable for 
proceeding with the proposed randomized Phase 2 clinical trial. As of Protocol Revision 03, the 
benefit-risk profile of the abemaciclib-containing combination is no longer considered favorable; 
thus BMS will not move forward with randomization to nivolumab in combination with 
abemaciclib and anastrozole (see Section 5.1).
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 reached at any dose 
tested up to 10 mg/kg. Most AEs were low-grade (Grade 1 to Grade 2) with relatively few related 
high-grade (Grade 3 to Grade 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.
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Additional details on the safety profile of nivolumab, including results from other clinical studies, 
are also available in the nivolumab IB.3
3.3.2
CDK 4/6 Inhibitor and Endocrine Therapy Combination Safety Profile
Overall, the safety profile of palbociclib monotherapy, as well as in combination with ET is
manageable and generally consistent across completed and ongoing clinical trials.
For palbociclib, the most common adverse reactions (incidence ≥10%) were neutropenia, 
infections, leukopenia, fatigue, nausea, stomatitis, anemia, alopecia, diarrhea, thrombocytopenia, 
rash, vomiting, decreased appetite, asthenia, and pyrexia.4
For anastrozole:
•
In the early BC study (ATAC), the most common (incidence of > 10%) side effects were hot 
flashes, asthenia, arthritis, pain, arthralgia, pharyngitis, hypertension, depression, nausea and 
vomiting, rash, osteoporosis, fractures, back pain, insomnia, headache, peripheral edema, and 
lymphedema, regardless of causality.2
•
In the advanced BC studies, the most common (> 10%) side effects were hot flashes, nausea, 
asthenia, pain, headache, back pain, bone pain, increased cough, dyspnea, pharyngitis, and 
peripheral edema.2
Extensive details on the safety profile of palbociclib and anastrozole are available in the Patient
Information Leaflet, Package Insert, or SmPC.
3.3.3
CDK4/6 Inhibitor and Nivolumab Combination Safety Profile
The safety profile of nivolumab is well characterized and manageable when administered alone or 
in combination with other treatments, including regimens where it is administered in combination 
with chemotherapy, targeted agents, as well as additional IO products. In a Phase Ib study, the 
combination of pembrolizumab (a PD-1 inhibitor with similar safety profile) and abemaciclib at 
Food & Drug Administration (FDA)-approved doses of the respective agents demonstrated a 
manageable safety profile, with a confirmed ORR of 28.6% in 28 heavily pretreated participants
with metastatic BC (HR+, HER2- subtype)11
In a Phase 2 study of pembrolizumab, palbociclib and letrozole (AI) in patients with metastatic 
ER+, HER2- BC (NCT02778685), of 20 patients treated with the triple combination, Grade 3 
pneumonitis was reported in 1 patient during the DLT assessment period. The median follow up 
for this study was 13.7 months (95% CI 6.4-16.9) and progression-free survival (PFS) has not been 
reached.51 Also in a phase 1 study exploring safety and efficacy of avelumab, palbociclib and 
axitinib (tyrosine kinase inhibitor) in patients with advanced non-small cell lung cancer 
(NCT03386929), of 13 patients treated at 3 dose levels, 1 patient with baseline chronic obstructive 
pulmonary disease at dose level 3 developed a respiratory failure event possibly related to study 
treatment and died. No Grade 3 or above ILD/pneumonitis events were reported.52 A randomized 
Phase 2 trial assessing a triple combination regimen of palbociclib + avelumab (anti-PD-L1 
inhibitor) + fulvestrant (estrogen receptor antagonist) for patients with pre-treated metastatic 
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ER+/HER2- BC has been ongoing since Aug-2017; no clinical data have been reported to date.
(NCT03147287). Thus, the potential benefit of the palbociclib combination therapy appears to 
outweigh the known risks and warrants clinical investigation.
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4
OBJECTIVES AND ENDPOINTS
Table 4-1:
Objectives and Endpoints
Objectives
Endpoints
Primary
•
Safety Run-in Phase: Number of participants
with occurrence of DLT.
•
DLT is defined as TEAE (graded according to the NCI 
CTCAE v5.0) that occurs during the first 4 weeks after 
treatment start and that meets specific criteria (see 
Section 5.1.2.1).
•
Randomized Phase: To assess RCB 0-I rate by 
central
assessment of palbociclib
plus 
anastrozole with or without nivolumab in all 
participants with untreated primary BC
≥2 cm (ER+, HER2-).
•
RCB 0-I rate assessed by central assessment at the time 
of definitive surgery.
•
RCB is a continuous index combining pathological 
measurements of primary tumor (size and cellularity) and 
nodal metastases (number and size) defined by a point 
system at surgery (refer to Appendix 7 [RCB Methods]).
Secondary
•
To assess the safety and tolerability of 
palbociclib plus anastrozole with or without 
nivolumab.
•
Incidence of AEs, SAEs, AEs leading to discontinuation, 
immune-related 
AEs, 
deaths, 
and 
laboratory 
abnormalities in all participants.
•
To assess pCR rate by local assessment of 
palbociclib plus anastrozole with or without 
nivolumab in participants with untreated 
primary BC ≥2 cm (ER+, HER2-).
•
pCR rate in all participants assessed by the local 
pathologist at the time of definitive surgery.
−
pCR, defined as no invasive residual disease in 
breast or lymph nodes (ie, ypT0/is, ypN0) in the 
current AJCC staging system.
•
To assess ORR (clinical and radiological 
[ultrasound (preferred) or mammography]) by 
Investigator assessment and BCS rate of 
palbociclib plus anastrozole with or without 
nivolumab in participants with untreated 
primary BC ≥2 cm (ER+, HER2-).
•
ORR is defined as the number of participants with a BOR 
of CR or PR divided by the number of randomized 
participants for each treatment group at the end of the 
study treatment period. 
•
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.
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Table 4-1:
Objectives and Endpoints
Objectives
Endpoints
Abbreviations: 
 AE = adverse event; AJCC = American Joint Committee on Cancer; 
BC = breast cancer; BCS = breast-conserving surgery; BOR = best overall response; CR = complete response; 
CTCAE = Common Terminology Criteria for Adverse Events; DLT = dose-limiting toxicity;
 
 
 HER2- = human epidermal growth factor receptor 2-negative; 
 
NCI = National Cancer Institute; ORR = objective response rate; pCR = pathological complete response; 
 
PR = partial response; 
 
RCB = residual cancer burden; SAE = serious adverse event; TEAE = treatment-emergent adverse event; 
TIL = tumor-infiltrating lymphocyte; 
.
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5
STUDY DESIGN
5.1
Overall Design
This randomized, open-label Phase 2 study was to evaluate whether the combination of nivolumab, 
with abemaciclib or palbociclib, plus anastrozole is a safe and effective neoadjuvant treatment for 
men and postmenopausal women with primary BC ≥2 cm that is ER+ and HER2- subtype who 
are suitable to receive NET and willing to undergo SOC breast surgery after completion of the 
study treatment. 
On 6-Mar-2020, Bristol Myers Squibb (BMS) decided to permanently discontinue enrollment and 
dosing in the nivolumab + abemaciclib + anastrozole cohorts of the CA2097A8 study during the 
Safety Run-in Phase. 
 
 
 
 
 
At implementation of Revised Protocol 03, the study will only evaluate whether the combination of 
nivolumab, with palbociclib, plus anastrozole is a safe and effective neoadjuvant treatment for men 
and postmenopausal women with primary BC ≥2 cm that is ER+ and HER2- subtype who are 
suitable to receive NET and willing to undergo SOC breast surgery after completion of the study 
treatment. Participants must have histologically confirmed invasive breast carcinoma meeting the 
characteristics described in Section 6.1 (Inclusion Criteria). Participants in screening and not yet 
treated were offered the option to join the safety lead-in of the nivolumab + palbociclib + 
anastrozole arm. Participants on treatment with nivolumab + abemaciclib + anastrozole were to be 
re-consented and continue on anastrozole alone, OR taken off study. In addition, baseline chest X-
ray and periodic pulse oximetry are implemented to monitor ILD/pneumonitis in patients who will 
be treated with nivolumab + palbociclib + anastrozole.
The study is divided into 3 periods: Screening Period, On-treatment Pre-surgery (neoadjuvant) 
Period (Safety Run-in Phase and Randomized Phase), and Safety Follow-up Period.
The study started with a Safety Run-in Phase for the combination of nivolumab, with abemaciclib 
or palbociclib, plus anastrozole and will begin the Randomized Phase after the regimen is 
determined to be safe. Participants in the Safety Run-in Phase will move to the Safety Follow-up 
Period upon completion of the neoadjuvant treatment or upon discontinuation. Potential needs for 
additional enrollment or for dose de-escalation will be discussed with Investigators and BMS 
during the Safety Run-in Phase. Once a safe dose for the regimen has been determined by BMS in 
collaboration with Investigators, the Randomized Phase of the study will begin.
In the Randomized Phase, participants will be randomly assigned by an IRT system to 3 different 
treatment arms and stratified by the following factors: 
 
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 2) evaluation of lymph nodes (cytologically positive vs radiologically or 
cytologically negative); and 3) tumor size (> 3 cm or ≤3 cm).
For both the Safety Run-in Phase and Randomized Phase, participants will be treated for a 
maximum of 5 cycles (1 cycle = 4 weeks). Participants with progressive disease prior to 
completion of the 5-cycle study treatment must discontinue all study drugs and proceed to the 
Safety Follow-up Period. Participants who permanently discontinue the study drugs for any reason 
are considered to have completed the On-treatment Pre-surgery (neoadjuvant) Period, and hence 
reach end of treatment (EOT). After Cycle 5 or EOT, participants must continue to receive 
anastrozole (as concomitant medication and not as study treatment) until subsequent SOC breast 
surgery. Following the completion of neoadjuvant treatment, all participants who remain operative 
candidates will undergo definitive surgery for BC within 4 weeks of the last neoadjuvant treatment 
administration. If anastrozole can no longer be administered after EOT, participants will go to 
breast surgery right away. Pre-surgical lymph node biopsy is not allowed. Information on the type 
of the surgery will be collected and recorded in the electronic case report form (eCRF). Surgical
specimens will be collected for the analyses outlined in the protocol. Depending on treatment 
assignment, up to 2 safety follow-up visits will be conducted in person. The first safety follow-up 
visit (FU1) will be completed for all participants within 30 days (± 7 days) from the last study 
treatment (oral or intravenous [IV], whichever occurs later). The second safety follow-up visit 
(FU2) will occur approximately within 100 days (± 7 days) from the last dose of nivolumab and 
will be required for participants in the Safety Run-in Phase and participants randomized to Arms 
A or B in the Randomized Phase. Further planned treatment of participants in the adjuvant setting 
(ie, radiotherapy, endocrine treatment, chemotherapy or any other treatment modality) will be at 
the discretion of the treating physician, following local clinical guidelines, and collected in the 
appropriate eCRF. 
The study design schematic is presented in Figure 5.1-1.
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Figure 5.1-1:
Study Design Schematic
Abbreviations: Abema = abemaciclib; ANZ = anastrozole; BID = twice daily; cm = centimeter; ECOG = Eastern Cooperative Oncology Group; 
ER+ = estrogen-receptor-positive; FU1 = follow-up visit 1; FU2 = follow-up visit 2; HER2- = human epidermal growth factor receptor 2-negative;
IV = intravenous; mg = milligram; N = number; Nivo = nivolumab; Palbo = palbociclib; 
 PO = per os (by mouth); 
PS = performance status; Q4W = every 4 weeks; QD = once daily; Rand = randomized; wk = week.
a FU1 begins at the end of study treatment.
b Cytologically positive vs radiologically or cytologically negative.
Screening Period
Pre-surgery Treatment Period (N = 115~136)
Safety Follow-up Period
Key Inclusion 
Criteria
• Newly diagnosed, 
histologically 
proven ER+, 
HER2- primary 
breast cancer
≥ 2 cm
• Men and 
postmenopausal 
women
• ECOG PS 0-1
Safety Run-in Phase
(3 + 3 Approach)
(n = 3~24)c
Randomized Phase
(n = 110)d
FU1a
(All Participants in he 
Safety Run-in Phase and 
the Randomized Phase)
FU2
(All Participants in the 
Safety Run-in Phase and 
Arms A and B Only in 
the Randomized Phase)
Investigator’s Choice
Cohort 1 (n = 3~24)
Nivo 480 mg Q4W IV
+ Abema 150 mg BID PO 
+ ANZ 1 mg QD PO
x 5 cycles
Cohort 2 (n = 3~24)
Nivo 480 mg Q4W IV
+ Pa bo 125 mg QD PO 
3 wks on 1 wk off
+ ANZ 1 mg QD PO
x 5 cycles
Arm A (n = 40)
Nivo 480 mg Q4W IV + Palbo 125 mg QD PO 3 wks on 
1 wk off + ANZ 1 mg QD PO x 5 cycles
Arm B (n = 40)
Palbo 125 mg QD PO 3 wks on 1 wk off + ANZ 1 mg 
QD PO x 1 cycle THEN Nivo 480 mg Q4W IV + Palbo
125 mg QD PO 3 wks on 1 wk off + ANZ 1 mg QD PO 
x 4 cycles
Arm C (n = 30)
Palbo 125 mg QD PO 3 wks on 1 wk off + ANZ 1 mg 
QD PO x 5 cycles
Rand
4:4:3
30-Day Safety 
Follow-up
100-Day Safety 
Follow-up
(from last Nivo dose)
30-Day Safety 
Follow-up
100-Day Safety 
Follow-up
(from last Nivo dose)
30-Day Safety 
Follow-up
Stratify Randomized 
Phase Participants by:
•
Node (+ or -)b
•
Tumor size
(> 3 cm or ≤ 3 cm)
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c At the time of Revised Protocol 03, 2 participants had been treated in Cohort 1 (nivolumab + abemaciclib + anastrozole), which was subsequently closed for 
enrollment.
d At time of Revised Protocol 03, the decision was made to no longer evaluate abemaciclib in combination with nivolumab plus anastrozole; thus, the abemaciclib-
containing combination arms have been removed from the Randomization Phase of the study.
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5.1.1
Screening Period
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 evaluated for 
entry criteria and be enrolled into Interactive Response Technology (IRT). The screening 
assessments are shown in Table 2-1.
Participants must provide a pretreatment (baseline) tumor tissue, which must be either in FFPE 
tissue block containing 20 mm3 of tissue collected ≤90 days prior to enrollment (strongly 
preferred) or unstained tumor tissue sections (22 unstained slides) sectioned ≤60 days prior to 
enrollment from a tissue sample collected ≤90 days prior to enrollment from primary tumor lesion. 
If a recent tumor specimen is not available, a fresh tumor biopsy (containing 20 mm3 of tissue) is 
required. At least 15 unstained slides must be submitted for a participant to be eligible. If < 15
unstained slides are available, the participant is not eligible. Submit samples to the designated 
central laboratory with an associated pathology report. 
 
Safety Run-in participants: Participant can start study treatment before confirmation of receipt of 
the tumor sample by the central laboratory. However, receipt of the tumor sample by the central 
laboratory must occur within 28 days of the first dose.
Randomized participants: 
 
 Documentation of tumor size and node status (cytologically positive vs 
radiologically or cytologically negative) must be provided to IRT prior to 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 [or treated in the Safety Run-in Phase]). If re-enrolled, 
the participant must be re-consented.
5.1.2
On-treatment Pre-surgery (neoadjuvant) Period
A schedule of on-treatment visits and assessments is provided in Table 2-2.
5.1.2.1
Safety Run-in Phase
As of Revised Protocol 03, Cohort 1 will be discontinued. Participants in screening and not yet 
treated were offered the option to join the nivolumab + palbociclib + anastrozole arm. Participants 
on treatment were to be re-consented and continue on anastrozole alone, OR taken off study.
The Safety Run-in Phase will be conducted in advance of the Randomized Phase to evaluate the 
safety and tolerability of the combination of nivolumab, with palbociclib, plus anastrozole, which 
will be administered during the Randomized Phase.
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Participants will receive palbociclib in combination with nivolumab plus anastrozole (Cohort 2) 
for 5 cycles as neoadjuvant therapy and be followed up for safety (see Section 5.1.3 [Safety 
Follow-up Period]). . For the purpose of guiding alternative dose levels, all AEs will be graded 
according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse 
Events (CTCAE) v5.0 and dose-limiting toxicities (DLTs) will be defined based on the incidence, 
intensity, and duration of the AEs for which no clear alternative cause is identified. For the purpose 
of participant management, any drug-related AE that meets DLT criteria will lead to 
discontinuation of study treatment.
Participants who have discontinued due to a DLT or who have received 1 dose of nivolumab and 
75% of accumulative doses of palbociclib of the cycle, and have completed the 4-week DLT period 
will be considered as DLT-evaluable participants. Participants who withdraw from the study 
during the DLT evaluation period or have received less than 1 dose of nivolumab and 75% of 
accumulative doses of palbociclib of the cycle for reasons other than a DLT will not be considered 
as DLT-evaluable participants and may be replaced with new participants at the same dose level. 
Dose De-escalation Rules
For Cohort 2, 3 DLT-evaluable participants will be treated with the below starting doses:
•
Nivolumab: 480 mg every 4 weeks (Q4W) intravenously (IV)
•
Palbociclib 125 mg once daily (QD) PO for 3 weeks of each cycle (1 week off)
•
Anastrozole: 1 mg QD PO
If no participants (0 of 3 DLT-evaluable participants) experience a DLT during the DLT period 
(4 weeks), the Randomized Phase will be initiated at this dose level. If 1 evaluable participant
(1 of 3 DLT-evaluable participants) experiences DLT, then the cohort will be expanded to 
6 DLT-evaluable participants. If no more DLTs are observed (1 of 6 DLT-evaluable participants), 
then the Randomized Phase will be initiated at the dose level tested. If 1 or more additional 
evaluable participants (2 of 6 DLT-evaluable participants) experiences DLT during the DLT 
period, a lower dose will be tested using the same 3 + 3 schema. See Figure 5.1.2.1-1 for an 
overview of the 3 + 3 approach to be used for the Safety Run-in Phase.
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Figure 5.1.2.1-1:
Schematic of Safety Run-in Phase 3 + 3 Approach
Abbreviations: DLT = dose-limiting toxicity.
a For additional details see Section 7.4 (Dosage Modification).
Continuous evaluation of toxicity events will be performed. If at any time, the aggregate rate of 
treatment-related toxicities meeting DLT criteria exceeds 33% across participants treated in a 
cohort, the findings will be discussed with the Investigators and further enrollment may be 
interrupted. Any toxicities that occur beyond the DLT period will be accounted for in making final 
dose level decisions.
Generally, if a cohort is discontinued due to DLT of unclear relevance to nivolumab, a lower dose 
level of CDK4/6 inhibitor per product label will be tested in the next cohort. See Section 7.4
(Dosage Modification) for additional details on permitted dose adjustment. If a cohort is 
discontinued due to DLT related to nivolumab, a different dose or dose schedule will be explored 
per Investigator and Medical Monitor discussion. 
For cohort expansion or dose de-escalation decisions, the available toxicity information (including
AEs and laboratory abnormalities that are not DLTs), clinical judgment
 
will be evaluated by the Investigators and BMS study personnel
(including the Medical Monitor and statistician) during a dose decision meeting by teleconference.
Drug administration at the next dose level or proceeding to the Randomized Phase must not occur 
until the Investigator receives written confirmation from BMS indicating that the results of the
previous dose level were evaluated and that it is permissible to proceed.
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Definition of DLTs: DLTs are defined as any TEAEs specified below that occur during the first 
4 weeks (1 cycle) except those clearly and incontrovertibly due to disease progression or 
extraneous causes.
Gastrointestinal DLTs
•
Grade 2 colitis that lasts longer than 7 days, despite best supportive treatment.
•
Grade 3 diarrhea or colitis that lasts longer than 72 hours with adequate supportive treatment.
•
Grade ≥4 diarrhea or colitis.
Hepatic DLTs
•
Grade 4 elevations in serum transaminases (aspartate aminotransferase [AST] and alanine 
aminotransferase [ALT], alkaline phosphatase [ALP]) or total bilirubin.
•
Grade 3 elevations in serum AST, ALT, or bilirubin.
•
Bilirubin > 2 x upper limit of normal (ULN) in the absence of cholestasis.
•
Grade 2 elevations in AST or ALT with symptomatic liver inflammation (eg, right upper 
quadrant tenderness, jaundice).
•
Grade 3 ALP elevation that last longer than 5 days, or is associated with clinical symptoms.
•
AST or ALT > 3 × ULN and concurrent total bilirubin > 2 × ULN without initial findings of 
cholestasis (elevated ALP; eg, findings consistent with Hy’s law or FDA definition of potential 
drug-induced liver injury [p-DILI]). Note that this specific category of DLT uses ULN rather 
than NCI CTCAE grade for definition.
Hematologic DLTs
•
Grade 4 neutropenia ≥7 days in duration.
•
Grade 4 thrombocytopenia.
•
Grade 3 thrombocytopenia with bleeding or any requirement for platelet transfusion.
•
Grade 3 hemolysis (ie, requiring transfusion or medical intervention such as steroids).
•
Neutropenic fever of any duration.
•
Grade 4 anemia not explained by underlying disease.
Dermatologic DLTs
•
Grade 4 rash or confirmed Stevens-Johnson Syndrome or Toxic Epidermal Necrolysis.
•
Grade 3 rash if no improvement (ie, resolution to ≤Grade 1) after a 1- to 2-week infusion 
omission for nivolumab.
Other DLTs
•
Recurrence of same Grade 3 adverse reactions.
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•
Any AE that required discontinuation of nivolumab per approved label.
•
Any Grade immune-related encephalitis.
•
Any incidence of Grade ≥3 prolongation of QT interval corrected using Fridericia's Correction 
Formula (QTcF) on electrocardiograms (ECGs).Grade 3 hypersensitivity reaction/infusion 
reaction that does not resolve to Grade 1 in < 6 hours.
•
Grade 2 pneumonitis that does not respond to dose modification for nivolumab and systemic 
steroids within 14 days.
•
Any death not clearly due to the underlying disease or extraneous causes.
•
Grade 2 uveitis, episcleritis, iritis, eye pain, or blurred vision that does not respond to topical 
therapy and does not improve to Grade 1 severity within 2 weeks OR requires systemic 
treatment.
•
Grade ≥3 electrolyte abnormality associated with clinical symptoms.
•
Grade 3 fatigue lasting ≥1 week.
•
Other Grade 3 ≥toxicity will be considered a DLT, except those clearly and incontrovertibly 
due to disease progression and extraneous causes. However, the following Grade 3 or 4 events 
will not be considered DLTs:
−
Isolated Grade 3 or 4 electrolyte imbalances/abnormalities not associated with clinical 
symptoms
and 
either 
resolve 
spontaneously 
or 
are 
corrected 
with 
supplementation/appropriate management within 72 hours of their onset. Confirmatory 
laboratory test is required within 72 hours.
−
Grade ≥3 amylase or lipase elevation not associated with symptoms or clinical 
manifestations of pancreatitis.
−
Grade 3 nausea or vomiting that lasts less than 48 hours and either resolves spontaneously 
or responds to medical intervention. 
−
Grade 3 fever not associated with hemodynamic compromise (eg, hypotension, clinical or 
laboratory evidence of impaired end-organ perfusion).
−
Grade 3 endocrinopathy that is well controlled by hormone replacement.
−
Grade 3 tumor flare (defined as pain, irritation, or rash that localizes to sites of known or 
suspected tumor).
5.1.2.2
Randomized Phase
The Randomized Phase will start after the combinations tested in the Safety Run-in Phase are 
confirmed to be safe by BMS in collaboration with Investigators, and the appropriate dose level 
communicated to Investigators. Following confirmation of eligibility criteria, participants will be 
randomized to either Arm A, Arm B, or Arm C in a 4:4:3 ratio, respectively. Participant 
randomization will be stratified using the following factors:
2) Evaluation of lymph nodes (cytologically positive vs radiologically or cytologically negative), 
and
3) Tumor size (> 3 cm or ≤3 cm).
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Treatment must begin within 3 calendar days following randomization.
Participants will be randomly assigned to 1 of the 3 treatment arms below:
As of Revised Protocol 03, the abemaciclib-containing combination arms have been removed from 
the randomization phase of the study.
1) Arm A
(concurrent palbociclib treatment arm): nivolumab 480 mg Q4W IV + 
palbociclib 125 mg QD PO for 3 weeks (1 week off) + anastrozole 1 mg QD PO for 5 cycles
2) Arm B (phased palbociclib treatment arm):
a) palbociclib 125 mg QD PO for 3 weeks of each cycle (1 week off) + anastrozole 1 mg QD 
PO for 1 cycle followed by
b) nivolumab 480 mg Q4W IV + palbociclib 125 mg QD PO for 3 weeks (1 week off) + 
anastrozole 1 mg QD PO for 4 cycles
3) Arm C (control palbociclib arm): palbociclib 125 mg QD PO for 3 weeks of each cycle (1 
week off) + anastrozole 1 mg QD PO for 5 cycles
5.1.3
Safety Follow-up Period
Depending on the treatment arms, there may be up to 2 in-person safety follow-up visits. FU1 will 
occur 30 days from the last dose (± 7 days) of the study treatment (PO or IV; whichever occurs 
later) for all arms. FU2 occurs approximately 100 days (± 7 days) from the last dose of nivolumab 
for Safety Run-in participants and Arms A and B in the Randomized Phase.
5.1.4
External Committees
5.1.4.1
Study Steering Committee
A SSC will be established to obtain scientific guidance and advice on 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
A total of approximately 115~136 participants will be treated in the study. It is anticipated that 
approximately 3~24 participants (up to approximately 30 screened) will be treated in each cohort 
in the Safety Run-in Phase. At the time of Revised Protocol 03, 2 participants had been treated in 
Cohort 1 (nivolumab + abemaciclib + anastrozole), which was subsequently closed for enrollment.
Approximately 138 participants will be screened for 110 participants to be treated in the 
Randomized Phase, assuming a screen failure rate of approximately 20%. See Section 10.1
(Sample Size Determination) for additional details.
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5.3
End of Study Definition
The start of the trial is defined as the first participant’s first visit. End of study is defined as the 
last participant’s last study visit or scheduled procedure shown in Section 2 (Schedule of 
Activities). Study completion is defined as the final date on which data for the primary endpoint 
was or is expected to be collected.
5.4
Early Study Termination Criteria
The Sponsor has the right to terminate this study at any time. Reasons for terminating the study 
may include, but are not limited to, the following:
•
The incidence and/or severity of AEs in this or other studies that incorporate similar treatment 
arm(s) indicates a potential health hazard to participants.
•
Further clinical data that might occur from other studies that incorporate similar treatment 
arm(s) that indicate a potential inappropriate benefit-risk balance for participants in the study, 
due to lack of activity.
Such decisions shall be communicated promptly, in order to allow the termination procedure to be 
properly followed. BMS will also notify Investigators if the study is terminated early.
5.5
Scientific Rationale for Study Design
5.5.1
Rationale for the Choice of Patient Population
Men or postmenopausal women with newly diagnosed, histologically proven ER+, HER2- primary 
BC ≥2 cm who are eligible for NET will be included in the study population. Due to the low 
pathological complete response (pCR) rate, there remains an unmet medical need in this patient 
population.
Historically, NET has been offered to women with HR+ tumors who are unfit for surgery or refuse 
this procedure, or to elderly women with short life expectancy, as established by a qualified 
specialist and based on a validated geriatric assessment tool. NET has also been used to reduce 
tumor size and third-generation aromatase inhibitors increased likelihood of breast conserving 
surgery to 36-45%. In patients with a low recurrence score, NET demonstrated a clinical response 
rate of 59% and a BCS rate of 91%. 
NET not only confers clinical benefit to patients with HR+, HER2- BC but also provides important 
prognostic information and is an excellent platform for the development of investigational drugs, 
triaging of novel combinations, 
 and discovery of mechanisms of drug 
resistance. Several key mechanisms of action have been assessed in the neoadjuvant space in an 
exploratory setting, where results from metastatic trials mirror those from their respective 
neoadjuvant trials (ie, mammalian target of rapamycin [mTOR] blockade + endocrine therapies,53
phosphoinositide-3 kinase (PI3K) blockade + endocrine therapies,54,55 and CDK4/6 blockade plus 
endocrine therapies49,56,57,58). Those examples suggest that knowledge gained from NET studies 
provide information to predict if a new combination is likely to be successful in large adjuvant or 
metastatic Phase 3 trials. We anticipate that the current study may help to focus the development 
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of the combination of nivolumab, palbociclib, and anastrozole for use in patients with BC that is 
ER+ and HER2-.
5.5.2
Rationale for Choice of Endpoint (Residual Cancer Burden 0-I Rate)
There are lack of clinical endpoints predictive of event-free survival after NET in the HR+, HER2-
primary BC setting, since pCR is uncommon and is not an effective surrogate of long-term 
outcome for this tumor type. Failure to achieve a pCR does not imply poor patient outcome since 
these patients still receive 5-10 years of adjuvant ET. Additionally, many patients with HR+, 
HER2- BC are likely cured with local treatment and standard adjuvant ET, which is also informed 
by several well validated prognostic gene signatures. For patients who did not achieve pCR, RCB 
is a type of pathological response quantification for the extent of residual disease with the RCB 
index evaluating 5 post-treatment variables: 2-dimensional tumor bed, cellularity, percentage of 
carcinoma in situ, number of metastatic lymph nodes, and the diameter of the largest nodal 
metastases. The RCB index classifies the surgical specimen into 4 categories that include RCB-0
(pCR), RCB-I (minimal residual disease), RCB-II (moderate residual disease), and RCB-III 
(extensive residual disease), and predicts risk of relapse after neoadjuvant chemotherapy to be 
highest for RCB-III (53.6%), while similar for RCB-0 and RCB-I (2.4% and 5.4%, 
respectively).59,60 RCB (0-I) determined by local site pathologists was also prognostic for better 
long-term survival after neoadjuvant chemotherapy in all subtypes of BC.61,62 Hence, RCB index 
is increasingly used in NET studies 
 
. In addition, a RCB (0-I) rate endpoint can be assessed within several 
months of initiation of an investigational drug in the neoadjuvant setting that could potentially 
address an unmet need in a far shorter time frame than would be required via the conventional 
approach to BC drug development. Use of this surrogate endpoint is expected to innovate the 
development of novel therapies for BC.
5.5.3
Rationale for CDK 4/6 Plus PD-1 Inhibition
PD-1 inhibition prevents interaction with the receptors PD-1 and B7-1 (a costimulatory 
cell-surface protein), reversing T-cell suppression and leading to tumor response. The PD-1 
inhibitor pembrolizumab as a single agent led to ORR of 12% (3/25) in heavily pretreated patients 
with ER+ BC that was also PD-L1 positive. In combination with chemotherapy, pembrolizumab 
improved pCR rates in all HER2- BCs in the neoadjuvant setting.5 Several preclinical studies point 
towards PD-1/CDK4/6 blockade synergy as it has become more apparent that CDK4/6 inhibitors 
affect the tumor immune microenvironment.6 Within tumor cells, selective CDK4/6 inhibitors 
increase expression of PD-L1 through the E3 ligase adapter protein, Speckle-type POZ protein 
(SPOP),7 and enhance antigen presentation via reduced activity of the E2F target, 
deoxyribonucleic acid (DNA) methyltransferase 1 (DNMT).8 Secretion of cytokines from both 
tumor and CD8+ T cells is also enhanced with CDK4/6 inhibitor treatment,9,10 whereas 
proliferation of immunosuppressive Tregs is suppressed.8 In murine models of BC, selective 
CDK4/6 inhibitors promote anti-tumor immunity via indirect stimulation of type III interferon 
(IFN) production and enhancing tumor antigen presentation, plus suppression of the proliferation 
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of Tregs.8,10 In addition, treatment with the CDK4/6 inhibitor abemaciclib alone resulted in tumor 
growth delay that was associated with an increased T-cell inflammatory signature in tumors. 
Combination of a CDK4/6 inhibitor with an anti-PD-(L)1 therapy led to complete tumor regression 
and immunological memory, accompanied by enhanced antigen presentation, a T-cell inflamed 
phenotype, and enhanced cell-cycle control.63
Clinically, in a Phase Ib study, the combination of pembrolizumab and abemaciclib demonstrated 
a confirmed ORR of 28.6% in heavily pretreated participants with metastatic HR+, HER2- BC.11
In agreement with the previously mentioned preclinical data indicating CDK4/6 blockade as a 
mediator of the cancer immunity, abemaciclib alone or in combination with anastrozole has been 
associated with upregulation of gene expression signatures related to T-cell immune response and 
antigen presentation in the neoMONARCH study, where 10-16 paired samples in each arm were 
examined in the primary disease setting.11 Clinical data on combinations of other CDK4/6 
inhibitors with PD-(L)1 blocking agents are being generated in multiple clinical trials spanning 
from the neoadjuvant to metastatic settings (ClinicalTrials.gov: NCT03573648, NCT02778685, 
NCT03294694).
The aim of CA2097A8 is to assess the potential synergistic activity of nivolumab, with palbociclib,
and anastrozole in participants with newly diagnosed, previously untreated primary HR+, HER2-
BC ≥2 cm, defined by significantly improved RCB (0-I) rate. 
 
 This trial is part of a broader effort to establish nivolumab as a SOC for the 
treatment of HR+, HER2- BC.
5.5.4
Rationale for Phased Therapy (Arm B)
Strategies to render the tumor micro-environment (TME) more susceptible to anti-PD(L)1 therapy 
has been investigated in a phase 2 study (TONIC trial) of 50 participants with metastatic TNBC 
who received palliative chemotherapy.44 Priming the anti-cancer immune response with low-dose 
chemotherapy for 2 weeks or radiation therapy before starting nivolumab resulted in a best 
objective response rate (ORR) of 24%. In CT26 syngeneic mouse tumor model, a phased 
administration of abemaciclib and an anti-PD-L1 therapy improves anti-tumor efficacy and 
induced complete tumor regression.12 In the same animal model, abemaciclib monotherapy 
induced intra-tumor immune inflammation on D13 and D20. In agreement with the previously 
mentioned preclinical data indicating CDK4/6 blockade as a mediator of cancer immunity, 
abemaciclib in combination with anastrozole has been associated with upregulation of gene 
expression signatures related to T-cell immune response and antigen presentation in the 
neoMONARCH study, where 10-16 paired samples in each arm were examined in the primary 
disease.49 We therefore chose to test a phased therapy approach in Arm B to investigate whether 
additional treatment benefit will be observed with these regimens.
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5.6
Justification for Dose
5.6.1
Justification for Dose of Nivolumab
Nivolumab 480 mg Q4W infused over 30 minutes was FDA approved in Mar-2018 for the majority 
of the nivolumab approved indications. The European Medicines Agency’s (EMA’s) Committee 
for Medicinal Products for Human Use has also recommended adding the option of a 4-week 
dosing schedule to the label for nivolumab for the treatment of patients with advanced melanoma 
and previously treated RCC.
Nivolumab 480 mg Q4W infused over 30 minutes will be examined in combination with 
palbociclib and anastrozole in this study.
5.6.2
Justification for Dose of CDK4/6 Inhibitors
Abemaciclib 150 mg BID PO or palbociclib 125 mg QD PO for 3 weeks of each cycle (1 week 
off) were approved by FDA in Sep-2017 and Feb-2015, respectively, and by EMA in Sep-2018 
and Nov-2016, respectively, in combination with ET for ER+, HER2- BC, based on clinical safety 
and efficacy.
Abemaciclib 150 mg BID PO or palbociclib 125 mg QD PO for 3 weeks of each cycle (1 week 
off) will be examined in combination with nivolumab and anastrozole in this study.
As of Revised Protocol 03, examination of abemaciclib + nivolumab + anastrozole will not be 
continued in this study.
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5.6.3
Justification for Dose of Anastrozole
Anastrozole 1 mg QD PO was approved by FDA and in Europe in Jan-1996 and Aug-1995, 
respectively, for BC.
Anastrozole 1 mg QD PO will be examined in combination with nivolumab and palbociclib in this 
study.
6
STUDY POPULATION
For entry into the study, the following criteria MUST be met.
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 schedule, 
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 
the following characteristics:
i)
Primary tumor ≥ 2 cm in largest diameter (cT1-3) by US/mammogram. In the case of 
a multifocal tumor (defined as the presence of two 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. Please note: N3 disease (defined so either 
clinically or radiologically) is excluded.
ii) 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 (staging imaging reports).
iii) Not applicable per Revised Protocol 03.
b) Participants must have ER+ and HER2- BC meeting below characteristics:
i)
ER+ BC and with or without progesterone-receptor (determined on the most recently 
analyzed tissue sample and tested by a local laboratory as defined in the relevant 
American Society of Clinical Oncology [ASCO]-College of American Pathologists
[CAP] Guidelines).72
ii) HER2- BC defined as a negative in situ hybridization test or an 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 Guidelines73 is required (tested by 
a local laboratory).
c) Participants must have neoadjuvant endocrine monotherapy deemed to be a suitable 
therapy.
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d) Participants must agree to provide tumor tissue at baseline, on-treatment, and at surgery. 
The tumor tissue at baseline must be either in FFPE tissue block (20 mm3) collected within 
90 days prior to enrollment or unstained tumor tissue sections (22 slides sectioned within 
60 days prior to enrollment from a tissue sample collected within 90 days prior to 
enrollment) from primary tumor lesion. If a recent tumor specimen is not available, a fresh 
tumor biopsy (containing 20 mm3 of tissue) collection is required. At least 15 unstained 
slides must be submitted for a participant to be eligible. If < 15 unstained slides are 
available, the participant is not eligible. 
 
 
 
e) Participants must have the ability to swallow oral medication.
f)
Participants must have a performance status (PS) ≤1 on the Eastern Cooperative Oncology 
Group (ECOG) scale.
g) Participants must be deemed eligible for surgery and must agree to undergo surgery after 
completion of neoadjuvant therapy.
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 (or treated in 
the Safety Run-in Phase). If re-enrolled, the participant must be re-consented and 
inclusion/exclusion criteria reassessed.
3) Age and Reproductive Status
a) Women not of childbearing potential (WNOCBP; refer to Appendix 4) and Men, ages 18 
or local age of majority and older, inclusive.
b) Women participants must have documented proof that they are not of childbearing 
potential including postmenopausal status defined as:
i)
Women over age 55 years who, in the absence of other biological or physiological 
causes, have 12 months of amenorrhea.
ii) Age 55 or younger with no menses (eg, spontaneous or secondary to hysterectomy) for 
at least 12 months prior to enrollment (in the absence of chemotherapy, tamoxifen, 
toremifen, or ovarian suppression) and with a documented serum follicle stimulating 
hormone (FSH) level > 40 mIU/mL and estradiol level in the postmenopausal range 
according to local institutional/laboratory standard; or
iii) Age ≥18 with documented bilateral oophorectomy at least 28 days prior to D1 of 
treatment.
Note: For women with therapy-induced amenorrhea, serial measurements of FSH 
and/or estradiol are needed to ensure postmenopausal status. Ovarian radiation or 
treatment with a luteinizing hormone-releasing hormone agonist (LH-RHa; goserelin 
acetate or leuprolide acetate) is not permitted for induction of ovarian suppression in 
this trial.
c) Women who are not of childbearing potential are exempt from contraceptive requirements.
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d) Men 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 treatment with study 
treatment(s) plus 5 half-lives of the study treatment plus 90 days (duration of sperm 
turnover) for a total of 7 months post-treatment completion. In addition, male participants 
must be willing to refrain from sperm donation during this time.
e) Azoospermic men are not exempt from contraceptive requirements, even if the participant 
has undergone a successful vasectomy or if the partner is pregnant.
6.2
Exclusion Criteria
1) Medical Conditions
a) Women who are of childbearing potential or breastfeeding
b) The following BC characteristics:
i)
History of ipsilateral invasive BC, regardless of treatment, or ipsilateral ductal 
carcinoma in situ treated with radiotherapy or contralateral invasive BC at any time.
ii) Definitive clinical or radiologic evidence of metastatic disease.
iii) Inflammatory/inoperable BC.
iv) Multicentric BC (the presence of more than 1 tumor in different quadrants of the 
breast).
v)
Bilateral invasive BC.
c) Not applicable per Protocol Revision 03.
d) Participants with a history of or active, known or suspected autoimmune disease, or other 
syndrome that requires systemic steroids above physiological replacement dose or 
autoimmune agents for the past 2 years, except:
i)
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.
ii) Inhaled or topical steroids, and adrenal replacement steroid doses up to physiological 
replacement dose, are permitted in the absence of active autoimmune disease.
e) Known human immunodeficiency virus (HIV) positive with an AIDS defining 
opportunistic infection within the last year, or a current CD4 count <350 cells/uL. NOTE: 
Testing for HIV must be performed at sites where mandated locally (refer to Appendix 9).
f)
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.
g) Participants with serious or uncontrolled medical disorders.
h) Personal history of any of the following conditions: syncope of either unexplained or 
cardiovascular etiology, ventricular arrhythmia (including but not limited to ventricular 
tachycardia and ventricular fibrillation), long or short QT syndrome, Brugada syndrome, 
or known history of corrected QT prolongation, Torsade de Pointes, or sudden cardiac 
arrest. Exception: participants with controlled atrial fibrillation for > 30 days prior to study 
treatment are eligible.
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i)
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 GI 
function.
iii) Chronic daily treatment with corticosteroids at a dose above physiological replacement 
dose (excluding inhaled steroids).
iv) Seizure disorders requiring medication.
v) History of interstitial lung disease or pneumonitis. 
j)
Class III or Class IV myocardial disease as described by the New York Heart Association
(refer to Appendix 11)74; a recent history (within 6 months prior to enrolment) of
myocardial infarction, or symptomatic arrhythmia at the time of randomization/treatment.
k) Any psychological, familial, sociological, or geographical condition potentially hampering 
compliance with the study protocol and follow-up schedule. 
2) Prior/Concomitant Therapy
a) Any treatment, including radiotherapy, chemotherapy, and/or targeted therapy, 
administered for the currently diagnosed BC prior to enrollment.
b) Surgical axillary staging procedure prior to enrollment (with exception of fine-needle 
aspiration or core biopsy).
c) Surgical excisional biopsy of primary tumor.
d) Participants for whom upfront chemotherapy is clinically judged appropriate as optimal 
neoadjuvant treatment
e) Prior ET or CDK4/6 inhibitors for BC within 5 years.
Note: Participants who received ≤7 days of letrozole or anastrozole for current disease 
prior to randomization/treatment are eligible.
f)
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.
g) Use of any medication or substances that are strong inhibitors or inducers of cytochrome 
p-450 (CYP)3A isoenzymes, or CYP3A substrates with narrow therapeutic index (see 
Section 7.7 [Concomitant Therapy]). 
h) Treatment with botanical preparations (eg, herbal supplements or traditional Chinese 
medicines) intended for general health support or to treat the disease under study within 
2 weeks prior to randomization/treatment. See Section 7.7 for prohibited therapies.
i)
Participants who have received a live/attenuated vaccine within 30 days before first 
treatment.
j)
Concurrent use (defined as use within 4 weeks prior to baseline tissue sample being taken) 
of hormone replacement therapy or any other estrogen-containing medication (including 
vaginal estrogens).
3) Physical and Laboratory Test Findings
a) White blood cells < 2000/μL
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b) Neutrophils < 1500/μL
c) Platelets < 100 ×103/μL
d) Hemoglobin < 10.0 g/dL
e) Serum creatinine > 1.5 × ULN, or estimated creatinine clearance < 60 mL/min (as 
calculated using the method standard for the institutions)
f)
AST/ALT: > 1.5 × ULN
g) Total bilirubin > ULN or > 1.5 × ULN in participants with Gilbert Syndrome or similar 
syndrome involving slow conjugation of bilirubin
h) ALP > 1.5 × ULN
i)
Not applicable per Protocol Revision 03.
j)
Have corrected QT interval of > 470 milliseconds on screening ECG.
k) International normalized ratio must be within normal limits of the local laboratory ranges. 
l)
Serologic evidence of chronic hepatitis B virus (HBV) infection with an HBV viral load 
above the limit of quantification. Patients with chronic HBV infection must be on 
concurrent viral suppressive therapy.
m) Serologic evidence of current hepatitis C virus (HCV) infection with an HCV viral load 
above the limit of quantification.
4) Allergies and Adverse Drug Reaction
a) History of allergy or hypersensitivity 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 written 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
6.3.1
Meals and Dietary Restrictions for CDK 4/6 Inhibitor
•
Participants must avoid consumption of grapefruit, grapefruit hybrids, pummelos, star-fruit, 
Seville oranges, pomegranates, or products containing the juice of each during the entire study 
treatment and preferably 7 days before the first dose of study medications, as they affect CYP
and P-glycoprotein (PgP) activity and have a potential to increase exposure to palbociclib 
(NOTE: Oranges and orange juice are allowed.)
•
Herbal or dietary supplements known as strong inhibitors or inducers of CYP3A4 (refer to 
Appendix 10 [Concomitant Medications]) are prohibited. 
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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 or Lead-In Phase
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 or Safety 
Run-in Phase 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.
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:
•
BMS-936558 (nivolumab)
•
Abemaciclib
•
Palbociclib
•
Anastrozole
An IP, also known as an IMP in some regions, is defined 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.
Description and storage information for the 4 drugs used in this open-label study are provided in
Table 7-1.
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.
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Premedications or medications used to treat infusion-related reactions should be sourced by the 
investigative sites if available and permitted by local regulations.
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Table 7-1:
Study Treatments for Study Number CA2097A8
Product Description/ 
Class and Dosage 
Form
Potency
IP/Non-IMP
Blinded or 
Open Label
Packaging/ 
Appearance
Storage Conditions
(per label)
Nivolumab Injectiona
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
Abemaciclib Tabletsb
150 mg, 100 mg, and 50 mg
IP
Open Label
Tablets
Refer to the label or container and/or 
Pharmacy Manual
Palbociclib Capsulesb
125 mg, 100 mg, and 75 mg
IP
Open Label
Capsules
Refer to the label or container and/or 
Pharmacy Manual
Anastrozole Tabletsb
1 mg
IP
Open Label
Tablets
Refer to the label or container and/or 
Pharmacy Manual
Abbreviations: IP = investigational product; IMP, investigational medicinal product; mg = milligram; mL = milliliter; 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 institutional standards.
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7.1
Treatments Administered
The selection and timing of dose for each participant are shown in Table 7.1-1 and Table 7.1-2.
Table 7.1-1:
Selection and Timing of Dose - Safety Run-in Phase
Cohort
Study 
Treatment
Dosage Levela
Frequency of
Administration
Start and Duration 
of Treatment
Route of 
Administration
1
Nivolumab
480 mg
Q4W
Cycle 1-5
IV
Abemaciclib
150 mg
BID
Cycle 1-5
PO (with or 
without food)
Anastrozole
1 mg
QD
Cycle 1-5b
PO (with or 
without food)
2
Nivolumab
480 mg
Q4W
Cycle 1-5
IV
Palbociclib
125 mg
QD × 3 weeks on
(1 week off)
Cycle 1-5
PO (with food)
Anastrozole
1 mg
QD
Cycle 1-5b
PO (with or 
without food)
Abbreviations: BID = twice daily; EOT = end of treatment; IV = intravenous; mg = milligram; PO = per os (by mouth); 
Q4W = every 4 weeks; QD = once daily.
Note: At the time of Revised Protocol 03, 2 participants had been treated in Cohort 1 (nivolumab + abemaciclib + 
anastrozole), which was subsequently closed for enrollment.
a For abemaciclib and palbociclib, this is the starting dose level. Dose levels may be reduced per Section 7.4 (Dosage 
Modification).
b After 5 cycles or EOT, all participants should continue to receive anastrozole until breast surgery. Anastrozole is 
not considered study therapy beyond completion of Cycle 5 or EOT.
Table 7.1-2:
Selection and Timing of Dose - Randomized Phase
Arm
Study 
Treatment
Dosage Levela
Frequency of
Administration
Start and Duration 
of Treatment
Route of 
Administration
A
Nivolumab
480 mg
Q4W
Cycle 1-5
IV
Palbociclib
125 mg
QD × 3 weeks on 
(1 week off)
Cycle 1-5
PO (with food)
Anastrozole
1 mg
QD
Cycle 1-5b
PO (with or 
without food)
B
Palbociclib
125 mg
QD × 3 weeks on 
(1 week off)
Cycle 1-5
PO (with food)
Anastrozole
1 mg
QD
Cycle 1-5b
PO (with or 
without food)
Nivolumab
480 mg
Q4W
Cycle 2-5
IV
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Table 7.1-2:
Selection and Timing of Dose - Randomized Phase
Arm
Study 
Treatment
Dosage Levela
Frequency of
Administration
Start and Duration 
of Treatment
Route of 
Administration
C
Palbociclib
125 mg
QD × 3 weeks on 
(1 week off)
Cycle 1-5
PO (with food)
Anastrozole
1 mg
QD
Cycle 1-5b
PO (with or 
without food)
Abbreviations: BID = twice daily; EOT = end of treatment; IV = intravenous; mg = milligram; PO = per os (by mouth); 
Q4W = every 4 weeks; QD = once daily.
Note: As of Revised Protocol 03, the abemaciclib-containing combination arms have been removed from the 
Randomization Phase of the study.
a For palbociclib, the starting dose level will be the safe dose determined upon completion of the Safety Run-in 
Phase.
b After 5 cycles or EOT, all participants should continue to receive anastrozole until breast surgery. Anastrozole is 
not considered study therapy beyond completion of Cycle 5 or EOT.
Randomized participants should begin study treatment within 3 calendar days of randomization.
7.1.1
Nivolumab Dosing (Safety Run-in Cohorts and Randomized Phase 
Arms A and B)
Participants are to start nivolumab within 3 calendar days of randomization.Participants will 
receive nivolumab at a dose of 480 mg as a 30-minute IV infusion for a maximum of 5 cycles 
(maximum 4 cycles for Arm B).
Doses of nivolumab may be interrupted, omitted, or discontinued, depending on how well the 
participant tolerates the treatment. There will be no dose escalations or reductions of nivolumab 
allowed. For Q4W dosing cycles, participants may be dosed within a ± 3-day window. 
If a participant cannot receive nivolumab within a ± 3-day window, nivolumab must be omitted 
(skipped) for that cycle. If nivolumab is omitted, the other study medications may continue. If a 
participant discontinues nivolumab, the entire study treatment (CDK4/6 inhibitor and anastrozole) 
must be discontinued.
When nivolumab is scheduled to be administered on the same day with palbociclib plus
anastrozole, nivolumab dosing should be started > 1 hour after palbociclib plus anastrozole 
ingestion. If nivolumab can not be given within 3 days of palbociclib plus anastrozole 
administration for a given cycle, nivolumab must be omitted for that cycle. 
Premedications are not recommended for the first dose of nivolumab.
Participants should be carefully monitored for infusion reactions during nivolumab administration. 
If an acute infusion reaction is noted, participants should be managed according to Section 7.4.4.3
(Treatment of Nivolumab Infusion Reaction). 
Instructions for dilution and infusion of nivolumab injection may be provided in the clinical 
protocol, pharmacy binder, or pharmacy reference sheet. Care must be taken to assure sterility of 
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the prepared solution, as the product does not contain any antimicrobial preservative or 
bacteriostatic agent.
7.1.2
CDK4/6 Inhibitors and Anastrozole Dosing
Premedications are not recommended for the first dose.
In the Safety Run-in Phase, participant assignment to abemaciclib or palbociclib will be carefully 
managed by the study team with the Investigator. The selected CDK4/6 inhibitor cannot be 
changed or switched to another one once the study treatment has been initiated. At implementation 
of Revised Protocol 03, the study will only evaluate the combination of nivolumab with palbociclib 
plus anastrozole. Patients in screening and not yet treated were offered the option to join the nivolumab 
+ palbociclib + anastrozole arm. Patients on treatment were to be re-consented and continue on 
anastrozole alone, OR taken off study. 
Study treatment must be taken within 3 calendar days following randomization.
In the Randomized Phase, participants will be randomly assigned by an IRT system.
Palbociclib should be taken together with anastrozole as follows:
•
Palbociclib is dosed QD PO for the first 3 weeks of the cycle (with the 4th week off). 
Anastrozole is dosed continuously, BID and QD PO, respectively.
•
On scheduled visit days, participants must hold taking study treatments at home. They must 
take them in the clinic under the supervision of the Investigator or designee after all study 
procedures for the visit have been completed. On all other days, participants may take study 
treatments at home.
•
Participants should be instructed to take palbociclib and anastrozole with a large glass of water 
(~250 mL or ~8 oz) at the same time each day.
•
Palbociclib should be administered with food. Anastrozole can be administered either with or 
without food.
•
Participants should be instructed to swallow the tablets whole and not to chew, crush, or open 
them.
•
If vomiting occurs during the course of treatment, no re-dosing of the participant is allowed 
before the next scheduled dose. The occurrence and frequency of any vomiting during a 
treatment cycle must be noted in the AEs section of the eCRF. 
•
Any doses that are missed (not taken within 6 hours of the intended time) should be skipped 
and should not be replaced or made up on a subsequent day.
•
Multivitamins, glucosamine, probiotics, and fish oil are permitted. 
•
After 5 cycles or EOT, all participants should continue to receive anastrozole until subsequent 
breast surgery. If anastrozole can no longer be administered after EOT (ie, due to related 
toxicities), breast surgery will be performed right away. Anastrozole is not considered study 
therapy beyond completion of Cycle 5 or EOT.
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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. The Investigator or designee will register the participant for enrollment by 
following the enrollment procedures established by BMS.
The following information is required for enrollment in the IRT:
•
Date that informed consent was obtained
•
Year of birth
•
Gender at birth
Safety Run-in participants who have met all eligibility criteria will be enrolled in the IRT. 
 
After the Safety Run-in Phase is complete (safety of the combination is confirmed), randomization 
of participants to Arms A, B, and C can begin. 
The following information is required for participant randomization:
•
Participant number
•
Year of birth
•
Tumor characteristics (involvement of lymph nodes, tumor size at baseline)
Participants meeting all eligibility criteria will be randomized in a 4:4:3 ratio and stratified by 
 
 2) involvement of lymph node
(cytologically positive vs radiologically or cytologically negative), and 3) tumor size (> 3 cm or 
≤3 cm).
The exact procedures for using the IRT will be detailed in the IRT manual. Study treatment will 
be dispensed at the study visits as listed in Section 2 (Schedule of Activities).
7.3
Blinding
This is a randomized, non-comparative, open-label study; blinding procedures are not applicable.
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. No dose re-escalation will be allowed.
Please refer to individual approved drug labels for recommendations on dose reduction, 
interruption or discontinuation of individual study drugs in the management of study drug-related 
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adverse reactions. 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 eCRF.
7.4.1
Dose Modifications for Abemaciclib
At the implementation of Revised Protocol 03, abemaciclib dosing will be discontinued in all 
patients. 
7.4.2
Dose Modifications for Palbociclib
Palbociclib can be interrupted, reduced, or discontinued both within a cycle and between cycles.
The dose modifications permitted for palbociclib in combination with anastrozole are based on the 
dose level changes outlined in Table 7.4.2-1.
Table 7.4.2-1:
Dose Levels for Palbociclib
Dose Level
Oral Dose
Frequency
Starting dose
125 mg
QD × 3 weeks on (1 week off)
First dose reduction
100 mg
QD × 3 weeks on (1 week off)
Second dose reduction
75 mg
QD × 3 weeks on (1 week off)
Third dose reduction
Discontinue
Not applicable
Abbreviations: mg = milligram; QD = once daily.
7.4.3
Dose Modification for Anastrozole
No dose modification for anastrozole is listed per full prescribing information.
7.4.4
Dose Modifications for Nivolumab
Participants who require a dose omission for nivolumab should be re-evaluated and resume 
treatment at the next cycle when re-treatment criteria are met. Drug-drug interaction between 
nivolumab and palbociclib are not expected. Nivolumab is a monoclonal antibody given IV, and 
is unlikely to cause any cytokine mediated changes in CYP isoenzymes.
7.4.4.1
Dose Omission Criteria for Nivolumab
Nivolumab administration should be omitted for the following:
•
Grade 2 non-skin, drug-related AE, with the exception of fatigue.
•
Grade 2 drug-related creatinine, AST, ALT, and/or total bilirubin abnormalities.
•
Grade 3 skin, drug-related AE.
•
Grade 3 drug-related laboratory abnormality, with the following exceptions:
−
Grade 3 lymphopenia or asymptomatic amylase or lipase does not require dose omission.
−
Grade ≥3 AST, ALT, total bilirubin will require dose discontinuation (see Section 8.1.1
[Nivolumab Dose Discontinuation]).
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•
Any AE, laboratory abnormality, or intercurrent illness which, in the judgment of the 
Investigator, warrants an omission of the dose.
For the nivolumab omission criteria and criteria to resume treatment, please refer to the nivolumab 
dose delay criteria in Appendix 6.
7.4.4.2
Criteria to Resume Treatment with Nivolumab
Participants may resume treatment with study treatment when the drug-related AE(s) resolve to 
Grade ≤1 or baseline value, 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.
•
For participants with Grade 2 AST, ALT, and/or total bilirubin abnormalities, dosing may 
resume when laboratory values return to baseline and management with corticosteroids, if 
needed, is complete.
•
Drug-related pulmonary toxicity, diarrhea or colitis must have resolved to baseline before 
treatment is resumed. Participants with persistent Grade 1 pneumonitis after completion of a 
steroid taper over at least 1 month may be eligible for retreatment if discussed with and 
approved by Medical Monitor (or designee).
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.
7.4.4.3
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, arthralgias, 
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 and reported 
as a serious adverse event (SAE) if it meets the criteria. Infusion reactions should be graded 
according to NCI CTCAE v5.0 guidelines.
Treatment recommendations are provided below 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 occurs. The 
following 
prophylactic 
pre-medications 
are 
recommended 
for 
future 
infusions: 
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diphenhydramine 50 mg (or equivalent) and/or acetaminophen/paracetamol 325 to 1000 mg at 
least 30 minutes before subsequent nivolumab 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 30 minutes, the rate may be 
increased to 100% of the original infusion rate. Monitor 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 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 participant until recovery of the 
symptoms.
In 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).
7.5
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.
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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 (Study Governance Considerations).
7.5.1
Retained Samples for Bioavailability/Bioequivalence/Biocomparability
Not applicable.
7.6
Treatment Compliance
Study treatment compliance will be periodically monitored by drug accountability, dosing diary 
cards, participant’s medical records, and eCRF. On the day of a scheduled visit, study drug will be 
administered in the clinic by trained site personnel and drug accountability should be reviewed by 
the site study staff. 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 and safety follow-up in the appropriate section of the 
eCRF at each visit.
All medications (prescription and over-the-counter), vitamin and mineral supplements, and/or 
herbs taken by the participant from Screening through the Safety 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.
Anastrozole administered after completion of 5 cycles of neoadjuvant treatment (or EOT) up to 
subsequent breast surgery must be collected as concomitant medication.
Any subsequent anti-cancer therapy (ie, adjuvant treatment, radiotherapy) will be recorded up to 
100 days after last dose of nivolumab or 30 days after last dose of study treatment (Arm C), in the 
appropriate section of the eCRF.
7.7.1
Prohibited and/or Restricted Treatments for Nivolumab
The following medications are prohibited during the study (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]) during treatment and until 100 days post last dose.
•
Immunosuppressive agents.
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•
Supraphysiological doses of systemic corticosteroids.
•
Any concurrent anti-neoplastic therapy (ie, chemotherapy, hormonal therapy, immunotherapy, 
extensive, non-palliative radiation therapy, or standard or investigational agents for treatment 
of ER-, HER+ BC).
•
Any botanical preparation (eg, herbal supplements or traditional Chinese medicines) intended 
to treat the disease under study or provide supportive care. Use of marijuana and its derivatives 
for treatment of symptoms related to cancer or cancer treatment are permitted if obtained by 
medical prescription or if its use (even without a medical prescription) has been legalized 
locally.
7.7.2
Prohibited and/or Restricted Treatments for Abemaciclib and 
Palbociclib
•
Anticancer agents: No additional investigational or commercial anticancer agents (including 
specifically aromatase inhibitors, anti-estrogens other than fulvestrant, chemotherapy, and 
immunotherapy) other than those mentioned in this study will be permitted during the 
On-treatment Pre-surgery (neoadjuvant) Period. In general, any drugs containing “for the 
treatment of breast cancer” on the product insert are not permitted on the study. Additionally, 
use of megestrol acetate as an appetite stimulant is not permitted.
•
Strong CYP3A inhibitors/inducers and CYP substrates (refer to Appendix 10
[Concomitant Medications]): The results from human disposition (I3Y-MC-JPBD) and 
in vitro human recombinant CYP phenotyping studies indicate that abemaciclib is extensively 
metabolized primarily via CYP3A. Co-administration with drugs that are CYP3A inhibitors 
and inducers may change the plasma concentrations of abemaciclib in humans. 
−
Co-administration with strong CYP3A inhibitors and strong inducers should be avoided 
while on treatment. Participants treated with those drugs within the last 5 days prior to 
randomization/study treatment cannot be included in the trial. 
−
Co-administration with moderate CYP3A inhibitors and moderate inducers should also be 
avoided if possible, or otherwise be subject to caution (eg, increased frequency of safety 
monitoring).
−
CYP substrates: In vitro studies in cultured human hepatocytes indicate that abemaciclib 
and its major metabolites LSN2839567 and LSN3106726 downregulate messenger 
ribonucleic acid (mRNA) of CYPs at clinically relevant concentrations. The mechanism of 
downregulation and its clinical relevance are presently not understood. Therefore, care 
should be taken when co-administering substrate drugs of CYPs (CYP1A2, CYP2B6, 
CYP2C8, CYP2C9, CYP2D6, and CYP3A) with narrow therapeutic margin. Participants
treated on CYP3A Substrates with Narrow Therapeutic Index (NTI) can only be included 
in the trial after discontinuation of the drug for longer than 5 half-lives prior to 
randomization/study treatment. 
•
Herbal/alternative remedies: Participants are to avoid Seville oranges and grapefruit and 
grapefruit juice, as they affect CYP and PgP activity.
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•
Chronic immunosuppressive therapies: Chronic immunosuppressive therapies should be 
avoided, including systemic corticosteroids. Steroids given for physiological replacement, as 
anti-emetics, or inhaled, as well as short courses of oral/topical steroids given for allergic 
reactions or asthma flares are allowed.
•
Erythropoietin: Erythropoietin is not to be used. Any potential indication should be discussed 
with the Investigator and the Sponsor.
7.7.3
Other Restrictions and Precautions
Participants with a condition requiring systemic treatment with either corticosteroids at above 
physiological replacement dose or other immunosuppressive medications within 14 days of 
randomization/study treatment are excluded.
7.7.3.1
Imaging Restriction and Precautions
It is the local imaging facility’s responsibility to determine, based on participant attributes 
(eg, allergy history, diabetic history, 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 < 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. 
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.
7.7.4
Permitted Therapy
Participants are permitted the use of topical, ocular, intra-articular, intranasal, and inhalational 
corticosteroids (with minimal systemic absorption). 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.
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:
1) The study is terminated due to safety concerns.
2) The development of the study treatment is terminated for other reasons, including but not 
limited to lack of efficacy and/or not meeting the study objectives.
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3) 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 vs from study): Participants are expected to complete 
5 cycles of neoadjuvant therapy except in the event of disease progression, death, unacceptable 
toxicity, symptomatic deterioration, Investigator’s decision to discontinue treatment, the 
participant’s decision to discontinue treatment or withdraw consent, the participant being lost to 
follow-up, or BMS decides to terminate 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 participant to 
provide this information
•
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.)
•
Disease progression
Refer to Section 2 (Schedule of Activities) for data to be collected at the time of treatment 
discontinuation and follow-up and for any further evaluations that can be completed.
All participants who discontinue study treatment should comply with protocol specified follow-up 
procedures as outlined in Section 2 (Schedule of Activities). The only exception to this requirement 
is when a participant withdraws consent for all study procedures 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.
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8.1.1
Nivolumab Dose Discontinuation
If a participant discontinues nivolumab, the entire study treatment (CDK4/6 inhibitor and 
anastrozole) must be discontinued.
Nivolumab treatment should be permanently discontinued for the following:
•
Any Grade 2 drug-related uveitis, eye pain, or blurred vision that does not respond to topical 
therapy and does not improve to Grade 1 severity within the re-treatment period OR requires 
systemic treatment.
•
Any Grade 3 non-skin, drug-related AE lasting > 7 days or recurs, with the following 
exceptions for laboratory abnormalities, drug-related uveitis, pneumonitis, bronchospasm, 
neurologic toxicity, hypersensitivity reactions, infusion reactions, and endocrinopathies:
−
Grade 3 drug-related uveitis, pneumonitis, bronchospasm, neurologic toxicity, 
myocarditis, hypersensitivity reaction, or infusion reaction of any duration requires 
discontinuation.
−
Grade 3 drug-related endocrinopathies, adequately controlled with only physiologic 
hormone replacement do not require discontinuation. Adrenal insufficiency requires 
discontinuation regardless of control with hormone replacement.
−
Grade 3 drug-related laboratory abnormalities do not require treatment discontinuation 
except:
♦Grade 3 drug-related thrombocytopenia > 7 days or associated with bleeding requires 
discontinuation.
♦Grade ≥3 drug-related AST, ALT, or total bilirubin requires discontinuation (see 
below).
♦Concurrent AST or ALT > 3 × ULN and total bilirubin > 2 × ULN.
NOTE: In most cases of Grade 3 AST or ALT elevation, study treatment will be permanently 
discontinued. If the Investigator determines a possible favorable benefit-risk ratio that warrants 
continuation of study treatment, a discussion between the Investigator and the Medical 
Monitor/designee must occur.
•
Any Grade 4 drug-related AE or laboratory abnormality (including, but not limited to,
creatinine, AST, ALT, or total bilirubin), except for the following events which do not require 
discontinuation:
−
Grade 4 neutropenia ≤7 days.
−
Grade 4 lymphopenia or leukopenia or asymptomatic amylase or lipase elevation.
−
Isolated Grade 4 electrolyte imbalances/abnormalities that are not associated with clinical 
sequelae and are corrected with supplementation/appropriate management within 72 hours 
of their onset.
−
Grade 4 drug-related endocrinopathy AEs, such as, hyper- or hypothyroidism, or glucose 
intolerance, which resolve or are adequately controlled with physiologic hormone 
replacement (corticosteroids, thyroid hormones) or glucose-controlling agents, 
respectively, may not require discontinuation after discussion with and approval from the 
Medical Monitor.
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•
Any event that leads to a dose omission lasting > 10 weeks from the previous dose requires 
discontinuation, with the following exceptions:
−
Dose omissions to allow for prolonged steroid tapers to manage drug-related AEs are 
allowed. 
−
Dose omissions lasting > 10 weeks from the previous dose that occur for non-drug-related 
reasons may be allowed if approved by the Medical Monitor (or designee).
−
NOTE: Prior to re-initiating treatment in a participant with a dose omission lasting 
> 10 weeks, the Medical Monitor (or designee) must be consulted. Tumor assessments 
should continue per protocol, even if a dose is omitted. Periodic study visits to assess safety 
and laboratory studies should also continue Q4W or more frequently if clinically indicated 
during such dose omissions.
•
Any AE, laboratory abnormality, or intercurrent illness which, in the judgment of the 
Investigator, presents a substantial clinical risk to the participant with continued nivolumab 
dosing.
8.1.2
Abemaciclib Dose Discontinuation
At the implementation of Revised Protocol 03, abemaciclib dosing will be discontinued in all 
patients. 
8.1.3
Palbociclib Dose Discontinuation
Scenarios in which palbociclib should be discontinued are included in the dose modification details 
provided in Section 7.4.2 (Dose Modifications for Palbociclib). If palbociclib needs to be 
discontinued, the participant may continue nivolumab and anastrozole.
8.1.4
Anastrozole Dose Discontinuation
If anastrozole needs to be discontinued, the participant must also stop the other study treatments
and subsequent breast surgery must be performed right away.
8.1.5
Post-study Treatment Study Follow-up
Participants who discontinue study treatment must continue to be followed per Table 2-3.
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. 
•
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.
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•
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 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 a 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 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 Section 2 (Schedule of Activities).
•
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 Section 2 (Schedule 
of Activities), 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 treatment assignment. The Investigator will 
maintain a 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 the 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 Section 2 (Schedule of Activities).
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Some of the assessments referred to in this section may not be captured as data in 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
Blinded Independent Pathology Review
Blinded independent pathology review will be established for central review and central
assessment of RCB. Tumor and lymph node collection from definitive surgical resection 
 
 should be performed on the day of surgery. 
Processing of the remainder of the specimens for histopathologic analysis should be performed 
within 72 hours of the procedure. Sections will be used for central pathology review assessing 
pathologic response. All hematoxylin and eosin (H&E) slides prepared from the specimens that 
are reviewed locally must be sent for central pathology review, along with a copy of the completed 
pathology report. Diagnostic H&E slides are preferred, but recut sections from all the tissue blocks 
are acceptable. Pathology samples acquisition guidelines and submission process will be outlined 
in the laboratory manual.
9.1.2
Pathologic Assessment of Effect
9.1.2.1
RCB Determination
Central 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 includes the following:
1) 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.
2) The overall cancer cellularity (percentage of area).
3) The percentage of cancer that is in situ disease (percentage of area).
4) The number of positive lymph nodes.
5) 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
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Detailed procedures are provided in Appendix 7 (Detailed Pathology Methods For Using Residual 
Cancer Burden).
9.1.2.2
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). No histological evidence of invasive tumor cells in the 
surgical breast.
9.1.3
Clinical Response Assessments
For the purposes of this study, all clinical response assessments, including 1) clinical breast 
examination by palpation of breast and axilla, and 2) imaging assessment of breast and axilla via
ultrasound (preferred) or mammography, will be assessed by the Investigator and performed 
locally. Every attempt should be made to image each participant using an identical imaging 
modality and acquisition protocol for all imaging time points. Tumor measurements should be 
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made by the same Investigator or Imager for each assessment, whenever possible. Tumor 
assessments for all participants should continue per protocol, even if dosing is delayed or 
discontinued. The longest diameter (LD) of the initial lesion(s) will be reported as the baseline 
measurement and used as reference to characterize the objective tumor response. The LD of the 
same lesion(s) will be measured during subsequent imaging studies.
A best overall response of stable disease requires a minimum of 49 days on study from the first 
dose of treatment.
Screening and on-study images should be acquired as outlined in Section 2 (Schedule of 
Activities). Tumor assessments at other time points may be performed if clinically indicated.
Bone scans and other SOC imaging, including pathologic examination of suspicious lesions, may 
be acquired per local standards, as clinically indicated.
At the Sponsor’s discretion, images may be collected for review.
9.1.3.1
Objective Response Rate Assessed by Imaging
ORR will be assessed at the end of the neoadjuvant treatment prior to Surgery.
For the purposes of this study, tumor response assessments will be performed by bilateral breast
and axilla ultrasound (preferred) or mammography. 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.
Radiographic Response Assessments:
•
Radiographic complete response: Disappearance of the target lesion.
•
Radiographic partial response (PR): At least a 30% decrease in the LD of the target lesion
taking as reference the baseline LD.
•
Radiographic progression (PD): At least a 20% increase in the LD of target lesion taking as
references the baseline LD or the appearance of one or more new lesions.
•
Radiographic stable disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient
increase to qualify for PD taking as reference the baseline LD.
Note:
1) Target lesions should be selected on the basis of their size (lesions with the longest diameter)
and should lend themselves to reproducible repeated measurements. Up to 2 lesions in the 
breast may be identified as target lesions. Per this protocol, target lesion #1 must be ≥2 cm
and, if selected, target lesion #2 must be ≥ 10 mm. A sum of the diameters of all target lesions
will be calculated and reported as the baseline sum of diameters. The baseline sum of diameters
will be used as a reference to further characterize any objective tumor regression in the
measurable dimension of the disease. Lesions that meet the criteria for radiographically defined
simple cysts should not be considered malignant lesions (neither target nor non-target) since
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they are, by definition, simple cysts. Pathologic axillary lymph nodes are not to be designated
at target lesions, and lymph node measurements are not to be included in the sum of diameters.
2) Target Lesions that become too small to measure: all lesions recorded at baseline should have
their actual measurements recorded at each subsequent evaluation, even when very small (e.g.,
2 mm). However, sometimes lesions that 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 eCRF as follows:
−
If it is the opinion of the radiologist that the lesion has likely disappeared, the measurement
should be recorded as 0 mm.
−
If the lesion is believed to be present and is faintly seen but too small to accurately measure,
too small to measure should be indicated.
3) 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.
For further information please refer to Appendix 8 (RECIST v1.1).
9.1.4
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 breast surgery (mastectomy or BCS) at the time of diagnosis or baseline 
and the actual surgery patient undergo after completion of the study treatment will be captured on 
the eCRF to assess BCS rate with palbociclib plus anastrozole with or without nivolumab in 
participants with untreated primary BC ≥2 cm (ER+, HER2-).
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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 
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
Time Period and Frequency for Collecting AE and SAE Information
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 nivolumab dosing. For participants randomized in Arm C, SAEs should be collected for 30 days 
from the date of last dose. For participants randomized/assigned to treatment and never treated 
with study drug, SAEs should be collected for 30 days from the date of randomization/treatment 
assignment.
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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 eCRF 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 updated information being available.
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 
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.
9.2.2
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.
All non-serious AEs (not only those deemed to be treatment-related) should be collected 
continuously during the On-treatment Pre-surgery (neoadjuvant) Period and for a minimum of 
100 days following discontinuation of nivolumab. For participants randomized in Arm C, non-
serious AEs should be collected for 30 days from the date of last dose.
Every AE must be assessed by the Investigator with regard to whether it is considered 
immune-mediated. For events which are potentially immune-mediated, additional information will 
be collected on the participant’s eCRF.
9.2.3
Follow-up of AEs and SAEs
•
Non-serious AEs should be followed to resolution or stabilization, or reported as SAEs if they 
become serious (refer to Appendix 3).
•
Follow-up is also required for non-serious AEs that cause interruption or discontinuation of 
study treatment and for those present at the end of study treatment as appropriate.
•
 All identified non-serious AEs must be recorded and described on the non-serious AE page of 
the eCRF (paper or electronic). Completion of supplemental eCRFs 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 non-serious AEs of special interest (as defined in 
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Section 9.2 [Adverse Events]) will be followed until resolution, until the condition stabilizes, until 
the event is otherwise explained, or until the participant is lost to follow-up (as defined in 
Section 8.3 [Lost to Follow-up]).
Further information on follow-up procedures is given in Appendix 3.
9.2.4
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.
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 SUSAR (Suspected, Unexpected Serious Adverse 
Reaction) is a subset of SAEs and will be reported to the appropriate regulatory authorities and 
Investigators following local and global guidelines and requirements.
9.2.5
Pregnancy
Protocol-required procedures for study discontinuation and follow-up must be performed on the 
participant.
Any pregnancy that occurs in a female partner of a male study participant should be reported to 
Sponsor or designee. In order for Sponsor or designee to collect any pregnancy surveillance 
information from the female partner, the female partner must sign an informed consent form 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 
Sponsor or designee to collect any pregnancy surveillance information from the female partner, 
the female partner(s) must sign an informed consent form for disclosure of this information. 
Information on the pregnancy will be collected on the Pregnancy Surveillance Form.
9.2.6
Laboratory Test Result Abnormalities
The following laboratory test result abnormalities should be captured on the non-serious 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).
9.2.7
Potential Drug-Induced Liver Injury
Wherever possible, timely confirmation of initial liver-related laboratory abnormalities should 
occur prior to the reporting of a p-DILI event. All occurrences of p-DILIs, meeting the defined 
criteria, must be reported as SAEs (see Section 9.2 [Adverse Events] 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.
9.2.8
Other Safety Considerations
Any significant worsening noted during interim or final physical examinations, ECG, x-ray 
filming, any other potential safety assessment required or not required by protocol should also be 
recorded as a non-serious or serious AE, as appropriate, and reported accordingly.
9.2.9
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
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•
Skin
•
Neurological
•
Myocarditis
The algorithms recommended for the management of IMAEs in this protocol are in Appendix 6.
Please note that for this protocol, nivolumab delay means nivolumab omission.
•
Checkpoint inhibitor molecules have been uncommonly associated with ocular drug-related 
AEs. Inflammation of components within the eye (eg, episcleritis, uveitis) are uncommon 
events of nivolumab monotherapy (< 1% of cases). These events are usually of low or 
intermediate grade, reversible, detected early in the course of therapy, and manageable with 
topical or systemic steroids.
−
Routine eye examinations should be performed in participants receiving immune 
checkpoint inhibitors (Section 2 [Schedule of Activities]). Upon clinical suspicion of an 
ocular event consider ophthalmic consult, dose omission, or dose discontinuation.
−
Permanently discontinue for clinically significant or severe immune-mediated adverse 
reactions. Initiate systemic corticosteroids for severe immune-mediated adverse reactions.
−
Permanently discontinue for immune-mediated ocular disease that is unresponsive to local 
immunosuppressive therapy.
−
Administer corticosteroid eye drops to participants who develop uveitis, iritis, or 
episcleritis.
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 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 Dosage 
Administration Record eCRF.
For this study, any dose of nivolumab, abemaciclib, palbociclib, or anastrozole that is greater than 
the scheduled dose within a 24-hour time period will be considered an overdose.
In the event of an overdose the Investigator should:
1) Contact the Medical Monitor immediately.
2) Closely monitor the participant for AEs/SAEs and laboratory abnormalities until study 
treatment can no longer be detected systemically (at least 5 days for abemaciclib or palbociclib, 
and at least 10 days for anastrozole).
3) Document the quantity of the excess dose as well as the duration of the overdosing in the eCRF.
Decisions regarding dose interruptions or modifications will be made by the Investigator in 
consultation with the Medical Monitor based on the clinical evaluation of the participant.
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9.4
Safety
Planned time points for all safety assessments are listed in Section 2 (Schedule of Activities).
9.4.1
Physical Examinations
Refer to Schedule of Activities (Section 2).
9.4.2
Vital Signs
Refer to Schedule of Activities (Section 2).
9.4.3
Electrocardiograms/ECHO (preferred) or MUGA
Refer to 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 (performed by local laboratory) must be available within 
3 calendar days prior to dosing. Complete blood counts must be performed within 7 days prior to 
the first dose.
A list of the clinical laboratory analyses to be tested is provided below in Table 9.4.4-1.
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 or creatinine clearance (as calculated using
the method standard for the institutions)
Blood urea nitrogen (BUN) or serum urea
glucose
Lipase and amylase (if pancreatitis is suspected)
Albumin - screening only
Sodium
Potassium
Chloride
Calcium
Phosphorus
TSH, free T3 and free T4 - screening
TSH, with reflexive fT3 and fT4 if TSH is abnormal -
on-treatment and follow-up
Serology
Hepatitis B/C, (HBVsAG, HCV antibody or HCV RNA) - screening only
Other Analyses
FSH screening - only required to confirm menopause in women ≤age 55
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Table 9.4.4-1:
Clinical Safety Laboratory Assessments
Estradiol level - only required to confirm menopause in women ≤ age 55
INR
Abbreviations: FSH = follicle stimulating hormone; HBV sAG = hepatitis B surface antigen; HCV = hepatitis C virus; 
INR = international normalized ratio; RNA = ribonucleic acid; TSH = thyroid-stimulating hormone.
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9.9
Health Economics OR Medical Resource Utilization and Health 
Economics
Health Economics/Medical Resource Utilization and Health Economics parameters will not be 
evaluated in this study.
10
STATISTICAL CONSIDERATIONS
10.1
Sample Size Determination 
A total of approximately 115~136 participants will be treated in the study. Approximately 3~24
participants will be treated in the Safety Run-in Phase in each cohort (Cohort 1: nivolumab + 
abemaciclib + anastrozole for 5 cycles; n = 3∼6 per dose level of abemaciclib; Cohort 2: nivolumab 
+ palbociclib + anastrozole for 5 cycles; n = 3∼6 per dose level of palbociclib). At the time of 
Revised Protocol 03, 2 participants had been treated in Cohort 1 (nivolumab + abemaciclib + 
anastrozole), which was subsequently closed for enrollment. Approximately 110 participants are 
planned to be randomized in this study at a 4:4:3 ratio into Arm A (nivolumab + palbociclib + 
anastrozole for 5 cycles; n = 40), Arm B (palbociclib + anastrozole for 1 cycle, followed by 
nivolumab + palbociclib + anastrozole for 4 cycles; n = 40), and Arm C (palbociclib + anatrozole 
for 5 cycles; n = 30), respectively. No stratification variables will be included for formal analysi  
 
.
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10.2
Populations for Analyses
Populations for purposes of analysis are defined in Table 10.2-1 below.
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
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 primary efficacy analyses.
All Treated
All randomized participants who receive 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 Treated from 
Safety Run-in Phase
All enrolled participants who received at least 1 dose of study drug in the Safety Run-
in Phase. Participants are grouped within the All Treated from Safety Run-in Phase 
population according to the treatment and dose level they actually received. This is 
part of the analysis set for all safety analysis and study drug administration. 
All RCB Evaluable
All Treated participants who have an RCB of 0, I, II, or III from both the Safety 
Run-in Phase and Randomized Phase.
Abbreviations: ICF = informed consent form; IRT = Interactive Response Technology; 
 
RCB = residual cancer burden.
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 and secondary endpoints.
A description of the participant population will be included in a statistical output report, including 
subgroups of age, gender, and race.
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10.3.1
Efficacy Analyses
Statistical analyses for efficacy are shown in Table 10.3.1-1.
Table 10.3.1-1:
Efficacy - Statistical Analyses
Endpoint
Statistical Analysis Methods
Primary
•
RCB (0-I) rate per central assessment
Estimates of response rate and corresponding exact 90% 
and 95% CIs will be generated for each arm in the 
Randomized Phase. CIs will be constructed using the 
Clopper-Pearson method.
Secondary
•
pCR per local assessment
•
ORR by Investigator assessment
•
BCS
Estimates of response rate and corresponding exact 95% 
CIs will be generated for each arm. CIs will be constructed 
using the Clopper-Pearson method.
Abbreviations: BCS = breast-conserving surgery; CI = confidence interval; 
 ORR = objective 
response rate; pCR = pathological complete response; 
 RCB = residual cancer 
burden.
After review of the efficacy data in each arm and upon agreement of the study team, efficacy 
endpoints might also be estimated based on pooled arms (eg, RCB [0-I] rate in Arm A and Arm B), 
when appropriate. Details of the analyses will be defined in the SAP. 
10.3.2
Safety Analyses
Statistical analyses for safety are shown in Table 10.3.2-1.
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Table 10.3.2-1:
Safety - Statistical Analyses
Endpoint
Statistical Analysis Methods
Primary
•
Number of participants with occurrence of 
DLT (Time frame: from start of study 
treatment up to 4 weeks).
•
DLT rate by treatment and dose level in the Safety Run-in 
Phase.
Secondary
•
Incidence of AEs, SAEs, immune-related 
AEs, AEs leading to discontinuation, and 
death.
•
Laboratory abnormalities.
AEs will be graded according to NCI CTCAE v5.0.Frequency 
distribution of treated participants with AE using 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.
Laboratory shift table using the worst CTC grade on treatment 
per participant.
Abbreviations: AE = adverse event; DLT = dose-limiting toxicity; CTC = Common Terminology Criteria; 
CTCAE = Common Terminology Criteria for Adverse Events; NCI = National Cancer Institute; PT = preferred term; 
SAE = serious adverse event.
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10.3.4
Interim Analysis
Not applicable.
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Anastrozole (Arimidex) US Prescribing Information. ANI Pharmaceuticals, Inc.; Revised 
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3
Nivolumab (BMS-936558) Investigator Brochure Version 17. Bristol-Myers Squibb 
Company, 2018. 
4
Palbociclib (Ibrance) US Prescribing Information. Pfizer; Revised April 2019.
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Nanda R, Liu MC, Yau C, et al. Pembrolizumab Plus Standard Neoadjuvant Therapy for High-
risk Breast Cancer (BC): Results from I-SPY 2. Journal of Clinical Oncology: Official Journal 
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Teh JLF, Aplin AE. Arrested Developments: CDK4/6 Inhibitor Resistance and Alterations in 
the Tumor Immune Microenvironment. Clinical Cancer Research: An Official Journal of the 
American Association for Cancer Research 2019;25(3): 921-927.
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Zhang J, Bu X, Wang H, et al. Cyclin D-CDK4 Kinase Destabilizes PD-L1 Via Cullin 3-SPOP 
to Control Cancer Immune Surveillance. Nature 2018; 553(7686): 91-5.
8
Goel S, DeCristo MJ, Watt AC, et al. CDK4/6 Inhibition Triggers Anti-tumour Immunity. 
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10 Deng J, Wang ES, Jenkins RW, et al. CDK4/6 Inhibition Augments Antitumor Immunity by 
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11 Tolaney SM, Kabos P, Dickler MN, et al. Updated Efficacy, Safety, & PD-L1 Status of Patients 
with HR+, HER2- Metastatic Breast Cancer Administered Abemaciclib Plus Pembrolizumab. 
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12 Schaer DA, Beckmann RP, Dempsey JA, et al. The CDK4/6 Inhibitor Abemaciclib Induces a 
T Cell Inflamed Tumor Microenvironment and Enhances the Efficacy of PD-L1 Checkpoint 
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13 Siegel RL, Miller KD, Jemal A. Cancer Statistics, 2019. CA: A Cancer Journal for Clinicians 
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15 Perou CM, Sorlie T, Eisen MB, et al. Molecular Portraits of Human Breast Tumours. Nature 
2000; 406(6797): 747-52.
16 Huang H, Groth J, Sossey-Alaoui K, et al. Aberrant Expression of Novel and Previously 
Described Cell Membrane Markers in Human Breast Cancer Cell Lines and Tumors. Clinical 
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11(12): 4357-64.
17 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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Endocrine Therapy Versus Chemotherapy in Postmenopausal Patients with Estrogen 
Receptor-positive Breast Cancer. Cancer 2007; 110(2): 244-54.
19 Alba E, Calvo L, Albanell J, et al. Chemotherapy (CT) Versus Hormone Therapy (HT) as 
Neoadjuvant Treatment in Luminal Breast Cancer: A Multicenter, Randomized Phase II Study 
(GEICAM/2006-03). Journal of Clinical Oncology 2010; 28(15_suppl): 500-.
20 Palmieri C, Cleator S, Kilburn LS, et al. NEOCENT: A Randomised Feasibility and 
Translational Study Comparing Neoadjuvant Endocrine Therapy With Chemotherapy in ER-
rich Postmenopausal Primary Breast Cancer. Breast Cancer Research and Treatment 2014; 
148(3): 581-90.
21 Spring LM, Gupta A, Reynolds KL, et al. Neoadjuvant Endocrine Therapy for Estrogen 
Receptor-positive Breast Cancer: A Systematic Review and Meta-analysis. JAMA Oncology 
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22 Alba E, Calvo L, Albanell J, et al. Chemotherapy (CT) and Hormonotherapy (HT) as 
Neoadjuvant Treatment in Luminal Breast Cancer Patients: Results From the 
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23 Ellis MJ, Ma C. Letrozole in the Neoadjuvant Setting: The P024 Trial. Breast Cancer Research 
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25 Smith IE, Dowsett M, Ebbs SR, et al. Neoadjuvant Treatment of Postmenopausal Breast 
Cancer with Anastrozole, Tamoxifen, or Both in Combination: The Immediate Preoperative 
Anastrozole, Tamoxifen, or Combined with Tamoxifen (IMPACT) Multicenter Double-blind 
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Clinical Oncology 2005; 23(22): 5108-16.
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26 Cataliotti L, Buzdar AU, Noguchi S, et al. Comparison of Anastrozole Versus Tamoxifen as 
Preoperative Therapy in Postmenopausal Women with Hormone Receptor-positive Breast 
cancer: The Pre-Operative "Arimidex" Compared to Tamoxifen (PROACT) Trial. Cancer 
2006; 106(10): 2095-103.
27 Leal F, Liutti VT, Antunes dos Santos VC, et al. Neoadjuvant Endocrine Therapy for 
Resectable Breast Cancer: A Systematic Review and Meta-analysis. Breast (Edinburgh, 
Scotland) 2015; 24(4): 406-12.
28 Ellis MJ, Suman VJ, Hoog J, et al. Randomized Phase II Neoadjuvant Comparison Between 
Letrozole, Anastrozole, and Exemestane for Postmenopausal Women with Estrogen Receptor-
rich Stage 2 to 3 Breast Cancer: Clinical and Biomarker Outcomes and Predictive Value of the 
Baseline PAM50-based Intrinsic Subtype-ACOSOG Z1031. Journal of Clinical Oncology: 
Official Journal of the American Society of Clinical Oncology 2011; 29(17): 2342-9.
29 Seo JH, Kim YH, Kim JS. Meta-analysis of Pre-operative Aromatase Inhibitor Versus 
Tamoxifen in Postmenopausal Woman with Hormone Receptor-positive Breast Cancer. 
Cancer Chemotherapy and Pharmacology 2009; 63(2): 261-6.
30 Pardoll D. Does the Immune System See Tumors as Foreign or Self? Annual Review of
Immunology. 2003;21:807-39.
31 Zitvogel L, Tesniere A, Kroemer G. Cancer Despite Immunosurveillance: Immunoselection 
and Immunosubversion. Nature Reviews Immunology. 2006; 6:715-27.
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Tumor Escape. Nature Immunology. 2002; 3:991-8.
33 Greenwald RJ, Freeman GH, Sharpe AH. The B7 Family Revisited. Annual Review of
Immunology. 2004; 23:515-48.
34 Freeman GJ, Long AJ, Iwai Y, et al. Engagement of the PD-1 Immunoinhibitory Receptor by 
a Novel B7 Family Member Leads to Negative Regulation of Lymphocyte Activation. Journal 
of Experimental Medicine. 2000; 192(7): 1027-34.
35 Sharpe AH, Wherry EJ, Ahmed R, et al. The Function of Programmed Cell Death 1 and its 
Ligands in Regulating Autoimmunity and Infection. Nature Immunology. 2007; 8:237-45.
36 Wolchok JD, Hoos A, O’Day S, et al. Guidelines for the Evaluation of Immune Therapy 
Activity in Solid Tumors: Immune-related Response Criteria. Clinical Cancer Research. 2009;
15:7412-20.
37 Musgrove EA, Caldon CE, Barraclough J, et al. Cyclin D as a therapeutic target in cancer. Nat 
Rev Cancer. 2011 Jul 7;11(8):558-72.
38 Holm K, Staaf J, Jonsson G, et al. Characterisation of amplification patterns and target genes 
at chromosome 11q13 in CCND1-amplified sporadic and familial breast tumours. Breast 
Cancer Res Treat. 2012 Jun;133(2):583-94.
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39 Cancer Genome Atlas Network. Comprehensive molecular portraits of human breast tumours. 
Nature. 2012 Oct 4, 490(7418):61-70.
40 Beroukhim R, Mermel CH, Porter D, et al. The landscape of somatic copy-number alteration 
across human cancers. Nature. 2010 Feb 18;463(7283):899-905.
41 Thangavel C, Dean, JL, Ertel A, et al. Therapeutically activating RB: reestablishing cell cycle 
control in endocrine therapy-resistant breast cancer. Endocr Relat Cancer. 2011 Apr 
28;18(3):333-45.
42 Bosco EE, Knudsen ES. RB in breast cancer: at the crossroads of tumorigenesis and treatment. 
Cell Cycle. 2007 Mar 15;6(6):667-71.
43 Finn RS, Dering J, Conklin D, et al. PD 0332991, A Selective Cyclin D Kinase 4/6 Inhibitor, 
Preferentially Inhibits Proliferation of Luminal Estrogen Receptor-positive Human Breast 
Cancer Cell Lines in Vitro. Breast Cancer Research: BCR 2009; 11(5): R77-R.
44 Kok M, Voorwerk L, Horlings H, et al. Adaptive phase II randomized trial of nivolumab after 
induction treatment in triple negative breast cancer (TONIC trial): Final response data stage I 
and first translational data. J Clin Oncol. 2019;36(15_suppl):1012-1012.
45 Zardavas D, Pondé N, Tryfonidis K. CDK4/6 Blockade in Breast Cancer: Current Experience 
and Future Perspectives. Expert Opinion on Investigational Drugs 2017; 26(12): 1357-72.
46 Turner NC, Slamon DJ, Ro J, et al. Overall Survival with Palbociclib and Fulvestrant in 
Advanced Breast Cancer. New England Journal of Medicine 2018; 379(20): 1926-36.
47 Dickler MN, Tolaney SM, Rugo HS, et al. MONARCH 1, A Phase II Study of Abemaciclib, 
a CDK4 and CDK6 Inhibitor, as a Single Agent, in Patients with Refractory HR+/HER2-
Metastatic Breast Cancer. Clin Cancer Res. 2017;23(17):5218-5224.
48 Johnston S, Puhalla S, Wheatley D, et al. Randomized Phase II Study Evaluating Palbociclib 
in Addition to Letrozole as Neoadjuvant Therapy in Estrogen Receptor-positive Early Breast 
Cancer: PALLET Trial. Journal of Clinical Oncology: Official Journal of the American Society 
of Clinical Oncology 2019; 37(3): 178-89.
49 Hurvitz SA, Schilder JM, Frenzel M, et al. Abstract CT092: A Phase II Study of Neoadjuvant 
Abemaciclib (LY2835219) in Postmenopausal Women with Hormone Receptor Positive 
(HR+), Human Epidermal Growth Factor Receptor 2 Negative (HER2-) Breast Cancer 
(neoMONARCH). Cancer Research 2016; 76(14 Supplement): CT092-CT.
50 Abemaciclib (Verenzio) US Prescribing Information. Eli Lilly and Company; Revised August 
2018.
51 Yuan Y, Yost SE, Lee JS, et al. Abstract P3-11-04: A phase II study of pembrolizumab, 
letrozole and palbociclib in patients with metastatic estrogen receptor positive breast cancer. 
Cancer Research 2020; 80(4 Supplement): P3-11-04-P3-11-04.
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52 Solomon B, Callejo A, Bar J, et al. Survival prolongation by rationale innovative genomics 
(SPRING): An international WIN consortium phase I study exploring safety and efficacy of 
avelumab, palbociclib, and axitinib in advanced non-small cell lung cancer (NSCLC) with 
integrated genomic and transcriptomic correlates. Annals of Oncology 2019;30:v648.
53 Baselga J. Targeting the Phosphoinositide-3 (PI3) Kinase Pathway in Breast Cancer. 
Oncologist 2011; 16 Suppl 1: 12-9.
54 Azambuja ED, Saura C, Oliveira M, et al. LORELEI: A Phase II Randomized, Double-blind 
Study of Neoadjuvant Letrozole Plus Taselisib (GDC-0032) Versus Letrozole Plus Placebo in 
Postmenopausal Women with ER-positive/HER2-negative, Early-stage Breast Cancer. Journal 
of Clinical Oncology: Official Journal of the American Society of Clinical Oncology 2015; 
33(15_suppl): TPS627-TPS.
55 Saura C, de Azambuja E, Hlauschek D, et al. LBA10_PR - Primary Results of LORELEI: A 
Phase II Randomized, Double-blind Study of Neoadjuvant Letrozole (LET) Plus Taselisib 
Versus LET Plus Placebo (PLA) in Postmenopausal Patients (pts) with ER+/HER2-negative 
Early Breast Cancer (EBC). Annals of Oncology 2017; 28(suppl_5): mdx440.001-
mdx440.001.
56 Ma C, Gao F, Northfelt D, et al. Abstract S6-05: A Phase II Trial of Neoadjuvant Palbociclib, 
a Cyclin-dependent Kinase (CDK) 4/6 Inhibitor, in Combination with Anastrozole for Clinical 
Stage 2 or 3 Estrogen Receptor Positive HER2 Negative (ER+HER2-) Breast Cancer (BC). 
Cancer Research 2016; 76(4 Supplement): S6-05.
57 Hortobagyi GN, Stemmer SM, Burris HA, et al. Ribociclib as First-Line Therapy for HR-
Positive, Advanced Breast Cancer. The New England Journal of Medicine 2016; 375(18): 
1738-48.
58 Finn RS, Martin M, Rugo HS, et al. Palbociclib and Letrozole in Advanced Breast Cancer. The 
New England Journal of Medicine 2016; 375(20): 1925-36.
 
 
 
 
 
 
 
 
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63 Schaer DA, Beckmann RP, Dempsey JA, et al. The CDK4/6 Inhibitor Abemaciclib Induces a 
T Cell Inflamed Tumor Microenvironment and Enhances the Efficacy of PD-L1 Checkpoint 
Blockade. Cell Reports 2018; 22(11): 2978-94.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
72 Hammond ME, Hayes DF, Wolff AC, et al. American Society of Clinical Oncology/College 
of American Pathologists Guideline Recommendations for Immunohistochemical Testing of 
Estrogen and Progesterone Receptors in Breast Cancer. Journal of Oncology Practice 2010;
6(4):195-7.
73 Wolff AC, Hammond MEH, Allison KH, et al. Human Epidermal Growth Factor Receptor 2 
Testing in Breast Cancer: American Society of Clinical Oncology/College of American 
Pathologists Clinical Practice Guideline Focused Update. Journal of Clinical Oncology. 2018;
36(20):2105-2122.
74 Bennett JA, Riegel B, Bittner V, et al. Validity and Reliability of the NYHA Classes for 
Measuring Research Outcomes in Patients with Cardiac Disease. Heart & Lung: The Journal 
of Critical Care 2002; 31(4):262–270.
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12
APPENDICES
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APPENDIX 1
ABBREVIATIONS AND TRADEMARKS
Term
Definition
°C
degrees Celsius
μL
microliter
Abema
abemaciclib
ACOSOG
American College of Surgeons Oncology Group
ADL
activities of daily living
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
ANZ
anastrazole
ASCO
American Society of Clinical Oncology
AST
aspartate aminotransferase
AT
aminotransaminases
BC
breast cancer
Bcl-xL
B-cell lymphoma-extra large
BCS
breast-conserving surgery
BID
bis in die, twice daily
BMS
Bristol-Myers Squibb
BOR
best overall response
BP
blood pressure
BTLA
B- and T-lymphocyte attenuator
BUN
blood urea nitrogen
C
cycle
CAP
College of American Pathologists
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Term
Definition
CBC
complete blood count
CCND1
cyclin D1
CD28
cluster of differentiation 28
CDK
cyclin-dependent kinase
CFR
Code of Federal Regulations 
CI
confidence interval
CISH
chromogenic in situ hybridization
Cm
Centimeter
CMV
Cytomegalovirus
CONSORT
Consolidated Standards of Reporting Trials
CR
complete response
CRC
colorectal cancer
CRF
case report form
CRO
contract research organization
CTAg
Clinical Trial Agreement
CTCAE
Common Terminology Criteria for Adverse Events
CTLA-4
cytotoxic T-lymphocyte-associated protein-4
CYP
cytochrome p-450
D
Day
dL
deciliter
DLT
dose-limiting toxicity
DNA
deoxyribonucleic acid
DNMT
DNA methyltransferase 1
EC50
half-maximal effective concentration
ECG
Electrocardiogram
ECHO
Echocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic case report form
eg
exempli gratia (for example)
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Term
Definition
EMA
European Medicines Agency
EOT
end of treatment
ER
estrogen receptor
ER+
estrogen receptor-positive
ET
endocrine therapy
etc
et cetera
EU
Europe
 
FDA
Food and Drug Administration
FFPE
formalin-fixed, paraffin-embedded
FISH
fluorescence in situ hybridization
FSH
follicle-stimulating hormone
FU1
follow-up visit 1
FU2
follow-up visit 2
g
gram
GCP
Good Clinical Practice
GI
Gastrointestinal
H&E
hematoxylin and eosin
HBsAg
hepatitis B surface antigen
HCC
hepatocellular carcinoma
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
HIV
Human Immunodeficiency Virus
HR
heart rate
HR+
hormone receptor-positive
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Term
Definition
HRT
hormone replacement therapy
IB
Investigator Brochure
INR
international normalized ratio
IC50
half-maximal inhibitory concentration
ICF
informed consent form
ICH
International Conference on Harmonisation 
ICOS
inducible T cell co-stimulator
ie
id est (that is)
IEC
Independent Ethics Committee
IFN
interferon
IFN-γ
interferon-γ
IHC
Immunohistochemistry
IL
Interleukin
IMAE
immune-mediate adverse event
IMP
investigational medicinal product
IND
Investigational New Drug
IO
immuno-oncologic
IP
investigational product
IRB
Institutional Review Board
IRT
Interactive Response Technology
IU
International Unit
IV
Intravenous
kg
kilogram
LDH
lactate dehydrogenase
LH-RHa
luteinizing hormone-releasing hormone agonist
LLN
lower limit of normal
mAb
monoclonal antibody
MD
medical doctor
MDSC
myeloid-derived suppressor cells
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Term
Definition
mg
Milligram
min
minute
mL
Milliliter
MLR
mixed lymphocyte reaction
m2
meters squared
mm3
cubic millimeters
MMR
measles, mumps, rubella
MRI
magnetic resonance imaging
mRNA
messenger ribonucleic acid
msec
milisecond
mTOR
mammalian target of rapamycin
MUGA
multiple gated acquisition
N
number of subjects or observations
NCI
National Cancer Institute
NET
neoadjuvant endocrine treatment
Nivo
Nivolumab
nM
Nanomolar
NSAI
nonsteroidal aromatase inhibitors
NSCLC
non-small cell lung cancer
ORR
objective response rate
OS
overall survival
oz
ounce
Palbo
Palbociclib
pCR
pathological complete response
PD-1
programmed cell death-1
p-DILI
potential drug-induced liver injury
PD-L1
programmed death-ligand 1
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Term
Definition
PD-L2
programmed death-ligand 2
PE
physical examination
PFS
progression-free survival
PgP
P-glycoprotein
PgR
progesterone receptor
PI3K
phosphoinositide-3 kinase
PK
Pharmacokinetics
PO
per os (by mouth route of administration)
PPK
population pharmacokinetics
PR
partial response
 
PS
performance status
PT
preferred term
Q4W
every 4 weeks
QD, qd
quaque die, once daily
QTc
corrected QT interval
QTcF
Fridericia's Correction Formula
Rand
Randomized
Rb
retinoblastoma
RCB
residual cancer burden
RCC
renal cell carcinoma
RECIST
Response Evaluation Criteria in Solid Tumors
RFS
relapse-free survival
RNA
ribonucleic acid
SAE
serious adverse event
SAP
statistical analysis plan
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Term
Definition
SCCHN
squamous cell carcinoma of the head and neck
SISH
silver in situ hybridization
SmPC
summary of product characteristics
SOC
standard of care
SOP
Standard Operating Procedures
SPOP
speckle-type POZ protein
SSC
Study Steering Committee
SUSAR
Suspected, Unexpected Serious Adverse Reaction
TCR
T cell receptor
TEAE
treatment-emergent adverse event
TIL
tumor-infiltrating lymphocyte
TME
tumor microenvironment
TNBC
triple-negative breast cancer
Treg
regulatory T cell
TSH
thyroid-stimulating hormone
ULN
upper limit of normal
US
United States
USP
United States Pharmacopeia
vs
versus
WHO
World Health Organization
Wk
week
WOCBP
women of childbearing potential
WNOCBP
women not of childbearing potential
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APPENDIX 2
STUDY GOVERNANCE CONSIDERATIONS
The term ‘Participant’ is used in the protocol to refer to a person who has consented to participate 
in the clinical research study. The term ‘Subject’ used in the eCRF is intended to refer to a person 
(Participant) who has consented to participate in the clinical research study.
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 GuidelinesGood Clinical Practice (GCP), 
•
as defined by the International Council on Harmonisation (ICH)
•
in accordance with the ethical principles underlying European Union Directive 2001/20/EC
•
United States Code of Federal Regulations, Title 21, Part 50 (21CFR50) 
•
applicable local requirements.
The study will be conducted in compliance with the protocol. The protocol and any amendments 
and the participant informed consent will receive approval/favorable opinion by Institutional 
Review Board/Independent Ethics Committee (IRB/IEC), and regulatory authorities according to 
applicable local 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, etc) that is likely to 
affect, to a significant degree, one or more of the following: (1) the physical, safety, or mental 
integrity of one or more subjects/participants; or (2) the scientific value of the 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, consent form, participant recruitment materials 
(eg, advertisements), and any other written information to be provided to subjects/participants. The 
investigator or BMS should also provide the IRB/IEC with a copy of the Investigator Brochure or 
product labeling information to be provided to subjects/participants and any updates. 
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The investigator, Sponsor or designee should provide the IRB/IEC with reports, updates and other 
information (eg, expedited safety reports, amendments, and administrative letters) according to 
regulatory requirements or institution procedures.
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 local health authority) except where necessary to eliminate an immediate 
hazard(s) to study subjects/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 local health authority must be sent to BMS.
If an amendment substantially alters the study design or increases the potential risk to the 
participant: (1) the consent form 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 
subjects/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 subjects/participants prior to enrollment.
If the revision is done via an administrative letter, investigators must inform their IRB(s)/IEC(s).
FINANCIAL DISCLOSURE
Investigators and sub-Investigators will provide the Sponsor with sufficient, accurate financial 
information in accordance with local regulations to allow the Sponsor to submit complete and 
accurate financial certification or disclosure statements to the appropriate health authorities. 
Investigators are responsible for providing information on financial interests during the course of 
the study and for 1 year after completion of the study.
INFORMED CONSENT PROCESS
Investigators must ensure that subjects/participants are clearly and fully informed about the 
purpose, potential risks, and other critical issues regarding clinical studies in which they volunteer 
to participate. 
In situations where consent cannot be given by subjects/participants, their legally acceptable 
representatives (as per country guidelines) are clearly and fully informed about the purpose, 
potential risks, and other critical issues regarding clinical studies in which the participant 
volunteers to participate. 
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Sponsor or designee will provide the investigator with an appropriate (ie, Global or Local) sample 
informed consent form which will include all elements required by ICH, GCP and applicable 
regulatory requirements. The sample informed consent form will adhere to the ethical principles 
that have their origin in the Declaration of Helsinki.
Investigators must:
•
Provide a copy of the consent form and written information about the study in the language in 
which the participant is most proficient prior to clinical study participation. The language must 
be non-technical and easily understood. 
•
Allow time necessary for participant or participant's legally acceptable representative to 
inquire about the details of the study.
•
Obtain an informed consent signed and personally dated by the participant or the participant's 
legally acceptable representative and by the person who conducted the informed consent 
discussion. 
•
Obtain the IRB/IEC’s written approval/favorable opinion of the written informed consent form 
and any other information to be provided to the subjects/participants, prior to the beginning of 
the study, and after any revisions are completed for new information.
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.
Revise the informed consent 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 the participant's legally acceptable representative or legal 
guardian, 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 subjects/participants must be protected, 
respecting the privacy and confidentiality rules applicable to regulatory requirements, the 
subjects'/participants’ signed ICF and, in the US, the subjects’ signed HIPAA Authorization.
The consent form must also include a statement that BMS and regulatory authorities have direct 
access to participant records. 
Subjects/participants unable to give their written consent (eg, stroke or subjects/participants with 
or severe dementia) may only be enrolled in the study with the consent of a legally acceptable 
representative. The participant must also be informed about the nature of the study to the extent 
compatible with his or her understanding, and should this participant become capable, he or she 
should personally sign and date the consent form as soon as possible. The explicit wish of a 
participant who is unable to give his or her written consent, but who is capable of forming an 
opinion and assessing information to refuse participation in, or to be withdrawn from, the clinical 
study at any time should be considered by the investigator.
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The rights, safety, and well-being of the study subjects/participants are the most important 
considerations and should prevail over interests of science and society.
SOURCE DOCUMENTS
The Investigator is responsible for ensuring that the source data are accurate, legible, 
contemporaneous, original and attributable, whether the data are hand-written 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/health records (EMRs/EHRs), 
adverse event tracking/reporting, protocol required assessments, and/or drug accountability 
records).
When paper records from such systems are used in place of 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 treatments (whether supplied by BMS, its vendors, or the site) must substantiate 
study treatment 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 SOPs/standards of the sourcing 
pharmacy.
BMS or 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 tool, electronic CRFs will be 
prepared for all data collection fields except for fields specific to SAEs and pregnancy, which will 
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be reported on the electronic SAE form and Pregnancy Surveillance form, respectively. If 
electronic SAE form is not available, a paper SAE form can be used. 
The confidentiality of records that could identify subjects/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, 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 electronic CRFs, review and approval/signature is completed electronically through the 
BMS electronic data capture tool. The investigator must retain a copy of the CRFs including 
records of the changes and corrections.
Each individual electronically signing electronic CRFs must meet Sponsor or designee training 
requirements and must only access the BMS electronic data capture tool using the unique user 
account provided by 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 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 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 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.
BMS or designee will notify the investigator (or head of the study site in Japan) when the study 
records are no longer needed.
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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 designee. 
RETURN OF STUDY TREATMENT
For this study, study treatments (those supplied by BMS, 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 treatments 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).
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) (examples include 
study treatments sourced from the sites 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, 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.
•
Written procedures for on-site disposal are available and followed. The procedures must be 
filed with the site’s SOPs 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, ie, 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 Monitor to 
review throughout the clinical trial period.
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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.
CLINICAL STUDY REPORT
A Signatory Investigator must be selected to sign the clinical study report. 
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 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 
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 subjects 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.
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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. 
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 
preexisting medical condition in a clinical investigation participant administered study treatment 
and 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, ECG, 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/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
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 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; 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 potential drug induced liver injury (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 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 (IB) 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 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 Sponsor.
•
The investigator may change his/her opinion of causality in light of follow-up information 
and send a 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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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.
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 eCRF.
−
The paper SAE Report Form is only intended as a back-up option when the electronic 
data capture (EDC) 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 (fax) 
transmission
♦When paper forms are used, the original paper forms are to remain on site
•
Pregnancies must be recorded on a paper Pregnancy Surveillance Form and transmitted via 
email or confirmed facsimile (fax) transmission 
SAE Email Address: Refer to Contact Information list.
SAE Facsimile Number: Refer to Contact Information list.
SAE Telephone Contact (required for SAE and pregnancy reporting): Refer to Contact 
Information list
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APPENDIX 4
WOMEN OF CHILDBEARING POTENTIAL DEFINITIONS AND 
METHODS OF CONTRACEPTION
DEFINITIONS
Woman of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming post-menopausal 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. The duration of 
the washout period below are suggested guidelines and the 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
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.
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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 participants are required to use a condom for study duration and until end of relevant 
systemic exposure defined as 7 months after the end of study treatment.
•
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 7 months after the end of 
study treatment in the male participant.
•
Male participants with a pregnant or breastfeeding partner must agree to remain abstinent from 
penile vaginal intercourse or use a male condom during each episode of penile penetration 
during the treatment and until 7 months after the end of study treatment.
•
Refrain from donating sperm for the duration of the study treatment and until 7 months after 
the end of study treatment plus an additional 90 days.
COLLECTION OF PREGNANCY INFORMATION
Guidance for collection of Pregnancy Information and outcome of pregnancy on the Pregnancy 
Surveillance Form is provided in Section 9.2.5 and the Appendix for Adverse Events and Serious 
Adverse Events Definitions and procedures for Evaluating, Follow-up and Reporting.
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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
NIVOLUMAB 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 
therapeutic 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
DETAILED PATHOLOGY METHODS FOR USING RESIDUAL 
CANCER BURDEN
Residual cancer burden (RCB) is estimated from routine pathologic sections of the primary breast 
tumor site and the regional lymph nodes (LNs) after the completion of neoadjuvant therapy. 
Six variables are included in a calculation formula. The calculated RCB index value can also be 
categorized as 1 of 4 RCB classes. The calculation formula (see image below) and detailed 
description can be found at a dedicated website: http://www.mdanderson.org/breastcancer_RCB.
Relevant information can be included within a pathology report (diagnoses or comment) without 
a need for reporting calculated RCB index results. An example of relevant information from a 
report would be:
•
Residual invasive carcinoma with chemotherapy effect
•
Residual carcinoma measures 2.4 × 1.8 cm (d1 × d2) and contains approximately 10% cancer 
cellularity (proportion of cancer; %CA)
•
Residual intraductal carcinoma, solid type with necrosis, comprising 5% of the residual 
carcinoma (proportion of in situ component; %CIS)
•
Metastatic carcinoma involving 3 of 14 axillary LNs (3/14)
•
The largest metastasis measures 4 mm in greatest dimension (diameter of the largest nodal 
metastasis; dmet)
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From the results above, one could calculate RCB using these results: d1 = 24 mm; d2 = 18 mm; 
%CA = 10%; %CIS = 5%; LN = 3; dmet = 4 mm.
Primary Tumor Bed
In general terms, pathologic evaluation of the primary tumor bed in the breast requires that the 
pathologist make 3 judgments about the primary tumor bed:
1) Identify the cross-sectional dimensions of the residual tumor bed (d1 and d2).
2) Estimate of the proportion of that residual tumor bed area that is involved by cancer (%CA). 
3) Estimate the proportion of the cancer that is in situ component (%CIS).
Defining the Tumor Bed
In cases of multicentric disease, the RCB measurements are from the largest residual tumor bed. 
In cases where the extent of residual cancer under the microscope does not correlate with the gross 
measurement of the residual tumor bed, the tumor bed dimensions are to be revised according to 
the microscopic findings. 
Schematic diagrams are shown below to illustrate how gross residual tumor bed dimensions are 
first estimated from the gross findings (pink area) but may be revised after review of the slides 
from the gross tumor bed area according to the extent of residual cancer (blue).
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In the diagrams above, the macroscopic tumor bed dimensions in examples A, C, and D also define 
the final dimensions of the residual tumor bed after microscopic review. However, the macroscopic 
tumor bed dimensions in example B overestimate the extent of residual cancer, and so the 
dimensions of the residual tumor bed (d1 and d2) would be revised after microscopic evaluation 
of the extent of residual cancer in the corresponding slides from the gross tumor bed. In a different 
example (E), microscopic residual cancer extends beyond the confines of the macroscopic tumor 
bed. Again, the dimensions of the residual tumor bed (d1 and d2) would be revised after 
microscopic evaluation of the recognizable extent of residual cancer beyond the macroscopic 
tumor bed.
This approach accounts for differences in the concentration and distribution of residual cancer 
within a tumor bed. In the illustration above, the estimated %CA in example A would be high (in 
a small area), whereas the estimated %CA for examples C and D would be lower (in a larger area). 
In examples C and D, the estimated %CA would likely be similar, even though the distribution of 
cancer within the residual tumor bed is different in those 2 examples.
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Estimating Cellularity within the Tumor Bed
The %CA and the %CIS are estimated from microscopic evaluation of the slides from the residual 
tumor bed area. The most effective way to obtain this information is to measure and submit for 
histology the largest cross-sectional area of residual tumor bed, and to designate in the report which 
slides represent the cross section of tumor bed. After reviewing those slides, the pathologist can 
estimate the average cellularity in the tumor bed on each slide in order to estimate the overall 
average cellularity of the tumor bed area, as illustrated below.
The key is to simply:
1) Define the gross tumor bed as the largest cross-sectional area.
2) Submit sections representing that tumor bed area as individual slides.
3) Review those slides to estimate the %CA and %CIS within the residual tumor bed.
A practical way to estimate %CA in a slide is to encircle with ink dots the tumor bed on each slide 
from the grossly defined residual tumor bed (eg, slides A1-A5 in the example above). Then use 
the microscope to estimate the cellularity in each microscopic field across the area of tumor bed. 
In each microscopic field, %CA can be estimated by comparing the proportion of residual tumor 
bed area containing cancer (invasive or in situ). Estimate an average of the readings for %CA in 
the cross-sectional area. The same can be done for %CIS. Estimates are to the nearest 10%, but 
include 0%, 1%, and 5% for areas with low cellularity. The average cellularity within the tumor 
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bed from each slide across the tumor bed can then be estimated, as illustrated above. The website 
provided above contains computer-generated diagrams of % cellularity per area to assist 
pathologists with accurately estimating the cellularity of a microscopic field. Those diagrams are 
provided at the end of this Appendix.
Regional Lymph Nodes: Pathologic evaluation of the primary tumor bed in the breast requires 
that the pathologist make 2 judgments:
1) Count the number of positive LNs.
2) Measure the dmet.
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Footnotes
Inoperable or Progressive Disease
The RCB index cannot be accurately calculated for patients whose disease remains inoperable at 
the completion of the neoadjuvant treatment course (eg, requiring subsequent additional treatments 
before surgical resection is possible), or those who experience disease progression and so do not 
undergo surgical resection at the completion of the neoadjuvant treatment course. For those 
patients, RCB is assigned as extensive (ie, RCB-III).
Internal Mammary Lymph Node Metastasis
There were no examples of internal mammary nodal metastasis in the published study that 
evaluated the prognostic value of RCB. However, it is reasonable to include internal mammary 
nodes with the other regional (axillary) nodes in the assessment of RCB.
Pre-treatment Sentinel Lymph Node Biopsy
Surgical excision of a positive sentinel LN before the neoadjuvant treatment would invalidate the 
accuracy of measuring RCB after the treatment to assess response. If all sentinel LNs were negative 
before treatment began, this would not affect the assessment of RCB after treatment ended.
Summary of Key Points for Pathologic Assessment of the Primary Tumor Bed
Define the dimensions of residual tumor bed and estimate the percent of that area that is cancer.
3) GROSS. Identify the residual tumor bed and describe this macroscopic finding:
a) Report the measurements of the largest gross dimensions (prefer 3 dimensions, but 
minimum is 2 dimensions).
b) Submit the largest cross-sectional area for histology and specifically describe those blocks 
in the Section Code:
i)
Try to indicate how they are oriented by photography, or a scheme or intelligent 
description (eg, “blocks B1 – B7 cross section of tumor bed in rows from 
antero-superior to postero-inferior”).
ii) If additional blocks are from surrounding tissues, then describe those as well.
iii) Five representative sections from a big, obvious tumor bed should be sufficient.
4) MICROSCOPY. Review the slides that correspond to the tumor bed (± surrounding tissues):
a) Estimate the extent of spread of residual cancer relative to the gross tumor bed:
i)
If similar to the gross description, then keep the original measurements.
ii) If obviously different, then revise the dimensions of the tumor bed based on the 
microscopic review of the tumor bed.
iii) Suggestion: Dotting the perimeter of cancer in each slide can be helpful to reconstruct 
the tumor extent across multiple slides (see point 1) b) i)).
b) Using the microscope, make visual snapshots of cancer cellularity as you go from field to 
field across the defined tumor bed from one end to the opposite (eg, left to right, then top 
to bottom) to estimate the:
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i)
Average cancer cellularity (%) across the entire tumor bed. Considering both invasive 
and in situ components.
ii) Average percent of the cancer within the tumor bed that is in situ.
iii) Cellularity estimates are to the nearest 10%, with additional selections of 1% and 5% 
for very low cellularity. For reference, there are images of computer generated 
examples at the following website: http://www.mdanderson.org/breastcancer_RCB.
iv) The usual misunderstanding is to only make estimates in foci of the tumor bed that 
contain lots of cancer. The estimates are supposed to represent the average across the 
entire residual tumor bed area.
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APPENDIX 8
RESPONSE EVALUATION CRITERIA IN SOLID TUMORS 
GUIDELINES (VERSION 1.1) 
1
EVALUATION OF LESIONS
Solid tumors will be evaluated using Response Evaluation Criteria In Solid Tumors version 1.1 
(RECIST 1.1) guideline 
.1
At baseline, tumor lesions/lymph nodes will be categorized as measurable or non-measurable as 
follows:
2
MEASURABLE
Tumor lesions: Must be accurately measured in at least one dimension (longest diameter in the 
plane of measurement is to be recorded) with a minimum size of:
•
10 mm by CT/MRI scan (scan slice thickness no greater than 5 mm), or ≥2x slice thickness if 
greater than 5mm.
Malignant lymph nodes: To be considered pathologically enlarged and measurable, a lymph node 
must be ≥15 mm in short axis when assessed by CT/MRI scan (scan slice thickness recommended 
to be no greater than 5 mm).
Lymph nodes merit special mention since they are normal anatomical structures which may be 
visible by imaging even if not involved by tumor. Pathological nodes which are defined as 
measurable and may be identified as target lesions must meet the criterion of a short axis of 
≥15 mm by CT/MRI scan. Only the short axis of these nodes will contribute to the baseline sum. 
The short axis of the node is the diameter normally used by radiologists to judge if a node is 
involved by solid tumor. Nodal size is normally reported as two dimensions in the plane in which 
the image is obtained (for CT scan this is almost always the axial plane; for MRI the plane of 
acquisition may be axial, sagittal or coronal). The smaller of these measures is the short axis. For 
example, an abdominal node which is reported as being 20 mm x 30 mm has a short axis of 20 mm 
and qualifies as a malignant, measurable node. In this example, 20 mm should be recorded as the 
node measurement. All other pathological nodes (those with short axis ≥10 mm but < 15 mm) 
should be considered non-target lesions. Nodes that have a short axis < 10 mm are considered 
non-pathological and should not be recorded or followed.
Note: Lesions on X-Ray are not to be selected as Target or Non-Target Lesions.
3
NON-MEASURABLE
All other lesions are considered non-measurable, including small lesions (longest diameter 
< 10mm or pathological lymph nodes with ≥10 to < 15 mm short axis) as well as truly 
non-measurable lesions. Lesions considered truly non-measurable include: leptomeningeal 
disease, inflammatory breast disease, lymphangitic involvement of skin or lung, abdominal 
masses/abdominal organomegaly identified by physical exam that is not measurable by 
reproducible imaging techniques.
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Note: Lesions on X-Ray are not to be selected as Target or Non-Target Lesions.
3.1
Special Considerations Regarding Lesion Measurability
3.1.1
Bone Lesions
•
Bone scan, PET scan and plain films are not considered adequate imaging techniques to 
measure bone lesions. However, these techniques can be used to confirm the presence or 
disappearance of bone lesions. 
•
Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue components, that 
can be evaluated by cross sectional imaging techniques such as CT or MRI can be considered 
as measurable lesions if the soft tissue component meets the definition of measurability 
described above.
•
Blastic bone lesions are non-measurable.
4
BASELINE DOCUMENTATION OF ‘TARGET’ AND ‘NON-TARGET’ 
LESIONS
When more than one measurable lesion is present at baseline all lesions up to a maximum of five 
lesions total (and a maximum of two lesions per organ) representative of all involved organs should 
be identified as target lesions and will be recorded and measured at baseline (this means in 
instances where patients have only one or two organ sites involved a maximum of two and four 
lesions respectively will be recorded).
Note: A maximum of two lesions can be selected per organ system. For example, a maximum of 
two lung lesions can be selected (selected from one lung or one lesion from each). A maximum of 
two lymph nodes can be selected at baseline, as the lymphatic system is considered one organ.
Target lesions should be selected on the basis of their size (lesions with the longest diameter), be 
representative of all involved organs, but in addition should be those that lend themselves to 
reproducible repeated measurements. It may be the case that, on occasion, the largest lesion does 
not lend itself to reproducible measurement in which circumstance the next largest lesion which 
can be measured reproducibly should be selected.
A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target 
lesions will be calculated and reported as the baseline sum diameters. If lymph nodes are to be 
included in the sum, then as noted above, only the short axis is added into the sum. 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 lesions (or sites of disease) including pathological lymph nodes should be identified as 
non-target lesions and should also be recorded at baseline. Measurements are not required and 
these lesions should be followed as ‘present’, ‘absent’, or in rare cases ‘unequivocal progression’ 
(more details to follow). In addition, it is possible to record multiple non-target lesions involving 
the same organ as a single item on the case record form (eg, ‘multiple enlarged pelvic lymph nodes’ 
or ‘multiple liver metastases’).
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5
RESPONSE CRITERIA
5.1
Evaluation of Target Lesions
•
Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes 
(whether target or non-target) must have reduction in short axis to < 10 mm.
•
Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, 
taking as reference the baseline sum 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. (Note: the appearance of one or more new lesions is also 
considered progression).
•
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest sum 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. 
5.1.1
Special Notes on the Assessment of Target Lesions
5.1.1.1
Lymph Nodes
Lymph nodes identified as target lesions should always have the actual short axis measurement 
recorded (measured in the same anatomical plane as the baseline examination), even if the nodes 
regress to below 10 mm on study. This means that when lymph nodes are included as target lesions, 
the ‘sum’ of lesions may not be zero even if complete response criteria are met, since a normal 
lymph node is defined as having a short axis of < 10 mm. Case report forms or other data collection 
methods may therefore be designed to have target nodal lesions recorded in a separate section 
where, in order to qualify for CR, each node must achieve a short axis < 10 mm. For PR, SD and 
PD, the actual short axis measurement of the nodes is to be included in the sum of target lesions.
5.1.1.2
Target Lesions that Become ‘too Small to Measure’
While on study, all lesions (nodal and non-nodal) recorded at baseline should have their actual 
measurements recorded at each subsequent evaluation, even when very small (eg, 2 mm). 
However, sometimes lesions or lymph nodes which are recorded as target lesions at baseline 
become so faint on CT scan that the radiologist may not feel comfortable assigning an exact 
measure and may report them as being ‘too small to measure’. When this occurs it is important 
that a value be recorded on the 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. (Note: It is less likely that this rule will be used for lymph nodes since 
they usually have a definable size when normal and are frequently surrounded by fat such as in the 
retroperitoneum; however, if a lymph node is believed to be present and is faintly seen but too 
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small to measure, a default value of 5 mm should be assigned in this circumstance as well). This 
default value is derived from the 5 mm CT slice thickness (but should not be changed with varying 
CT slice thickness). 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.
5.1.1.3
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’.
5.2
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. All lymph nodes must be 
non-pathological in size (< 10mm short axis). 
•
Non-CR/Non-PD: Persistence of one or more non-target lesion(s)
•
Progressive Disease (PD): Unequivocal progression of existing non-target lesions.
5.2.1
Special Notes on Assessment of Progression of Non-Target Disease
The concept of progression of non-target disease requires additional explanation as follows:
5.2.1.1
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.
5.2.1.2
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 
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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.
5.2.2
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 
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.
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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.
5.3
Response Assessment
5.3.1
Evaluation of Best Overall Response
The best overall response is the best response recorded from the start of the study treatment until 
disease progression or the last response recorded, taking into account any requirement for 
confirmation and censoring rules regarding subsequent therapy. 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. Furthermore, depending on the nature of the study 
and the protocol requirements, it may also require confirmatory measurement.
5.3.2
Time Point Response
At each protocol specified time point, a response assessment occurs. Table 5.3.2-1 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 5.3.2-2 is to be used. 
Table 5.3.2-1:
Time Point Response: Patients With Target (± Non-Target) Disease
Target Lesions
Non-Target Lesions
New Lesions
Overall Response
CR
CR
No
CR
CR
Non-CR/non-PD
No
PR
CR
Not evaluated
No
PR
PR
Non-PD or not all 
evaluated
No
PR
SD
Non-PD or not all 
evaluated
No
SD
Not all evaluated
Non-PD
No
NE
PD
Any
Yes or No
PD
Any
PD
Yes or No
PD
Any
Any
Yes
PD
CR = complete response, PR = partial response, SD = stable disease, PD = progressive disease and NE = inevaluable
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Table 5.3.2-2:
Time Point Response: Patients with Non-target Disease Only
Non-Target Lesions
New Lesions
Overall Response
CR
No
CR
Non-CR/non-PD
No
Non-CR/non-PDa
Not all evaluated
No
NE
Unequivocal PD
Yes or No
PD
Any
Yes
PD
CR = complete response, PD = progressive disease and NE = inevaluable
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.
5.3.3
Best Overall Response 
Best response determination of complete or partial response requires confirmation: Complete or 
partial responses may be claimed only if the criteria for each are met at a subsequent time point of 
≥4 weeks (28 days) later. In this circumstance, the best overall response can be interpreted as in 
Table 5.3.3-1. 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.
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.
Special note on response assessment: When nodal disease is included in the sum of target lesions 
and the nodes decrease to ‘normal’ size (< 10 mm), they may still have a measurement reported 
on scans. This measurement should be recorded even though the nodes are normal in order not to 
overstate progression should it be based on increase in size of the nodes. As noted earlier, this 
means that patients with CR may not have a total sum of ‘zero’ on the case report form (CRF).
Table 5.3.3-1:
Best Overall Response (Confirmation of CR and PR Required)
Overall Response 
First Time Point
Overall Response 
Subsequent Time Point
Best Overall Response
CR
CR
CR
CR
PR
SD, PD OR PRa
CR
SD
SD provided minimum criteria for SD duration met, otherwise, 
PD
CR
PD
SD provided minimum criteria for SD duration met, otherwise, 
PD
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Table 5.3.3-1:
Best Overall Response (Confirmation of CR and PR Required)
Overall Response 
First Time Point
Overall Response 
Subsequent Time Point
Best Overall Response
CR
NE
SD provided minimum criteria for SD duration met, otherwise, 
NE
PR
CR
PR
PR
PR
PR
PR
SD
SD
PR
PD
SD provided minimum criteria for SD duration met, otherwise, 
PD
PR
NE
SD provided minimum criteria for SD duration met, otherwise, 
NE
NE
NE
NE
CR = complete response, PR = partial response, SD = stable disease, PD = progressive disease, and 
NE = inevaluable
a If a CR is truly met at first time point, then any disease seen at a subsequent time point, even disease meeting PR 
criteria relative to baseline, makes the disease PD at that point (since disease must have reappeared after CR). Best 
response would depend on whether minimum duration for SD was met. However, sometimes ‘CR’ may be claimed 
when subsequent scans suggest small lesions were likely still present and in fact the patient had PR, not CR at the 
first time point. Under these circumstances, the original CR should be changed to PR and the best response is PR.
5.3.4
Confirmation Scans
Verification of Response: To be assigned a status of CR or PR, changes in tumor measurements 
must be confirmed by consecutive or subsequent repeat assessments that should be performed no 
less than 28 days after the criteria for response are first met. Subsequent documentation of a CR 
may provide confirmation of a previously identified CR even with an intervening NE or PR 
(eg, CR NE CR or CR PR CR). Subsequent documentation of a PR may provide confirmation of 
a previously identified PR even with an intervening NE or SD (eg, PR NE PR or PR SD PR). 
However, only one (1) intervening time point will be allowed between PR/CRs for confirmation.
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 AMENDMENTS
Argentina, Czech Republic, Germany, Italy, Spain, and Any Other Countries Where 
Exclusion of HIV Positive Participants Is Locally Mandated
Country-specific language
Section 2 Schedule of Activities, Table 2-1: 
ScreeningAssessments - LaboratoryTests
Add “HIV” to the list of laboratory tests
Section 6.2 Exclusion
Criteria, Exclusion criterion 1) e)
“Known human immunodeficiency virus (HIV) positive with 
an AIDS defining opportunistic infection within the last year, 
or a current CD4 count <350 cells/uL.” to be replaced with
“Positive test for HIV”.
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APPENDIX 10
CONCOMITANT MEDICATIONS
In general, the use of any concomitant medication deemed necessary for the care of the patient is 
permitted in this study, except as specifically prohibited below. Combination administration of 
study drugs could result in drug-drug interactions (DDI) that could potentially lead to reduced 
activity or enhanced toxicity of the concomitant medication and/or CDK4/6 inhibitors.
The following lists are based on the Oncology Clinical Pharmacology Drug-Drug Interaction and 
Co-Medication Considerations (v06 release date: 2016), which was compiled from the Indiana 
University School of Medicine’s “Clinically Relevant” Table 
(medicine.iupui.edu/clinpharm/ddis/main-table/) and supplemented with the FDA Draft 
Guidance for Industry, Drug Interaction Studies – Study Design, Data Analysis, and Implications 
for Dosing and Labeling (February 2012; 
fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm292362.pdf), 
and the University of Washington’s Drug Interaction Database (druginteractioninfo.org/). 
For current lists of medications that may cause QT prolongation and/or Torsades de Pointes (TdP), 
refer to the CredibleMeds® website (qtdrugs.org/).
The lists provided in the tables below are not comprehensive and are only meant to be used as a 
guide. Please contact the medical monitor with any questions.
Table 1:
List of Prohibited Medications During Study Drug Treatment
Category
Drug Name
Strong CYP3A4/5 Inhibitors
VIEKIRA PAK2, indinavir/ritonavir, tipranavir/ritonavir, ritonavir, cobicistat 
(GS-9350), indinavir, ketoconazole, troleandomycin, telaprevir, 
danoprevir/ritonavir, elvitegravir/ritonavir, saquinavir/ritonavir, 
lopinavir/ritonavir, itraconazole, voriconazole, mibefradil, clarithromycin, 
posaconazole, telithromycin, grapefruit juice, conivaptan, nefazodone, nelfinavir, 
saquinavir, idelalisib, boceprevir, darunavir/ritonavir
Strong CYP3A4/5 Inducers
Avasimibe,a,b carbamazepine, enzalutamide, mitotane, phenobarbital, phenytoin, 
rifabutin, rifampin (rifampicin)b St. John's wort (hypericum perforatum)b
CYP3A Substrates with 
Narrow Therapeutic Index 
(NTI)c
Alfentanil, apixaban (doses > 2.5 mg only), aprepitant, astemizole, cisapride, 
cyclosporine, diergotamine (dihydroergotamine), ergotamine, fentanyl, lovastatin, 
nicardipine, nisoldipine, pimozide, quinidine, rivaroxaban, simvastatin, sirolimus, 
tacrolimus, terfenadine, thioridazine, lomitapide
Medications with a Known 
Risk for QT Prolongationd
Amiodarone, anagrelide, arsenic trioxide, astemizole, azithromycin, bepridil, 
chloroquine, chlorpromazine, cilostazol, ciprofloxacin, cisapride, citalopram, 
clarithromycin, cocaine, disopyramide, dofetilide, domperidone, donepezil, 
dronedarone, droperidol, erythromycin, escitalopram, flecainide, fluconazole, 
grepafloxacin, halofantrine, haloperidol, ibutilide, levofloxacin, levomethadyl,
mesoridazine, methadone, moxifloxacin, ondansetron (i.v. only), oxaliplatin, 
papaverine HCl, pentamidine, pimozide, probucol, procainamide, propofol, 
quinidine, sevoflurane, sotalol, sparfloxacin, sulpiride, terfenadine, thioridazine, 
vandetanib, venlafaxine
Herbal 
Preparations/medications
Herbal preparations/medications known as string inducers or inhibitors of 
CYP3A/5 are prohibited throughout the study. These herbal medications include, 
but are not limited to: St. John’s wort, Kava, ephedra (ma huang), gingko biloba, 
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Table 1:
List of Prohibited Medications During Study Drug Treatment
Category
Drug Name
dehydroepiandrosterone (DHEA), yohimbe, saw palmetto, and ginseng. 
Participants should stop using these herbal medications 7 days prior to first dose 
of study drug.
Other Investigational and 
Antineoplastic Therapies
Other investigational therapies must not be used while the participant is on the 
study. Antineoplastic therapy (chemotherapy, biologic or radiation therapy, and 
surgery) other than the study treatments must not be given to participants while 
the participant is on the study medication. If such agents are required for a 
participant, then the participant must discontinue study drug.
a Herbal product.
b Pg inducer.
c Drugs with exposure-response that indicates that increases in their exposure levels by the concomitant use of potent 
inhibitors may lead to serious safety concerns (eg, Torsades de Pointes).
d Source: qtdrugs.org (as of 12-Dec-2016).
As far as possible, avoid co-administration of QT prolonging drugs or any other drugs with the 
potential to increase the risk of drug-related QT prolongation (eg, via a potential DDI that increases 
the exposure of ribociclib or the exposure of the QT prolonging drug). A definitive list of drugs 
with a known risk, possible risk, or conditional risk of QT prolongation and/or TdP is available 
online at qtdrugs.org.
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Table 2:
List of Medications to be Used with Caution During Study Drug 
Treatment
Category
Drug Name
Moderate CYP3A4/5 Inhibitors
Amprenavir, atazanavir, casopitant, cimetidine, darunavir, diltiazem, 
fosamprenavir netupitant, tofisopam, verapamil, crizotinib, faldaprevir, 
imatinib, nilotinib
Moderate CYP3A4/5 Inducers
Bosentan, efavirenz, etravirine, genistein, lersivirine, modafinil, nafcillin, 
talviraline, semagacestat, lopinavir 
Sensitive CYP3A4/5 Substratesa
Alpha-dihydroergocryptine, alisoporivir, almorexant, aplaviroc, apixaban 
(doses < 2.5 mg only), atazanavir, atorvastatin, avanafil, bosutinib, 
brecanavir, brotizolam, budesonide, buspirone, capravirine, casopitant, 
danoprevir,darifenacin, darunavir, dasatinib, ebastine, eletriptan, 
elvitegravir, eplerenone, everolimus,  felodipine, fluticasone, ibrutinib, 
ivacaftor, lumefantrine, lurasidone, maraviroc, midazolam, midostaurin, 
naloxegol, neratinib, perospirone, quetiapine, ridaforolimus, sildenafil, 
simeprevir, ticagrelor, tilidine, tipranavir, tolvaptan, triazolam, ulipristal, 
vardenafil, vicriviroc, voclosporin
Strong BSEP Inhibitors
Alectinib, Atazanavir, bromocriptine, Bosentan, clofaziminie, cerivastatin, 
fusidate, glibenclamide, glyburide, nefazadone, paritaprevir, pioglitazone, 
reserpine, rosiglitazone, sulindac, troglitazone (TGZ-sulfate), valinomycin
Medications That Carry a Possible 
Risk for QT Prolongationb
Alfuzosin, apomorphine, aripiprazole, artenimol+piperaquine, atazanavir, 
atomoxetine, asenapine, bedaquiline, bortezomib, buprenorphine, 
capecitabine, ceritinib, clomipramine, crizotinib, clozapine, cyamemazine 
(cyamepromazine), dabrafenib, dasatinib, degarilix, delamanid, 
desipramine, dexmedetomidine, dolasetron, eribulin, ezogabine,
famotidine, felbamate, fingolimod, foscarnet, gatifloxacin, gemifloxacin, 
granisertron, hydrocodone-ER, iloperidone, imipramine (melipramine),
isradipine, lapatinib, lenvatinib, leuprolide, lithium, mifepristone,
mirabegron, mirtazapine, moexipril, norfloxacin, nortriptyline, ofloxacin, 
olanzapine, osimertinib, ondansetron (PO only at 4 mg or 8 mg), oxytocin, 
paliperidone, panabinostat, pasireotide, pazopanib, pipamperone, 
promethazine, quetiapine, ranolazine, rilpivirine, risperidone, 
roxithromycin, sertindole, sorafenib, sunitinib, telavancin, tetrabenazine, 
tizanidine, tolterodine, toremifene, trimipramine, vardenafil, vemurafenib, 
vorinostat, ziprasidone
MATE1 and OCT2 substratesc
Acyclovir, amantadine, amiloride, apricitabine, carboplatin, cisplatin, 
cephalexin, cephradine, cimetidine, dofetilde, famotidine, fexofenadine, 
furamidine, ganciclovir, glycopyrronium, Ipratropium, lamivudine, 
linagliptin, memantine, metformin (also a substrate for OCT1, MATE1, 
and MATE2K), oxyplatin, pindolol, plisicainide, pramsorafenib, 
ranitidine, topotecan, tropisetron, trospium, umeclidinium, varencicline 
and zidovudine
BCRP substrates
Daunorubicin, doxorubicin, ethinyl estradiol methotrexate, mitoxantrone, 
pitavastatin rosuvastatin, sulfasalazine, sofosbuvir, tenofovir 
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Table 2:
List of Medications to be Used with Caution During Study Drug 
Treatment
Category
Drug Name
CYP2C9 substrates
with NTI (for participants
receiving tamoxifen)
Phenytoin, warfarin
a Sensitive substrates: Drugs whose plasma AUC values have been shown to increase 5-fold or higher when co-
administered with a potent inhibitor.
b Source: qtdrugs.org (as of 12-Dec-2016).
c Source: FDA Draft Guidance for Industry, Drug Interaction Studies – Study Design, Data Analysis, and 
implications for Dosing and Labeling (February 2012) and Yonezawa and Inui (2011) Importance of the multidrug 
and toxin extrusion MATE/SLC47A family to pharmacokinetics, pharmacodynamics/toxicodynamics and 
pharmacogenomics. Br J Pharmacology 164:1817-25; www.druginteractioninfo.org (May-2016).
Table 3:
List of Cytochrome P450 Substrates with Narrow Therapeutic 
Range Cytochrome P450
Cytochrome P450 Substrates with Narrow 
Therapeutic Range Cytochrome P450
Substrate
CYP1A2
Theophylline
Tizanidine
CYP2C8
Paclitaxel
CYP2C9
Warfarin Phenytoin
CYP2D6
Thioridazine Pimozide
CYP3A
Alfentanil Astemizole Cisapride Cyclosporine 
Dihydroergotamine Ergotamine Fentanyl
Pimozide Quinidine Sirolimus Tacrolimus Terfenidine
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APPENDIX 11
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 12
REVISED PROTOCOL SUMMARY OF CHANGE HISTORY
Overall rationale for Revised Protocol 02, 24-July-2019
The primary reasons for these changes
 
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.
Summary of key changes for Revised Protocol 02
Section Number & 
Title
Description of Change
Brief Rationale
2: Schedule of Activities
Modified Table 2-2 (screening procedural outline) 
to update inclusion criterion number in the notes for 
‘documentation of postmenopausal status.’
To align with updates made in 
Section 6.1, described below.
4: Objectives and Endpoints
5.1.2.1: Safety Run-in 
Phase
The following modifications were made:
•
Updated definition of DLT.
•
Added DLT criteria.
These changes were made to 
refine wording to facilitate 
Investigator interpretation.
5.1: Overall Study Design
Revised window to perform definitive breast cancer 
surgery to 4 weeks after last dose of neoadjuvant 
treatment.
Modified Figure 5.1-1 to update key inclusion 
criteria to include men in addition to 
postmenopausal women.
Allow flexibility to plan the 
breast surgery and reflect 
updated study design in which 
men are now also eligible.
5.4: Early Study 
Termination Criteria
Added early study termination criteria.
These changes were made to 
refine wording to facilitate 
Investigator interpretation.
6.1: Inclusion Criteria
The following modifications were made:
•
Moved eligibility criteria for women to sub-
criteria for criterion 3) b)
•
Added additional sub-criteria related to 
eligibility of men to criterion 3)
These changes were made to 
refine wording to facilitate 
Investigator understanding 
and include men in the study.
6.2: Exclusion Criteria
7.7.1: Prohibited and/or 
Restricted Treatments for 
Nivolumab
7.7.3: Other Restrictions 
and Precautions
7.7.4: Permitted Therapy
The following modifications were made:
•
Changed criteria 1) d) and 1) i) to exclude 
steroids above physiological replacement dose.
•
Changed from ‘immunosuppressive’ to 
‘supraphysiological’ when describing other 
restrictions and precautions.
•
Deleted the prednisone permitted dose.
•
Changed ‘> 10 mg daily prednisone 
equivalent’ to ‘at above physiological 
replacement dose’ when describing permitted 
therapy.
These changes were made to 
refine wording to facilitate 
Investigator understanding.
7.4.1: Dose Modifications 
for Abemaciclib
7.4.2: Dose Modifications 
for Palbociclib
The following modifications were made:
•
Aligned the section with the US prescribing 
information language for each medication.
These changes were made to 
refine wording to facilitate 
Investigator understanding.
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Summary of key changes for Revised Protocol 02
Section Number & 
Title
Description of Change
Brief Rationale
7.4.3: Dose Modification 
for Anastrozole
9.2.5: Pregnancy
Appendix 4: Women of 
Childbearing Potential 
Definitions and Methods of 
Contraception
Added language describing male contraception 
expectations.
Aligned methods of 
contraception with the update 
to the study design to now 
include men.
Appendix 6: Nivolumab 
Management Algorithms
Updated management algorithms and added 
myocarditis.
These changes were made to 
reflect updates made to the IB.
Appendix 9: Country-
specific Amendments
Removed France from list of countries.
France does not mandate HIV 
testing.
All
The following global updates were made:
•
Added males.
•
Minor formatting and typographical 
corrections.
These changes were made to:
•
Clarify that men are 
eligible.
•
Incorporate corrections 
for clarity and 
consistency within the 
document. These changes 
were minor, and therefore 
have not been 
summarized.
Overall rationale for revised protocol 01, 12-June-2019
The primary reasons for these changes are to clarify and decrease the frequency of assessments 
and sample collections, clarify participant eligibility and stratification, and reduce the 
dose-limiting toxicity (DLT) period. These changes were made to reduce participant burden and 
increase overall feasibility of the study. Additional amendments, including to sections of the 
Synopsis, have been made to align the protocol with respect to these changes.
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Summary of key changes for Revised Protocol 01
Section Number & 
Title
Description of Change
Brief Rationale
2: Schedule of Activities
•
The following modifications were 
made:
• Table 2-1: 
−
Added row describing Original 
Diagnosis IHC Tumor Slides 
Submission.
−
Updated number of unstained 
slides for tumor tissue sections 
from 25 to 22 and lowered 
minimum number of slides for 
participant eligibility from 20 to 
15.
−
Added respiratory rate to safety 
assessments.
−
Updated “Tumor Assessment by 
PE” to “Clinical Breast 
Examination.”
−
Added “axilla” to breast 
ultrasound (preferred) or 
mammogram.
−
Added Axillary Lymph Nodes 
Fine Needle Biopsy or Core 
Biopsy row.
• Table 2-2:
−
Decreased the frequency of ocular 
exams and electrocardiograms.
−
Updated “Tumor Assessment by 
PE” to “Clinical Breast 
Examination.”
−
Added “axilla” to breast 
ultrasound (preferred) or 
mammogram and aligned timing 
of this assessment with on-
treatment biopsy (now on Cycle 2 
Day 22).
• Table 2-3:
−
Updated ocular assessments to be 
as clinically indicated.
These changes were made to clarify
assessment expectations and/or 
decrease the number of assessments 
to reduce participant burden.
4: Objectives and Endpoints
•
Removed text describing timeframe of 
Safety Run-in Phase.
•
Streamlined text to improve 
readability.
4: Objectives and Endpoints;
9.1.2.1: RCB Determination
•
Removed local assessment of residual 
cancer burden (RCB) 0-1 rate as a 
secondary endpoint.
•
Updated to improve study 
feasibility.
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Summary of key changes for Revised Protocol 01
Section Number & 
Title
Description of Change
Brief Rationale
4: Objectives and Endpoints; 
5.1.2.1: Safety Run-in Phase; 
10.3.2: Safety Analyses
Shortened the DLT period from 8 weeks to 
4 weeks and redefined DLT-evaluable 
participants as those who receive 1 dose.
Aligned with clinical experience 
regarding safety feasibility of the 
study drugs.
5.1: Overall Design; 
5.1.2.2: Randomized Phase; 
7.2: Method of Treatment 
Assignment
Specified axillary node status for 
stratification factor as “cytologically 
positive vs radiologically or cytologically 
negative.”
Clarified expectations for node 
status stratification factor.
5.1.1: Screening Period
Added details related to documentation and 
tumor samples for central review.
Clarified expectations for central 
review.
5.1.1: Screening Period; 
6.1: Inclusion Criteria; 
 
Modified number of unstained slides for 
tumor tissue sections from 25 to 22 and 
lowered minimum number of slides for 
participant eligibility from 20 to 15.
Updated to improve study 
feasibility.
5.1: Overall Design;
5.2: Number of Participants; 
10.1: Sample Size 
Determination;
 
Provided range of anticipated number of 
study participants for the Safety Run-in 
Phase within text and Study Design 
Schematic in Figure 5.1-1.
Clarified expectations for number 
of participants.
5.1.2.1: Safety Run-in Phase
Modified criteria for gastrointestinal and 
dermatologic DLTs.
Updated for participant safety.
6.1: Inclusion Criteria
The following modifications were made:
• Updated sub-criteria for criterion 2) b) to 
remove staging requirement but specify 
primary tumor size per radiological 
assessment.
• Incorporated details in previous criterion 
2) e) related to measurable disease into 
sub-criteria for criterion 2) b) iii).
These changes were made to:
• Clarify expectations for 
participant inclusion criteria 
and improve study feasibility.
• Remove repetitive information 
per changes to 2) b) sub-
criteria.
7.4.1: Dose Modifications for 
Abemaciclib
Added “Third dose reduction” row to 
Table 7.4.1-2.
Clarified dose levels for 
abemaciclib.
9.1.1: Blinded Independent 
Pathology Review
Changed “mandatory” sample collections to 
“should be performed” and removed 
statement on site training.
Aligned expectations for sample 
collections with update described 
above to remove local RCB 
assessment as a secondary endpoint.
9.1.2.1: RCB Determination
Slightly modified variables included in the 
RCB calculations.
Updated for clarity and consistency 
with RCB calculator referenced in 
this section.
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Summary of key changes for Revised Protocol 01
Section Number & 
Title
Description of Change
Brief Rationale
9.1.3: Clinical Response 
Assessments
The following modifications were made:
•
Replaced “targeted PE” with “clinical 
breast examination by palpation of 
breast and axilla.”
•
Added “axilla” to ultrasound 
(preferred) or mammogram.
•
Added “including pathologic 
examination of suspicious lesions.”
•
Added statement: “At the Sponsor’s 
discretion, scans may be collected for 
review.”
These changes were made to:
• Align description of clinical 
response assessments with 
changes made to the Schedule 
of Activities described above.
•
•
• Clarify expectations for clinical 
response assessments.
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Summary of key changes for Revised Protocol 01
Section Number & 
Title
Description of Change
Brief Rationale
10.3.1: Efficacy Analyses
Updated Table 10.3.1-1 for consistency 
with changes to Table 4-1.
Aligned efficacy analyses with 
updates to objectives and endpoints 
described above.
Appendix 8: Staging Criteria
Prior Appendix 8 containing American 
Joint Committee on Cancer (AJCC) criteria 
was removed.
AJCC criteria no longer relevant per 
updates made to Section 6.1.
All
The following global updates were made:
• Replaced “Stage II-III” with “≥2 cm” in 
titles, text, and in Figure 5.1-1.
• Minor formatting and typographical 
corrections.
These changes were made to:
• Clarify breast cancer type 
throughout protocol.
• Incorporate corrections for clarity 
and consistency within the 
document. These changes were 
minor, and therefore have not 
been summarized.
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SAP_001.pdf: 
Official Title of Study: 
Randomized, Non-comparative Neoadjuvant Phase II Study in Patients with ER+/HER2- Breast Cancer ≥ 2 
cm with Safety Run-in, Assessing Nivolumab + Palbociclib + Anastrozole  
(CheckMate 7A8: CHECKpoint pathway and nivoluMAb clinical Trial Evaluation 7A8) 
 
 
PROTOCOL(S) CA209-7A8 
 
NCT Number: NCT04075604 
  
Document Date (Date in which document was last revised): December 16, 2021 


STATISTICAL ANALYSIS PLAN
RANDOMIZED, NON-COMPARATIVE NEOADJUVANT PHASE II STUDY IN 
PATIENTS WITH ER+/HER2- BREAST
CANCER >= 2 CM WITH SAFETY RUN-IN, ASSESSING NIVOLUMAB + 
PALBOCICLIB + ANASTROZOLE
PROTOCOL CA2097A8
VERSION # 1.0
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STATISTICAL ANALYSIS PLAN
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BMS-936558
Nivolumab
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TABLE OF CONTENTS
STATISTICAL ANALYSIS PLAN ............................................................................................1
TABLE OF CONTENTS............................................................................................................2
LIST OF TABLES......................................................................................................................5
LIST OF FIGURES ....................................................................................................................5
1
BACKGROUND AND RATIONALE......................................................................6
2
STUDY DESCRIPTION ..........................................................................................7
2.1
Study Design ............................................................................................................7
2.2
Treatment Assignment............................................................................................12
2.3
Blinding and Unblinding.........................................................................................13
2.4
Protocol Amendments.............................................................................................14
3
OBJECTIVES ........................................................................................................14
3.1
Primary...................................................................................................................14
3.2
Secondary...............................................................................................................14
4
ENDPOINTS..........................................................................................................15
4.1
Primary Endpoints..................................................................................................15
4.1.1
Dose-limiting Toxicity.............................................................................................15
4.1.2
Residual Cancer Burden.........................................................................................15
4.2
Secondary Endpoints ..............................................................................................15
4.2.1
Pathological Complete Response, Primary Definition.............................................15
4.2.2
Objective Response Rate.........................................................................................15
4.2.3
Breast-conserving Surgery Rate..............................................................................16
4.2.4
Safety and Tolerability............................................................................................16
5
SAMPLE SIZE AND POWER...............................................................................19
6
STUDY PERIODS, TREATMENT REGIMENS AND POPULATIONS 
FOR ANALYSES ..................................................................................................21
6.1
Study Periods..........................................................................................................21
6.2
Treatment Regimens...............................................................................................22
6.3
Populations for Analyses ........................................................................................22
7
STATISTICAL ANALYSES..................................................................................23
7.1
General Methods ....................................................................................................23
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7.1.1
Adverse Events, Serious Adverse Events, Multiple events, and Immune-
Mediated Adverse Events........................................................................................24
7.1.1.1
Select Adverse Events (EU/ROW Submissions) .......................................................25
7.1.1.2
Other Events of Special Interest..............................................................................25
7.1.1.3
Immune-Mediated Adverse Events (US Submission)................................................25
7.1.2
Laboratory Tests.....................................................................................................26
7.2
Study Conduct........................................................................................................26
7.2.1
Relevant Protocol Deviations..................................................................................26
7.2.2
Accrual...................................................................................................................27
7.3
Study Population ....................................................................................................27
7.3.1
Subject Disposition.................................................................................................27
7.3.2
Demographics and Other Baseline Disease Characteristics....................................28
7.3.3
Medical History......................................................................................................28
7.3.4
Prior Therapy Agents .............................................................................................28
7.3.5
Physical Examinations............................................................................................28
7.3.6
Baseline Physical Measurements ............................................................................28
7.4
Extent of Exposure .................................................................................................29
7.4.1
Administration of Study Therapy.............................................................................29
7.4.2
Modifications of Study Therapy ..............................................................................30
7.4.2.1
Infusion Interruptions and Rate Changes................................................................31
7.4.3
Concomitant Medications.......................................................................................31
7.4.3.1
Immune modulating medication..............................................................................32
7.4.3.2
Subsequent Cancer Therapy ...................................................................................32
7.5
Efficacy..................................................................................................................33
7.5.1
Analysis of Residual Cancer Burden (RCB) ............................................................33
7.5.2
Analysis of Pathological Complete Response (pCR)................................................33
7.5.3
Analysis of Breast-Conserving Surgery (BCS) Rate ................................................33
7.5.4
Analysis of Objective Response Rate (ORR)............................................................34
7.6
Safety.....................................................................................................................35
7.6.1
Dose Limiting Toxicities (Safety Run-In Phase) ......................................................35
7.6.2
Deaths ....................................................................................................................35
7.6.3
Serious Adverse Events...........................................................................................35
7.6.4
Adverse Events Leading to Discontinuation of Study Therapy.................................35
7.6.5
Adverse Events Leading to Dose Modification........................................................36
7.6.6
Adverse Events .......................................................................................................36
7.6.7
Select Adverse Events (EU/ROW Submissions) .......................................................36
7.6.7.1
Incidence of Select AE ............................................................................................36
7.6.7.2
Time-to Onset of Select AE .....................................................................................37
7.6.7.3
Time-to Resolution of Select AE..............................................................................37
7.6.8
Immune-Mediated Adverse Events (US Submission)................................................38
7.6.9
Other Events of Special Interest..............................................................................38
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7.6.10
Adverse Events of pneumonitis and lung disease.....................................................39
7.6.11
Multiple Events.......................................................................................................39
7.6.12
Laboratory Parameters...........................................................................................39
7.6.12.1
Hematology ............................................................................................................39
7.6.12.2
Serum Chemistry ....................................................................................................40
7.6.12.3
Electrolytes.............................................................................................................40
7.6.12.4
Additional Analyses................................................................................................40
7.6.13
Vital Signs and Pulse Oximetry...............................................................................41
7.6.14
Physical Measurements ..........................................................................................41
7.6.15
Electrocardiograms (ECG) /ECHO or MUGA........................................................41
7.6.16
Non-Protocol Medical Procedures..........................................................................41
7.6.18
Pregnancy ..............................................................................................................42
7.6.19
Adverse Events by Subgroup (Randomized Phase only) ..........................................42
7.10
Analyses at the time of the decision for the dose level to be evaluated in the 
randomized phase. ..................................................................................................46
8
CONVENTIONS....................................................................................................47
APPENDIX 1
TIME-TO ONSET AND TIME-TO RESOLUTION DEFINITION 
AND CONVENTIONS FOR SELECT ADVERSE EVENTS, 
IMMUNE-MEDIATED ADVERSE EVENTS AND EVENTS OF 
SPECIAL INTEREST............................................................................49
APPENDIX 2
MISSING AND PARTIAL RADIOTHERAPY AND SURGERY 
DATES IMPUTATION ALGORITHMS ...............................................51
9
DOCUMENT HISTORY........................................................................................55
10
REFERENCES.......................................................................................................55
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LIST OF TABLES
Table 2.2-1:
Abemaciclib Dose Modifications for Adverse Reactions ........................12
Table 2.2-2:
Dose Levels for Palbociclib....................................................................13
Table 4.3.5.2-1:
PRO-CTCAE symptoms collected in CA209-7A8..................................18
Table 4.3.5.2-2:
Time Windows for FACIT GP5 and PRO-CTCAE Assessments ............19
Table 6.3-1:
Populations for Analyses ........................................................................23
Table 7.4.1-1:
Administration of study therapy: definition of parameters, IV 
therapy ...................................................................................................29
Table 7.4.1-2:
Administration of study therapy: definition of parameters, PO 
therapies in Randomized Phase...............................................................29
Table 8-1:
Derivation of clustered AE .....................................................................50
Table 9-1:
Document History ..................................................................................55
LIST OF FIGURES
Figure 2.1-1:
Study Design Schematic.........................................................................10
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1
BACKGROUND AND RATIONALE
CA2097A8 is an open-label, randomized, non-comparative Phase 2 study assessing 
nivolumab, plus abemaciclib (per original protocol) or palbociclib, and anastrozole as either 
concurrent or phased neoadjuvant treatment for men and postmenopausal women with primary 
breast cancer (BC) ≥2 cm that are estrogen receptor-positive (ER+) and human epidermal growth 
factor receptor 2-negative (HER2-) with safety run-in. As of Revised Protocol 03, abemaciclib 
related cohorts will no longer be investigated in this trial. 
Nivolumab (BMS-936558) is a fully human, IgG4 (kappa) isotype monoclonal antibody (mAb),
an immuno-oncologic (IO) checkpoint inhibitor that binds programmed cell death-1 (PD-1) on 
activated immune cells and disrupts engagement of the receptor with its ligands programmed 
death-ligand 1 (PD-L1; B7-H1/CD274) and programmed death-ligand 2 (PD-L2; B7-DC/CD273), 
thereby abrogating inhibitory signals and augmenting the host anti-tumor response. Abemaciclib 
and palbociclib are orally bioavailable and highly selective small-molecule inhibitors against 
cyclin-dependent kinases (CDK)4/cyclin-D1 and CDK6/cyclin-D3 enzyme complexes, lead to 
reactivation of retinoblastoma (Rb) protein, binding back of E2F transcription factor and 
subsequent cell cycle arrest, thus abrogating endocrine-resistant cell proliferation. Anastrozole is 
a reversible, third-generation, selective nonsteroidal aromatase inhibitor (NSAI) that reduces
peripheral estrogen synthesis by blocking the conversion of androgens to estrogens in non-ovarian 
tissues. A detailed description of the chemistry, pharmacology, efficacy, and safety of the study 
treatments is provided in the Investigator Brochures (IBs) and package inserts.
The study will assess the efficacy and safety of: i) concurrent therapy with nivolumab in 
combination with palbociclib, and anastrozole (Arm A), ii) phased therapy with one initial priming 
cycle of palbociclib and anastrozole followed by nivolumab in combination with palbociclib, and 
anastrozole (Arm B), and iii) control treatment with palbociclib and anastrozole (Arm C). 
Participants with newly diagnosed, previously untreated primary ER+ and HER2- BC ≥2 cm will 
be subjected to a total 5 cycles (4 weeks per cycle) of neoadjuvant therapy before definitive 
surgery. Efficacy will be measured by significantly improved residual cancer burden (RCB) 0-I 
rate. 
 
 
PD-1 pathway inhibition has demonstrated clinical activity across multiple tumor types, including
BC. An accumulating body of evidence supports PD-1/CDK4/6 blockade potential synergy, as it 
has become more apparent that CDK4/6 inhibitors modulate the tumor immune microenvironment 
(ie, increases expression of PD-L1, enhances antigen presentation and secretion of cytokines from 
both tumor and CD8+ T cells, and suppresses proliferation of immunosuppressive regulatory 
T cells [Tregs]). Preliminary clinical data in support of synergistic activity of the combination of 
pembrolizumab and abemaciclib has been demonstrated in a Phase 1b study on heavily pretreated 
participants with metastatic hormone receptor-positive (HR+), HER2- BC. Clinical data on 
combinations of other CDK4/6 inhibitors with PD-(L)1 blocking agents are being generated in 
multiple clinical trials spanning from the neoadjuvant to metastatic setting (ClinicalTrials.gov: 
NCT03573648, NCT02778685, NCT03294694). Additional treatment benefit (improved anti-
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tumor efficacy and complete tumor regression) was observed in a syngeneic mouse tumor model
by priming the anti-cancer immune response with abemaciclib in a phased administration of 
abemaciclib and an anti-PD-L1 therapy. Therefore, an additional phased therapy arm has been 
added for each CDK4/6 inhibitor to explore possible treatment benefit in patients.
The aim of the CA2097A8 study is to assess the potential synergistic activity of nivolumab, with
palbociclib, and anastrozole in participants with newly diagnosed, previously untreated primary 
ER+, HER2- BC ≥2 cm, defined by significantly improved RCB (0-I) rate.
 
 
 
Additional objectives of the study include characterization of safety and 
tolerabilit
 
. 
 
Research Hypothesis:  
The combination of nivolumab, with palbociclib, and anastrozole is a safe and effective 
neoadjuvant treatment for patients with ER+, HER2- primary BC ≥2 cm.
Schedule of Analyses:
An analysis will be conducted when enrollment to the safety run-in phase is completed and all 
patients have completed at least one cycle of study treatment (1 cycle = 4 weeks) and have been 
followed up for an additional 4 weeks or discontinued from the study prior to that in order to 
support the dose selection for the randomized phase.
Final analysis will be conducted when all participants in the Randomized Phase are treated and 
evaluated in terms of RCB and pCR and completed the study, including the follow up phase, or 
discontinued from the study prior to that.
2
STUDY DESCRIPTION
2.1
Study Design
This randomized, open-label Phase 2 study was to evaluate whether the combination of nivolumab,
with abemaciclib or palbociclib, plus anastrozole is a safe and effective neoadjuvant treatment for
men and postmenopausal women with primary BC ≥2 cm that is ER+ and HER2- subtype who
are suitable to receive NET and willing to undergo SOC breast surgery after completion of the
study treatment.
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At implementation of Revised Protocol 03, the study will only evaluate whether the combination 
of nivolumab, with palbociclib, plus anastrozole is a safe and effective neoadjuvant treatment for 
men and postmenopausal women with primary BC ≥2 cm that is ER+ and HER2- subtype who 
are suitable to receive NET and willing to undergo SOC breast surgery after completion of the 
study treatment. Participants must have histologically confirmed invasive breast carcinoma 
meeting the characteristics described in Section 6.1 of protocol (Inclusion Criteria). Participants 
in screening and not yet treated were offered the option to join the safety lead-in of the nivolumab 
+ palbociclib + anastrozole arm. Participants on treatment with nivolumab + abemaciclib + 
anastrozole were to be re-consented and continue on anastrozole alone, or taken off study. In 
addition, baseline chest Xray and periodic pulse oximetry were implemented to monitor 
ILD/pneumonitis in patients who will be treated with nivolumab + palbociclib + anastrozole.
The study is divided into 3 periods: Screening Period, On-treatment Pre-surgery (neoadjuvant) 
Period (Safety Run-in Phase and Randomized Phase), and Safety Follow-up Period.
The study will start with a Safety Run-in Phase for the combination of nivolumab, with 
abemaciclib or palbociclib, plus anastrozole and will begin the Randomized Phase after the 
regimen is determined to be safe. Participant assignment will be carefully managed by the study 
team with the Investigator in the Safety Run-in Phase to ensure equal distribution of participants 
in both cohorts (abemaciclib or palbociclib). The abemaciclib cohort (cohort 1) was closed after 
two participants were dosed per Revised Protocol 03. No further investigation of abemaciclib 
related arms is planned in the Randomized Phase. Participants in the Safety Run-in Phase will 
move to the Safety Follow-up Period upon completion of the neoadjuvant treatment or upon 
discontinuation. Potential needs for additional enrollment or for dose de-escalation will be 
discussed with Investigators and BMS during the Safety Run-in Phase. Once a safe dose for each 
regimen has been determined by BMS in collaboration with Investigators, the Randomized Phase 
of the study will begin.
In the Randomized Phase, participants will be randomly assigned by an IRT system to 3 different 
treatment arms and stratified by the following factors: 
 
 2) evaluation of lymph nodes (cytologically positive vs radiologically or 
cytologically negative); and 3) tumor size (> 3 cm or ≤3 cm).
For both the Safety Run-in Phase and Randomized Phase, participants will be treated for a 
maximum of 5 cycles (1 cycle = 4 weeks). Participants with progressive disease prior to 
completion of the 5-cycle study treatment must discontinue all study drugs and proceed to the 
Safety Follow-up Period. Participants who permanently discontinue the study drugs for any reason 
are considered to have completed the On-treatment Pre-surgery (neoadjuvant) Period, and hence 
reach end of treatment (EOT). After Cycle 5 or EOT, participants must continue to receive 
anastrozole (as concomitant medication and not as study treatment) until subsequent SOC breast 
surgery. Following the completion of neoadjuvant treatment, all participants who remain operative 
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candidates will undergo definitive surgery for BC within 4 weeks of the last neoadjuvant treatment 
administration. If anastrozole can no longer be administered after EOT, participants will go to 
breast surgery right away. Pre-surgical lymph node biopsy is not allowed. Information on the type 
of the surgery will be collected and recorded in the electronic case report form (eCRF). Surgical 
specimens will be collected for the analyses outlined in the protocol. Depending on treatment 
assignment, up to 2 safety follow-up visits will be conducted in person. The first safety follow-up 
visit (FU1) will be completed for all participants within 30 days (± 7 days) from the last study 
treatment (oral or intravenous [IV], whichever occurs later). The second safety follow-up visit 
(FU2) will occur approximately within 100 days (± 7 days) from the last dose of nivolumab and 
will be required for participants in the Safety Run-in Phase and participants randomized to Arms 
A and B in the Randomized Phase. Further planned treatment of participants in the adjuvant setting 
(i.e., radiotherapy, endocrine treatment, chemotherapy or any other treatment modality) will be at 
the discretion of the treating physician, following local clinical guidelines, and collected in the 
appropriate eCRF. The study design schematic is presented in Figure 2.1-1.
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Figure 2.1-1:
Study Design Schematic
Abbreviations: Abema = abemaciclib; ANZ = anastrozole; BID = twice daily; cm = centimeter; ECOG = Eastern Cooperative Oncology Group; 
ER+ = estrogen-receptor-positive; FU1 = follow-up visit 1; FU2 = follow-up visit 2; HER2- = human epidermal growth factor receptor 2-negative; 
IV = intravenous; mg = milligram; N = number; Nivo = nivolumab; Palbo = palbociclib; 
 PO = per os (by mouth); 
PS = performance status; Q4W = every 4 weeks; QD = once daily; Rand = randomized; wk = week.
a FU1 begins at the end of study treatment.
b Cytologically positive vs radiologically or cytologically negative.
Screening Period
Pre-surgery Treatment Period (N = 115~136)
Surgery
Safety Follow-up Period
Key Inclusion 
Criteria
• Newly diagnosed,
histologically
proven ER+,
HER2- primary
breast cancer
≥ 2 cm
• Men and
postmenopausal
women
• ECOG PS 0-1
Safety Run-in Phase
(3 + 3 Approach)
(n = 3~24)c
Randomized Phase
(n = 110)d
FU1a
(All Participants in he 
Safety Run-in Phase and 
the Randomized Phase)
FU2
(All Participants in the 
Safety Run-in Phase and 
Arms A and B Only in 
the Randomized Phase)
Investigator’s Choice
Cohort 1 (n = 3~24)
Nivo 480 mg Q4W IV
+ Abema 150 mg BID PO
+ ANZ 1 mg QD PO
x 5 cycles
Cohort 2 (n = 3~24)
Nivo 480 mg Q4W IV
+ Pa bo 125 mg QD PO
3 wks on 1 wk off
+ ANZ 1 mg QD PO
x 5 cycles
Arm A (n = 40)
Nivo 480 mg Q4W IV + Palbo 125 mg QD PO 3 wks on 
1 wk off + ANZ 1 mg QD PO x 5 cycles
Arm B (n = 40)
Palbo 125 mg QD PO 3 wks on 1 wk off + ANZ 1 mg 
QD PO x 1 cycle THEN Nivo 480 mg Q4W IV + Palbo
125 mg QD PO 3 wks on 1 wk off + ANZ 1 mg QD PO 
x 4 cycles
Arm C (n = 30)
Palbo 125 mg QD PO 3 wks on 1 wk off + ANZ 1 mg 
QD PO x 5 cycles
Rand
4:4:3
Surgery
Surgery
Surgery
30-Day Safety 
Follow-up
100-Day Safety
Follow-up
(from last Nivo dose)
30-Day Safety
Follow-up
100-Day Safety
Follow-up
(from last Nivo dose)
30-Day Safety 
Follow-up
Stratify Randomized 
Phase Participants by:
•
Node (+ or -)b
•
Tumor size
(> 3 cm or ≤ 3 cm)
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c At the time of Revised Protocol 03, 2 participants had been treated in Cohort 1 (nivolumab + abemaciclib + anastrozole), which was subsequently closed for 
enrollment.
d At time of Revised Protocol 03, the decision was made to no longer evaluate abemaciclib in combination with nivolumab plus anastrozole; thus, the abemaciclib-
containing combination arms have been removed from the Randomization Phase of the study.
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2.2
Treatment Assignment
CA2097A8 is an open-label, randomized trial. After the participant’s initial eligibility is 
established and informed consent has been obtained, the participant must be enrolled into the study
by calling the IRT to obtain a participant number. Every participant that signs the informed consent 
form must be assigned a participant number in IRT. 
Safety Run-in Phase
Participants will receive either abemaciclib in combination with nivolumab plus anastrozole 
(Cohort 1) or palbociclib in combination with nivolumab plus anastrozole (Cohort 2). Participant 
assignment will be carefully managed by the study team with the Investigator in the Safety Run-
in Phase to ensure equal distribution of participants in both cohorts (abemaciclib or palbociclib).
As per Revised Protocol 03, Cohort 1 (abemaciclib + nivolumab + anastrozole) was closed 
permantely. For cohort 2, 3 DLT-evaluable participants will be treated with the below starting 
doses:
•
Nivolumab: 480 mg every 4 weeks (Q4W) intravenously (IV)
•
Palbociclib 125 mg (once daily; QD) PO for 3 weeks of each cycle (1 week off)
•
Anastrozole: 1 mg QD PO
If any DLT evaluable participants experiences DLT during DLT period, a lower dose of
Palbociclib will be tested using a 3 + 3 schema. If no participants (0 of 3 DLT-evaluable 
participants) experience a DLT during the DLT period (4 weeks), the Randomized Phase will be 
initiated at this dose level. If 1 evaluable participant (1 of 3 DLT-evaluable participants) 
experiences DLT, then the cohort will be expanded to 6 DLT-evaluable participants. If no more 
DLTs are observed (1 of 6 DLT-evaluable participants), then the Randomized Phase will be 
initiated at the dose level tested. If 1 or more additional evaluable participants (2 of 6 DLT-
evaluable participants) experiences DLT during the DLT period, a lower dose will be tested using 
the same 3 + 3 schema.
The recommended abemaciclib dose modifications for adverse reactions are provided in Table 2.2-
1. Discontinue abemaciclib for participants unable to tolerate 50 mg BID.
Table 2.2-1:
Abemaciclib Dose Modifications for Adverse Reactions
Dose Level
Abemaciclib Dose Combination with an Aromatase Inhibitor
Recommended starting dose
150 mg BID
First dose reduction
100 mg BID
Second dose reduction
50 mg BID
Third dose reduction
NA
Abbreviations: BID = twice daily; NA = not applicable.
The dose modifications permitted for palbociclib in combination with anastrozole are based on the 
dose level changes outlined in Table 2.2-2.
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Table 2.2-2:
Dose Levels for Palbociclib
Dose Level
Oral Dose
Frequency
Starting dose
125 mg
QD × 3 weeks on (1 week off)
First dose reduction
100 mg
QD × 3 weeks on (1 week off)
Second dose reduction
75 mg
QD × 3 weeks on (1 week off)
Third dose reduction
Discontinue
Not applicable
Abbreviations: mg = milligram; QD = once daily.
Randomized Phase
Once enrolled in IRT, enrolled participants who have met all eligibility criteria will be ready to be 
randomized through IRT in a 4:4:3 ratio to treatment Arm A, B or C, respectively.
1) Arm A
(concurrent palbociclib treatment arm): nivolumab 480 mg Q4W IV + 
palbociclib 125 mg QD PO for 3 weeks (1 week off) + anastrozole 1 mg QD PO for 5 cycles
2) Arm B (phased palbociclib treatment arm):
a) palbociclib 125 mg QD PO for 3 weeks of each cycle (1 week off) + anastrozole 1 mg QD 
PO for 1 cycle followed by
b) nivolumab 480 mg Q4W IV + palbociclib 125 mg QD PO for 3 weeks (1 week off) + 
anastrozole 1 mg QD PO for 4 cycles
3) Arm C (control palbociclib arm): palbociclib 125 mg QD PO for 3 weeks of each cycle (1 
week off) + anastrozole 1 mg QD PO for 5 cycles
The randomization will be stratified by the following factors:
•
Evaluation of lymph nodes (cytologically positive vs radiologically or cytologically negative)
•
Tumor size (> 3 cm or ≤3 cm)
The exact procedures for using the IRT will be detailed in the IRT manual.
2.3
Blinding and Unblinding
This is an open-label study. Blinding procedures between participants and investigators are not 
applicable. 
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2.4
Protocol Amendments
Document
Date of Issue
Summary of Change
Revised 
Protocol 03
13-Mar-2020
Closed the abemaciclib safety run-in Cohort 1 and removed the 
abemaciclib-containing combinations from the randomization phase.
Removed eligibility criteria based on RECIST 1.1 as it has been covered by 
inclusion criteria 2.a.i. Added further instructions on unidimensional 
measurement for response assessment using ultrasound and mammogram as 
modifications.
Incorporated Administrative Letter 01 and Germany specific amendment.
Revised 
Protocol 02
24-Jul-2019
Added men, additional dose-limiting toxicity (DLT) criteria, and early 
study termination criteria. Updated definition of DLT, inclusion/exclusion 
criteria, and dose modifications.
Revised 
Protocol 01
12-Jun-2019
Decreased and clarified the frequency of assessments and sample 
collections, clarified participant eligibility and stratification, and reduced 
the dose-limiting toxicity period. These changes were made to reduce 
participant burden and increase overall feasibility of the study.
Original 
Protocol
02-May-2019
Not applicable
3
OBJECTIVES
3.1
Primary
Safety Run-in Phase: Number of participants with occurrence of DLT. 
Randomized Phase: To assess RCB 0-I rate by central assessment of palbociclib plus anastrozole 
with or without nivolumab in all participants with untreated primary BC ≥ 2 cm (ER+, HER2-).
3.2
Secondary
•
To assess the safety and tolerability of palbociclib plus anastrozole with or without nivolumab. 
•
To assess pCR rate by local assessment of palbociclib plus anastrozole with or without 
nivolumab in participants with untreated primary BC ≥ 2 cm (ER+, HER2-)
•
To assess ORR (clinical and radiological [ultrasound (preferred) or mammography]) by 
Investigator assessment and BCS rate of palbociclib plus anastrozole with or without 
nivolumab in participants with untreated primary BC ≥ 2 cm (ER+, HER2-)
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4
ENDPOINTS
4.1
Primary Endpoints
4.1.1
Dose-limiting Toxicity 
Dose-limiting Toxicity (DLT) is defined as treatment-emergent adverse event (TEAE, graded 
according to the NCI CTCAE v5.0) that occurs during the first 4 weeks after treatment start and 
that meets specific criteria. 
4.1.2
Residual Cancer Burden
Residual Cancer Burden (RCB) is a continuous index combining pathological measurements of 
primary tumor (size and cellularity) and nodal metastases (number and size) defined by a point 
system at surgery (refer to Appendix 7 of protocol [RCB Methods]). RCB is assessed by central 
assessment at the time of definitive surgery. RCB 0-I rate is defined as number of randomized 
subjects who achieve a RCB 0 or RCB I divided by the number of all randomized subjects. 
4.2
Secondary Endpoints
4.2.1
Pathological Complete Response, Primary Definition
Pathological Complete Response (pCR) is defined as the absence of residual invasive cancer on 
hematoxylin and eosin evaluation of the complete resected breast specimen and all sampled 
regional lymph nodes following completion of neoadjuvant systemic therapy (ie, ypT0/Tis ypN0 
in the current AJCC staging system). Pathological complete response is assessed by the local 
pathologist at the time of definitive surgery. The pCR rate is defined as number of randomized 
subjects who achieve a pCR divided by the number of all randomized subjects. 
4.2.2
Objective Response Rate
Objective Response Rate (ORR) is defined as the number of randomized subjects who achieve a 
best response of complete response (CR) or partial response (PR) based on investigator 
assessments (using RECIST v1.1 criteria, by clinical or radiological) divided by the number of all 
randomized subjects. Best Overall Response (BOR) is defined as the best response, as determined 
by the investigator (using RECIST v1.1 criteria, by clinical or radiological), recorded between the 
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date of randomization and the date of objectively documented progression per RECIST v1.1
criteria, the date of surgery, or date of subsequent therapy, whichever occurs first. For subjects 
without documented progression or subsequent therapy before surgery, all available pre-surgery 
response designations will contribute to the BOR determination. Confirmation of response is not 
required due to the limited number of planned tumor measurement before surgery.
4.2.3
Breast-conserving Surgery Rate
Breast-conserving Surgery (BCS) rate is defined as the number of randomized subjects who 
undergo BCS after completing the study treatments divided by the number of all randomized 
subjects. 
4.2.4
Safety and Tolerability
Other safety endpoints will include the incidence of deaths, adverse events, serious adverse events, 
adverse events leading to discontinuation, immune-related adverse events and specific laboratory 
abnormalities (worst grade) in each treatment group. Toxicities will be graded using the National 
Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. 
See details in the IO Core SAP1.
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5
SAMPLE SIZE AND POWER
A total of approximately 115~136 participants will be treated in the study. Before randomization, 
approximately 3~24 participants will be treated in the Safety Run-in Phase in each cohort (Cohort 
1: nivolumab + abemaciclib + anastrozole for 5 cycles; n = 3∼6 per dose level of abemaciclib, and 
Cohort 2: nivolumab + palbociclib + anastrozole for 5 cycles; n = 3∼6 per dose level of 
palbociclib). At the time of Revised Protocol 03, 2 participants had been treated in Cohort 1 which 
was subsequently closed for enrollment. Approximately 110 participants are planned to be 
randomized in this study at a 4:4:3 ratio into Arm A (nivolumab + palbociclib + anastrozole for 5 
cycles; n = 40), Arm B (palbociclib + anastrozole for 1 cycle, followed by nivolumab + palbociclib 
+ anastrozole for 4 cycles; n = 40), and Arm C (palbociclib + anatrozole for 5 cycles; n = 30), 
respectively. No stratification variables will be included for formal analysis; however, participants 
will be stratified 
 node status, and tumor size 
for enrollment 
.
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6
STUDY PERIODS, TREATMENT REGIMENS AND POPULATIONS FOR 
ANALYSES
6.1
Study Periods
•
Baseline period:
−
Baseline evaluations or pre-treatment events will be defined as evaluations or events that 
occur before the date and time of the first dose of study treatment. Evaluations (laboratory 
tests, pulse oximetry, vital signs
) on the same date and time of the first 
dose of study treatment will be considered as baseline evaluations. Events (AEs) on the 
same date and time of the first dose of study treatment will not be considered as pre-
treatment events.
−
In cases where the time (onset time of event or evaluation time and dosing time) is missing 
or not collected, the following definitions will apply:
♦Pre-treatment AEs will be defined as AEs with an onset date prior to but not including 
the day of the first dose of study treatment;
♦Baseline evaluations (laboratory tests, pulse oximetry, vital signs
) will 
be defined as evaluations with a date (and time if collected) on or prior to the date of 
first dose of study treatment.
−
If there are multiple valid observations in the baseline period, then the latest non missing 
observation will be used as the baseline in the analyses. If multiple observations exist on 
the latest collection date (and time if collected), the record with the latest data entry date 
and time will be used. If multiple observations exist on the latest collection date (and time 
if collected) and data entry date and time, then the first observation is used as baseline, 
unless otherwise specified.
♦Refer to the study-specific protocol for potential additional baseline evaluations 
definition such as baseline tumor evaluation, etc.
•
Post baseline period:
−
On-treatment AEs will be defined as AEs with an onset date and time on or after the date 
and time of the first dose of study treatment (or with an onset date on or after the day of 
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first dose of study treatment if time is not collected or is missing). For subjects who are off 
study treatment, AEs will be included if event occurred within a safety window of 30 days 
(or 100 days depending on the analysis) after the last dose of study treatment. No 
“subtracting rule” will be applied when an AE occurs both pre-treatment and post-
treatment with the same preferred term and grade.
−
On-treatment evaluations (laboratory tests, pulse oximetry and vital signs) will be defined 
as evaluations taken after the day (and time, if collected and not missing) of first dose of 
study treatment. For subjects who are off study treatment, evaluations should be within a 
safety window of 30 days (or 100 days depending on the analysis) after the last dose of 
study treatment.
•
6.2
Treatment Regimens
Treatment group in Safety Run-in Phase (Align with IRT Data Specification):
Cohort 1 Dose Level 1: Nivo 480mg Q4W + Abema 150mg BID + Anast 1mg QD
Cohort 2 Dose Level 1: Nivo 480mg Q4W + Palbo 125mg QD + Anast 1mg QD
Cohort 2 Dose Level 2: Nivo 480mg Q4W + Palbo 100mg QD + Anast 1mg QD
Cohort 2 Dose Level 3: Nivo 480mg Q4W + Palbo 75mg QD + Anast 1mg QD
Cohort 2 Dose Level 4: Nivo 480mg Q4W + Anast 1mg QD
Treatment group in Randomized Phase (Align with IRT Data Specification): 
A: Nivo + Palbo + Anast for 5 cycles
B: Palbo + Anast for 1 cycle + Nivo 4 cycles
C: Palbo + Anast for 5 cycles
Treatment group “as randomized” corresponds to the treatment group assigned by the Interactive 
Response Technology (IRT) system.
The treatment group “as treated” will be same as the treatment group “as randomized” by IRT 
unless a subject received the incorrect study treatment for the entire period of treatment, in which 
case the subject’s treatment group “as treated” will be defined as the incorrect study treatment.
Unless otherwise specified, the safety analysis will be based on the treatment group “as treated”.
Unless otherwise specified, the efficacy analysis will be based on the treatment group “as 
randomized”.
6.3
Populations for Analyses
Populations for purposes of analysis are defined in Table 6.3-1 below.
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Table 6.3-1:
Populations for Analyses
Population
Description
All Enrolled
All participants who signed an ICF and were registered into the IRT.
All Randomized
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 primary efficacy analyses.
All Treated
All randomized participants who receive 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 Treated from 
Safety Run-in Phase
All enrolled participants who received at least 1 dose of study drug in the Safety Run-
in Phase. Participants are grouped within the All Treated from Safety Run-in Phase 
population according to the treatment and dose level they actually received. This is 
part of the analysis set for all safety analysis and study drug administration. 
All DLT-Evaluable 
All participants treated in Safety Run-in Phase who have discontinued due to a DLT 
or who have received 1 dose of nivolumab and 75% of accumulative doses of 
abemaciclib or palbocicllib of the cycle, and have completed the 4-week DLT period.
All RCB Evaluable
All Treated participants who have an RCB of 0, I, II, or III from both the Safety 
Run-in Phase and Randomized Phase.
7
STATISTICAL ANALYSES
7.1
General Methods
Unless otherwise noted, discrete variables will be tabulated by the frequency and proportion of 
subjects falling into each category, grouped by treatment. Percentages given in these tables will be 
rounded to the first decimal and, therefore, may not always sum to 100%. Percentages less than 
0.1 will be indicated as ‘< 0.1’. Continuous variables will be summarized by treatment group using 
the mean, standard deviation, median, minimum, and maximum values.
Time-to-event variables (e.g. time-to resolution) will be analyzed using the Kaplan-Meier 
technique. When specified, the median will be reported along with 95% CI using Brookmeyer and 
Crowley method2 (using log-log transformation for constructing the confidence intervals3).
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The conventions to be used for imputing missing and partial dates for analyses requiring dates are 
described in Section 8.
7.1.1
Adverse Events, Serious Adverse Events, Multiple events, and Immune-
Mediated Adverse Events
Drug-related AEs are those events with relationship to study drug “Related”, as recorded on the 
CRF. If the relationship to study drug is missing, the AE will be considered as drug-related. 
Serious adverse events consist of AEs deemed serious by the Investigator and flagged accordingly 
in the CRF and clinical database.
Adverse events leading to study drug discontinuation are AEs with action taken regarding study 
drug(s) = “Drug was discontinued”. 
Adverse events that led to dose interruption of the drug will be coded with action “Drug was 
interrupted”.
Adverse events that led to dose omission of the drug will be coded with action “Dose was omitted”.
Adverse events leading to dose reduction are AEs with action taken regarding study drug(s) = 
“Dose was reduced”.
Adverse events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA), 
and the most recent version of the dictionary at the time of the database lock will be used. Adverse 
event results will be graded for severity using the NCI Common Terminology Criteria for Adverse 
Events (CTCAE) and the version of the criteria specified in the protocol will be used.
In the AE summary tables, unless otherwise specified, subjects will be counted only once at the 
Preferred Term (PT), only once at the System Organ Class (SOC), and only once at subject level 
for the counting of total number of subjects with an AE. The AE tables will be sorted by the SOCs 
and then PTs. SOC will be ordered by descending frequency overall and then alphabetically. PTs 
will be ordered within SOC by descending frequency overall and then alphabetically. The sorting 
will be done based on the ‘Any Grade’ column of the experimental arm when arms are presented 
side-by-side.
Unless otherwise specified, the AE summary tables will be restricted to on-treatment events 
regardless of the causality.
Analyses that take into account the multiple occurrences of a given adverse event will be conducted 
(see Section 7.6.11). To prepare these analyses, the CRF data will be processed according to 
standard BMS algorithms4 in order to collapse adverse event records into unique records based on 
the preferred term. These data will be presented as the rate per 100 person-years of exposure. These 
analyses will take into account all on-treatment events (allowing more than 1 event per subject) 
and the total exposure time. The person-year exposure will be computed as the sum over the 
subjects’ exposure expressed in years where the exposure time is defined as 
•
Patients treated in Arm C of randomized phase: (Date of last dose of study treatment - date of 
first dose of study treatment + 31 days)/365.25, for subject who are off study treatment and 
were followed for at least 30 days after last dose of study treatment.
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•
Patients treated in Safety run-in phase and Arm A, B of randomized phase: (Date of last dose 
of study treatment - date of first dose of study treatment + 101 days)/365.25, for subject who 
are off study treatment and were followed for at least 100 days after last dose of nivolumab.
•
(Last known alive date - date of first dose of study treatment +1)/365.25, for subjects who are 
still on-treatment or who are off study treatment and were followed less than 30 days in Arm 
C (or 100 days in Arm A or B) after last dose of study treatment.
7.1.1.1
Select Adverse Events (EU/ROW Submissions)
The select Adverse Events (select AEs) consist of a list of preferred terms grouped by specific 
category (e.g. pulmonary events, gastrointestinal events categories, etc.). AEs that may differ from 
or be more severe than AEs caused by non-immunotherapies and AEs whose early recognition and 
management may mitigate severe toxicity are included as select AEs. Categories of select AEs 
may include subcategories (e.g. adrenal disorders, diabetes, pituitary disorders, and thyroid 
disorders are subcategories of the endocrine event category). 
The list of MedDRA preferred terms used to identify select adverse events is revisited quarterly 
and updated accordingly. The preferred terms used for the selection at the time of the database 
lock will be provided by categories/subcategories.
In addition to the frequency and worst severity of select AEs, time-to onset, time-to resolution,
and time-to resolution where immune modulating medication was initiated will be analyzed for 
each specific category/subcategory of drug-related select AEs when applicable.
Further details on the definitions time-to onset and time-to resolution are described in APPENDIX 
1.
7.1.1.2
Other Events of Special Interest
Other events of special interest (OEOSI) consist of a list of preferred terms grouped by specific 
category (e.g. Myositis Event, Myocarditis Event, Demyelination Event, Guillain-Barre 
Syndrome, Pancreatitis Event, Uveitis Event, Encephalitis Event, Myasthenic Syndrome, 
Rhabdomyolysis Event, Graft Versus Host Disease). The list of MedDRA preferred terms used to 
identify OEOSI is revisited quarterly and updated accordingly. The preferred terms used for the 
selection at the time of the database lock by categories will be provided.
7.1.1.3
Immune-Mediated Adverse Events (US Submission)
In order to further characterize AEs of special clinical interest, analysis of immune-mediated AEs 
(IMAE) will be conducted. IMAEs are specific events (or groups of PTs describing specific events) 
that include pneumonitis, diarrhea/colitis, hepatitis, nephritis/renal dysfunction, rash, endocrine 
(adrenal insufficiency, hypothyroidism/thyroiditis, hypothyroidism, thyroiditis, hyperthyroidism, 
diabetes mellitus, and hypophysitis), and other specific events, considered as potential immune-
mediated events by investigator that meet the definition summarized below: 
•
those occurring within 100 days of the last dose, 
•
regardless of causality,
•
treated with immune-modulating medication (of note, endocrine AEs such as adrenal 
insufficiency, hypothyroidism/thyroiditis, hypothyroidism, thyroiditis, hyperthyroidism, 
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diabetes mellitus, and hypophysitis are considered IMAEs regardless of immune-modulating 
medication use, since endocrine drug reactions are often managed without immune-modulating 
medication).
•
with no clear alternate etiology based on investigator assessment, or with an immune-mediated 
component.
The list of MedDRA preferred terms used to identify IMAEs is revisited quarterly and updated 
accordingly. The preferred terms used for the selection at the time of the database lock by 
categories will be provided.
7.1.2
Laboratory Tests
Clinical laboratory parameters (hematology, serum chemistry and electrolytes) will be evaluated.
Laboratory tests will be graded using the NCI Common Terminology Criteria, and the most recent 
version of the criteria at the time of the database lock will be used.
Clinical laboratory data will be first analyzed using International System of Units (SI). 
Analyses will be repeated using US conventional units if needed.
In the laboratory summary tables, unless otherwise specified, subjects will be counted only once 
for each lab parameter according to their worst on treatment CTC grade (worst being the highest 
CTC grade). The laboratory tables and listings will be sorted by laboratory category, laboratory 
subcategory and laboratory test code sequence number.
7.2
Study Conduct
Unless otherwise specified, the study conduct data will be presented by cohort and all treated 
subjects (for safety run-in phase), or by treatment arm and all randomized subjects (for 
randomized phase).
7.2.1
Relevant Protocol Deviations
The following programmable deviations will be considered as relevant protocol deviations and 
summarized by treatment group and overall in all treated subjects (for safety run-in phase) and in 
all randomized subjects (for randomized phase). Non-programmable relevant eligibility and on-
study protocol deviations, as well as significant (both programmable and non-programmable) 
eligibility and on-study protocol deviations will be reported through 
 listings.
Eligibility:
•
Subjects without measurable disease at baseline as per investigator, or with measurable 
baseline primary tumor of < 2 cm in largest diameter
•
Subjects with unknown or negative ER 
•
Subjects with unknown or positive HER2
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•
Subjects received any treatment, including radiotherapy, chemotherapy, and/or targeted 
therapy, administered for the currently diagnosed BC prior to enrollment.
•
Subjects with baseline ECOG performance status > 1
•
Subjects with misclassified stratification factor levels (IVRS vs clinical database; for 
randomized phase only) 
On-study:
•
Subjects receiving any concurrent anti-cancer therapy (chemotherapy, hormonal therapy, 
immunotherapy, standard or investigational agents for treatment of cancer) outside of the 
protocol-specified neoadjuvant therapy while on study.
•
Subjects whose “as treated” arm different than their as randomized arm (subjects who 
received the wrong treatment for the entire neoadjuvant treatment period, excluding the 
never treated)
7.2.2
Accrual
Enrollment by country and site, and enrollment by month will be summarized and listed for all 
enrolled subjects.
A by-subject listing of batch numbers for all treated subjects will be provided.
7.3
Study Population
Analyses in this section will be tabulated for all randomized subjects in randomized phase by 
treatment group as randomized; and for all treated subjects in Safety Run-in phase by cohort group, 
unless otherwise specified.
7.3.1
Subject Disposition
The total number of subjects enrolled (randomized or not randomized for randomized phase; 
treated or not treated for safety run-in phase) will be presented along with the reason for not being 
randomized/treated. This analysis will be performed on all enrolled subjects population only.
Number of subjects randomized but not treated along with the reason for not being treated will be 
tabulated by treatment group as randomized in randomized phase.
Number of subjects who discontinued study treatment along with corresponding reason will be 
tabulated by treatment group as treated. Reason for discontinuation will be derived from subject 
status CRF page. Number of subjects who did not receive surgery along with corresponding reason 
will be tabulated by treatment group as treated. Reason for not receiving surgery will be derived 
from subject status CRF page. This analysis will be performed only on all treated subjects 
population.
A by-subject listing for all treated subjects will be provided showing the subjects off treatment 
date, whether the subject continue in the treatment period/study along with the reason for going 
off treatment period/study, and whether subject received surgery along with the reason for not 
receiving surgery. A by-subject listing for all enrolled subjects will also be provided, showing 
whether the subject was randomized/treated
along with the reason for not being 
randomized/treated.
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7.3.2
Demographics and Other Baseline Disease Characteristics
The following demographic and baseline disease characteristics will be summarized and listed by 
treatment group as randomized (in randomized phase) or treatment group as treated (in safety run-
in phase):
•
Age (continuous)
•
Age categorization (< 65, ≥65 and < 75, ≥75 and < 85, ≥85, ≥75, ≥65)
•
Sex (Male vs. Female)
•
Race (White, Black or African American, Asian, American Indian or Alaska Native, Native 
Hawaiian or Other Pacific, Asian Indian, Chinese, Japanese, Malay, Asian Other, Other)
•
Ethnicity (Hispanic/Latino and Not Hispanic/Latino)
•
Country by geographic region
•
ECOG performance status (0, 1, >1)
•
Tumor size (> 3 cm or ≤ 3 cm) (randomized phase only)
•
Evaluation of lymph nodes (cytologically positive vs radiologically or cytologically negative)
(randomized phase only) 
Summary table (cross-tabulation) by treatment group for stratification factor (except for region)
will be provided to show any discrepancies between what was reported through IRT vs. other data 
sources at baseline. This summary will be performed based on all randomized subjects
(randomized phase only).
A listing of randomization scheme presenting randomized treatment group and as treated treatment 
group will be provided for all randomized subjects (randomized phase only).
A by-subject listing of FSH level and/or Estradiol level for female participants with age ≤ 55 will 
be provided to confirm menopause at screening.
7.3.3
Medical History
A by-subject listing of general medical history for all randomized subjects in the randomized phase 
and for all treated subjects in the Safety Run-in phase will be provided.
7.3.4
Prior Therapy Agents
•
Prior cancer therapy will be summarized by treatment group and overall.
•
Prior systemic cancer therapy will be summarized by treatment group and overall and listed by 
subject.
•
Prior radiotherapy and prior surgery related to other cancer will be listed by subject.
7.3.5
Physical Examinations
Subjects with abnormal baseline physical examination will be listed by subject.
7.3.6
Baseline Physical Measurements
Baseline physical measurements will be listed by subject.
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7.4
Extent of Exposure
Listings will include all available exposure data. Analyses will be performed by treatment group 
“as treated” in all treated subjects, unless otherwise specified.
7.4.1
Administration of Study Therapy 
The following parameters will be summarized (descriptive statistics) by treatment group (groups 
are also differentiated by phase: Safety Run-in Phase, Randomized Phase):
•
Time from randomization to first dose of study therapy (0 to 3 days, > 3 to 7, >7 to 14, >14 to 
21, >21 to 28, >28), for randomized phase only. 
•
The following parameters will be summarized (descriptive statistics) by study therapy and
treatment group:
•
Number of doses received (nivolumab, anastrozole, palbociclib and abemaciclib [for 
participants in cohort 1])
•
Cumulative dose
•
Relative dose intensity (%) using the following categories: < 50%; 50 - < 70%; 70 - < 90%; 
90 - < 110%; ≥110%
•
Average daily dose
Duration of study therapy will be summarized (descriptive statistics) by treatment group. 
A by-subject listing of dosing of study medication (record of study medication, infusion details,
and dose changes) will be also provided. 
Table 7.4.1-1:
Administration of study therapy: definition of parameters, IV 
therapy
Nivolumab
Dosing schedule per protocol
480 mg every 4 weeks
Dose
Dose (mg) is defined as Total Dose administered (mg). Dose administered 
in mg at each dosing date and weight are collected on the CRF.
Cumulative dose
Cum dose (mg is sum of the doses (mg) administered to a subject during 
the treatment period.
Relative dose intensity (%)
[Cum dose (mg)/((Last dose date - Start dose date + 28) x 480 / 28)] x 100
Duration of study therapy
Last dose date - Start dose date +1
Table 7.4.1-2:
Administration of study therapy: definition of parameters, PO 
therapies in Randomized Phase
Anastrozole
Abemaciclib
Palbociclib
Dosing schedule per 
protocol
1 mg QD
150a mg BID
125b mg QD × 3 weeks 
on and 1 week off
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Table 7.4.1-2:
Administration of study therapy: definition of parameters, PO 
therapies in Randomized Phase
Anastrozole
Abemaciclib
Palbociclib
Dose
Dose (mg) is defined as 
Total Dose administered 
(mg). Dose administered 
in mg at each dosing date 
and weight are collected 
on the CRF.
Dose (mg) is defined as 
Total Dose administered 
(mg). Dose administered 
in mg at each dosing date 
and weight are collected 
on the CRF.
Dose (mg) is defined as 
Total Dose administered 
(mg). Dose administered 
in mg at each dosing date 
and weight are collected 
on the CRF.
Cumulative dose
Cum dose (mg) is sum of 
the doses (mg) 
administered to a subject 
during the treatment 
period.
Cum dose (mg) is sum of 
the doses (mg) 
administered to a subject 
during the treatment 
period.
Cum dose (mg) is sum of 
the doses (mg) 
administered to a subject 
during the treatment 
period.
Average daily dose
(actual)
Cumulative dose in mg / 
duration of treatment in 
days
Cumulative dose in mg / 
duration of treatment in 
days
Cumulative dose in mg / 
duration of treatment in 
days
Average daily dose 
(planned)
1 mg
300c mg
93.75d mg (125 mg × 21 
days / 28 days)
Relative dose intensity 
(%)
(Actual average daily 
dose / planned average 
daily dose) × 100
(Actual average daily 
dose / planned average 
daily dose) × 100
(Actual average daily 
dose / planned average 
daily dose) × 100
Duration of treatment
Last dose date - Start dose 
date +1
Last dose date - Start dose 
date +1
Last dose date - Start dose 
date +8
a Scheduled dose of abemaciclib could be 150 mg, 100 mg or 50 mg BID depending on the dose cohort in safety run-
in phase and the recommended phase 2 dose (RP2D) identified from safety run-in phase which is applied in 
randomized phase. 
b Scheduled dose of palbociclib could be 125 mg, 100 mg or 75 mg QD × 3 weeks on (1 week off) depending on the 
dose cohort in safety run-in phase and RP2D in randomized phase.
c Planned average daily dose of abemaciclib could be 300 mg, 200 mg or 100 mg depending on the dose cohort in 
safety run-in phase and RP2D in randomized phase. 
d Planned average daily dose of palbociclib could be 93.75 mg, 75 mg or 56.25 mg depending on the dose cohort in 
safety run-in phase and RP2D in randomized phase.
7.4.2
Modifications of Study Therapy
Participants are to start nivolumab within 3 calendar days of randomization. Participants will 
receive nivolumab at a dose of 480 mg as a 30-minute IV infusion for a maximum of 5 cycles 
(maximum 4 cycles for Arm B). Doses of nivolumab may be interrupted, omitted, or discontinued, 
depending on how well the participant tolerates the treatment. There will be no dose escalations or 
reductions of nivolumab allowed. For Q4W dosing cycles, participants may be dosed within a ±
3-day window. If a participant cannot receive nivolumab within a ± 3-day window, nivolumab 
must be omitted (skipped) for that cycle. If nivolumab is omitted, the other study medications may 
continue. If a participant discontinues nivolumab, the entire study treatment (CDK4/6 inhibitor 
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and anastrozole) must be discontinued. When nivolumab is scheduled to be administered on the 
same day with palbociclib plus anastrozole, nivolumab dosing should be started > 1 hour after 
palbociclib plus anastrozole ingestion. If nivolumab cannot be given within 3 days of palbociclib 
plus anastrozole administration for a given cycle, nivolumab must be omitted for that cycle. 
Participants who require a dose omission for nivolumab should be re-evaluated and resume 
treatment at the next cycle when re-treatment criteria are met.
Palbociclib can be interrupted, reduced, or discontinued both within a cycle and between cycles.
No dose modification for anastrozole is listed per full prescribing information.
Dose escalations (within subject) are not permitted for any study drugs. 
Reason for dose modification will be retrieved from CRF dosing pages.
•
The following parameters will be summarized by treatment group:
•
Number of subjects with at least one dose modification (interrupted nivolumab dose, omitted 
nivolumab dose, interrupted palbociclib dose, reduced palbociclib dose). 
•
Number of nivolumab and/or palbociclib dose modifications per subject. 
•
Reason of nivolumab and/or palbociclib dose modification. 
7.4.2.1
Infusion Interruptions and Rate Changes
Each nivolumab infusion can be interrupted and/or the IV infusion rate can be reduced. This 
information will be retrieved from CRF dosing pages.
•
The following parameters will be summarized by treatment group:
•
Number of subjects with at least one dose infusion interruption, the reason for interruption, 
and the number of infusion interruptions per subject.
•
Number of subjects with at least one IV infusion rate reduction, the reason for reduction and 
the number of infusions with IV rate reduction per subject.
7.4.3
Concomitant Medications
Concomitant medications, defined as medications other than study medications which are taken at 
any time on-treatment (i.e. on or after the first day of study therapy and within 100 days following 
the last dose of nivolumab in Arm A, B and Safety Run-in cohorts; on or after the first day of study 
therapy and within 30 days following the last dose of study treatment in Arm C), will be coded 
using the UMC WHO Drug Global Dictionary. Anastrozole administered after completion of 5
cycles of neoadjuvant treatment (or EOT) up to subsequent breast surgery must be collected as 
concomitant medication.
The following summary table will be provided: 
•
Concomitant medications (subjects with any concomitant medication, subjects by medication 
class and generic term) 
A by-subject listing(s) will accompany the table(s).
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7.4.3.1
Immune modulating medication 
Immune modulating concomitant medications are medications entered on an immune modulating 
medication form or available from the most current pre-defined list of immune modulating 
medications. The list of anatomic class, therapeutic class and generic name used for the selection 
at the time of the database lock will be provided.
The percentage of subjects who received immune modulating concomitant medication for
•
management of adverse event 
•
premedication 
•
other use
•
any use
•
management of drug-related select adverse event (any grade, grade 3-5) by select AE category/ 
subcategory (EU/ROW Submissions)
•
management of IMAEs (any grade, grade 3-5) by IMAE category (US Submission)
will be reported separately for each treatment group (percentages of treated subjects by medication 
class and generic term).
For each category/subcategory of drug-related select AEs (any grade, grade 3-5) and IMAEs (any 
grade, grade 3-5), the following will be reported for each treatment group:
•
The total immune modulating medication treatment duration (excluding overlaps), duration of 
high dose of corticosteroid, initial dose of corticosteroid, and tapering duration (summary 
statistics)
Duration represents the total duration the subject received the concomitant medication of interest. 
If the subject took the medication periodically, then DURATION in the summation of all use. 
Initial dose represents the dose of the concomitant medication of interest received at the start of 
the event. In the case multiple medications started on the same date, the highest equivalent dose is 
chosen and converted to mg/kg by dividing by the subject’s recent weight.
These analyses, except the ones related to IMAEs will be conducted using the 30-day safety 
window. The analyses related to IMAEs will be conducted using the 100-day safety window.
7.4.3.2
Subsequent Cancer Therapy
Number and percentage of subjects receiving subsequent cancer therapies will be summarized for 
all treated subjects (in safety run-in period) and all randomized subjects (in randomized phase). 
Categories include: 
•
Subsequent systemic therapy
•
Subsequent surgery for treatment of tumors
•
Subsequent radiotherapy for treatment of tumors
A by-subject listing of subsequent therapies will also be produced.
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7.5
Efficacy
Analyses in this section will be tabulated for all randomized subjects by treatment group as 
randomized, unless otherwise specified.
CIs for all efficacy endpoints will be at the two-sided 95% level and two-sided 90% level. Point 
estimates and confidence bounds for efficacy variables will be rounded to the second decimal 
place.
•
A by-subject listing of efficacy results will be presented including treatment group, planned 
and actual surgery type, RCB, pCR, ORR, death date, etc. 
7.5.1
Analysis of Residual Cancer Burden (RCB)
The primary objective of the Randomized phase of the study is to estimate the RCB 0-I rate per 
central assessment in the treatment groups among all randomized subjects.
The number and percentage of subjects in each category of RCB per central assessment (0, I, II, 
III) will be presented, by treatment group. Estimates of RCB 0-I rate along with its exact two-sided 
95% and two-sided 90% CI by Clopper and Pearson5 will be presented, by treatment group. 
•
A by-subject listing of RCB will be presented including treatment group, RCB, randomization 
date, surgery date 
. 
7.5.2
Analysis of Pathological Complete Response (pCR)
One of the secondary objectives of the study is to estimate the pCR rate per local assessment in 
the treatment groups among all randomized subjects.
The number and percentage of subjects in each category of pathological response per local 
assessment (pCR, non-pCR) will be presented, by treatment group. Estimates of pCR rate along 
with its exact two-sided 95% CI by Clopper and Pearson5 will be presented, by treatment group.
•
A by-subject listing of pCR will be presented including treatment group, pCR, randomization 
date, surgery date 
. 
7.5.3
Analysis of Breast-Conserving Surgery (BCS) Rate
One of the secondary objectives of the study is to estimate the BCS rate in the treatment groups 
among all randomized subjects. 
The number and percentage of subjects in each category of planned surgery (breast-conserving, 
mastectomy) and actual surgery (breast-conserving, mastectomy) will be presented, by treatment 
group. BCS rate is defined as the number of participants who actually undergo BCS after 
completing the study treatment divided by the number of all randomized participants in each 
treatment group. Estimates of BCS rate along with its exact two-sided 95% CI by Clopper and 
Pearson5 will be presented, by treatment group.
•
A by-subject listing of planned and actual surgery will be presented including treatment group, 
randomization date, planned surgery type, actual surgery type, surgery date 
. 
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7.5.4
Analysis of Objective Response Rate (ORR)
One of the secondary objectives of the study is to estimate the ORR per investigator radiographic 
assessment in the treatment groups among all randomized subjects.
The number and percentage of subjects in each category of BOR per investigator assessment 
(complete response [CR], partial response [PR], stable disease [SD], progressive disease [PD], or 
not evaluable [NE]) will be presented, by treatment group. Estimates of response rate, along with 
its exact two-sided 95% and two-sided 90% CI by Clopper and Pearson5 will be presented, by 
treatment group. 
•
A by-subject listing of best overall response will be presented including treatment group, best 
overall response and dates of CR/PR/progression. 
•
A by-subject, by-visit, by-lesion listing of tumor assessment will be presented.
Similar analyses will be repeated based on the investigator clinical assessment of ORR. A by-
subject listing of per time point tumor response per clinical assessment will be presented.
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7.6
Safety
Analyses in this section will be tabulated for all treated subjects by treatment group as treated, 
unless otherwise specified.
7.6.1
Dose Limiting Toxicities (Safety Run-In Phase)
Dose limiting toxicities will be summarized by cohort and dose level. A corresponding by-subject 
listing will be provided for all treated subjects.
7.6.2
Deaths
Deaths will be summarized by treatment group:
•
All deaths, reasons for death.
•
Deaths within 30 days of last dose received, reasons for death.
•
Deaths within 100 days of last dose received, reasons for death.
A by-subject listing of deaths will be provided for all enrolled subjects population.
7.6.3
Serious Adverse Events
Serious adverse events will be summarized by treatment group:
•
Overall summary of SAEs by worst CTC grade (any grade, grade 3-4, grade 5) presented by 
SOC/PT.
•
Overall summary of drug-related SAEs by worst CTC grade (any grade, grade 3-4, grade 5) 
presented by SOC/PT.
•
All analyses will be conducted using the 30-day safety window. 
A by-subject SAE listing will be provided for the “enrolled subjects” population.
7.6.4
Adverse Events Leading to Discontinuation of Study Therapy
AEs leading to discontinuation will be summarized by treatment group:
•
Overall summary of AEs leading to discontinuation by worst CTC grade (any grade, grade 
3-4, grade 5) presented by SOC/PT.
•
Overall summary of drug-related AEs leading to discontinuation by worst CTC grade (any 
grade, grade 3-4, grade 5) presented by SOC/PT.
The analyses will be conducted using the 30-day safety window.
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A by-subject AEs leading to discontinuation listing will be provided.
7.6.5
Adverse Events Leading to Dose Modification
AEs leading to dose delay/reduction will be summarized by treatment group:
•
Overall summary of AEs leading to dose delay/reduction by worst CTC grade (any grade, 
grade 3-4, grade 5) presented by SOC/PT.
•
Overall summary of related AEs leading to dose delay/reduction by worst CTC grade (any 
grade, grade 3-4, grade 5) presented by SOC/PT.
The analysis will be conducted using the 30-day safety window.
A by-subject AEs leading to dose delay/reduction listing will be provided.
7.6.6
Adverse Events
Adverse events will be summarized by treatment group.
The following analyses will be conducted using the 30 days safety window only:
•
Overall summary of any AEs by worst CTC grade (1, 2, 3, 4, 5, not reported, total) presented 
by SOC/PT.
•
Overall summary of any AEs presented by worst CTC grade (any grade, grade 3-4, grade 5) 
by SOC/PT. This table will be restricted to events with an incidence greater or equal to 5% in 
any treatment group.
•
Overall summary of any non-serious AEs presented by SOC/PT. This table will be restricted 
to events with an incidence greater or equal to 5% in any treatment group.
•
Overall summary of any AEs that required immune modulating medication by worst CTC 
grade (any grade, grade 3-4, grade 5) presented by SOC/PT.
•
Overall summary of drug-related AEs by worst CTC grade (1, 2, 3, 4, 5, not reported, total) 
presented by SOC/PT. 
The following analyses will be conducted using the 30 days safety window and repeated using the 
100 days safety window:
•
Overall summary of drug-related AEs by worst CTC grade (any grade, grade 3-4, grade 5) 
presented by SOC/PT.
A by-subject AE listing will be provided. A by-subject listing of any AE requiring immune 
modulating medications will also be provided.
7.6.7
Select Adverse Events (EU/ROW Submissions)
Unless otherwise specified, analyses will be performed by select AE category. Analyses will also 
be repeated by subcategory of endocrine events.
7.6.7.1
Incidence of Select AE
Select AEs will be summarized by treatment group for each category/subcategory. 
The following analyses will be conducted using the 30-day safety window only:
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•
Overall summaries of any select AEs by worst CTC grade (any grade, grade 3-4, grade 5)
presented by Category or Subcategory/PT.
•
Overall summaries of any drug-related select AEs by worst CTC grade (any grade, grade 3-4, 
grade 5) presented by Category or Subcategory/PT.
•
Overall summaries of any serious select AEs by worst CTC grade (any grade, grade 3-4, grade 
5) presented by Category or Subcategory /PT.
•
Overall summaries of drug-related serious select AEs by worst CTC grade (any grade, grade 
3-4, grade 5) presented by Category or Subcategory /PT.
•
Overall summaries of any select AEs leading to discontinuation by worst CTC grade (any 
grade, grade 3-4, grade 5) presented by Category or Subcategory /PT.
•
Overall summaries of drug-related select AEs leading to discontinuation by worst CTC grade
(any grade, grade 3-4, grade 5) presented by Category or Subcategory /PT.
•
Summary of frequency of unique select AEs by Category.
A by-subject select AE listing will be provided.
7.6.7.2
Time-to Onset of Select AE
Time-to onset of drug-related select AEs (any grade, grade 3-5) will be summarized for each 
category/subcategory by treatment group.
Time-to onset analyses are restricted to treated subjects who experienced at least one drug-related 
select AE in the category/subcategory. The analyses will be conducted using the 30-day safety 
window.
Additional details regarding the time-to onset definition are described in time-to onset definition 
subsection of APPENDIX 1.
7.6.7.3
Time-to Resolution of Select AE
Time-to resolution of the following specific events will be summarized separately for each 
category/subcategory.
•
Time-to resolution of drug-related select AE (any grade, grade 3-5) by treatment group.
•
Time-to resolution of drug-related select AE (any grade, grade 3-5) where immune modulating 
medication was initiated, by treatment group.
Time-to resolution analyses are restricted to treated subjects who experienced the specific events. 
Time-to resolution where immune modulating medication was initiated analyses are restricted to 
treated subjects who experienced the specific events and who received immune modulating 
medication during the longest select AE.
The analyses will be conducted using the 30-day safety window.
The following summary statistics will be reported: percentage of subjects with resolution of the 
longest select AE, median time-to resolution along with 95% CI (derived from Kaplan-Meier 
estimation) and ranges.
See time-to resolution definition subsection of APPENDIX 1 for additional details.
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7.6.8
Immune-Mediated Adverse Events (US Submission)
IMAEs will be summarized by treatment group for each immune-mediated category / PT using the 
100-day safety window:
•
Overall summary of non-endocrine IMAEs by worst CTC grade (any grade, grade 3-4, grade 
5) where immune modulating medication was initiated presented by Category / PT.
•
Overall summary of endocrine IMAEs by worst CTC grade (any grade, grade 3-4, grade 5)
presented by Category / PT.
•
Overall summary of non-endocrine IMAEs leading to discontinuation by worst CTC grade 
(any grade, grade 3-4, grade 5) where immune modulating medication was initiated presented 
by Category / PT.
•
Overall summary of endocrine IMAEs leading to discontinuation by worst CTC grade (any 
grade, grade 3-4, grade 5) presented by Category / PT.
•
Overall summary of non-endocrine IMAEs leading to dose delay or reduction by worst CTC 
grade (any grade, grade 3-4, grade 5) where immune modulating medication was initiated 
presented by Category / PT
•
Overall summary of endocrine IMAEs leading to dose delay or reduction by worst CTC grade 
(any grade, grade 3-4, grade 5) presented by Category / PT.
•
Summaries of time-to onset and time-to resolution of non-endocrine IMAEs where immune 
modulating medication was initiated presented by Category.
•
Summaries of time-to onset and time-to resolution of endocrine IMAEs presented by Category.
A by-subject listing of IMAEs will be provided. By-subject listings of time-to resolution for 
longest IMAEs cluster (any grade and grade 3-5 in separate summaries) will also be provided. For 
new studies which collect investigator assessment of potential IMAE data, a by-subject listing of 
AEs considered as immune-mediated events per investigator but not qualified for IMAEs 
definition will also be provided.
In addition, for all nivolumab treated subjects who experienced at least one IMAE, the following 
data presentation will be provided:
•
Summary of subjects who were re-challenged with nivolumab by IMAE category, with 
extended follow-up.
•
Summary of subjects who were re-challenged with nivolumab by IMAE category, with 
extended follow-up.
For these, re-challenge is considered to have occurred when last nivolumab infusion was 
administered after the onset of an IMAE.
7.6.9
Other Events of Special Interest
OEOSI will be summarized by treatment group for each category.
The following analyses will be conducted using the 100-day safety window:
•
Overall summary of OEOSI by worst CTC grade (any grade, grade 3-4, grade 5) presented by 
Category / PT
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•
Overall summary of drug-related OEOSI by worst CTC grade (any grade, grade 3-4, grade 5)
presented by Category / PT
A by-subject listing of OEOSI will be provided.
7.6.10
Adverse Events of pneumonitis and lung disease
The following adverse events will be summarized by treatment group:
•
Interstitial Lung Disease 
•
Pneumonitis 
•
Immune-Mediated Pneumonitis
The following analyses will be conducted using the 100-day safety window:
•
Overall summary by worst CTC grade (any grade, grade 3-4, grade 5) presented by Category
/ PT
A by-subject listing will be provided.
7.6.11
Multiple Events
The following summary tables will be provided:
•
A table showing the total number and rate (exposure adjusted) of occurrences for all AEs. 
•
A table showing the total number and rate (exposure adjusted) of occurrences for AEs
occurring in at least 5% of subjects in any treatment group.
A listing displaying the unique instances of all AEs, i.e., after duplicates have been eliminated and 
overlapping and contiguous occurrences of the same event (i.e. same PT) have been collapsed will 
be provided. No formal comparisons will be made between treatment groups.
7.6.12
Laboratory Parameters
In the laboratory summary tables, unless otherwise specified, subjects will be counted only once 
for each lab parameter according to their worst on treatment CTC grade (worst being the highest 
CTC grade). The laboratory tables and listings will be sorted by laboratory category, laboratory 
subcategory and laboratory test code sequence number.
The analysis population for each laboratory test is restricted to treated subjects who underwent that 
laboratory test. Laboratory tests (in addition to the tests specified below) with CTC criteria 
collected in the specific studies may also be included in the summaries.
A by-subject listing of differences in categorization of SI and US laboratory test results will be 
provided.
The analyses will be conducted using the 30-day.
7.6.12.1
Hematology
The following will be summarized by treatment group as worst CTC grade on-treatment per 
subject and as shift table of worst on-treatment CTC grade compared to baseline CTC grade per 
subject: hemoglobin (HB), hematocrit, total leukocyte count (including differential), platelets, 
white blood counts (WBC), absolute neutrophils count (ANC) and lymphocyte count (LYMPH). 
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A by-subject listing of these laboratory parameters will be provided.
7.6.12.2
Serum Chemistry
The following will be summarized by treatment group as worst CTC grade on-treatment per 
subject: ALT, AST, alkaline phosphatase (ALP), lactate dehydrogenase (LDH), total bilirubin, 
creatinine, blood urea nitrogen (BUN) or serum urea, lipase and amylase. 
A by-subject listing of these laboratory parameters will be provided.
7.6.12.3
Electrolytes
The following will be summarized by treatment group as worst CTC grade on-treatment per 
subject and as shift table of worst on-treatment CTC grade compared to baseline CTC grade per 
subject: sodium (high and low), potassium (high and low), chloride (high and low), calcium (high 
and low), phosphorus (high and low), and Glucose Serum (fasting hyperglycemia and 
hypoglycemia regardless of fasting status).
A by-subject listing of these laboratory parameters will be provided.
7.6.12.4
Additional Analyses
In addition, further analyses on specific laboratory parameters will be performed by treatment 
group:
Abnormal Hepatic Function Test
The number of subjects with the following laboratory abnormalities from on-treatment evaluations 
will be summarized by treatment group:
•
ALT or AST > 3 x ULN, > 5 x ULN, > 10 x ULN and > 20 x ULN
•
Total bilirubin > 2 x ULN
•
ALP > 1.5 x ULN
•
Concurrent (within 1 day) ALT or AST > 3 x ULN and total bilirubin > 1.5 x ULN
•
Concurrent (within 30 days) ALT or AST > 3 x ULN and total bilirubin > 1.5 x ULN
•
Concurrent (within 1 day) ALT or AST > 3 x ULN and total bilirubin > 2 x ULN
•
Concurrent (within 30 days) ALT or AST > 3 x ULN and total bilirubin > 2 x ULN
A by-subject listing of these specific abnormalities will be provided.
Abnormal Thyroid Function Test
The number of subjects with the following laboratory abnormalities from on-treatment evaluations 
will be summarized by treatment group:
•
TSH value > ULN and
−
with baseline TSH value ≤ULN
−
with at least one FT3/FT4 test value < LLN within 2-week window after the abnormal TSH 
test
−
with all FT3/FT4 test values ≥ LLN within 2-week window after the abnormal TSH test
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−
with FT3/FT4 missing within 2-week window after the abnormal TSH test.
•
TSH < LLN and
with baseline TSH value ≥LLN
−
with at least one FT3/FT4 test value > ULN within 2-week window after the abnormal 
TSH test
−
with all FT3/FT4 test values ≤ ULN within 2-week window after the abnormal TSH test
−
with FT3/FT4 missing within 2-week window after the abnormal TSH test
A by-subject listing of these specific abnormalities will be provided.
7.6.13
Vital Signs and Pulse Oximetry
Vital signs and pulse oximetry (i.e. % oxygen saturation) collected on the CRF will be provided 
in separate listings.
7.6.14
Physical Measurements
Physical measurements will be listed by subject.
7.6.15
Electrocardiograms (ECG) /ECHO or MUGA
A by-subject listing of ECG abnormalities and the corresponding grading information will be 
provided. 
Normal ranges for ECG parameters
•
HR: 60 to 100 beats per minute
•
PR interval: 120-200 milliseconds
•
QRS complex: 80-100 milliseconds
•
QT interval: 390-450 milliseconds in men; 390-460 milliseconds in women
•
QTcB and QTcF: <= 430 milliseconds in men; <= 450 milliseconds in women
7.6.16
Non-Protocol Medical Procedures
Non-protocol medical procedures will be listed by subject.
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7.6.18
Pregnancy
Not applicable. This study allows only for women not of childbearing potential.
7.6.19
Adverse Events by Subgroup (Randomized Phase only)
Overall summary of any AEs and drug-related AEs by worst CTC grade (any grade, grade 3-4, 
grade 5) presented by SOC/PT and for each treatment group for the following subgroups:
•
Sex (Male vs. Female)
•
Race
•
Age (< 65 vs. 65 - < 75 vs. 75 - < 85 vs. ≥85 vs. ≥75 vs. ≥65)
•
Region (US/Canada, Europe, Rest of the World)
These analyses will be conducted using the 30-day safety window only.
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7.10
Analyses at the time of the decision for the dose level to be evaluated 
in the randomized phase.
At the time of the analysis for the selection of the dose to be evaluated in the randomized phase of 
the study (see paragraph Schedule of Analyses in Section 1 for the timing of the analysis), the 
following analyses will be produced using all available data from the safety run-in phase:
•
Summary and listing of the relevant protocol deviations during the safety run-in phase
•
Summaries and listings of subject disposition for each study period of the safety run-in phase
•
Summaries of demographic and baseline disease characteristics
•
Listing of medical history
•
Summaries and listings of prior therapy agents 
•
Listing of physical examinations
•
Summaries and listings of administration of study therapy
•
Summaries of modifications of study therapy
•
Summary and listing of concomitant medications
•
Summary and listing of dose-limiting toxicities
•
Summary and listing of deaths
•
Summaries of SAEs, drug-related SAEs, AEs leading to discontinuation, drug-related AEs 
leading to discontinuation, AEs leading to dose delay/reduction, drug-related AEs leading to 
dose delay/reduction, AEs, drug-related AEs, any select AEs, any non-endocrine and endocrine
IMAEs where immune modulating medication was initiated, OEOSI, AEs of Interstitial Lung 
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Disease (ILD), pneumonitis and immune-mediated pneumonitis. All these summaries will be 
presented by worst CTC grade (any grade, grade 3-4, grade 5) using the 30 days safety window.
•
Listing of AEs
•
Summary and listing of marked laboratory abnormalities in both US and SI units using the 30 
days safety window.
At the time of this analysis, the safety run-in phase will not be completed. A clinical study report 
may not be prepared at this point. For the analyses for the clinical study report, the full set of 
analyses for the safety run-in phase, as described in this statistical analysis plan, will be produced 
when all patients in the safety run in phase either completed the study duration or discontinued 
from it.
8
CONVENTIONS
The following conventions may be used for imputing partial dates for analyses requiring dates: 
•
For missing and partial adverse event onset dates, imputation will be performed using the 
Adverse Event Domain Requirements Specification6
•
For missing and partial adverse event resolution dates, imputation will be performed as follows 
(these conventions may change):
−
If only the day of the month is missing, the last day of the month will be used to replace 
the missing day. If the imputed date is after the death date or the last known alive date, then 
the latest known alive date or death date is considered as the resolution date. 
−
If the day and month are missing or a date is completely missing, it will be considered as 
missing.
•
Missing and partial non-study medication domain dates will be imputed using the derivation 
algorithm described in 4.1.3 of BMS Non-Study Medication Domain Requirements 
Specification7.
•
Missing and partial radiotherapy and surgery dates will be imputed using algorithm described 
in APPENDIX 2.
•
For death dates, the following conventions will be used for imputing partial dates:
−
If only the day of the month is missing, the 1st of the month will be used to replace the 
missing day. The imputed date will be compared to the last known alive date and the 
maximum will be considered as the death date. 
−
If the month or the year is missing, the death date will be imputed as the last known alive 
date. 
−
If the date is completely missing but the reason for death is present, the death date will be 
imputed as the last known date alive. 
•
For date of progression after start of study therapy, the following conventions will be used for 
imputing partial dates: 
−
If only the day of the month is missing, the 1st of the month will be used to replace the 
missing day. In case of the date of death is present and complete, the imputed progression
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date will be compared to the date of death. The minimum of the imputed progression date 
and date of death will be considered as the date of progression. 
−
If the day and month are missing or a date is completely missing, it will be considered as 
missing. 
•
For date of progression to prior therapies, the following conventions will be used for imputing 
partial dates: 
−
If only the day of the month is missing, the 1st of the month will be used to replace the 
missing day. 
−
If the day and month are missing or a date is completely missing, it will be considered as 
missing. 
•
For other partial/missing dates, the following conventions were used: 
−
If only the day of the month is missing, the 15th of the month will be used to replace the 
missing day. 
−
If both the day and the month are missing, “July 1” will be used to replace the missing 
information. 
−
If a date is completely missing, it will be considered as missing. 
The following conversion factors will be used to convert days to months or years: 
1 month = 30.4375 days and 1 year = 365.25 days.
Duration (e.g. time-to onset, time-to resolution) will be calculated as follows:
Duration = (Last date - first date + 1)
Last known alive date will be defined based on all appropriate dates collected on the CRF.
All statistical analyses will be carried out using SAS (Statistical Analysis System software, SAS 
Institute, North Carolina, USA) unless otherwise noted.
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APPENDIX 1
TIME-TO ONSET AND TIME-TO RESOLUTION DEFINITION AND 
CONVENTIONS FOR SELECT ADVERSE EVENTS, IMMUNE-
MEDIATED ADVERSE EVENTS AND EVENTS OF SPECIAL 
INTEREST
Time-to onset definition
Time-to onset of AE (any grade) for a specific category is defined as the time between the day of 
the first dose of study treatment and the onset date of the earliest AE (of any grade) in this category.
The time-to onset of AE (grade 3-5) for a specific category is defined similarly with an onset date 
corresponding to a grade 3-5 AE.
Time-to onset of drug-related AE (any grade or grade 3-5) for a specific category is defined 
similarly but restricted to drug-related AE.
Time-to onset for a specific subcategory is defined similarly but restricted to event of this
subcategory.
Time-to resolution definition
In order to derive the time-to resolution, overlapping or contiguous AEs within a specific category
or subcategory will be collapsed into what will be termed “clustered” AEs. For example, if a 
subject (without pre-treatment AE) experienced an AE from 1st to 5th January, another AE (with 
different PT but within same category) from 6th to 11th January and same AE from 10th to 
12th January, these will be collapsed into one clustered AE from 1st to 12th January. Table 8-1 is 
summarizing key derivation steps for each type of clustered AEs.
Time-to resolution of AE (any grade) for a specific category is defined as the longest time from 
onset to complete resolution or improvement to the grade at baseline among all clustered AEs
experienced by the subject in this category per adverse event criteria category. Events which 
worsened into grade 5 events (death) or have a resolution date equal to the date of death are 
considered unresolved. If a clustered AE is considered as unresolved, the resolution date will be 
censored to the last known alive date. Improvement to the grade at baseline implies that all 
different events in the clustered adverse event should at least have improved to the corresponding 
(i.e. with same preferred term) baseline grade. This measure is defined only for subjects who 
experienced at least one AE in the specific category.
The time-to resolution of AE (grade 3-5) for a specific category is defined similarly with an onset 
date corresponding to a grade 3-5 AE.
Time-to resolution of drug-related AE (any grade or grade 3-5) for a specific category is defined 
similarly but restricted to drug-related AE.
The time-to resolution of AE (any grade or grade 3-5, drug-related or all) where immune 
modulating medication was initiated is defined similarly. For data presentation not restricted to 
IMAE, the additional condition that the subject started an immune modulating medication during 
the longest AE resolution period will be applied.
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Time-to resolution for a specific subcategory is defined similarly but restricted to event of this 
subcategory.
Table 8-1:
Derivation of clustered AE
Type of clustered AE
Derivation
Any grade
Collapse any on-treatment AE from the same category
Drug-related of any grade
Collapse any on-treatment drug-related
AE from the same category
Grade 3-5
Collapse any on-treatment AE from the same category.
Resolution will be based on the onset date of the earliest grade 3-
5 records (if no grade 3-5 record, clustered AE is excluded)
Drug-related of Grade 3-5
Collapse any on-treatment drug-related AE from the same 
category
Resolution will be based on the onset date of the earliest grade 3-
5 record (if no Grade 3-5 record, clustered AE is excluded)
The algorithm for collapsing adverse event records is using the following conventions:
For each subject and specified category, the corresponding adverse event records will be collapsed 
when:
4) Multiple adverse event records have the same onset date.
5) The onset date of an event record is either the same day or 1 day later than the resolution date 
of a preceding event record (contiguous events).
6) The onset date of an event record is after the onset date and prior to or on the resolution date 
of a preceding event record (overlapping events).
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APPENDIX 2
MISSING AND PARTIAL RADIOTHERAPY AND SURGERY 
DATES IMPUTATION ALGORITHMS
Procedures – Imputation Rules. 
If reported procedure start date is a full valid date, then set start date equal to the date part of 
procedure start date. 
In case of partial date use imputation rules described below: 
•
If only day is missing, then 
−
If month and year of procedure match month and year of first dose date, then impute as 
date of first dose.
−
If month and year of procedure don't match month and year of first dose date, then impute 
as first day of that month and year. 
•
If both day and month are missing, then impute as maximum between 01JAN of the year and 
date of the first dose.
•
If date is completely missing or invalid, then leave missing. 
Note: Imputation is not applicable to data where start date is not collected (for example "PRIOR 
RADIOTHERAPY" CRF). Set start date to missing in this case. 
If reported end date is a full valid date, then set end date equal to the date part of the reported end 
date. 
In case of partial date use imputation rules described below: 
•
If reported end date is partial, then set end date equal to the last possible reported end date 
based on the partial entered reported end date. 
•
If reported end date is missing, continuing, unknown or invalid then set end date equal to the 
most recent database extraction date. 
If end date was imputed, then compare end date to the death date or last known alive date if subject 
is not dead. If posterior, then end date should be imputed to death date (or last known alive date if 
subject not dead). 
Note: Imputation of partial dates only applies to data entered on "RADIOTHERAPY” CRF page. 
For other CRF pages in case of partial dates set end date to missing.  
Surgeries – Imputation Rules. 
If reported surgery date is a full valid date, then set start date equal to the date part of surgery date. 
In case of partial date, use one of the two imputation rules described below: 
A. For data collected on "PRIOR SURGERY RELATED TO CANCER" CRF page: 
•
If only day is missing, then impute as the first day of the month; 
•
If both day and month are missing, then then impute as 01JAN of the year; 
•
If date is completely missing or invalid, then leave missing. 
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B. For data collected on other CRF pages (deemed to be on-treatment/subsequent surgeries): 
•
If only day is missing, then 
−
If month and year of surgery match month and year of first dose date, then impute the 
missing date as the date of first dose; 
−
If month and year of surgery don't match month and year of first dose date, then impute as 
first day of that month and year; 
•
If both day and month are missing, then impute as maximum between 01JAN of the year and 
date of the first dose; 
•
If date is completely missing or invalid, then leave missing. 
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9
DOCUMENT HISTORY
Table 9-1:
Document History
Version 
Number
Author(s)
Description
1.0
Original Issue
10
REFERENCES
1
IO Core Statistical Analysis Plan for Multiple Indications 
2
Brookmeyer R. and Crowley J. A confidence interval for the median survival time. Biometrics 
38:29-41, 1982
3
Klein, J. P. and Moeschberger, M. L. (1997), Survival Analysis: Techniques for Censored and 
Truncated Data, New York: Springer-Verlag
4
Global Biometric Sciences, SAS Analysis Dataset Specification, Unique Adverse Events. 
Version 2.0, April 22, 2015
5
Clopper, C.; Pearson, E. S. (1934). "The use of confidence or fiducial limits illustrated in the 
case of the binomial". Biometrika 26: 404–413.
6
Adverse Event Domain Requirements Specification Bristol Myers Squibb Co. PRI. Version 
2.3.0 April 23, 2018
7
Non-Study Medication Domain Requirements Specification Bristol Myers Squibb Co. PRI. 
Version 2.10.0 April 23, 2018
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