Conditions: Breast Cancer
Keywords: Nivolumab
Allocation: NON_RANDOMIZED | Intervention model: PARALLEL
Enrollment: 8
Healthy volunteers: no

Brief summary:
Study of efficacy of nivolumab with neoadjuvant chemotherapy in patients with IBC

Detailed description:
The purpose of this study is to determine whether the addition of nivolumab to chemotherapy improves pathologic complete response (pCR) in the breast and post-therapy lymph nodes evaluated histologically (ypT0/Tis ypN0) in patients with inflammatory breast cancer (IBC).

Arms:
arm 1: None arm 2: None

Interventions: intervention 1: Nivolumab 360mg intervention 2: Paclitaxel 80mg/m^2 intervention 3: Doxorubicin 60mg/m^2 intervention 4: Cyclophosphamide 600mg/m^2 intervention 5: Paclitaxel 80mg/m^2 or Docetaxel 75mg/m^2 intervention 6: Trastuzumab 8mg/kg and 6 mg/kg intervention 7: Pertuzumab 840mg and 420mg
Intervention descriptions: intervention 1: Nivolumab 360 mg IV on Day 1 of every 21 day cycle (Cycle 1-4) intervention 2: Paclitaxel 80mg/m\^2 IV on Day of 1, 8, 15 of every 21 day cycle (Cycle 1-4) intervention 3: Doxorubicin 60 mg/m\^2 IV on Day 1 of every 14 day cycle (Cycle 5-8) intervention 4: Cyclophosphamide 600mg/m\^2 on Day 1 of every 14 day cycle (Cycle 5-8) intervention 5: Paclitaxel 80mg/m\^2 on Day 1, 8, 15 of every 21 day cycle (Cycle 1-4) OR Docetaxel 75mg/m\^2 on Day 1 of every 21 day cycle (Cycle 1-4) intervention 6: Trastuzumab 8mg/kg IV on Day 1 of Cycle 1 and then 6mg/kg IV on Day 1 of Cycle 2-4 intervention 7: Pertuzumab 840mg on Day 1 of Cycle 1 and then 420mg IV on Day 1 of Cycle 2-4

Protocol document:
Prot_SAP_001.pdf: 
  
CONFIDENTIAL 
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authorized in writing by the Study Sponsor. 
 
 
 
 
 
 
Phase II trial of nivolumab with chemotherapy as 
neoadjuvant treatment in inflammatory breast cancer (IBC) 
 
 
 
 
 
  Regulatory Sponsor/ 
  Principal Investigator:              Maryann Kwa, MD 
                                                      Assistant Professor of Medicine 
 
 
 
 
       NYU Perlmutter Cancer Center  
       160 East 34th Street, Fourth Floor 
       New York, NY 10016 
       Tel: (212) 731-6364 
       Email: maryann.kwa@nyulangone.org 
 
  
Funding Sponsor: 
Bristol-Myers Squibb, Inc 
 
Study Product: 
Nivolumab (Opdivo®) 
 
Protocol Number: 
CA209-8NL 
 
IND Number:  
141788   
 
 
Study Number: 
 
        s17-00890 
 
ClinicalTrials.gov Identifier:        NCT03742986 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Clinical Research Protocol 


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Coordinating Center: 
Laura & Isaac Perlmutter Cancer Center / NYU Langone Health 
Clinical Trials Office 
PCC-QAU@nyulangone.org 
 
Participating sites: 
1. Laura & Isaac Perlmutter Cancer Center / NYU Langone Health  
2. Bellevue Hospital  
3. Indiana University  
 
ClinicalTrials.gov Number:  NCT03742986  
 
Initial version:  BMS 7/13/2018  
Protocol Development & Progress Monitoring Unit / Clinical Trials Office 10/4/2018 
FDA 11/28/2018 
PRMC 1/4/2019 
 
Amended: 06/11/2019 
Amended: 2/4/2020 
Amended: 8/4/2020 
Amended: 10/1/20 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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PROTOCOL APPROVAL SIGNATURES 
 
 
Protocol Title: PHASE II TRIAL OF NIVOLUMAB WITH CHEMOTHERAPY AS NEOADJUVANT 
TREATMENT IN INFLAMMATORY BREAST CANCER (IBC) 
 
 
Protocol Number: s17-00890 
 
This study will be conducted in compliance with the clinical study protocol (and amendments), 
International Conference on Harmonisation of Technical Requirements for Registration of 
Pharmaceuticals for Human Use guidelines for current Good Clinical Practice, and applicable 
regulatory requirements. 
 
 
 
 
 
 
 
 
 
 
 
Signature 
 
 
 
 
 
 
 
 
 
Date 
 
 


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Table of Contents 
 
STUDY SUMMARY ....................................................................................................................................... 1 
1 
INTRODUCTION ................................................................................................................................... 3 
1.1 
BACKGROUND .................................................................................................................................... 3 
1.1.1 
Inflammatory Breast Cancer (IBC) and Current Therapies ..................................................... 3 
1.1.2 
IBC Biology and PD-L1 Expression ......................................................................................... 4 
1.1.3 
Study Rationale and Hypothesis .............................................................................................. 5 
1.2 
INVESTIGATIONAL AGENT .................................................................................................................... 5 
1.2.1  NIVOLUMAB AND MECHANISM OF ACTION ............................................................................................ 5 
1.2.2  PRECLINICAL DATA FOR NIVOLUMAB ................................................................................................... 5 
1.2.3  NIVOLUMAB PHARMACOKINETIC DATA IN HUMANS ............................................................................... 5 
1.2.4  NIVOLUMAB CLINICAL EFFICACY.......................................................................................................... 6 
1.2.5  NIVOLUMAB CLINICAL SAFETY ............................................................................................................. 6 
1.3 
CLINICAL DATA TO DATE ..................................................................................................................... 7 
1.3.1 
Combined Modality Treatment with Anthracycline-based Chemotherapy in IBC .................... 7 
1.3.2 
Addition of Taxanes to Preoperative Systemic Therapy in IBC ............................................... 7 
1.3.3 
Targeted Therapies in HER2-positive IBC ............................................................................... 8 
1.3.4 
Neoadjuvant Treatment with Bevacizumab in IBC .................................................................. 9 
1.3.5 
Neodjuvant Therapy with Carboplatin in TNBC ..................................................................... 10 
1.3.6 
Neoadjuvant Therapy with Anti-PD-1/PD-L1 Antibodies in TNBC ........................................ 10 
1.3.7 
Treatment with Anti-PD-1/PD-L1 Antibodies in HER2-positive Advanced Breast Cancer .... 11 
1.3.8 
Select Ongoing Neoadjuvant Studies in IBC ......................................................................... 12 
1.4 
DOSE RATIONALE AND SCHEDULE ..................................................................................................... 13 
1.4.1  RATIONALE FOR NIVOLUMAB DOSE AND SCHEDULE ........................................................................... 16 
1.4.2  RATIONALE FOR CHEMOTHERAPY DOSE AND SCHEDULE .................................................................... 16 
1.5 
RESEARCH RISKS & BENEFITS .......................................................................................................... 17 
1.5.1 
Risk of Study Drug ................................................................................................................. 17 
1.5.2 
Other Risks of Study Participation ......................................................................................... 17 
1.5.3 
Potential Benefits ................................................................................................................... 17 
2 
STUDY OBJECTIVES AND HYPOTHESES...................................................................................... 18 
2.1 
STUDY OBJECTIVES .......................................................................................................................... 18 
2.2 
HYPOTHESES ................................................................................................................................... 18 
3 
STUDY DESIGN ................................................................................................................................. 19 
3.1 
GENERAL DESIGN............................................................................................................................. 19 
3.2 
PRIMARY STUDY ENDPOINT .............................................................................................................. 20 
3.3 
SECONDARY STUDY ENDPOINTS ....................................................................................................... 20 
3.4 
CORRELATIVE ENDPOINTS ................................................................................................................ 20 
4 
SUBJECT SELECTION AND STUDY ASSESSMENTS ................................................................... 21 
4.1 
INCLUSION CRITERIA ......................................................................................................................... 21 
4.2 
EXCLUSION CRITERIA ....................................................................................................................... 22 
4.3 
SUBJECT RECRUITMENT/SCREENING AND CLINICAL PROCEDURES/ASSESSMENTS .............................. 23 
4.3.1  Informed Consent ...................................................................................................................... 24 
4.3.2 Documentation of Consent ........................................................................................................ 25 
4.3.3  Multi-Site Surveillance............................................................................................................... 25 
4.3.4 Patient Informed Consent at Additional Sites ............................................................................ 25 
4.3.5  Inclusion/Exclusion Criteria ....................................................................................................... 25 
4.3.6  Medical History .......................................................................................................................... 25 
4.3.7  Prior Medications ...................................................................................................................... 25 
4.3.8  Concomitant Medications .......................................................................................................... 25 
4.3.9  Disease Details ......................................................................................................................... 25 


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4.3.10  Adverse Event (AE) Monitoring............................................................................................... 26 
4.3.11 Full Physical Exam ................................................................................................................... 26 
4.3.12  Directed Physical Exam .......................................................................................................... 26 
4.3.13  Vital Signs ............................................................................................................................... 26 
4.3.14  Eastern Cooperative Oncology Group (ECOG) Performance Status..................................... 26 
4.3.15 Collection of Tumor Tissue Prior To Treatment ....................................................................... 26 
4.3.16  Tumor Imaging/Cardiac Imaging............................................................................................. 26 
4.3.17  Laboratory Procedures/Assessments ..................................................................................... 27 
4.3.18  Tumor Assessment during Study Treatment .......................................................................... 26 
4.3.19  Screening Period ..................................................................................................................... 26 
4.4 
REGISTRATION PROCEDURES ........................................................................................................... 27 
4.4.1 
General Guidelines ................................................................................................................ 27 
4.4.2 
Patient Registration at Other Participating Institutions .......................................................... 28 
4.5 
EARLY WITHDRAWAL OF SUBJECTS ................................................................................................... 28 
4.5.1 
When and How to Withdraw Subjects.................................................................................... 28 
4.5.2 
Data Collection and Follow-up for Withdrawn Subjects ......................................................... 28 
5 
STUDY DRUG ..................................................................................................................................... 28 
5.1 
DESCRIPTION ................................................................................................................................... 28 
5.1.1 
Pharmaceutical Properties and Formulation .......................................................................... 29 
5.1.2 
Drug Product Preparation ...................................................................................................... 29 
5.1.3 
Recommended Storage and Use Conditions ........................................................................ 29 
5.2 
TREATMENT REGIMEN ...................................................................................................................... 29 
5.2.1 
Treatment of Nivolumab-Related Infusion Reactions ............................................................ 30 
5.3 
DOSAGE MODIFICATION .................................................................................................................... 31 
5.3.1 
Nivolumab Dose Delay Criteria for Study Treatment ............................................................. 31 
5.3.2 
Criteria for Discontinuation of Nivolumab .............................................................................. 32 
5.3.3 
Criteria To Resume Treatment with Nivolumab ..................................................................... 33 
5.3.4 
Recommendations for Chemotherapy Delays and Modifications .......................................... 33 
5.4 
PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY ....................................................................... 37 
5.5 
SUBJECT TREATMENT COMPLIANCE MONITORING .............................................................................. 37 
5.6 
CONCOMITANT THERAPY .................................................................................................................. 37 
5.6.1 
Prohibited Therapies with Nivolumab .................................................................................... 39 
5.6.2 
Permitted Therapies with Nivolumab ..................................................................................... 39 
6 
STUDY PROCEDURES ...................................................................................................................... 38 
6.1 
STUDY CALENDAR/STUDY SCHEDULE OF EVENTS .............................................................................. 38 
6.2 
TREATMENT DISCONTINUATION DUE TO EARLY PROGRESSION OR TOXICITY.......................................... 44 
6.3 
SURGERY AND POST-OPERATIVE THERAPY ........................................................................................ 44 
6.4 
POST-TREATMENT FOLLOW-UP/END OF TREATMENT/END OF STUDY VISITS ....................................... 45 
6.4.1 
End of Treatment ................................................................................................................... 46 
6.4.2 
Post-treatment Follow-up and End of Study .......................................................................... 46 
6.4.3 
Subjects Lost to Follow Up .................................................................................................... 46 
6.4.4 
Post-Study Access ................................................................................................................. 46 
6.5 
CORRELATIVE STUDIES..................................................................................................................... 46 
6.5.1 
Tumor Tissue Samples .......................................................................................................... 46 
6.5.2 
Characterization of Tumor Immune Cells ………………………………………………………..47 
6.5.3 
Tumor Genomic Analysis ....................................................................................................... 47 
6.5.4 
Peripheral Blood Samples...................................................................................................... 47 
6.5.5 
Banked Biospecimens............................................................................................................ 48 
6.5.6 
Specimen Shipment ............................................................................................................... 48 
7 
STATISTICAL PLAN .......................................................................................................................... 48 
7.1 
PRIMARY ENDPOINT AND SAMPLE SIZE DETERMINATION .................................................................... 48 
7.2 
STATISTICAL METHODS ..................................................................................................................... 48 
7.3 
SUBJECT POPULATION(S) FOR ANALYSIS ........................................................................................... 49 
8 
SAFETY AND ADVERSE EVENTS ................................................................................................... 50 


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8.1 
DEFINITIONS ..................................................................................................................................... 50 
8.2 
RECORDING OF ADVERSE EVENTS .................................................................................................... 52 
8.3 
REPORTING OF SERIOUS ADVERSE EVENTS AND UNANTICIPATED PROBLEMS ..................................... 52 
8.3.1 
Investigator Reporting: Notifying the Study Sponsor ............................................................. 53 
8.3.2 
Pregnancy .............................................................................................................................. 55 
8.3.3 
Overdose ................................................................................................................................ 57 
8.3.4 
Other Safety Considerations .................................................................................................. 57 
8.3.5 
Investigator Reporting: Notifying the IRB ............................................................................... 57 
8.3.6 
Sponsor Reporting: Notifying the FDA ................................................................................... 58 
8.3.7 
Sponsor Reporting: Notifying Participating Investigators ...................................................... 59 
8.4 
MEDICAL MONITORING ...................................................................................................................... 59 
8.4.1 
Data Safety Monitoring Committee (DSMC) .......................................................................... 59 
9 
DATA HANDLING AND RECORD KEEPING ................................................................................... 59 
9.1 
CONFIDENTIALITY ............................................................................................................................. 59 
9.2 
CONFIDENTIALITY AND HIPAA .......................................................................................................... 60 
9.3 
SOURCE DOCUMENTS....................................................................................................................... 60 
9.4 
RECORDS RETENTION ...................................................................................................................... 60 
10 
STUDY MONITORING, AUDITING, AND INSPECTING ................................................................... 61 
10.1 STUDY MONITORING PLAN ................................................................................................................ 61 
10.2 AUDITING AND INSPECTING ............................................................................................................... 62 
11 
ETHICAL CONSIDERATIONS ........................................................................................................... 62 
12 
STUDY FINANCES ............................................................................................................................. 62 
12.1 FUNDING SOURCE ............................................................................................................................ 62 
12.2 CONFLICT OF INTEREST .................................................................................................................... 62 
13 
PUBLICATION PLAN ......................................................................................................................... 62 
14 
REFERENCES .................................................................................................................................... 64 
15    APPENDICES ...................................................................................................................................... 68 
 
 
LIST OF TABLES  
Table 1: Select ongoing neoadjuvant studies in IBC………………………………………………………..…..12 
Table 2: Treatment dose and schedule for Cohort 1………………………………………………………..…..14 
Table 3: Treatment schedule for Cohort 1…………………………………………………………………….....14 
Table 4: Treatment dose and schedule for Cohort 2……………………………………………………………15 
Table 5: Treatment schedule for Cohort 2…………………………………………………………………….....15 
Table 6: Adequate organ function laboratory values…………………………………………………………...21 
Table 7: Dose modification levels for docetaxel/ paclitaxel……..………….…………………………….…….33 
Table 8: Dose modifications for taxane-related neurosensory toxicity……………………………….............33 
Table 9: Dose modifications for taxane-related musculoskeletal pain not controlled by analgesic.….……34 
Table 10: Dose modification levels for doxorubicin/ cyclophosphamide  ……..………………………….......34 
Table 11: Dose modifications and delays for docetaxel/ paclitaxel/ doxorubicin/ cyclophosphamide..…..34 
Table 12: Left ventricular systolic dysfunction………………………………………………………………..…36 
 
 
 


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Abbreviations 
 
AC 
Doxorubicin and cyclophosphamide 
AE 
Adverse event 
AJCC 
American Joint Committee on Cancer 
ALN 
Axillary lymph nodes 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase  
ANC 
Absolute neutrophil count 
AUC 
Area under the curve 
aPTT 
Activated partial thromboplastin time 
ASCO 
American Society of Clinical Oncology 
AST 
Aspartate aminotransferase  
AUC 
Area under the curve 
BC360 
Breast Cancer 360 Panel  
BMS 
Bristol-Myers Squibb 
BOR 
Best overall response  
C 
Clinical 
CAP 
College of American Pathologists 
Cavgss 
Time averaged steady state concentration 
CBRD 
Center for Biospecimen Research and Development 
CHF 
Congestive heart failure 
cHL 
classical Hodgkin Lymphoma 
CI 
Confidence interval 
CL 
Clearance 
CLss 
Steady state clearance 
Cmaxss 
Maximum plasma concentration 
CMF 
Cyclophosphamide, methotrexate, fluorouracil 
Cmin 
Minimum serum concentration  
CR 
Complete response 
CrCl 
Creatinine clearance 
CRF 
Case report form 
CT 
Computed tomography 
CTC 
Circulating tumor cell 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTO 
Clinical Trials Office 
CV 
Coefficient of variation 
DFS 
Disease-free survival 
DLT 
Dose limiting toxicity 
DNA 
Deoxyribonucleic Acid  
DSMC 
Data and Safety Monitoring Committee 
EBCTCG 
Early Breast Cancer Trialists' Collaborative Group  
EC 
Epirubicin and cyclophosphamide 
EC 
Ethics Committee  
ECI 
Events of clinical interest  
ECOG 
Eastern Cooperative Oncology Group 
EFS 
Event free survival 
EKG 
Electrocardiogram 
ER 
Estrogen receptor 
FAC 
5-fluorouracil, doxorubicin, and cyclophosphamide 
FEC 
5-fluorouracil, epirubicin, and cyclophosphamide 
FDA 
United States Food and Drug Administration 
FFPE 
Formalin fixed paraffin embedded 
FISH 
Fluorescence in situ hybridization 


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G-CSF 
Granulocyte-colony stimulating factor 
GFR 
Glomerular filtration rate 
HBV 
Hepatitis B virus 
HCV 
Hepatitis C virus 
HER2 
Human epidermal growth factor receptor 2 
HIV 
Human Immunodeficiency Virus 
HR 
Hazard ratio 
HR 
Hormone receptor 
IB 
Investigator’s Brochure 
IBC 
Inflammatory Breast Cancer 
ICF 
Informed consent form 
IFN 
Interferon 
IHC 
Immunohistochemistry 
INR 
Internationalized Normalized Ratio 
IP 
Investigational product 
irAESI 
immune related adverse events of special interest  
IRB 
Institutional Review Board  
IRFI 
Invasive recurrence-free survival 
IV 
Intravenous 
Kg 
Kilogram 
L 
Liter 
LDH 
Lactate dehydrogenase  
LFT 
Liver function test 
LVEF 
Left ventricular ejection fraction 
LVSD 
Left ventricular systolic dysfunction 
MDACC 
MD Anderson Cancer Center  
 
mcL 
Microliter 
Mg 
Milligram 
MP 
Multiplexing 
MRI 
Magnetic resonance imaging  
mRNA 
Messenger ribonucleic acid 
MUGA 
Multigated acquisition 
N 
Number 
NCI 
National Cancer Institute 
NCT 
ClinicalTrials.gov registry number 
NGS 
Next generation sequencing  
NSCLC 
Non-small cell lung cancer 
NYULH 
NYU Langone Health  
ORR 
Overall response rate 
OS 
Overall survival 
PCC 
NYU Perlmutter Cancer Center 
pCR 
Pathologic complete response 
PCR 
Polymerase chain reaction 
PD 
Progression of disease 
PD-1 
Programmed cell death-1 
PD-L1 
Programmed cell death-ligand 1 
PD-L2 
Programmed cell death-ligand 2 
PET 
Positron Emission Tomography  
PFS 
Progression-free survival 
PI 
Principal Investigator 
PK 
Pharmacokinetic 
PPK 
Population pharmacokinetic (s) 
PR 
Partial response 
PR 
Progesterone receptor 


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PS 
Performance status 
PT 
Prothrombin Time 
Q2W 
Every two weeks 
Q3W 
Every three weeks 
Q4W 
Every four weeks 
QA 
Quality assurance 
QT 
Time between the start of the Q wave and the end of the T wave in the 
heart's electrical cycle 
QTc 
QT interval corrected for heart rate 
RCC 
Clear-cell renal cell carcinoma 
SAE 
Serious adverse event 
SD 
Stable disease 
T 
Tumor 
TBD 
To be determined 
T-DM1 
Ado-trastuzumab emtansine 
TFT 
Thyroid function test 
TIL 
Tumor infiltrating lymphocytes 
TMB 
Tumor mutation burden  
TNBC 
Triple negative breast cancer 
TTE 
Transthoracic echocardiogram  
UC 
Urothelial carcinoma 
ULN 
Upper limit of normal 
VEGF 
Vascular endothelial growth factor  
VP 
Vincristine and prednisone  
Vss 
Volume of distribution at steady state 


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Study Summary 
Title 
Phase II trial of nivolumab with chemotherapy as neoadjuvant treatment in 
inflammatory breast cancer (IBC) 
Brief Summary 
Study of efficacy of nivolumab with neoadjuvant chemotherapy in patients with 
IBC  
Protocol Number 
CA209-8NL  
Study Number 
S17-00890 
Phase 
Phase II 
Methodology 
Multi-center open label, phase II study 
Study Duration 
6 years 
Participant Duration 
Up to 24 months 
Study Center(s) 
Multi-center: NYU Perlmutter Cancer Center, Bellevue Hospital and Indiana 
University 
Objectives 
 
Primary Objective 
• 
To determine whether the addition of nivolumab to chemotherapy 
improves pathologic complete response (pCR) in the breast and post-
therapy lymph nodes evaluated histologically (ypT0/Tis ypN0) in 
patients with inflammatory breast cancer (IBC). 
 
Secondary Objectives 
• 
To evaluate the safety and tolerability of the combination of nivolumab 
with neoadjuvant chemotherapy in IBC. 
• 
To evaluate the invasive recurrence-free interval (IRFI) [time frame: up 
to 24 months after study entry].   
 
Correlative Studies  
• 
To explore predictive markers of response/sensitivity as well as 
markers of resistance to therapy. 
• 
To assess the frequency of mutational and neoantigen load and to 
explore mutational and neoantigen load as predictive markers of 
response. 
• 
To assess changes in expression levels of biomarkers or biomarker 
panels before, during, and after treatment. 
  
Number of Subjects 
52 
Diagnosis and Main 
Inclusion Criteria 
Patients >18 years with newly diagnosed inflammatory breast cancer without 
distant metastases and have not received prior chemotherapy or 
immunotherapy.  All breast cancer subtypes are allowed: 
 
 Triple negative breast cancer (TNBC) 
 Hormone receptor (HR)-positive and human epidermal growth factor 
receptor 2 (HER2)-negative 
 HR-positive or HR-negative and HER2-positive   
 


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Treatment Product, 
Dose, Route 
 
Cohort 1: TNBC or HR-positive/HER2-negative: (n=26) 
 
1. Cycle 1-4, 21 day cycle 
• 
Nivolumab 360 mg IV on Day 1 x 4 cycles and Paclitaxel 80 mg/m2 IV 
on Day 1, 8, and 15 x 4 cycles, followed by 
2.  Cycle 5-8, 14 day cycle 
• 
Doxorubicin 60 mg/m2 IV on Day 1 x 4 cycles and Cyclophosphamide 
600 mg/m2 IV on Day 1 x 4 cycles  
 
Cohort 2: HR-positive/HR-negative and HER2-positive: (n=26) 
 
1. Cycle 1-4, 21 day cycle 
• 
Nivolumab 360 mg IV on Day 1 x 4 cycles, + Docetaxel* 75 mg/m2 IV 
on Day 1 x 4 cycles, + Trastuzumab** 8 mg/kg IV on Day 1 of Cycle 1 
and then 6 mg/kg IV on Day 1 of Cycle 2-4, + Pertuzumab 840 mg IV 
on Day 1 of Cycle 1 and then 420 mg IV on Day 1 of Cycle 2-4, 
followed by 
2. Cycle 5-8, 14 day cycle 
• 
Doxorubicin 60 mg/m2 IV on Day 1 x 4 cycles and Cyclophosphamide 
600 mg/m2 IV on Day 1 x 4 cycles  
 
*Paclitaxel 80 mg/m2 IV weekly x 12 (Cycle 1-4) may be substituted 
**Trastuzumab biosimilar may be used  
 
Statistical Analysis 
Summary statistics (percentage, mean, standard deviation, etc.) will be 
provided for the safety endpoints as appropriate.  Sequential boundaries will 
be used to monitor dose-limiting toxicity rate. There will be an interim safety 
analysis in Cohort 2.  Monitoring for toxicity will follow a Bayesian-based rule 
for the probability that the rate of DLT exceeds a maximal tolerated level of 
30%. We will assume a Beta(1,2) prior, which is prior information equivalent to 
one DLT observed in three treated patients. 
 
The association between biomarkers and best overall response (responder 
versus non-responder primary) will be described by response rate in 
subgroups, and assessed using the mid-p adjustment to Fisher’s exact test. 
The association between biomarkers and response will be described by 
graphical summaries and assessed using a two-sample t-test with 
transformation as needed. 
 
 


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1 Introduction 
 
This document is a protocol for a human research study. This study is to be conducted in accordance with 
United States government research regulations, and applicable international standards of Good Clinical 
Practice, and institutional research policies and procedures. 
 
1.1 Background 
 
1.1.1 Inflammatory Breast Cancer (IBC) and Current Therapies 
 
Inflammatory breast cancer (IBC) is the most aggressive form of breast cancer, and the incidence in the 
United States ranges from 1 to 5%1. IBC is a clinical presentation that is characterized by diffuse erythema, 
rapid enlargement of the breast, and a characteristic peau d’orange appearance of the skin2.  Pathologically, 
tumor emboli are often present in dermal lymphatics of the involved skin, however dermal lymphatic 
involvement itself is not required for a diagnosis of IBC.  IBC is characterized by younger age of onset, 
rapid disease progression, local and distant metastases, and worse overall survival (OS) when compared 
to non-IBC. The prognosis remains poor, with a 5-year OS of approximately 50%3, despite multimodality 
treatment.  The median OS duration of patients with IBC compared to those with non-IBC tumors for stage 
III disease is 4.75 years versus 13.40 years,4 and for stage IV disease, it is 2.27 years versus 3.40 years5. 
IBC is usually hormone receptor (HR)-negative and is more frequently human epidermal growth factor 
receptor 2 (HER2)-positive compared to the more common ductal breast cancer.  Gene expression profiling 
studies of IBC have shown a greater frequency of basal and HER2 overexpression.  
The multidisciplinary approach to treatment of IBC without distant metastases involves neoadjuvant 
(primary) systemic chemotherapy followed by definitive surgery with mastectomy and axillary lymph node 
dissection and radiotherapy6,7.  Before the use of systemic chemotherapy, the 5-year OS rate using surgery 
and/or radiation therapy ranged from 0 to 5%.  After the introduction of combination chemotherapy as part 
of a multimodality approach, survival has improved, with 15-year OS in 20%-30% of patients. Because IBC 
is a rare disease, there are no large randomized trials evaluating the optimal preoperative systemic therapy. 
The current systemic therapy recommendations are based on results from retrospective studies, smaller 
prospective studies, and data from locally advanced non-inflammatory breast cancer. A retrospective 
analysis demonstrated the benefit of preoperative systemic therapy followed by mastectomy compared to 
preoperative systemic therapy alone in which lower local recurrence rates and longer disease-free survival 
(DFS) were reported for the combined modality approach8.  A large retrospective study of patients with IBC 
at The University of Texas MD Anderson Cancer Center (MDACC) showed that initial treatment with 
anthracycline-based chemotherapy followed by local therapy—with radiation, mastectomy, or both—and 
additional post-operative chemotherapy resulted in a 15-year DFS rate of 28%9.   
 
Achieving a pathologic complete response (pCR) to neoadjuvant therapy is associated with favorable 
outcomes in earlier stage breast cancer.  A retrospective study demonstrated that the addition of a taxane 
to an anthracycline-based chemotherapy regimen improved progression-free survival (PFS) and OS in 
patients with hormone receptor (HR)-negative IBC10.  A study of patients with IBC and metastasis to axillary 
lymph nodes who were treated with anthracycline-based chemotherapy with or without taxanes revealed 
that more patients receiving the combination achieved a pCR compared to those that only received 
anthracycline-based chemotherapy11.  Furthermore, those with a pCR in the axillary lymph nodes had 
improved DFS and OS compared to those with residual axillary disease.   
For the initial treatment of patients with IBC, preoperative systemic therapy with an anthracycline-based 
regimen with taxane is recommended.  For patients with HER2-positive IBC, the addition of trastuzumab to 
systemic chemotherapy is associated with improvement in response rates.  A prospective study that 
randomized patients with locally advanced breast cancer, including IBC, to neoadjuvant anthracycline-
based chemotherapy with or without trastuzumab for one year demonstrated that the addition of 
trastuzumab significantly improved overall response rate (ORR) and event free survival12,13.  The inclusion 
of trastuzumab in the chemotherapy regimen is recommended for patients with HER2-positive IBC.  In 
addition, a phase II trial of patients with HER2-positive breast cancer including IBC showed improvement 


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in pCR with the addition of another HER2-targeting agent, pertuzumab14.  Pertuzumab may therefore be 
included in the preoperative systemic therapy in patients with HER2-positive IBC.  All patients with HR-
positive IBC are recommended to receive endocrine therapy sequentially after completion of planned 
preoperative systemic therapy and surgery.   
 
The response to preoperative chemotherapy is an important prognostic factor.  A retrospective analysis at 
MDACC looked at treatment efficacy in 527 patients with IBC by HR- and HER2-defined subtypes15.  The 
patients had received neoadjuvant chemotherapy, and the overall pCR rate was 15.2%.  Based on subtype, 
the pCR rates were 7.4% in HR-positive/HER2-negative, 12.4% in triple negative breast cancer (TNBC), 
15% in HR-positive/HER2-positive, and 30.5% in HR-negative/HER2-positive15. Features that were 
associated with improvement in DFS and OS were achieving a pCR, no evidence of vascular invasion, non-
TNBC subtype, and adjuvant hormonal therapy and radiotherapy.  
 
In summary, neoadjuvant systemic therapy, modified radical mastectomy and axillary lymph node 
dissection, post-mastectomy radiotherapy, adjuvant targeted therapy (as indicated) and hormonal therapy 
(as indicated) are the current recommended multimodality treatments for IBC6,7, however pCR rates are 
low and overall outcomes are poor, signifying an important need for better therapies.   
 
1.1.2 IBC Biology and PD-L1 Expression 
 
Several studies have documented a higher frequency of negative HR status in IBC tumors compared to 
non-IBC tumors, with some reporting up to 50% of tumors being estrogen receptor (ER)-negative16.  Lack 
of expression of hormone receptors has been shown to be associated with a more aggressive clinical 
course and decreased breast cancer-specific and overall survival.  A higher incidence of HER2-positive 
tumors has also been reported among IBC17. Tumor infiltrating lymphocytes (TILs) have been shown to be 
prognostic in the more highly proliferative and aggressive breast cancer subtypes, such as TNBC which 
lacks ER/PR expression, and HER2-positive breast cancer18-20.  The degree of infiltrating immune cells in 
the tumor microenvironment has correlated with response to treatment and clinical outcome in these two 
subtypes, providing important prognostic and possibly predictive information. IBC comprises similar 
molecular subtypes as other types of breast cancer, but may contain a more important role for the tumor 
microenvironment, including immune cell infiltration21.  
 
Advances in cancer immunotherapy and a growing body of research have focused on the role of the 
antitumor response in breast cancer. There is strong evidence that TILs have prognostic value and are 
associated with clinical outcome and improved survival. Immunotherapy studies have focused on the role 
of the programmed cell death-1 (PD-1) receptor/programmed death-ligand 1 (PD-L1) pathway in 
maintaining immunosuppression in the tumor microenvironment.  PD-1 is a member of the T-cell co-
regulatory receptor family and, when it binds to its ligands, PD-L1 and PD-L2, it attenuates T-cell function, 
survival, and expansion, thereby mediating immune tolerance. PD-L1 is expressed on activated T cells 
within the tumor microenvironment; however, tumors can also express PD-L1, which has been 
demonstrated in breast cancer, melanoma, lung cancer, and renal cell cancer, among other malignancies.  
This expression of PD-L1 enables inhibition of the local immune response. Blockade of the PD-1/PD-L1 
axis has emerged as a promising therapeutic option to enhance antitumor immunity and is actively being 
investigated in breast cancer, in particular TNBC, with encouraging results.  Atezolizumab (an anti-PD-1 
antibody), in combination with nab-paclitaxel, was recently granted accelerated approval by the FDA for 
patients with metastatic TNBC whose tumors express PD-L122. 
 
A study analyzed PD-L1 mRNA expression in 306 breast cancer tumor samples, including 112 samples 
from IBC23. IBC patients were younger than non-IBC patients and tumor samples were more often 
associated with poor prognosis features: higher grade and stage, ER and progesterone (PR)-negative, 
HER2-positive and aggressive molecular subtypes (basal, HER2-enriched).  The 5-year metastasis-free 
survival was 49% (95% confidence interval [CI]: 37–64%) in IBC patients and 82% (95% CI: 76–88%) in 
non-IBC patients (p= 2.7E-9; log-rank test).  Of the IBC samples, the frequency of PD-L1 mRNA 
overexpression was 38% (42 of 112), and in comparison, 28% of non-IBC samples showed PD-L1 
overexpression.  In IBC, PD-L1 expression was associated with ER-negative status, basal and HER2-
enriched subtypes, as well as CD8+ T-cell specific gene signatures.  Pathologic response to neoadjuvant 


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anthracycline-based chemotherapy was found in 66 out of 112 patients with IBC, of which 22 (33%) had 
achieved pCR.  Expression in tumors (T) was measured as discrete value after comparison with mean 
expression in normal breast samples (NB): overexpression, designated as ‘PD-L1-high’, was defined by a 
T/NB ratio ≥ 2 and no overexpression, or ‘PD-L1-low’, was designated by a T/NB ratio <2. Higher PD-L1 
expression correlated with improved pathological response to neoadjuvant anthracycline-based 
chemotherapy (pCR rate was 50% in the ‘PD-L1 high’ group and 20% in the ‘PD-L1 low’ group). Tumors 
with high PD-L1 expression also showed a more dense T-cell infiltration, with positive correlation between 
PD-L1 expression and the presence of elevated TILs, higher expression of T-cell-specific and CD8+ T-cell-
specific gene expression signatures, and higher expression of genes coding proteins related to the T-cell 
receptor.   
 
1.1.3 Study Rationale and Hypothesis 
 
IBC remains frequently resistant to standard treatment approaches, including neoadjuvant chemotherapy,  
and shows a predictable pattern of early recurrence and systemic spread of disease with poor prognosis.  
There is therefore an unmet need for identification of new therapeutic targets and novel systemic 
therapeutic approaches in this aggressive type of breast cancer.  Blockade of the PD-1/PD-L1 axis has 
emerged as a promising option to enhance anti-tumor immunity and clinical responses.  PD-L1 expression 
in IBC is frequent and may predict for improved response to chemotherapy and should be investigated in 
the neoadjuvant setting.  Achieving a pCR to neoadjuvant therapy is associated with favorable disease-free 
survival and OS.  We hypothesize that PD-1 blockade with nivolumab in combination with standard 
neoadjuvant (primary) systemic chemotherapy will be well tolerated and will increase the rate of pCR and 
reduce risk of recurrence in patients with IBC compared to known efficacy of neoadjuvant chemotherapy 
alone.   
1.2 Investigational Agent 
1.2.1  Nivolumab and Mechanism of Action  
 
Nivolumab (also referred to as BMS-936558, MDX1106, or ONO-4538) is a human monoclonal antibody 
(HuMAb; immunoglobulin G4 [IgG4]-S228P) that targets the PD-1 cluster of differentiation 279 (CD279) cell 
surface membrane receptor. PD-1 is a negative regulatory molecule expressed by activated T and B 
lymphocytes24. Binding of PD-1 to its ligands, PD-L1 and PD-L2, results in the downregulation of 
lymphocyte activation. Inhibition of the interaction between PD-1 and its ligands promotes immune 
responses and antigen-specific T-cell responses to both foreign antigens as well as self-antigens. 
OPDIVOTM (nivolumab) is approved for the treatment of several types of cancer and is also being 
investigated in various other types of cancer as monotherapy or in combination with other therapies. 
 
1.2.2  Preclinical Data for Nivolumab 
 
Nivolumab has been shown to bind specifically to the human PD-1 receptor and inhibits the interaction of 
PD-1 with its ligands, PD-L1 and PD-L2, resulting in enhanced T-cell proliferation and interferon-gamma 
(IFN-γ) release in vitro.25-27 Nivolumab binds with high affinity to activated human T-cells expressing cell 
surface PD-1 and to cynomolgus monkey PD-1. In a mixed lymphocyte reaction, nivolumab promoted a 
reproducible concentration-dependent enhancement of IFN- release28. In intravenous repeat-dose 
toxicology studies in cynomolgus monkeys, nivolumab was well tolerated at doses up to 50 mg/kg, 
administered weekly for 5 weeks, and at doses up to 50 mg/kg administered twice weekly for 27 doses. In 
addition, an enhanced pre- and postnatal development study in pregnant cynomolgus monkeys with 
nivolumab was conducted29.  Administration of nivolumab at up to 50 mg/kg 2QW was well tolerated by 
pregnant monkeys. 
 
1.2.3   Nivolumab Pharmacokinetic Data in Humans  
 
The pharmacokinetics (PK), clinical activity, and safety of nivolumab have been assessed in subjects with 
non-small cell lung cancer (NSCLC), melanoma, clear-cell renal cell carcinoma (RCC), classical Hodgkin 


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Lymphoma (cHL), urothelial carcinoma (UC), squamous cell carcinoma of the head and neck (SCCHN), in 
addition to other tumor types. Nivolumab monotherapy is approved in the United States for unresectable or 
metastatic melanoma, previously treated metastatic NSCLC, previously treated recurrent or metastatic 
SCCHN, previously treated advanced RCC, previously treated relapsed or refractory cHL, and previously 
treated advanced or metastatic UC. In addition, nivolumab has been approved for use in combination with 
ipilimumab for unresectable melanoma. Nivolumab is being investigated both as monotherapy and in 
combination with chemotherapy, targeted therapies, and other immunotherapies for the treatment of 
several types of cancer.  
 
The PK of nivolumab was studied in subjects with cancer over a dose range of 0.1 to 20 mg/kg administered 
as a single dose or as multiple doses of nivolumab every 2 or 3 weeks. Nivolumab clearance (CL) decreases 
over time, with a mean maximal reduction (% coefficient of variation [CV%]) from baseline values of 
approximately 24.5% (47.6%) resulting in a geometric mean steady state clearance (CLss) (CV%) of 8.2 
mL/h (53.9%); the decrease in CLss is not considered clinically relevant. The geometric mean volume of 
distribution at steady state (Vss) was 6.8 L (27.3%), and geometric mean elimination half-life (t1/2) was 25 
days (77.5%). Steady-state concentrations of nivolumab were reached by 12 weeks when administered at 
3 mg/kg Q2W, and systemic accumulation was approximately 3.7-fold. The exposure to nivolumab 
increased dose proportionally over the dose range of 0.1 to 10 mg/kg administered every 2 weeks. 
Additionally, nivolumab has a low potential for drug-drug interactions.  The clearance of nivolumab 
increased with increasing body weight. The PPK analysis suggested that the following factors had no 
clinically important effect on the CL of nivolumab: age (29 to 87 years), gender, race, baseline LDH, PD-L1 
status, solid tumor type, baseline tumor size, and hepatic impairment. 
 
PPK and exposure response analyses have been performed to support use of nivolumab 240 mg Q2W, 
360 mg Q3W, and 480 mg Q4W dosing regimens in subjects with cancer in addition to the 3 mg/kg Q2W 
regimen. A flat dose of nivolumab 240 mg Q2W was selected since it is identical to a dose of 3 mg/kg for 
subjects weighing 80 kg, the observed median body weight in nivolumab treated cancer patients, while the 
nivolumab 360 mg Q3W and 480 mg Q4W regimens allow flexibility of dosing with less frequent visits and 
in combination with other agents using alternative dosing schedules to Q2W.   
 
Using a PPK model, the overall distributions of nivolumab exposures (Cavgss, Cminss, Cmaxss, and 
Cmin1) are comparable after treatment with either nivolumab 3mg/kg or 240 mg Q2W. Following nivolumab 
360 mg Q3W and 480 mg Q4W, Cavgss are expected to be similar to those following nivolumab 3 mg/kg 
or 240 mg Q2W, while Cminss are predicted to be 6% and about 16% lower, respectively, and are not 
considered to be clinically relevant. Following nivolumab 360 mg Q3W and 480 mg Q4W, Cmaxss are 
predicted to be approximately 23% and about 43% greater, respectively, relative to that following nivolumab 
3 mg/kg Q2W dosing. However, the range of nivolumab exposures (median and 90% prediction intervals) 
following administration of 240 mg flat Q2W, 360 mg Q3W, and 480 mg Q4W regimens across the 35 to 
160 kg weight range are predicted to be maintained well below the corresponding exposures observed with 
the well tolerated 10 mg/kg nivolumab Q2W dosing regimen.   
 
1.2.4   Nivolumab Clinical Efficacy 
 
Nivolumab has demonstrated durable responses exceeding six months as monotherapy and in combination 
with ipilimumab in several tumor types, including NSCLC, melanoma, RCC, cHL, small cell lung cancer, 
gastric cancer, SCCHN, urothelial cancer, hepatocellular carcinoma, and colorectal cancer. In confirmatory 
trials, nivolumab as monotherapy demonstrated a statistically significant improvement in OS as compared 
with the current standard of care in subjects with advanced or metastatic NSCLC, unresectable or 
metastatic melanoma, advanced RCC, or SCCHN. Nivolumab in combination with ipilimumab improved 
PFS and ORR over ipilimumab alone in subjects with unresectable or metastatic melanoma.  
 
1.2.5   Nivolumab Clinical Safety 
 
The overall safety experience with nivolumab, as monotherapy or in combination with other therapeutics, 
is based on experience in approximately 16,900 subjects treated to date.  For monotherapy, the safety 


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profile is similar across tumor types. There is no pattern in the incidence, severity, or causality of AEs to 
nivolumab dose level. In phase 3 controlled studies, the safety profile of nivolumab monotherapy is 
acceptable in the context of the observed clinical efficacy, and manageable using established safety 
guidelines. Clinically relevant AEs typical of stimulation of the immune system were infrequent and 
manageable by delaying or stopping nivolumab treatment and timely immunosuppressive therapy or other 
supportive care.  In several ongoing clinical trials, the safety of nivolumab in combination with other 
therapeutics such as ipilimumab, cytotoxic chemotherapy, anti-angiogenics, and targeted therapies is being 
explored. Most studies are ongoing and, as such, the safety profile of nivolumab combinations continues 
to evolve.  
1.3 Clinical Data to Date 
 
1.3.1 Combined Modality Treatment with Anthracycline-based Chemotherapy in IBC  
 
Between May 1973 and September 1993, 178 previously untreated patients with IBC without distant 
metastasis were treated at MDACC by a combined-modality approach under four different protocols30. Each 
protocol included induction chemotherapy, then local therapy (radiotherapy or mastectomy), then adjuvant 
chemotherapy, and if mastectomy was performed, adjuvant radiotherapy. Chemotherapy consisted of 5-
fluorouracil, doxorubicin, and cyclophosphamide (FAC) with or without vincristine and prednisone (VP). In 
one protocol, patients received an alternate adjuvant chemotherapy regimen, methotrexate and vinblastine 
(MV), if they did not achieve a complete response (CR) to induction chemotherapy. Results of the study 
showed that 28% of patients were currently free of disease beyond 15 years. An important prognostic factor 
was initial response to induction chemotherapy. At 15 years, DFS was 44% in patients who had a CR to 
induction chemotherapy, 31% in those who had a partial response (PR), and 7% in those who had less 
than a PR.  These long-term follow-up data show that with a combined modality approach a significant 
fraction of patients (28%) remained free of disease beyond 15 years. In contrast, single-modality treatments 
had a DFS of less than 5%. Therefore, using combined-modality treatment is recommended as a standard 
of care for IBC. 
 
1.3.2   Addition of Taxanes to Preoperative Systemic Therapy in IBC 
 
A later retrospective study at MDACC demonstrated that the addition of paclitaxel to anthracycline-based 
therapy resulted in a statistically significant improvement in outcome in patients with ER-negative IBC10.  A 
total of 240 patients treated between 1973 and 2000 in six consecutive trials were included in the analysis. 
Group 1 (n= 178) consisted of patients treated in the first 4 trials (1973-1993) with FAC (5-fluorouracil, 
doxorubicin, cyclophosphamide). Group 2 (n= 62) consisted of patients treated in the last 2 trials (1994-
2000) with FAC followed by paclitaxel given every 3 weeks or given in a high-dose weekly schedule. The 
two groups differed with respect to median follow-up durations, which were 148 months (range, 85-283 
months) in Group 1 and 45 months (range, 21-99 months) in Group 2. ER status was negative in 58 cases 
(33%) in Group 1 and 40 cases (65%) in Group 2. The objective response rates were similar (Group 1, 
74%; Group 2, 82%). The median overall PFS and OS were improved in the patients treated with paclitaxel, 
and these differences reached statistical significance in the patients with ER-negative disease (median OS: 
Group 1, 32 months; Group 2, 54 months; p= 0.03; median PFS: Group 1, 18 months; Group 2, 27 months; 
p= 0.04). 
 
A systematic review of 27 studies of IBC totaling 1232 patients found that pCR rates after no anthracycline 
induction, low-dose anthracycline induction, moderate-dose anthracycline induction, and neoadjuvant high-
dose chemotherapy subgroups were 4% (95% CI, 1%-18%), 11% (95% CI, 7%-17%), 14% (95% CI, 8%-
22%), and 32% (95% CI, 24%-41%), respectively31.  The criteria and reporting of IBC and treatment 
response was notably variable, with significant potential for subject heterogeneity. pCR rates appeared to 
be related to intensity of neoadjuvant treatment.   
 
Metastases to axillary lymph nodes (ALN) is a known prognostic factor in breast cancer, with pCR in ALN 
after chemotherapy being associated with significantly higher recurrence-free survival (RFS) and OS rates.  
A study evaluated the long-term outcome in patients with IBC achieving a pCR of cytologically proven ALN 


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metastases after primary chemotherapy11. Patients with cytologically documented ALN metastases from 
IBC were treated in three prospective primary chemotherapy trials. After surgery, patients were subdivided 
into those with and without residual ALN carcinoma. Of 175 patients treated, 61 had cytologically confirmed 
ALN metastases. Fourteen patients (23%) achieved a pCR of the ALNs after primary chemotherapy. The 
5-year OS and RFS rates were found to be improved in those patients achieving a pCR of the ALNs (82.5% 
[95% CI, 62.8-100], and 78.6% [95% CI, 59.8-100], respectively, vs. 37.1% [95% CI, 25.4-54.2] and 25.4% 
[95% CI, 15.5-41.5], respectively) (p=0.01 [for OS] and p=0.001 [for RFS]). In addition, combination 
anthracycline and taxane-based primary chemotherapy resulted in significantly more patients achieving an 
ALN pCR (45% vs. 16%; p=0.01).  
1.3.3   Targeted Therapies in HER2-positive IBC  
 
HER2-positive IBC is associated with an overall poor prognosis17, although the introduction of HER2-
targeting antibodies has improved outcomes.  The phase III NOAH trial compared one year of treatment 
with trastuzumab (given as neoadjuvant and adjuvant treatment; n=117) with no trastuzumab (n=118), in 
patients with HER2-positive locally advanced or IBC receiving neoadjuvant chemotherapy with doxorubicin, 
paclitaxel, cyclophosphamide, methotrexate, and fluorouracil13.  A total of 62 patients with IBC were 
included in the study, of which 32 patients received trastuzumab and 31 did not.  The primary endpoint was 
event-free survival 12.  The 5-year EFS was 58% (95% CI, 48–66) in the trastuzumab group and 43% (95% 
CI, 34–52) in the chemotherapy alone group; the unadjusted hazard ratio (HR) for event-free survival 
between the two randomized HER2-positive treatment groups was 0.64 (95% CI, 0.44-0.93; two-sided log-
rank p=0·016).  EFS was strongly associated with pCR in patients given trastuzumab. Of the 68 patients 
with a pCR (45 with trastuzumab and 23 with chemotherapy alone), the HR for EFS between those with 
and without trastuzumab was 0.29 (95% CI, 0.11-0.78).  Generally, patients with inflammatory disease or 
negative hormonal receptors had a more pronounced benefit from trastuzumab.  For the patients with IBC 
who received trastuzumab, the 5-year EFS was 64% versus 24% for those who did not receive trastuzumab 
(HR 0.34; 95% CI, 0.15-0.80).   The 5-year OS for the patients with IBC was 74% versus 44%, respectively 
(HR 0.38; 95% CI, 0.15-0.95)32. 
 
There was multicenter open-label, phase 2 neoadjuvant study (NeoSphere, NCT00545688), of women with 
locally advanced HER2-positive breast cancer and IBC who were randomly assigned to receive four cycles 
of: trastuzumab plus docetaxel (group A), or pertuzumab and trastuzumab plus docetaxel (group B), or 
pertuzumab and trastuzumab (group C), or pertuzumab plus docetaxel (group D)14.  Pertuzumab is a 
monoclocal antibody that binds to a different epitope on HER2 and blocks the formation of HER2 and HER3 
heterodimers.  The primary endpoint of this study was pCR in the breast.  Of 417 eligible patients, 107 were 
randomly assigned to group A (7 with IBC), 107 to group B (10 with IBC), 107 to group C (7 with IBC), and 
96 to group D (5 with IBC). Patients who were given pertuzumab and trastuzumab plus docetaxel (group 
B) had a significantly improved pCR rate (49 of 107 patients; 45.8% [95% CI, 36.1-55.7]) compared with 
those given trastuzumab plus docetaxel (group A; 31 of 107; 29.0% [95% CI, 20.6-38.5]; p=0.0141). There 
were no substantial differences in tolerability or toxicity with the addition of pertuzumab to trastuzumab and 
docetaxel, including the risk of cardiac adverse events.  The mean maximum decrease in left ventricular 
ejection fraction (LVEF) measurement was 4-5% and was balanced across the four treatment groups. No 
significant change was detected when pertuzumab was added to trastuzumab and no patient had an LVEF 
decrease to less than 40% at any time during the study.   
 
The main objective of the phase II TRYPHAENA trial (NCT00976989) was to evaluate tolerability, with a 
focus on cardiac safety, of pertuzumab plus trastuzumab in combination with standard neoadjuvant 
anthracycline-containing and anthracycline-free chemotherapy regimens in patients with HER2-positive 
locally advanced or IBC33.  A total of 225 patients (13 with IBC) were randomized to 5-fluorouracil, 
epirubicin, cyclophosphamide [FEC] followed by docetaxel, with trastuzumab and pertuzumab starting 
either concurrently with FEC (Arm A) or upon initiation of docetaxel (Arm B) or to docetaxel, carboplatin, 
trastuzumab, and pertuzumab (Arm C).  The combination of trastuzumab and pertuzumab was generally 
well tolerated regardless of whether it was given sequentially or concomitantly with anthracycline-based 
chemotherapy, or combined with carboplatin-based chemotherapy.  During neoadjuvant treatment, two 
patients (2.7%; Arm B) experienced symptomatic left ventricular systolic dysfunction (LVSD) and 11 
patients (Arm A: 4 [5.6%]; Arm B: 4 [5.3%]; Arm C: 3 [3.9%]) had declines in LVEF of ≥10% points from 


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baseline to <50%.  Safety outcomes at 3 years were recently reported and no new safety signals were 
identified34.    
The phase III APHINITY trial (NCT01358877) assessed the combination of pertuzumab and trastuzumab 
with chemotherapy in the adjuvant setting35. The 3-year rate of invasive-disease-free survival were 94.1% 
in the pertuzumab group and 93.2% in the placebo group. In patients with node-positive disease, the 3-
year rate of invasive-disease-free survival was 92.0% in the pertuzumab group, as compared with 90.2% 
in the placebo group (HR for an invasive-disease event, 0.77; 95% CI, 0.62 to 0.96; p= 0.02). In the cohort 
of patients with node-negative disease, the 3-year rate of invasive-disease-free survival was 97.5% in the 
pertuzumab group and 98.4% in the placebo group (HR for an invasive-disease event, 1.13; 95% CI, 0.68 
to 1.86; p= 0.64). 
1.3.4  Neoadjuvant Treatment with Bevacizumab in IBC 
IBC is molecularly associated with high vascularity, increased microvessel density, and high expression of 
angiogenic factors such as vascular endothelial growth factor (VEGF)36. Bevacizumab is a humanized 
monoclonal antibody that targets VEGF-A. The multicenter, single-arm, phase II BEVERLY-1 study 
(NCT00820547) showed that the addition of bevacizumab to neoadjuvant and adjuvant chemotherapy did 
not provide clinical benefit to patients with HER2-negative IBC37.   A total of 101 patients were enrolled.  
Patients 
underwent 
3-week 
treatment 
cycles, 
receiving 
neoadjuvant 
fluorouracil, 
epirubicin, 
cyclophosphamide (FEC), and bevacizumab during cycles 1-4, then docetaxel and bevacizumab during 
cycles 5–8.  Two to four weeks after surgery, the patients received adjuvant radiotherapy, hormone therapy 
(if they had a HR-positive tumor), and adjuvant bevacizumab. The primary endpoint was pCR in breast and 
axillary lymph nodes after neoadjuvant treatment.  After neoadjuvant therapy, 19 (19% [95% CI 12–28]; 
p=0·16) of 100 patients achieved a pCR. The most frequent grade 3-4 events during the neoadjuvant phase 
were neutropenia (89 [89%] of 100 patients), febrile neutropenia (37 [37%]), and mucositis (23 [23%]) and 
during the adjuvant phase the most frequent grade 3-4 adverse event was proteinuria (5 [7%] of 75 
patients). Overall, the proportion of patients achieving a pCR was inferior or equal to that which has been 
reported without bevacizumab.    
Similarly, the phase 2 multicenter open label single arm BEVERLY-2 trial (NCT00717405) evaluated 
neoadjuvant and adjuvant bevacizumab in combination with chemotherapy for patients with HER2-positive 
inflammatory breast cancer38.  A total of 52 patients were enrolled.  One year of treatment with bevacizumab 
plus a trastuzumab and anthracycline-taxane-based regimen was well tolerated and 33 of 52 patients had 
a pCR (63.5%, 95% CI 49.4-77.5). The most common adverse events were asthenia and nausea (both 
occurred in 36 [69%] of 52 patients). A total of 25 (48%) patients had grade 3-4 neutropenia, which was the 
most common grade 3-4 adverse event. Only one grade 3 or worse adverse event regarded as related to 
bevacizumab was reported (hypertension, one patient). Four patients (8%) had cardiac failure. Survival 
rates at three years were encouraging, with 68% disease-free survival (DFS) and 90% overall survival 
(OS)9.  Furthermore, a pooled analysis of the BEVERLY-1 and BEVERLY-2 trials looking at the predictive 
and prognostic role of circulating tumor cells (CTCs) showed that the detection rate of CTCs was 39% with 
independent prognostic value for survival39.  After neoadjuvant therapy, the combination of pCR with no 
CTC detection at baseline yielded a subgroup of patients with IBC with improved prognosis (3-year OS of 
94%).  Further larger and randomized studies evaluating the potential benefit of antiangiogenic therapy in 
this setting, as well as the role of CTCs as part of IBC stratification, are needed. 
 
A recently published phase II trial studied the clinical efficacy of neoadjuvant treatment with weekly 
carboplatin and paclitaxel plus oral metronomic cyclophosphamide in association with bevacizumab for 
patients with primary or recurrent IBC who were candidates for locoregional treatment40. Patients with 
HER2-positive IBC tumors received trastuzumab. Patients with HR-positive disease received concomitant 
endocrine therapy.  Oral metronomic capecitabine and cyclophosphamide was continued for 6 months after 
surgery in those patients with a response.  Thirty-four patients with IBC were included and treatment was 
well tolerated and safe.  The overall response rate (ORR) was 88%, and the pCR rate was 29%, with the 
most significant effect of neoadjuvant therapy observed in patients with HER2-positive cancer. The 
achievement of pCR was associated with longer DFS and OS. 


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1.3.5 Neodjuvant Therapy with Carboplatin in TNBC 
The efficacy of the addition of carboplatin to neoadjuvant therapy for patients with previously untreated 
state II or III TNBC and HER2-positive breast cancer was assessed in the randomized phase II GeparSixto 
trial (NCT01426880)41.  Patients were treated for 18 weeks with paclitaxel and non-pegylated liposomal 
doxorubicin. Those with TNBC received simultaneous bevacizumab.  Patients with HER2-positive disease 
received simultaneous trastuzumab and lapatinib.  Patients were randomly assigned at the same to either 
carboplatin (AUC 1.5 [2.0 for the first 329 patients] once a week) or no carboplatin.  A total of 296 patients 
received carboplatin and another 296 patients did not receive carboplatin.  A total of 129 patients (95% CI, 
43.7; 38.1-49.4) in the carboplatin group achieved a pCR, compared with 108 patients (95% CI, 36.9; 31.3-
42.4) without carboplatin (odds ratio 1.33, 95% CI, 0.96-1.85; p=0.107). For the patients with TNBC, 84 
(53.2%, 54.4-60.9) of 158 patients achieved a pCR with carboplatin, compared with 58 (36.9%, 29.4–44.5) 
of 157 without carboplatin (p=0.005).  However, responses were not increased in patients with HER2-
positive breast cancer.  Toxicities were significantly more common in the carboplatin group than in the non 
carboplatin group including grade 3 or 4 neutropenia, anemia, thrombocytopenia, and diarrhea.  Carboplatin 
was also more often associated with dose discontinuations (141 [48%] with carboplatin and 114 [39%] 
without carboplatin; p=0.031).   
 
The CALGB 40603 (Alliance) trial was a 2x2 factorial, open-label, randomized phase II trial that evaluated 
the impact of adding carboplatin and/or bevacizumab to neoadjuvant paclitaxel followed by doxorubicin and 
cyclophosphamide in TNBC42.  Patients (n=443) with stage II to III TNBC received paclitaxel once per week 
for 12 weeks followed by doxorubicin plus cyclophosphamide once every 2 weeks for four cycles, and were 
randomly assigned to concurrent carboplatin (AUC 6) once every 3 weeks for four cycles and/or 
bevacizumab 10 mg/kg once every 2 weeks for nine cycles.   Results showed that patients assigned to 
either carboplatin or bevacizumab were less likely to complete weekly paclitaxel and doxorubicin plus 
cyclophosphamide without dose modification, skipped doses, or early discontinuation due to toxicity.  Grade 
3 or 4 neutropenia and thrombocytopenia were more common with carboplatin, and hypertension, infection, 
thromboembolic events, bleeding, and postoperative complications were more common with bevacizumab. 
The addition of either carboplatin (60% v 44%; p=0.0018) or bevacizumab (59% v 48%; p=0.0089) 
significantly increased pCR in the breast, whereas only carboplatin (54% v 41%; p=0.0029) significantly 
increased pCR in the breast/axilla. More-than-additive interactions between the two agents could not be 
demonstrated.  
Of note, these trials did not show specific results for patients with IBC (GeparSixto) or excluded IBC patients 
(CALGB 40603).  Per international consensus on the clinical management of IBC from the Morgan Welch 
Inflammatory Breast Cancer Research Program 10th Anniversary Conference held at MDACC in 2017, 
although neoadjuvant carboplatin has been shown to increase pCR rates in TNBC, there is still not enough 
evidence supporting long term clinical efficacy at this time to recommend routine use in IBC6.   
1.3.6 Neoadjuvant Therapy with Anti-PD-1/PD-L1 Antibodies in TNBC 
No neoadjuvant chemoimmunotherapy trial has been reported for IBC patients, however trials in TNBC are 
being conducted and early results have shown promise.  The recently reported phase 2 randomized, 
multicenter I-SPY2 study (an adaptive trial platform to test novel agents) achieved an increase in pCR in 
patients who had locally advanced (stage II/III) TNBC or HR-positive/HER2-negative breast cancer when 
pembrolizumab was added to the taxane segment of the standard neoadjuvant regimen, followed by 
doxorubicin and cyclophosphamide (NCT01042379)43.  In total, 249 patients were randomized, of whom 
69 were to receive pembrolizumab in combination with paclitaxel, 180 were to receive paclitaxel alone in 
the control arm, and all patients then continued to receive neoadjuvant doxorubicin and cyclophosphamide. 
The findings indicated that the estimated pCR rate (negative pathologic post-treatment tumor 
classification/tumor in situ and negative pathologic post-treatment lymph node status [ypT0/Tis ypN0]) was 
significantly higher with the addition of pembrolizumab in patients who had TNBC (60% vs 20%, 
respectively) and in those who had HR-positive/HER2-negative breast cancer (34% vs 13%) compared with 


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standard therapy, and the predictive probability of success in a phase 3 trial was 99%. No additive toxicities 
were observed except for an excess of adrenal insufficiency in the pembrolizumab arm, which appeared to 
be greater than that reported from chemoimmunotherapy trials conducted in other cancer types. This finding 
is significant, because management requires long-term steroid replacement for patients who are treated in 
the curative setting.  
 
Preliminary results from additional randomized neoadjuvant trials in TNBC combining standard cytotoxic 
regimens with immunotherapy also recently were reported. The phase 1b KEYNOTE-173 study evaluated 
pembrolizumab plus chemotherapy as neoadjuvant therapy for locally advanced TNBC in 2 cohorts 
(NCT02622074)44. Preliminary data were reported from 10 patients in cohort A (single-dose 
pembrolizumab, followed by 4 cycles of pembrolizumab every 3 weeks in combination with weekly nab-
paclitaxel, followed by 4 cycles of pembrolizumab in combination with doxorubicin 60 mg/m2 and 
cyclophosphamide 600 mg/m2 every 3 weeks) and 10 patients in cohort B (the same treatment as in cohort 
A plus carboplatin at an area under curve (AUC) of 6 every 3 weeks was added to pembrolizumab and nab-
paclitaxel). The ypT0/Tis ypN0 pCR rate (no invasive residual disease in the breast and lymph nodes) was 
60% (90% CI, 30%-85%) in cohort A and 90% (90% CI, 61%- 100%) in cohort B.  
 
In the randomized phase 2 GeparNuevo study, durvalumab, a monoclonal antibody that binds to PD-L1, 
was added to an anthracycline-containing and taxane- containing neoadjuvant regimen for patients with 
TNBC (NCT02685059)45.  The patients received durvalumab or placebo monotherapy for the first 2 weeks 
(window phase), followed by durvalumab or placebo plus nab-paclitaxel weekly for 12 weeks, followed by 
durvalumab or placebo plus dose-dense epirubicin and cyclophosphamide every 2 weeks for 4 cycles. Of 
the 50 patients enrolled, the addition of immune checkpoint blockade to standard neoadjuvant 
chemotherapy did not identify unexpected toxicity, and most AEs included chemotherapy-related toxicities.  
In the recently reported phase 2 portion, a total of 174 patients were enrolled and all had completed 
treatment46.  Median age was 49.5 years [range 23.0-76.0], and 44.5% of patients had cT1, 49.7% cT2, 
3.5% cT3, and 2.3% cT4 tumors. Eighty-three percent of the tumors were grade 3. Approximately 31% 
were cN-positive tumors.  Overall, the addition of durvalumab increased the pCR from 44.2 to 53.4%, 
although this was not statistically significant (OR 1.53).  As per subgroup analysis, the patients who started 
with durvalumab were found to have the greatest benefit with pCR of 61%. Additionally, patients with stage 
IIA or higher tumors and those who were 40 years of age or younger achieved a pCR rate of greater than 
60%.  A total of 86 serious adverse events (SAEs) and 65 immune related AEs of special interest (irAESI) 
were reported; 34.5% of pts had at least one SAE and 27.6% had at least one irAESI. The irAESI were 
related to endocrine disorders of the thyroid gland.  In addition, the safety of administering durvalumab 
concomitant with sequential taxane and anthracycline neoadjuvant chemotherapy was studied in a phase 
1/2 single-arm trial of stage I through III TNBC (NCT02489448). Patients received durvalumab in 
combination with weekly nab-paclitaxel, followed by dose-dense doxorubicin and cyclophosphamide with 
durvalumab. The phase 1 portion established the safety of the combination47.  
 
In summary, while there appears to be efficacy in terms of increased pCR rates in TNBC with the addition 
of immunotherapy to standard neoadjuvant chemotherapy, toxicity has been observed and may be worse 
with the combination with anthracycline.  Therefore at this time, only patients with poor prognosis—such as 
those with IBC—should be considered for these types of clinical studies, and concurrent therapy with 
immunotherapy should be given during the non-anthracycline containing segment. 
 
1.3.7 Treatment with Anti-PD-1/PD-L1 Antibodies in HER2-positive Advanced Breast 
Cancer  
 
The phase Ib/II PANACEA trial (BIG 4-13/IBCSG 45-13) (NCT02129556) evaluated the combination of 
pembrolizumab and trastuzumab in 58 patients with HER2-positive advanced breast cancer who had 
progressed on a prior trastuzumab-based therapy48. Tumors were assessed centrally for HER2-positivity 
and programmed cell death ligand 1 (PD-L1) status, and for quantity of tumor-infiltrating lymphocytes (TILs).  
The phase Ib portion was a dose-escalation study of pembrolizumab, an anti-PD-1 antibody, in conjunction 
with the standard dose of trastuzumab. No dose-limiting toxicities were observed. In the phase II portion, 
40 patients and 12 patients were enrolled to the PD-L1–positive and PD-L1–negative cohorts, respectively. 
Patients received 200mg of pembrolizumab every 3 weeks in combination with the standard dose of 


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trastuzumab for 24 months or until disease progression.  In the PD-L1–positive intent-to-treat population, 
the trial met its primary endpoint with an objective response rate of 15% and disease control rate of 25%. 
In a subgroup of PD-L1–positive patients with 5% or more TILs present in the metastatic lesion, the 
objective response rate was 39% and the disease control rate was 47%.  No responses were observed in 
the PD-L1–negative cohort.  Pembrolizumab with trastuzumab was well tolerated, with grade 1 to 2 fatigue 
as the most commonly reported adverse event (21%). The most common immune-related adverse events 
reported were hyper- and hypo-thyroidism (grade 1–2 at 6.7%) and pneumonitis (grade 3-4 at 3.4%). 
 
1.3.8    Select Ongoing Neoadjuvant Studies in IBC 
 
Table 1 lists select ongoing neoadjuvant clinical trials in IBC. 
Study Phase 
and Title 
Study Agents 
Population 
Enrollment 
Primary 
Endpoint 
NCT ID No. 
Randomized, phase 
II open label 
 
PELICAN: 
Immunotherapy in 
combination with 
chemotherapy in 
HER2-negative IBC 
 
FEC (if HR-positive IBC)
 
weekly paclitaxel 
 
dose-dense EC (if HR-
negative IBC) 
 weekly 
paclitaxel 
 
Experimental arm will 
receive pembrolizumab q 3 
weeks during neoadjuvant 
chemotherapy 
 
HER2-
negative IBC  
81/ongoing 
pCR 
(ypT0/is, 
ypN0) 
NCT03515798 
 
Single arm, phase II 
open label 
Panitumumab, nab-
paclitaxel and 
carboplatin for 
HER2-negative IBC 
PNC (panitumumab + nab-
paclitaxel + carboplatin) + 
FEC (5-fluorouracil, 
epirubicin, and 
cyclophosphamide) 
HER2-
negative IBC  
40/completed 
pCR  
(ypT0, 
ypN0) 
NCT01036087 
 
Single arm, phase II 
open label 
Eribulin followed by 
doxorubicin and 
cyclophosphamide 
as preoperative 
therapy for HER2-
negative IBC 
 
Eribulin 
 AC 
HER2-
negative IBC  
25/ongoing 
pCR (will 
be reported 
as residual 
cancer 
burden 
[RCB]) 
NCT02623972 
 
Randomized, phase 
II open label 
Ruxolitinib 
(INCB018424) with 
preoperative 
chemotherapy for 
triple negative IBC 
Paclitaxel +/- Ruxolitinib 
 
AC 
HR-/HER2- 
IBC  
64/ongoing 
Assess 
JAK 
inhibition 
with 
Ruxolitinib 
on pStat3+ 
expression 
 
NCT02876302 
 


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Randomized, phase 
II open label 
Carboplatin/ 
paclitaxel versus 
panitumumab/ 
carboplatin/ 
paclitaxel followed 
by anthracycline-
containing regimen 
for newly diagnosed 
primary triple-
negative IBC 
 
Carboplatin/Paclitaxel  
AC versus 
Panitumumab/Carboplatin/
Paclitaxel 
 AC 
HR-/HER2- 
IBC  
72/ongoing 
pCR 
NCT02876107 
 
Single arm, phase II 
open label 
 
Paclitaxel combined 
with trastuzumab 
and pertuzumab as 
pre-operative 
therapy for IBC 
 
Paclitaxel +Trastuzumab 
+Pertuzumab 
 
Mastectomy 
  
Option 1: AC 
 
Trastuzumab +Pertuzumab 
to complete one year of 
therapy 
Option 2: Trastuzumab 
+Pertuzumab to complete 
one year of therapy 
HER2+ IBC  
23/completed 
pCR 
NCT01796197 
 
 
1.4 Dose Rationale and Schedule 
 
The treatment to be used in this trial is outlined below and in Table 2/3 and Table 4/5. 
 
Cohort 1: TNBC or HR-positive/HER2-negative 
 
1. Cycle 1-4, 21 day cycle 
• 
Nivolumab 360 mg IV on Day 1 x 4 cycles and Paclitaxel 80 mg/m2 IV on Day 1, 8, and 15 x 4 
cycles, followed by 
 
2.  Cycle 5-8, 14 day cycle 
• 
Doxorubicin 60 mg/m2 IV on Day 1 x 4 cycles and Cyclophosphamide 600 mg/m2 IV on Day 1 x 4 
cycles  
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Table 2 
 
Drug 
Dose/ 
Potency 
Dose Frequency 
Route of 
Administration 
Use 
Nivolumab 
 
360 mg 
Day 1 of every 21 day cycle 
(Cycle 1-4) 
Intravenous (IV) 
Experimental 
Paclitaxel 
80 mg/m2 
Day of 1, 8, 15 of every 21 
day cycle (Cycle 1-4) 
IV 
Standard 
Doxorubicin 
60 mg/m2 
Day of 1 of every 14 day 
cycle (Cycle 5-8) 
IV 
Standard 
Cyclophosphamide 
600 mg/m2  
Day of 1 of every 14 day 
cycle (Cycle 5-8) 
IV 
Standard 
 
Table 3 
 
 
Cycle 1-4  
Cycle 5-8  
Nivolumab 
X 
 
Paclitaxel 
X 
 
Doxorubicin 
 
X 
Cyclophosphamide 
 
X 
 
Cohort 2: HR-positive/HR-negative and HER2-positive:  
 
1. Cycle 1-4, 21 day cycle 
• 
Nivolumab 360 mg IV on Day 1 x 4 cycles, + Docetaxel 75 mg/m2 IV on Day 1 x 4 cycles or 
Paclitaxel 80 mg/m2IV on Day 1, 8, and 15 x 4 cycles, + Trastuzumab* 8 mg/kg IV on Day 1 of 
Cycle 1 and then 6 mg/kg IV on Day 1 of Cycle 2-4, + Pertuzumab 840 mg IV on Day 1 of Cycle 1 
and then 420 mg IV on Day 1 of Cycle 2-4, followed by 
 
2. Cycle 5-8, 14 day cycle 
• 
Doxorubicin 60 mg/m2 IV on Day 1 x 4 cycles and Cyclophosphamide 600 mg/m2 IV on Day 1 x 4 
cycles  
 
*Trastuzumab biosimilar is allowed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Table 4 
 
Drug 
Dose/ 
Potency 
Dose Frequency 
Route of 
Administration 
Use 
Nivolumab 
 
360 mg 
Day 1 of every 21 day cycle 
(Cycle 1-4) 
Intravenous (IV) 
Experimental 
Docetaxel  
(or Paclitaxel) 
75 mg/m2  
(80 mg/m2) 
Day 1 of every 21 day cycle 
(Day 1, 8, 15 of every 21 day 
cycle)  
(Cycle 1-4) 
IV 
Standard 
Trastuzumab 
(biosimilar is 
allowed) 
8 mg/kg IV on 
Day 1 of Cycle 
1 and then 6 
mg/kg IV on 
Day 1 of Cycle 
2-4 
 Day 1 of Cycle 1 and then 
Day 1 of subsequent cycles 
(2-4) (Cycle 1-4) 
Each cycle is 21 days 
IV 
Standard 
Pertuzumab 
840 mg on Day 
1 of Cycle 1 
and then 420 
mg IV on Day 1 
of Cycle 2-4 
Day 1 of Cycle 1 and then 
Day 1 of subsequent cycles 
(2-4) (Cycle 1-4) 
Each cycle is 21 days 
IV 
Standard 
Doxorubicin 
60 mg/m2 
Day 1 of every 14 day cycle 
(Cycle 5-8) 
IV 
Standard 
 
Cyclophosphamide 
600 mg/m2  
Day 1 of every 14 day cycle 
(Cycle 5-8) 
IV 
Standard 
 
Table 5 
 
 
Cycle 1-4  
Cycle 5-8  
Nivolumab 
X 
 
Docetaxel (or Paclitaxel) 
X 
 
Trastuzumab 
X 
 
Pertuzumab 
X 
 
Doxorubicin  
 
X 
Cyclophosphamide 
 
X 
 
 
Postoperative Therapy: 
 
• 
After mastectomy and axillary lymph node dissection, radiation therapy is recommended as per 
institutional guidelines.  
• 
Patients with HR-positive tumors should receive a minimum of 5 years of adjuvant endocrine 
therapy.  Choice of endocrine therapy is at the discretion of the investigator.   
• 
For HER2-positive tumors, patients with residual disease after neoadjuvant therapy may receive 
ado-trastuzumab emtansine (T-DM1) in the adjuvant setting for 14 cycles49.  Another option is to 
continue trastuzumab with or without pertuzumab to complete one year of HER2-directed therapy35.  
For patients with pathologic complete response (no residual disease), adjuvant trastuzumab can 
be continued with or without pertuzumab to complete one year of HER2-directed therapy.   
Treatment regimen is at the discretion of the investigator.    


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• 
Use of adjuvant capecitabine for 6-8 cycles (permissible after surgery) for patients with TNBC with 
residual disease is at the discretion of the investigator50.   
 
1.4.1 Rationale for Nivolumab Dose and Schedule  
 
The FDA approved dose of nivolumab is 240 mg IV (flat dose) every 2 weeks or 480 mg IV (flat dose) every 
4 weeks in malignancies such colorectal cancer (microsatellite instability-high or mismatch repair deficient), 
recurrent or metastatic squamous cell head and neck cancer, hepatocellular carcinoma, melanoma, 
metastatic NSCLC, metastatic renal cell cancer, or urothelial carcinoma.  This is equal to 120 mg IV weekly.  
PPK and exposure response analyses have been performed to support use of nivolumab 360 mg every 
three weeks.  The phase III CheckMate-227 trial evaluated the combination of nivolumab and ipilimumab 
versus chemotherapy in treatment-naïve patients with NSCLC with high tumor mutation burden (TMB)51.  
Patients with a PD-L1 expression level of less than 1% were randomly assigned (in a 1:1:1 ratio), with 
stratification according to tumor histologic type, to receive nivolumab (3 mg per kilogram every 2 weeks) 
plus ipilimumab (1 mg per kilogram every 6 weeks), platinum doublet chemotherapy based on tumor 
histologic type every 3 weeks for up to four cycles, or nivolumab (360 mg) plus platinum doublet 
chemotherapy based on tumor histologic type every 3 weeks for up to four cycles. The combination 
schedule was overall tolerated and safety was similar to previous reported results52.   
In the current study, nivolumab will be administered every three weeks, therefore the dosing of nivolumab 
will be 360 mg IV every three weeks for four cycles.  Nivolumab will be given at the same time as standard 
taxane chemotherapy with paclitaxel and docetaxel or with HER2-targeted therapy with trastuzumab and 
pertuzumab.  It will not be given at the same time as the anthracycline-based therapy (doxorubicin and 
cyclophosphamide) due to a potential increased risk of cardiotoxicity. Of note, combination therapies of PD-
1/PD-L1 checkpoint inhibitors and taxane chemotherapy have not identified excessive toxicity.  A phase Ib 
study evaluated atezolizumab (anti-PD-1 antibody) plus nab-paclitaxel in patients with metastatic TNBC, 
and the combination was well-tolerated without additive toxicity53.  In the randomized IMpassion 130 trial 
(n=902) with nab-paclitaxel and atezolizumab or placebo, grade ≥3 adverse events occurred in 49% of 
patients receiving atezolizumab and 42% of patients receiving placebo, with grade 3 or 4 neuropathy 
occurring more frequently among those receiving atezolizumab (5.5% versus 2.8%)22.  A phase Ib/II trial 
studied pembrolizumab (anti-PD-1 antibody) and HER2-directed agent, trastuzumab, in advanced HER2-
positive breast cancer, and the combination was also found to be safe without excess cardiac toxicity48.   
1.4.2 Rationale for Chemotherapy Dose and Schedule 
 
Anthracycline and taxane based chemotherapy 
 
For patients with HER2-negative breast cancer who are candidates for neoadjuvant therapy, standard 
therapy consists of anthracycline- and taxane-based chemotherapy regimens.  The meta-analysis of 
adjuvant chemotherapy trials from the Early Breast Cancer Trialists' Collaborative Group (EBCTCG) 
demonstrated benefit for anthracycline-based regimens over cyclophosphamide, methotrexate, plus 
fluorouracil (CMF)54.  In addition, adding taxanes to anthracyclines further improved outcomes in the 
adjuvant setting.  Further rationale for the use of anthracyclines and taxanes in the preoperative setting 
comes from clinical trials of neoadjuvant treatment. In this setting, multiple studies have shown that addition 
of a taxane to an anthracycline-based regimen is associated with increased response rates55-58.   
 
The Neo-tAnGo neoadjuvant trial assessed the sequencing of chemotherapy by evaluating epirubicin and 
cyclophosphamide and paclitaxel (with or without gemcitabine)59. A total of 831 patients were randomized; 
207 received epirubicin and cyclophosphamide then paclitaxel; 208 were given paclitaxel then epirubicin 
and cyclophosphamide; 208 had epirubicin and cyclophosphamide followed by paclitaxel and gemcitabine; 
and 208 received paclitaxel and gemcitabine then epirubicin and cyclophosphamide. 828 patients were 
eligible for analysis. Median follow-up was 47 months, and 207 (25%) patients had inflammatory or locally 
advanced disease, 276 (33%) patients had estrogen receptor (ER)-negative disease, and 191 (27%) 
patients had HER2-positive disease. Addition of gemcitabine did not increase pCR: 70 (17%, 95% CI 14–
21) of 404 patients in the epirubicin and cyclophosphamide then paclitaxel group achieved pCR compared 


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with 71 (17%, 14–21) of 408 patients who received additional gemcitabine (p=0·98). Receipt of a taxane 
before the anthracycline was associated with improved pCR: 82 (20%, 95% CI 16–24) of 406 patients who 
received paclitaxel with or without gemcitabine followed by epirubicin and cyclophosphamide achieved pCR 
compared with 59 (15%, 11–18) of 406 patients who received epirubicin and cyclophosphamide first (p= 
0.03).  Although addition of gemcitabine to paclitaxel and epirubicin and cyclophosphamide chemotherapy 
does not improve pCR, sequencing chemotherapy so that taxanes are received before anthracyclines may 
improve pCR with standard neoadjuvant chemotherapy for breast cancer.   
 
In the current study, the taxane-based chemotherapy (paclitaxel or docetaxel) will be given prior to the 
anthracycline-based chemotherapy (doxorubicin and cyclophosphamide).  Standard dose and schedule of 
paclitaxel, docetaxal, doxorubicin, and cyclophosphamide will be used (Section 1.4). 
 
HER2-targeted therapy with trastuzumab and pertuzumab  
 
For patients with HER2-positive breast cancer that are candidates for preoperative systemic therapy, 
chemotherapy and trastuzumab-based therapy are recommended. Chemotherapy and dual anti-HER2 
blockade associated with trastuzumab plus pertuzumab have shown significant improvements in the pCR 
rate when compared with chemotherapy and one anti-HER2 agent in the preoperative setting. In the 
NeoSphere trial, the addition of pertuzumab to trastuzumab and docetaxel preoperatively led to a 
statistically significant increase in pCR in the breast (16.8% increase; 95% CI, 3.5–30.1; p= 0.0141)14.  In 
the TRYPHAENA trial, preoperative therapy with pertuzumab and trastuzumab given alone with or without 
anthracycline-containing chemotherapy regimens demonstrated pCR rates in all treatment arms ranging 
from 57% to 66%33.  The mean change in LVEF was similar in all treatment arms. The FDA granted 
accelerated approval in 2013 for the addition of pertuzumab to neoadjuvant chemotherapy and trastuzumab 
for patients with HER2-positive locally advanced, inflammatory, or early-stage (either greater than 2 cm in 
diameter or node positive) breast cancer. 
 
In the current study, the standard dose and schedule of trastuzumab and pertuzumab will be used (Section 
1.4).  Use of trastuzumab biosimilar is allowed. 
1.5 Research Risks & Benefits 
1.5.1 Risk of Study Drug 
 
Dose modifications for nivolumab are described in 5.3.  While this is a greater than minimal risk study, 
combination therapies of PD-1/PD-L1 checkpoint inhibitors with taxane chemotherapy or HER2-directed 
therapy with trastuzumab were found to be safe48,53.  The safety of the addition of nivolumab to standard 
chemotherapy will be closely monitored in this study, as described in Sections 4.3.11 and 6.1. 
1.5.2 Other Risks of Study Participation 
 
Additional risks to study participation are listed in the consent form and include breach of confidentiality, 
not deriving benefit from the study treatment, and procedures performed for research only (peripheral blood 
draws and tumor tissue biopsies for correlative studies). Privacy protection procedures are in place and 
good clinical practice guidelines are followed for the study to minimize risks associated with research 
procedures and participation. 
1.5.3 Potential Benefits 
 
It is not known if participation in the study will be beneficial for the patient, although it is anticipated that 
patients will derive clinical benefit from treatment with the combination of nivolumab and chemotherapy. 
 


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2 Study Objectives and Hypotheses 
2.1 Study Objectives 
 
Primary Objective 
 
• 
To determine whether the addition of nivolumab to chemotherapy improves pathologic complete 
response (pCR) in the breast and post-therapy lymph nodes evaluated histologically in patients 
with inflammatory breast cancer (IBC).  This is defined as no histologic evidence of invasive tumor 
cells in the surgical breast specimen, axillary nodes, or sentinel node identified after neoadjuvant 
chemotherapy (ypT0/Tis ypN0). 
 
Secondary Objectives 
 
• 
To evaluate the safety and tolerability of the combination of nivolumab with neoadjuvant 
chemotherapy in IBC. 
• 
To evaluate the invasive recurrence-free interval (IRFI) [time frame: up to 24 months after study 
entry]. This is assessed as the time from study entry until diagnosis of the first invasive local, 
regional, or distant breast cancer recurrence during the 24 months after study entry. 
 
Correlative Objectives 
 
• 
To evaluate PD-L1 expression on tumor and tumor-infiltrating immune cells as a predictor for pCR 
following treatment with neoadjuvant nivolumab and chemotherapy. 
• 
To assess the frequency of mutational and neoantigen load and to explore mutational and 
neoantigen load as predictive markers of response. 
• 
To assess changes in expression levels of biomarkers or biomarker panels before, during, and 
after treatment. 
 
2.2    Hypotheses 
 
Primary Hypothesis 
 
• 
For HER2-negative cohort (including TNBC or HR-positive), the combination of nivolumab with 
neoadjuvant chemotherapy will result in a pCR rate greater than 10% in IBC.   
• 
For HER2-positive cohort (independent of HR status), the combination of nivolumab with 
neoadjuvant chemotherapy will result in a pCR rate greater than 25% in IBC.   
 
Secondary Hypotheses 
 
• 
Treatment with the combination of nivolumab and chemotherapy is safe and well tolerated. 
• 
The combination of nivolumab and chemotherapy will be active (as determined by ORR and IRFI) 
in patients with IBC. 
• 
Subjects with tumoral PD-L1 expression will demonstrate improved pCR rate, clinical response, 
and IRFI compared to subjects without PD-L1 expression. 
 
Exploratory Hypotheses 
 
• 
Patients with tumors containing higher expression of PD-L1 and TILs will have higher pCR rate and 
IRFI compared with patients with tumors with little or no expression. 
• 
Predictive biomarkers in tumor tissue and peripheral blood can be detected. 


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• 
Changes in biomarkers during therapy are predictive of clinical response or resistance in patients 
treated with the combination of nivolumab and chemotherapy. 
 
3 Study Design 
3.1 General Design 
 
This is an open label, multicenter, phase II clinical trial designed to study the efficacy and safety of 
nivolumab in combination with neoadjuvant chemotherapy for patients with IBC (n=52).  
 
 Cohort 1: HER2-negative, including TNBC or HR-positive (26 patients) 
 Cohort 2: HER2-positive, independent of HR status (26 patients) 
 
Expression of tumoral PD-L1 is not required for study entry. 
 
There will be an interim safety analysis in Cohort 2 with 13 patients. If no more than 5 DLT is observed, 
then enrollment will continue to complete Cohort 2.  The subjects from the interim safety analysis will be 
included in the final analysis.  In all patients in both cohorts, safety will be closely monitored to confirm 
tolerability and to assess long-term impact of PD-1 blockade on immune function which remain to be 
established. 
 
We plan to open the study at three sites. Two of the locations will be at NYU Perlmutter Cancer Center and 
its public hospital affiliate, Bellevue Hospital Center.  Bellevue Hospital Center is the oldest public hospital 
in the United States, and the majority of patients cared for are underserved minorities and the indigent 
population. The breast cancer patients that are seen tend to be younger and with more aggressive disease 
biology including IBC. The third site will be at Indiana University. Guidelines for affiliate institutions in 
multicenter studies are described in Appendix 1. 
 
After completion of neoadjuvant therapy, patients will undergo surgery with mastectomy and axillary lymph 
node dissection. Post-mastectomy radiotherapy (per institutional guidelines) is warranted and targets 
should include the chest wall and supraclavicular, infraclavicular, and internal mammary chain nodes.  
Patients with HR-positive tumors should receive a minimum of 5 years of adjuvant hormonal therapy.  
Choice of hormonal therapy is at the discretion of the investigator.  For HER2-positive tumors, patients with 
residual disease after neoadjuvant therapy may receive ado-trastuzumab emtansine (T-DM1) in the 
adjuvant setting for 14 cycles49.  Another option is to continue trastuzumab with or without pertuzumab to 
complete one year of HER2-directed therapy35.  For patients with pathologic complete response (no residual 
disease), adjuvant trastuzumab can be continued with or without pertuzumab to complete one year of 
HER2-directed therapy. Treatment regimen is the discretion of the investigator. The use of adjuvant 
capecitabine for 6-8 cycles for patients (permissible after surgery) with TNBC with residual disease is at the 
discretion of the investigator50.   
 
 
 
 
 
 
 
 
 
 
 
 


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Study Schema (n=52) 
 
 
 
3.2 Primary Study Endpoint 
 
Pathologic complete response (pCR), which is defined as no histologic evidence of invasive tumor cells in 
the surgical breast specimen, axillary nodes, or sentinel node(s) identified after neoadjuvant chemotherapy 
(ypT0/Tis ypN0). 
3.3 Secondary Study Endpoints 
 
a) Patient tolerability and safety with the combination will be assessed using NCI Common Terminology 
Criteria for Adverse Events (CTCAE) version 5. 
 
b) To estimate the invasive recurrence-free interval (IRFI) [time frame: up to 24 months after study entry]. 
This is assessed as the time from study entry until diagnosis of the first invasive local, regional, or distant 
breast cancer recurrence during the 24 months after study entry (would exclude contralateral new 
primaries). 
3.4 Correlative Endpoints 
 
A variety of factors that could potentially predict clinical response to nivolumab will be investigated in tumor 
specimens and peripheral blood.  These will provide important information regarding biological effects of 
this combination therapy in IBC, and changes in patterns based on response to or resistance to therapy.  


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• 
Baseline tumoral expression of PD-L1 and expression of PD-L1 during and following treatment with 
nivolumab and chemotherapy as a predictor for pCR and IRFI will be evaluated. Composition of 
immune response will be investigated, including T cell repertoire, macrophage response, select 
cytokine, transcription factor, and protein kinase responses (e.g. JAK2, mTORC1, IL8, STAT3). 
• 
The frequency of mutational and neoantigen load will be studied as predictive markers of response. 
• 
Changes in expression levels of biomarkers or biomarker panels before, during, and after treatment 
will be evaluated. 
 
4 Subject Selection and Study Assessments 
4.1 Inclusion Criteria 
 
Patients must meet ALL of the following inclusion criteria to be eligible for study entry:  
 
• 
Histological diagnosis of invasive adenocarcinoma of the breast and a clinical diagnosis of IBC 
based on presence of inflammatory changes in the involved breast, including erythema and edema 
(peau d'orange), with or without an underlying palpable mass involving a third or more of the skin 
of the breast (T4d according to American Joint Committee on Cancer (AJCC) breast cancer 
staging, 8th ed.). Pathological evidence of dermal lymphatic invasion should be noted but is not 
required for diagnosis of IBC. 
• 
In case of bilateral cancer, the investigator should decide prospectively which side will be evaluated 
for the primary endpoint. 
• 
Local CLIA-certified laboratory testing on the tumor tissue specimen for ER, PR, and HER2 must 
be performed:  
o 
Hormone Receptor (HR)-positive: defined as estrogen receptor (ER) and/or progesterone  
             receptor (PR) ≥1% per ASCO-CAP guidelines60 
o 
HER2-positive: IHC 3+ or 2+ with HER2/CEP17 ratio >2.0 or average HER2 copy number 
>6.0 signals/cell per ASCO-CAP guidelines61 
o 
TNBC: defined as ER/PR<1% and HER2-negative per ASCO-CAP guidelines60  
• 
Age > 18 years, individuals of all races and ethnic groups are eligible 
• 
Eastern Cooperative Group (ECOG) performance status of 0 or 1 (see Appendix 2) 
• 
LVEF assessment performed by echocardiogram or MUGA scan based on institutional 
preferences.  Results must be at or above the normal limit of the institution and/or ≥50%.  
• 
All patients with disease that is deemed by the treating Investigator as safely accessible to biopsy 
are required to undergo research biopsies as outlined in this protocol 
• 
Ability to understand and willingness to sign a written informed consent document or if appropriate, 
have an acceptable surrogate capable of giving consent on the subject’s behalf 
• 
Adequate hematologic and end-organ function, as evidenced by the following local laboratory 
results obtained within 28 days prior to the first study treatment (Cycle 1, Day 1):  
 
Table 6: Adequate Organ Function Laboratory Values 
System 
Laboratory Value 
Hematologic 
 
Absolute neutrophil count (ANC) 
≥ 1,500/mcL 
Platelets 
≥ 100,000/mcL (without transfusion within 1 week 
prior to Cycle 1, Day 1) 
Hemoglobin 
≥ 9 g/dL or ≥ 5.6 mmol/L (without transfusion or EPO 
dependency within 1 week prior to Cycle 1, Day 1) 
Renal 
 
Serum creatinine OR 
≤ 1.5 X upper limit of normal (ULN)  


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Measured or calculated creatinine 
clearancea (can also be used in 
place of creatinine or CrCl) 
OR 
≥ 60 mL/min for subject with creatinine levels > 1.5 X 
institutional ULN 
Hepatic 
 
Serum total bilirubin 
≤ 1.5 X ULN OR 
 
Direct bilirubin ≤ ULN for subjects with total bilirubin 
levels > 1.5 ULN 
AST and ALT  
≤ 2.5 X ULN  
Albumin 
> 2.5 mg/dL 
Coagulation 
International Normalized Ratio 
(INR) or Prothrombin Time (PT) 
 
Activated Partial Thromboplastin 
Time (aPTT) 
≤ 1.5 X ULN unless subject is receiving 
anticoagulant therapy as long as PT or PTT is within 
therapeutic range of intended use of anticoagulants 
 
≤ 1.5 X ULN unless subject is receiving 
anticoagulant therapy as long as PT or PTT is within 
therapeutic range of intended use of anticoagulants 
aCreatinine clearance should be calculated per institutional standard 
 
• 
For women of childbearing potential (pre-menopausal women and women less than 12 months 
after the onset of menopause): must have a pregnancy test every 4 weeks and must have a 
negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) 
within 24 hours prior to the start of nivolumab. 
• 
For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual 
intercourse) or use adequate contraceptive measures (barrier methods, intrauterine contraceptive 
devices, sterilization) during study treatment and for a total of 5 months post-treatment completion.  
A woman is considered to be of childbearing potential if she is postmenarcheal, has not reached 
a postmenopausal state (≥ 12 continuous months of amenorrhea with no identified cause other 
than menopause), and has not undergone surgical sterilization (removal of ovaries and/or uterus). 
• 
For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use 
contraceptive measures, and agreement to refrain from donating sperm 
4.2 Exclusion Criteria 
 
Patients who meet any ONE of the following criteria will be excluded from study entry:  
 
• 
Definitive clinical or radiologic evidence of distant metastases 
• 
Has a known additional malignancy that progressed within the last five years 
• 
Cardiac disease (history of and/or active disease) that would preclude the use of the drugs included 
in the treatment regimens 
• 
Patients known to be HIV positive 
• 
Neuropathy ≥ Grade 2, per the NCI CTCAE v5.0 
• 
History of allogeneic stem cell or solid organ transplantation 
• 
Has active clinically significant autoimmune disease where in the opinion of the Investigator would 
preclude the use of immunotherapy  
• 
History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis obliterans), or 
evidence of active pneumonitis  
• 
Patients with clinically active tuberculosis 
• 
Pregnancy or lactation at the time of enrollment 
• 
Prior treatment with CD137 agonists or immune checkpoint−blockade therapies, including anti-
CD40, anti−CTLA-4, anti−PD-1, and anti−PD-L1 therapeutic antibodies 
• 
Treatment with systemic immunosuppressive medications (including but not limited to interferons, 
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• 
Treatment with systemic immunosuppressive medications (including but not limited to prednisone, 
cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti−tumor necrosis [anti-TNF] 
factor agents) within 2 weeks prior to randomization or anticipation of need for systemic 
immunosuppressive medications during the study. 
• 
Cardiopulmonary dysfunction as defined by: 
o 
Inadequate LVEF at baseline, <50% by either TTE or MUGA 
o 
History of symptomatic congestive heart failure (CHF): Grade ≥ 3 per NCI CTCAE 
version 5.0 or Class ≥ II per New York Health Association  
o 
History of a decrease in LVEF to <40% or symptomatic CHF  
o 
Myocardial infarction or unstable angina within 6 months of start of study treatment 
o 
Current dyspnea at rest due to complications of malignancy, or other disease requiring 
continuous oxygen therapy 
o 
Corrected QT interval (QTc) >450 msec on screening EKG 
• 
Clinically significant history of liver disease, including cirrhosis, autoimmune hepatic disorders, HIV 
infection, or active Hepatitis B or Hepatitis C 
o 
Active infection requiring treatment with antiviral therapy or presence of positive test 
results for Hepatitis B (e.g. Hepatitis B surface antigen and/or total Hepatitis B core 
antibody) or HCV antibody.  
o 
HBV and HCV assessments are required at screening. 
o 
Patients who test positive for Hepatitis B core antibody are eligible if polymerase chain 
reaction (PCR) is negative for HBV DNA 
o 
Patients who are positive for HCV serology are only eligible if testing for HCV RNA is 
negative 
• 
Subject is pregnant or nursing 
• 
Known documented or suspected hypersensitivity to the components of the study drugs(s) 
 
4.3 Subject Recruitment/Screening and Clinical Procedures/Assessments 
 
Target enrollment for this study is 52 patients.  Patients will be recruited from physicians at the NYU 
Perlmutter Cancer Center and its nearby public hospital affiliate, Bellevue Hospital Center, as well as 
through outside referrals.  In addition, patients will be recruited at Indiana University.     
 
Consenting, screening and treatment will take place under the supervision of the Investigator. Prospective 
subjects receive detailed information about this study and its investigational nature, required study 
procedures, alternative treatments, risks, and potential benefits of the study. They also receive the informed 
consent document to read. All questions are answered by the PI and qualified research personnel.  
Recruitment and consenting will take place in a private area such as an exam room to protect the patient’s 
privacy.   
 
Prior to study entry, a patient’s eligibility must be approved in writing (email is allowed) by the NYU CTO 
study coordinator. 
 
The Principal Investigator will: 
 
1. Obtain signed and dated informed consent from the potential subject before any study specific 
procedures are performed. 
 
2.  Determine patient eligibility (See Section 4.1 and 4.2). 
 
  3.  Submit registration to NYU Perlmutter Cancer Center CTO. 
 
               4.  Receive registration confirmation from NYU Perlmutter Cancer Center CTO, including unique     
       study identification number assigned to the patient that will be distributed to the study team      
       upon registration of the patient. 
 


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The informed consent process and documentation follows established procedures of the NYU Langone 
Health Perlmutter Cancer Clinical Trials Office. 
 
4.3.1  Informed Consent 
The Investigator must obtain documented consent from each potential subject prior to participating in a 
clinical trial. 
Consent must be documented by the subject’s dated signature or by the subject’s legally acceptable 
representative’s dated signature on a consent form along with the dated signature of the person conducting 
the consent discussion.  A copy of the signed and dated consent form should be given to the subject before 
participation in the trial. 
 
The initial informed consent form, any subsequent revised written informed consent form and any written 
information provided to the subject must receive the NYU Institutional Review Board’s (IRB) 
approval/favorable opinion in advance of use.  The subject or his/her legally acceptable representative 
should be informed in a timely manner if new information becomes available that may be relevant to the 
subject’s willingness to continue participation in the trial.  The communication of this information will be 
provided and documented via a revised consent form or addendum to the original consent form that 
captures the subject’s dated signature or by the subject’s legally acceptable representative’s dated 
signature. 
 
Specifics about a trial and the trial population will be added to the consent form template at the protocol 
level.   
 
The informed consent will adhere to NYU IRB requirements, applicable laws and regulations, and Sponsor 
requirements. 
 
For non-English speaking patients, institutional translation services will be utilized.  All procedures for 
consenting non-English speaking patients will be in accordance with NYU Langone Health PCC CTO 
guidelines and policies. 
 
For patients who cannot read, a witness, not related to the research study, will be present. The consent will 
be read to the patient. The patient will also be allowed to ask any questions s/he may have. The Investigator 
will ask the patient questions to ensure s/he understands the study. If the Investigator determines the 
subject understands the study, the patient will mark an X where his/her name would go and the witness will 
sign the consent form. 
 
4.3.2   Documentation of Consent 
The Principal Investigator or IRB approved sub-Investigator will be responsible for documentation in the 
medical record that consent has been obtained from all participants. A signed copy of the consent form will 
be given to each participant. Original consent forms will be stored in the subject’s medical chart. 
4.3.3   Multi-Site Surveillance 
As the lead investigator in a multi-site trial, the Overall Principal Investigator is responsible for organizing 
and conducting monthly teleconferences with all participating sites.  The PI will also be responsible for 
including data from all of the participating sites within the overall trial’s quarterly Data and Safety Monitoring 
reports to the Data Safety and Monitoring Committee (DSMC) to include minutes from monthly PI 
teleconferences. Each participating site will be responsible for submitting the results and recommendations 
from the DSMC’s quarterly review to their IRB of record at the time of continuing review.  Additionally, the 
NYU Langone Health PCC Clinical Trial Office, Quality Assurance Unit will provide a remote extensive 
monitoring including real-time review of all eCRF’s to ensure completeness and compliance with the 
protocol (100% source documentation verification).  Additionally, a first subject audit is to be completed 


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with four weeks of enrollment.   
4.3.4   Patient Informed Consent at Additional Sites 
See Appendix 1. 
 
4.3.5   Inclusion/Exclusion Criteria 
All inclusion and exclusion criteria will be reviewed by the Investigator or qualified research personnel to 
ensure that the subject qualifies for the trial.  
4.3.6   Medical History 
A medical history will be obtained by the Investigator or qualified designee.  Medical history will include all 
active conditions, including cardiac history, and any condition diagnosed within the prior 10 years that are 
considered to be clinically significant by the Investigator.  Details regarding the disease for which the subject 
has enrolled in this study will be recorded separately and not listed as medical history.   
4.3.7   Prior Medications 
The Investigator or qualified designee will review prior medication use and record prior medication(s) taken 
by the subject within 30 days before enrolled in this study.  Treatment for the disease for which the subject 
has enrolled in this study will be recorded separately and not listed as a prior medication.  
 
4.3.8   Concomitant Medications 
The Investigator or qualified designee will record medication, if any, taken by the subject during the trial.  
All medications related to reportable serious adverse events (SAE) and events of clinical interest (ECI) 
should be recorded as defined in Section 8.2. 
 
4.3.9  Disease Details 
The Investigator or qualified designee will obtain prior and current details regarding disease status as per 
AJCC 8th edition.  
 
Clinical Procedures/Assessments 
4.3.10  Adverse Event (AE) Monitoring 
The Investigator or qualified designee will assess each subject to evaluate for potential new or worsening 
AEs as specified in the Study Schedule of Events (Section 6.1) and more frequently if clinically indicated.  
Adverse experiences will be graded and recorded throughout the study and during the follow-up period 
according to NCI Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0. Toxicities will be 
characterized in terms regarding seriousness, causality, toxicity grading, and action taken with regard to 
trial treatment.  
4.3.11  Full Physical Exam 
The Investigator or qualified designee will perform a complete physical exam during the screening period.  
Clinically significant abnormal findings should be recorded as medical history.   


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4.3.12  Directed Physical Exam 
At subsequent visits (or as clinically indicated), directed physical examinations can be performed. Changes 
from baseline abnormalities should be recorded in the patient notes.  
4.3.13  Vital Signs 
The Investigator or qualified designee will take vital signs at screening, prior to the administration of each 
dose of trial treatment, and at treatment discontinuation as specified in the Study Schedule of Events 
(Section 6.1).  Vital signs should include temperature, pulse, respiratory rate, weight, height (Screening 
only) and blood pressure.  
4.3.14  Eastern Cooperative Oncology Group (ECOG) Performance Status 
The Investigator or qualified designee will assess ECOG performance status at screening, prior to the 
administration of each dose of trial treatment and discontinuation of trial treatment as specified in Study 
Schedule of Events (Section 6.1) and Appendix 2. 
4.3.15  Collection of Tumor Tissue Prior To Treatment 
Collection of formalin-fixed paraffin-embedded (FFPE) tumor tissue from diagnostic core biopsy within 60 
days prior to enrollment (Cycle 1 Day 1) is required. If available, a fresh biopsy sample is preferred.  Testing 
by a CLIA-certified local laboratory on the tumor tissue specimen for ER, PR, and HER2 must be performed.   
4.3.16  Tumor Imaging/ Cardiac Imaging  
 
Initial imaging assessments must include bilateral mammogram and/or bilateral ultrasound.  Bilateral breast 
MRI is optional.  Imaging must also be performed at screening to rule out distant disease.  CT scans (with 
IV contrast and oral contrast unless contraindicated) of the chest, abdomen, and pelvis or Positron emission 
tomography (PET)/CT may be used.  If a CT scan for tumor assessment is performed as part of a PET/CT, 
the CT acquisition must be consistent with the standards for a full-contrast diagnostic CT scan.  MRI scans 
of the chest, abdomen, and pelvis may be used in patients for whom CT scans with contrast are 
contraindicated (i.e., patients with contrast allergy or impaired renal clearance). A bone scan or PET scan 
should be performed to evaluate for bone metastases if there is clinical suspicion for osseous metastases.  
Imaging assessments should be done within 60 days prior to enrollment (Cycle 1 Day 1). 
 
LVEF assessment by echocardiogram (TTE) or by MUGA scan is required within 60 days prior to enrollment 
(Cycle 1 Day 1). 
 
4.3.17  Laboratory Procedures/Assessments 
Details regarding specific laboratory procedures/assessments to be performed in this trial are provided in 
the Study Schedule of Events (Section 6.1). 
 
Laboratory tests for screening or entry into the study should be performed within 30 days prior to enrollment 
(Cycle 1 Day 1).  For subsequent cycles after Cycle 1, pre-dose laboratory procedures can be conducted 
up to 72 hours prior to dosing.  Results must be reviewed by the treating Investigator and found to be 
acceptable prior to each dose of trial treatment. 
 
4.3.18  Tumor Assessment during Study Treatment  
Clinical evaluation, with a bidimensional measurement of the tumor, will be performed every three weeks 
during Cycle 1-4 and every two weeks during Cycle 5-8. For subjects with no palpable mass, changes in 
clinically evaluable skin criteria (such as erythema, edema, peau d’orange) will be considered as response 
criteria.  Patients should also have re-evaluation of the primary tumor by imaging with either mammography, 


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breast ultrasound, and/or breast MRI after the end of Cycle 8 (prior to surgery). In the case of progressive 
disease, see Section 6.2. 
4.3.19  Screening Period 
The screening phase is the interval between the signing of the Informed Consent Form (ICF) and the day 
the subject is enrolled in the study (Cycle 1 Day 1). Informed consent must be obtained prior to performing 
any study-specific procedures. Assessments that are required to demonstrate eligibility may be performed 
over 1 or more days during this phase.  
 
Screening procedure timeline:  
 
• 
Laboratory tests and EKG may be performed within 30 days prior to enrollment. 
• 
Women of reproductive potential must have a negative urine or serum pregnancy test within 24 
hours prior to first dose of study treatment. 
• 
Tumor tissue biopsy may be obtained within 60 days prior to enrollment 
• 
Tumor imaging assessment may be done within 60 days prior to enrollment. 
• 
Echocardiogram or MUGA assessment may be done within 60 days prior to enrollment.   
 
Results of tests done as standard of care prior to signing consent may be used for screening and 
confirmation of eligibility information if performed within the specified time frame.  
 
Results from the screening visit evaluations will be reviewed to confirm subject eligibility prior to 
enrollment/administration of study drug via investigator and CTO personnel. Tests with results that fail 
eligibility requirements may be repeated once during the screening phase, if the Investigator believes the 
results to be in error or not representative. Additionally, a subject who fails screening may repeat the 
screening process one time, if the Investigator believes there has been a change in eligibility status (e.g. 
following recovery from an infection). 
 
Additionally, the screening period will be utilized to determine the baseline assessments of clinical condition 
and disease status. Tumor assessments appropriate to the type of malignancy will be performed and 
recorded in the case report form (CRF). 
 
4.4 Registration Procedures 
 
4.4.1 General Guidelines 
 
Each patient must sign and date an informed consent form before undergoing any study specific procedure 
unless a procedure is being performed as part of the patient’s standard of care.  Enrollment in the study 
requires that all inclusion and exclusion criteria have been met.  Enrollment occurs upon confirmation of 
registration from the NYU PCC Clinical Trials Office.  The following materials must be submitted to the CTO 
for subject registration: 
 
1. Complete signed and dated informed consent form 
2. Complete signed and dated eligibility checklist 
3. All supporting documentation verifying each eligibility criterion has been met 
 
Registration will occur within 48 hours of research coordinator receipt of all of the above documents.  A 
written confirmation of enrollment including a unique study identification number assigned by the research 
coordinator will be disbursed to the study team upon registration. 
 
Once eligibility is verified, a unique patient study number will be issued within 48 hours of receiving all 
required registration material.  The patient will not be identified by name.  This is the point, at which, the 
patient is considered accrued on study. 
 


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4.4.2 Patient Registration at Other Participating Institutions 
 
See Appendix 1. 
4.5 Early Withdrawal of Subjects 
 
Subjects may be withdrawn from the study prior the expected completion of that subject for any of the 
following reasons:  
 
• 
The subject or legal representative (such as a parent or legal guardian) withdraws consent 
• 
Disease progression or occurrence of a secondary malignancy which requires systemic therapy 
or radiotherapy for treatment.  
• 
Unacceptable adverse events as described in Section 5.3 
• 
Intercurrent illness that prevents further administration of treatment 
• 
Investigator’s decision to withdraw the subject 
• 
The subject has a confirmed positive serum pregnancy test 
• 
Noncompliance with trial treatment or procedure requirements 
• 
The subject is lost to follow-up 
 
4.5.1 When and How to Withdraw Subjects 
 
Subjects may withdraw consent at any time for any reason or be dropped from the trial at the discretion of 
the Investigator should any untoward effect occur. In addition, a subject may be withdrawn by the 
Investigator or the Sponsor if enrollment into the trial is inappropriate, the trial plan is violated, or for 
administrative and/or other safety reasons.  Specific details regarding discontinuation or withdrawal are 
provided in Section 4.5. 
 
The End of Treatment and Follow-up visit procedures are listed in the Study Schedule of Events (Section 
6.1) and Section 6.4.  After the end of treatment, each subject will be followed for 100 days for adverse 
event monitoring.  This monitoring may be done remotely.  Subjects who discontinue for reasons other than 
progressive disease will have post-treatment follow-up after last dose of treatment for disease recurrence, 
initiating a non-study cancer treatment, withdrawing consent or becoming lost to follow-up.   
4.5.2 Data Collection and Follow-up for Withdrawn Subjects 
 
Even though subjects may be withdrawn prematurely from the study, it is imperative to collect at least 
survival data on such subjects throughout the protocol defined follow-up period for that subject.  Such data 
is important to the integrity of the final study analysis since early withdrawal could be related to the safety 
profile of the study drug.  If a subject withdraws consent to participate in the study, attempts should be 
made to obtain permission to record survival data up to the protocol-described end of subject follow-up 
period.   
 
5 Study Drug  
5.1 Description 
 
Nivolumab, also referred to as BMS-936558-01 or BMS-936558, is a soluble protein consisting of 4 
polypeptide chains, which include 2 identical heavy chains and 2 identical light chains. The physical and 
chemical properties of nivolumab are: 
 
Molecular Weight: 
 146,221 daltons (143,619.17 daltons, protein portion) 
Appearance: 
 
 Clear to opalescent, colorless to pale yellow liquid, light (few) particulates may  


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 be present 
Solution:  
 
 pH 5.5 to 6.5 
 
5.1.1 Pharmaceutical Properties and Formulation 
 
Nivolumab Injection, 100 mg/10 mL (10 mg/mL), is a clear to opalescent, colorless to pale yellow liquid, 
which may contain light (few) particulates. The drug product is a sterile, non-pyrogenic, single-use, isotonic 
aqueous solution formulated at 10 mg/mL in sodium citrate, sodium chloride, mannitol, 
diethylenetriaminepentacetic acid (pentetic acid), and polysorbate 80 (TweenTM 80), at pH 6.0 and includes 
an overfill to account for vial, needle, and syringe holdup. It is supplied in 10-cc Type I flint glass vials, 
stoppered with butyl rubber stoppers and sealed with aluminum seals. The only difference between the two 
drug product presentations is the vial fill volume.  
5.1.2 Drug Product Preparation 
 
Nivolumab injection is to be administered as an IV infusion through a 0.2-micron to 1.2-micron pore size, 
low-protein binding (polyethersulfone membrane) in-line filter at the protocol-specified doses and infusion 
times. It is not to be administered as an IV push or bolus injection. When the dose is based on patient 
weight (i.e., mg/kg), nivolumab injection can be infused undiluted (10 mg/mL) or diluted with 0.9% sodium 
chloride injection, USP or 5% dextrose injection, USP to protein concentrations as low as 0.35 mg/mL. 
When the dose is fixed (e.g., 240 mg, 360 mg, or 480 mg flat dose), nivolumab injection can be infused 
undiluted or diluted so as not to exceed a total infusion volume of 160 mL.  For patients weighing less than 
40 kg, the total volume of infusion must not exceed 4mL per kg of patient weight. 
 
During drug product preparation and handling, vigorous mixing or shaking is to be avoided. Instructions for 
dilution and infusion of nivolumab injection is available in current Investigator Brochure and Prescribing 
Information. Care must be taken to assure sterility of the prepared solution as the product does not contain 
any antimicrobial preservative or bacteriostatic agent.  Nivolumab infusions are compatible with polyvinyl 
chloride or polyolefin containers and infusion sets, and glass bottles.   
5.1.3 Recommended Storage and Use Conditions 
 
Vials of nivolumab injection must be stored at 2oC to 8oC (36oF to 46oF) and protected from light and 
freezing.  The unopened vials can be stored at room temperature (up to 25oC, 77oF) and room light for up 
to 48 hours. 
 
The administration of nivolumab infusion must be completed within 24 hours of preparation. If not used 
immediately, the infusion solution may be stored under refrigeration conditions (2°C to 8°C, 36°F to 46°F) 
for up to 24 hours, and a maximum of 8 hours of the total 24 hours can be at room temperature (20oC to 
25oC, 68oF to 77oF) and room light. The maximum of 8 hours under room temperature and room light 
conditions includes the product administration period. 
5.2 Treatment Regimen 
 
Treatment will be administered on an outpatient basis.  Nivolumab is the investigational product (IP) of this 
trial and will be provided by Bristol-Myers Squibb (BMS).  Chemotherapy with docetaxel, paclitaxel, 
doxorubicin, cyclophosphamide, trastuzumab, or pertuzumab is considered Non-IP as it represents routine 
or standard of care treatment for the respective patient population. Chemotherapy will not be provided by 
BMS and must be selected by the Investigator as part of standard of care therapy. 
IP treatment 
 
Nivolumab: Nivolumab will be given at 360mg intravenously (IV) on Day 1 of every 21 day cycle during 


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Cycle 1-4.   
 
Non-IP treatment 
 
Cohort 1: TNBC or HR-positive/HER2-negative:  
 
Paclitaxel: Paclitaxel will given at 80 mg/m2 IV weekly x 12 during Cycle 1-4. 
Doxorubicin: Doxorubicin will be given at 60 mg/m2 IV every two weeks x 4 during Cycle 5-8.  
Cyclophosphamide: Cyclophosphamide will be given at 600 mg/m2 IV every two weeks x 4 during Cycle 
5-8. 
 
Doxorubicin and Cyclophosphamide will be administered with G-CSF support. 
 
 
Cohort 2: HR-positive/HR-negative and HER2-positive:  
 
Docetaxel: Docetaxel will be given at 75 mg/m2 IV every three weeks x 4 during Cycle 1-4. 
Paclitaxel (may be substituted for Docetaxel): Paclitaxel will be given at 80 mg/m2 IV weekly x 12 during 
Cycle 1-4. 
Trastuzumab*: Trastuzumab will be given at 8 mg/kg IV on day 1 of Cycle 1 and then 6 mg/kg IV on day 1 
of Cycle 2-4 every three weeks. 
Pertuzumab: Pertuzumab will be given at 840 mg IV on day 1 of Cycle 1 and then 420 mg IV on day 1 of 
Cycle 2-4 every three weeks. 
Doxorubicin: Doxorubicin will be given at 60 mg/m2 IV every two weeks x 4 during Cycle 5-8.  
Cyclophosphamide: Cyclophosphamide will be given at 600 mg/m2 IV every two weeks x 4 during Cycle 
5-8. 
 
Doxorubicin and Cyclophosphamide will be administered with G-CSF support. 
*Trastuzumab biosimilar is allowed.   
 
5.2.1 Treatment of Nivolumab-Related Infusion Reactions  
Since nivolumab contains only human immunoglobulin protein sequences, it has a low incidence of 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 as an SAE if it meets the criteria. 
Infusion reactions should be graded according to NCI CTCAE (Version 5.0) guidelines.  
 
Treatment recommendations are provided below:  
 
For Grade 1 symptoms: (Mild reaction; infusion interruption not indicated; intervention not indicated).  
  
• 
Remain at bedside and monitor subject until recovery from symptoms. The following prophylactic 
premedications are recommended for future infusions: diphenhydramine 50 mg (or equivalent) 
and/or acetaminophen/paracetamol 325 to 1000 mg at least 30 minutes before additional 
nivolumab administrations.  
 
For Grade 2 symptoms: (Moderate reaction requires therapy or infusion interruption but responds  
promptly to symptomatic treatment [eg, antihistamines, non-steroidal anti-inflammatory drugs, narcotics,  
corticosteroids, IV fluids]; prophylactic medications indicated for ≤ 24 hours).  
 
 
• 
Stop the nivolumab infusion, begin an IV infusion of normal saline, and treat the subject with 
diphenhydramine 50 mg IV (or equivalent) and/or acetaminophen/paracetamol 325 to 1000 mg; 
remain at bedside and monitor subject until resolution of symptoms. Corticosteroid 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 


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minutes, the rate may be increased to 100% of the original infusion rate. Monitor subject closely. If 
symptoms recur, then no further nivolumab will be administered at that visit.  
 
• 
For 
future 
infusions, 
the 
following 
prophylactic 
pre-medications 
are 
recommended: 
diphenhydramine 50 mg (or equivalent) and/or acetaminophen 325 to 1000 mg should be 
administered at least 30 minutes before nivolumab infusions. If necessary, corticosteroids (up to 
25 mg of SoluCortef 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 nivolumab. Begin an IV infusion of normal saline and treat the 
subject 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. Subject should be monitored until the Investigator is comfortable that the 
symptoms will not recur. Nivolumab will be permanently discontinued.  Investigators should follow 
their institutional guidelines for the treatment of anaphylaxis.  Remain at bedside and monitor 
subject 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).  
5.3 Dosage Modification 
 
Dose reductions or dose escalations for nivolumab are not permitted.  
5.3.1 Nivolumab Dose Delay Criteria for Study Treatment 
 
Study drug administration should be delayed for the following: 
 
• 
Grade 2 non-skin, drug-related AE, with the exception of fatigue 
• 
Grade 2 drug-related creatinine 
• 
Grade 3 skin, drug-related AE 
• 
Grade 3 drug-related laboratory abnormality, with the following exceptions: 
o 
Grade 3 lymphopenia or asymptomatic amylase or lipase does not require dose delay 
• 
Any adverse event, laboratory abnormality, or intercurrent illness, which in the judgment of the 
investigator, warrants delaying the dose of study medication. 
• 
Dose delay for AST, ALT, or Total Bilirubin abnormalities should be managed as follows: 
o 
If a participant has a baseline AST, ALT, or Bilirubin that is within normal limits, delay 
dosing for drug-related Grade ≥ 2 toxicity  
o 
 If a participant has baseline AST, ALT, or Bilirubin within the Grade 1 toxicity range, delay 
dosing for drug-related Grade ≥ 3 toxicity  
o 
If a participant has baseline AST, ALT, or Bilirubin within the Grade 2 toxicity range, delay 
dosing for a 2-fold drug-related increase in AST, ALT or Bilirubin, or for AST, ALT 
or bilirubin values 8 x ULN (whichever is lower) 
 
Participants who require delay of study treatment should be re-evaluated weekly or more frequently if 
clinically indicated and resume study treatment when re-treatment criteria are met (See Section 5.3).  See 
also Appendix 3 (Algorithms for Management of Side Effects of Nivolumab) for guidance on appropriate 
management and follow-up of adverse events. 


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5.3.2   Criteria for Discontinuation of Nivolumab  
 
Study 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: 
o 
Grade 3 drug-related uveitis, pneumonitis, bronchospasm, neurologic toxicity, 
hypersensitivity reaction, or infusion reaction of any duration requires discontinuation.  
o 
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.  
o 
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  
 Any drug-related liver function test (LFT) abnormality that meets the following 
criteria require discontinuation  
 AST or ALT >10 x ULN for >2weeks 
 AST or ALT >15 x ULN irrespective of duration  
 Total bilirubin >5 x ULN for those participants with normal total bilirubin at 
entry or >8 x ULN for participants with elevated bilirubin at study entry, 
irrespective of duration 
• 
Any Grade 4 drug-related adverse event or laboratory abnormality, except for the following 
events which do not require discontinuation:  
o 
Grade 4 neutropenia ≤7 days  
o 
Grade 4 lymphopenia or leukopenia or asymptomatic amylase or lipase  
o 
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  
o 
Grade 4 drug-related endocrinopathy adverse events, 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 Sponsor’s Medical Monitor or designee.  
• 
Any event that leads to delay in dosing lasting >6 weeks from the previous dose requires 
discontinuation, with the following exceptions:  
o 
Dosing delays to allow for prolonged steroid tapers to manage drug-related adverse 
events are allowed.  
o 
Dosing delays lasting >6 weeks from the previous dose that occur for non-drug-related 
reasons may be allowed if approved by the Sponsor’s Medical Monitor or designee. 
• 
Any adverse event, laboratory abnormality, or intercurrent illness which, in the judgment of the 
Investigator, presents a substantial clinical risk to the participant with continued study 
treatment.  
 
5.3.3   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.  


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• 
Participants with baseline Grade 1 AST, ALT, or Total Bilirubin who require dose delays for reasons 
other than a drug-related hepatic event may resume treatment in the presence of Grade 2 AST, 
ALT, or Total Bilirubin.  
• 
Participants who require dose delays for drug-related increased AST, ALT, or Total Bilirubin may 
resume treatment when hepatic parameters are at baseline or Grade 1 and after discussion with 
Sponsor’s Medical Monitor or designee.  
• 
Participants with AST, ALT, or Total Bilirubin values meeting discontinuation should have treatment 
permanently discontinued.  
• 
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 Sponsor’s 
Medical Monitor or designee.  
• 
Participants with drug-related endocrinopathies adequately controlled with only physiologic 
hormone replacement may resume treatment after consultation with Sponsor’s Medical Monitor or 
designee. Adrenal insufficiency requires discontinuation regardless of control with hormone 
replacement.  
 
5.3.4  Recommendations for Chemotherapy Delays and Modifications 
 
In the opinion of the investigator, if a toxicity is considered to be attributable solely to one component of the 
study treatment and the dose of that component is delayed or modified in accordance with the guidelines 
below, the other component may be administered if there is no contraindication. 
 
Table 7 Dose Modification Levels for Docetaxel / Paclitaxel 
Level 
Dose Level 0 
(starting dose) 
(mg/m2) 
Dose Level -1 
(mg/m2) 
Dose Level -2 
(mg/m2) 
Dose Level -3 
(mg/m2) 
Docetaxel 
(mg/m2) 
75 
60 
50 
Discontinue 
Paclitaxel 
(mg/m2) 
80 
60 
50 
Discontinue  
 
General dose modification guidelines: 
 
• 
If a taxane-related hypersensitivity reaction occurs despite pre-medication, treatment as medically 
indicated will be instituted. 
 For hypersensitivity reaction less than CTCAE Grade 3, continuation of 
docetaxel/paclitaxel is at the Investigator’s discretion. 
 If Grade 4 hypersensitivity is experienced, docetaxel/paclitaxel must be permanently 
discontinued. 
 If the taxane is discontinued, an alternative taxane may be substituted (nab-paclitaxel 
or docetaxel if paclitaxel was discontinued).  Dosing and schedule of alternative taxane 
is as per institutional standard of care.    
• 
Taxane-related fluid retention will be treated as per the Investigator’s discretion. 
• 
For HER2-positive tumors, if the taxane must be discontinued before completion of the scheduled 
cycles, the remaining trastuzumab and pertuzumab can be administered. 
• 
For patients who are dose reduced due to Grade 2 or Grade 3 toxicity, they may return to the 
starting dose level if the AE returns to baseline or Grade 1, per discretion of the Investigator.  
• 
Dose level reductions that are below the recommended level in the tables can be made per 
discretion of the Investigator.    
 


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See Table 8 for the management of taxane-related neurosensory toxicity and Table 9 for taxane-related 
musculoskeletal pain. Instructions for management of all other toxicities related to docetaxel/paclitaxel are 
listed in Table 11. 
 
 
Table 8 Dose modifications for taxane-related neurosensory toxicity 
 
Paresthesias/Dysesthesias 
1 – 7 Days Duration 
Persistent for >7 Days  
Grade 1 
 
Maintain docetaxel/paclitaxel 
dose 
Maintain 
docetaxel/paclitaxel dose 
Grade 2 
 
Maintain docetaxel/paclitaxel 
dose 
Decrease 
docetaxel/paclitaxel one 
dose level 
Grade 3a 
 
First episode: 
Decrease docetaxel/paclitaxel 
one dose level 
 
Second episode: 
Decrease docetaxel/paclitaxel 
two dose levels 
Decrease docetaxel/paclitaxel 
two dose levels  
OR  
Discontinue 
docetaxel/paclitaxel 
 
a For persistent paresthesias/ dysesthesias that are disabling or life-threatening, docetaxel/paclitaxel should 
be discontinued. 
 
 
Table 9 Dose modifications for taxane-related musculoskeletal pain not controlled by analgesicsa 
 
Musculoskeletal pain 
1 – 7 Days Duration 
Persistent for >7 Days  
Grade 1 
 
Maintain docetaxel/paclitaxel 
dose 
Maintain 
docetaxel/paclitaxel dose 
Grade 2 
 
Maintain docetaxel/paclitaxel 
dose 
Decrease 
docetaxel/paclitaxel one 
dose level 
Grade 3 
 
First episode: 
Decrease docetaxel/paclitaxel 
one dose level 
 
Second episode: 
Decrease docetaxel/paclitaxel 
two dose levels 
 
First episode: 
Decrease docetaxel/paclitaxel 
one dose level 
OR 
Decrease docetaxel/paclitaxel 
two dose levels 
 
Second episode: 
Discontinue docetaxel/paclitaxel 
 
a Use of analgesics can be used to maintain dose of docetaxel/paclitaxel if possible. 
 
 
Table 10 Dose Modification Levels for Doxorubicin / Cyclophosphamide  
 
Level 
Dose Level 0 
(starting dose) 
(mg/m2) 
Dose Level -1 
(mg/m2) 
Dose Level -2 
(mg/m2) 
Dose Level -3 
(mg/m2) 


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Doxorubicin 
(mg/m2) 
60 
50 
40 
Discontinue 
Cyclophosphamide 
(mg/m2) 
600 
500 
400 
Discontinue 
 
• 
For patients who are dose reduced due to Grade 2 or Grade 3 toxicity, they can return to the starting 
dose if the AE returns to baseline or Grade 1, per discretion of the Investigator  
• 
Dose level reductions that are below the recommended level in the tables can be made per 
discretion of the Investigator.    
 
 
Table 11 Dose modifications and delays for docetaxel / paclitaxel / doxorubicin / cyclophosphamide  
 
NCI CTCAE v 5.0 [Category] 
Grade 
 
 
Modifications for AEsb 
 
HEMATOLOGICAL: 
Neutrophil count decreased  
Grades 2, 3, 4 
 
Hold until ≥ 1500/mm3 
 
If recovery takes: 
• 
1-3 wks: maintain dose 
and add G-CSF 
 
If previously receiving G-CSF 
and recovery takes: 
 
• 
1 wk: maintain dose 
• 
2-3 wks: decrease one 
dose level 
 
Platelet count decreased  
Grades 2, 3 
 
Hold until ≥ 75,000/mm3. 
 
If recovery takes: 
• 
1 wk: maintain dose 
• 
2-3 wks: decrease one 
dose level 
 
Grade 4 
 
Decrease one dose level 
BLOOD AND LYMPHATIC SYSTEM DISORDERS: 
Febrile Neutropenia 
Grade 2 
 
Maintain dose  
Grade 3 (first episode)  
 
Maintain dose and add G-CSF 
Grade 3 (subsequent episodes) 
 
Decrease one dose level 
Grade 4 (first episode) 
 
Decrease one dose level 
Grade 4 (subsequent episodes_ 
 
Decrease two dose levels or 
discontinue 
GASTROINTESTINAL DISORDERS (if related to chemotherapy): 
Diarrhea 
 
 
Grade 2 
 
Maintain dose  
Grade 3 
 
Decrease one dose level 


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Grade 4 
 
Decrease two dose levels or  
discontinue 
Mucositis 
 
 
Grade 2 
 
Maintain dose  
Grade 3 
 
Decrease one dose level 
Grade 4 
 
Decrease two dose levels or  
discontinue 
Vomiting (despite antiemetics) 
 
 
Grade 2 
 
Maintain dose  
Grade 3 
 
Decrease one dose level 
Grade 4 
 
Decrease two dose levels or 
discontinue  
HEPATIC FUNCTION: 
Bilirubin or AST or ALT increased 
Grade 2 
 
Hold until bilirubin returns to  
baseline and AST and ALT have 
returned to ≤ grade 1. Then 
decrease one dose level. 
Grade 3 
 
Hold until bilirubin returns to  
baseline and AST and ALT have 
returned to ≤ grade 1. Then 
decrease one dose level. 
Grade 4 
 
Discontinue 
OTHER CLINICALLY SIGNIFICANT AEs: 
Grade 3 
 
Decrease one dose level 
Grade 4 
 
Decrease two dose levels or 
discontinue 
 
 
Table 12 Left ventricular dysfunction 
 
Adverse Event  
Grade 
1 
2 
3 
4 
Left ventricular 
systolic 
dysfunction 
- 
- 
Symptomatic due to 
drop in ejection fraction 
responsive to 
intervention  
Refractory or poorly 
controlled heart failure 
due to drop in ejection 
fraction; intervention 
such as ventricular 
assist device, 
intravenous 
vasopressor support, 
or heart transplant 
indicated  
 
For symptomatic heart failure, treatment includes management per standard evidence-based guidelines 
and management of any concurrent conditions (such as hypertension) and fluid management with diuretic 
therapy as needed.   
 
For asymptomatic decline to an LVEF <40% and at least 15 percentage points to LVEF <50%, doxorubicin 
and cyclophosphamide should be held and repeat imaging with TTE or MUGA performed in two to four 
weeks.  If LVEF is improved to >50%, then treatment can be resumed.   
Dose modifications for trastuzumab and pertuzumab 
 
No dose reduction is recommended. In case of severe toxicity probably related to these compounds, 
treatment should be discontinued. If toxicity is recovered within three weeks to Grade 1, a restart of 


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treatment should be considered at the discretion of the treating investigator.  
 
If the patient misses a dose of trastuzumab or pertuzumab for any cycle, i.e., the two sequential 
administration times are 6 weeks or more apart, a re-loading dose of 8 mg/kg of trastuzumab and 
pertuzumab 840 mg IV should be given. If re-loading is required for a given cycle, the study therapies 
should be given at the same schedule. 
 
Refer to algorithm in Appendix 5 to assist in the decision as to whether to initiate, continue or discontinue 
therapy based on LVEF assessment in asymptomatic patients. 
5.4 Preparation/Handling/Storage/Accountability 
 
The investigational product should be stored in a secure area according to local regulations.  It is the 
responsibility of the investigator to ensure that the investigational produce is only dispensed to study 
participants.  The investigational product must only be dispensed from official study sites by authorized 
personnel according to local regulations.  The product storage manager should ensure that the study 
treatment is stored in accordance with the environmental conditions (temperature, light, and humidity) as 
determined by BMS.  If concerns regarding the quality or appearance of the study treatment arise, the study 
treatment should not be dispensed and contact BMS or designee immediately. 
 
Study treatment not supplied by BMS will be stored in accordance with the package insert. 
 
Investigational product documentation 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 (e.g., required dilutents, 
administration sets). 
5.5 Subject Treatment Compliance Monitoring 
 
Study treatment will be administered in the clinical facility.  Treatment compliance will be monitored by drug 
accountability as well as the participant’s medical record and eCRF.   
5.6 Concomitant Therapy 
 
Concomitant therapy includes any medication (e.g., prescription drugs, over-the-counter drugs, herbal or 
homeopathic remedies, nutritional supplements) used by a patient from 7 days prior to screening to the 
study treatment discontinuation visit. All such medications must be reported to the Investigator and recorded 
in the Concomitant Medications CRF. 
 
Subjects must be instructed not to take any additional medications during the study without prior 
consultation with the Investigator. Any medications including herbal supplements, vitamins, or treatment 
taken by the subject from 30 days prior to the start of study treatment and up to 30 days following the last 
dose of investigational products and the reason for their administration must be recorded on the CRF. 
 
5.6.1  Prohibited Therapies with Nivolumab 
 
The following medications are prohibited during the study (unless authorized to treat a drug related adverse 
event):  
 
• 
Immunosuppressive agents 
• 
Immunosuppressive doses of systemic corticosteroids 
• 
Traditional herbal medicines: These therapies are not fully studied and their use may result in 
unanticipated drug-drug interactions that may cause or confound the assessment of toxicity 
• 
Concurrent use if antiviral therapy containing IFN 


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• 
Excessive alcohol intake should be avoided (occasional to moderate use is permitted) 
 
5.6.2  Permitted Therapies with Nivolumab 
 
The following therapies are permitted as concomitant medications in the study:  
 
• 
Prophylactic or therapeutic anticoagulation therapy (such as low-molecular weight heparin or 
warfarin at a stable dose level) 
• 
Inactive influenza vaccinations during influenza season  
• 
Inhaled corticosteroids for chronic obstructive pulmonary disease  
• 
Mineralocorticoids (e.g., fludrocortisone)  
• 
Low-dose corticosteroids for subjects with orthostatic hypotension or adrenocortical insufficiency  
• 
Bisphosphonates for prevention of skeletal related events 
 
Subjects who experience infusion-associated symptoms may be treated symptomatically with 
acetaminophen, ibuprofen, diphenhydramine, and/or famotidine or another H2-receptor antagonist per 
standard practice. Serious infusion-associated events manifested by dyspnea, hypotension, wheezing, 
bronchospasm, tachycardia, reduced oxygen saturation, or respiratory distress should be managed with 
supportive therapies as clinically indicated (e.g., supplemental oxygen and β2-adrenergic agonists). 
 
6 Study Procedures 
6.1 Study Calendar/Study Schedule of Events 
 
See Study Schedule of Events on next page.  
 


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Study Activity 
Screening 
Phasea 
 
Treatment Phase  
(Cycle 1-4 = 21 days; Cycle 5-8 = 14 days)b 
After End of 
Treatment and 
Prior to 
Surgery 
 
 
Time of 
Surgery 
 
 
 
 
Post Surgery1 
 
 
 
 
End of 
Study 
Follow-
upj 
Treatment Cycle 
 
 
 
 
 
 
-60 to -1 
(days) 
 
 
 
 
 
 
1 
2  
3 
4 
 
 
 
 
5 
6 
 
 
 
 
7 
 
 
 
 
8 
 
 
 
 
 
 
 
 
≤ 12 
weeks  
after last 
treatment 
 
 
 
 
 
 
 
Scheduling Window 
 
 
 
± 3 
days 
 
 
± 3 
days 
 
 
± 3 
days 
 
 
± 3 
days 
 
 
  
 
 
± 3  
days 
 
 
 
± 3  
days 
 
 
 
 
 
± 3  
days 
 
 
 
± 3  
days 
 
Clinical Procedures/Assessments 
 
Informed Consentc 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
Criteriad 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics and 
Medical Historye 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Prior and Concomitant 
Medications Reviewf 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
Physical Examinationg 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
ECOG Performance 
Status 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 


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Vital Signs and Weightg 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
Heightg 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Neoadjuvant Treatment 
Administrationh 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
Review Adverse Eventsi 
 
X 
X 
X 
X 
 
X 
X 
 
X 
 
X 
 
 
 
 
 
Follow-up for recurrence-
free survivalj 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
(up to two 
years) 
Laboratory Procedures/Assessments 
 
Pregnancy Test – Urine 
or Serum β-HCG (women 
of childbearing 
potential)k 
 
X 
(within 24 hours 
prior to start of 
nivolumab) 
 
X 
X 
X 
X 
 
 
X 
 
 
X 
X 
 
 
X 
 
 
 
 
CBC with Differentiall 
X 
X 
X 
X 
X 
 
X 
 
X 
X 
 
X 
 
 
 
 
Comprehensive Serum 
Chemistry Panel (Blood 
Chemistry and Liver 
Function Tests)l 
X 
X 
X 
X 
X 
  X 
X 
X 
X 
 
 
 
 
TSH, free T3 (or total 
T3), and free T41 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
HBV and HCV testingl  
X 
 
 
 
 
 
 
 
 
 
 
 
 
Urinalysisl 
X 
 
 
 
 
 
 
 
 
 
 
 
 


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12-Lead EKGm 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Cardiac echo (TTE) or 
MUGA scann 
X 
(within 60 
days) 
Continue q 3 months 
 
 
 
 
Treatment 
 
Nivolumab (Day 1 of 
Cycle 1-4)o 
 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
Chemotherapyp 
 
X 
X 
X 
X 
 
X 
 
X 
X 
 
X 
 
 
 
 
Radiationq 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Adjuvant therapyr  
 
 
 
 
 
 
 
 
 
 
 
X 
 
Tumor Assessment and Imaging Procedures 
Clinical tumor 
assessments 
 
X 
 
X 
X 
X 
X 
 
X 
 
X 
X 
 
X 
 
 
 
 
 
Imaging testst 
X 
(within 60 
days) 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
Tumor Biopsies/Archival Tissue Collection/Blood for Correlative Studies  
 
Archival or Newly 
Obtained Tissue 
Collectionu 
X 
(within 60 
days) 
 
 
 
X 
(optio
nal) 
 
 
 
 
 
X 
(if 
residual 
disease) 
  
 
 
Peripheral Blood 
Collectionv 
 
X 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 


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1 Within 3 months (± 14 days) post-surgery 
a Screening Phase: All screening evaluations must be completed and reviewed to confirm that subjects meet all inclusion criteria and do not meet any of the 
exclusion criteria.  
b Treatment Phase: Assessments should be performed prior to dosing on the visit day unless otherwise indicated. For Cycle 1-4, a cycle is defined as 21 days, 
starting with the first dose of treatment drug at baseline (Cycle 1, Day 1) and following the pre-defined visit schedule throughout the treatment period (± 3 days).  
For Cycle 5-8, a cycle is defined as 14 days, starting with the first dose of treatment drug at baseline (Cycle 1, Day 1) and following the pre-defined visit schedule 
throughout the treatment period (± 3 days).   
c  Informed Consent:  Informed consent must be obtained prior to any protocol required screening assessments being performed, which is not performed as part of 
standard routine care. 
d Inclusion Criteria: See Section 4.1 for inclusion criteria and Section 4.2 for exclusion criteria. 
e Demographics and Medical History: Medical history includes clinically significant diseases that are currently active or that were active, including major surgeries, 
within the previous 10 years, any cancer history (including prior cancer therapies and procedures) and reproductive status. Demographic data includes age, sex, 
stratification factors, and self-reported race/ethnicity.  
f Any concomitant medications and treatments will be recorded from 30 days prior to starting treatment and up the end of the Treatment Phase.  
g At screening, a physical examination including palpation of breast/chest wall, axilla, supra- and infraclavicular region, height, weight, blood pressure and pulse 
rate is required.  This should be done within 30 days prior to enrollment (Cycle 1 Day 1). Directed physical examinations including clinical assessment of tumor, 
blood pressure, weight and pulse rate can be performed at subsequent visits.  
h. See Section 1.4 for dose and schedule of treatment administration with nivolumab (IP), chemotherapy, and/or HER2-targeted therapy.  At each visit, prior to IP 
dispensation, an AE and laboratory-based assessment must be performed by the Investigator for evaluation of potential dose delay, reduction, or discontinuation 
according to the protocol. 
i AEs/SAEs must be reported from the date of signature of informed consent form for all enrolled patients until a minimum of 100 days following the last dose of 
study treatment. Adverse Events that occur during the screening phase and are deemed to be serious and related to any study specific procedure should be reported 
to the Study Sponsor.  SAEs must be reported within 24 hours of site awareness (see Section 8.3 for further instructions). AEs fulfilling the criteria for expedited 
reporting have to be treated according to the reporting procedures described in Section 8.3 including a submission to the Sponsor within 24 hours of awareness.  
j After surgery, subjects will be followed every 3 months (± 14 days) thereafter until end of study which is up to 2 years.  Subjects will be followed for the 
occurrence of local or distant recurrence and/or death.  If an in-person visit is unable to be performed, a telemedicine encounter (video or telephone) is allowed.   
k Women of child-bearing potential must have a pregnancy test every 4 weeks and must have a negative serum or urine pregnancy test (minimum sensitivity 25 
IU/L or equivalent units of HCG) within 24 hours prior to the start of study treatment. 
l Laboratory tests:  Hematology includes hemoglobin, WBC, absolute neutrophil count, and platelet count. Blood chemistry includes AST/ALT, alkaline 
phosphatase, sodium, potassium, magnesium, total calcium, total bilirubin, blood urea nitrogen (or urea), serum creatinine, and albumin.  Hepatitis B and C 
screening is required. Thyroid Stimulating Hormone (TSH), free T3 (or total T3), and free T4 will be checked at screening and during Cycle 5. Abnormal 
endocrine results should be followed up per standard of care, and may require an endocrine consult and additional testing. Additional hematology/chemistry 
panels may be performed as clinically indicated. INR and aPTT will be done during screening period and afterward as clinically indicated.  Laboratory tests for 
screening or entry into the study should be performed within 30 days prior to enrollment (Cycle 1 Day 1).  
l Urinalysis will be done at screening and afterward as clinically indicated. Urinalysis includes specific gravity, pH, glucose, protein, ketones, and blood.  Laboratory 
tests for screening or entry into the study should be performed within 30 days prior to enrollment (Cycle 1 Day 1).  


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m A 12-lead EKG is required within 30 days prior to enrollment (Cycle 1 Day 1). Subsequent EKGs may be performed as clinically indicated. EKGs for each 
subject should be obtained from the same machine wherever possible.  EKG recordings must be performed after the subject has been resting in a supine position 
for at least 10 minutes.  
n LVEF assessment by TTE or by MUGA scan within 60 days prior to enrollment (Cycle 1 Day 1). The same method should be used throughout the study for each 
subject if possible.  LVEF assessment will be performed every three months (±7 days), during study treatment (Cycle 1-8). For subjects with HER2-positive 
tumors, LVEF assessment will continue every three months (±7 days) thereafter while receiving adjuvant T-DM1, trastuzumab, and/or pertuzumab. 
o Nivolumab (IP) will be administered at each Day 1 (±3 days) onsite visit during Cycle 1-4.  At each visit, prior to IP dispensation, an AE and laboratory-based 
assessment must be performed by the Investigator for evaluation of potential dose delay or discontinuation.   
p See Section 1.4 for dose and schedule of treatment administration with chemotherapy and/or HER2-targeted therapy.  At each visit, prior to IP dispensation, an 
AE and laboratory-based assessment must be performed by the Investigator for evaluation of potential dose delay, reduction, or discontinuation according to the 
protocol. 
q Radiation: Post-mastectomy radiotherapy as per institutional guidelines 
r See Section 1.4 for postoperative adjuvant therapy (regarding endocrine therapy, capecitabine, T-DM1, trastuzumab, and pertuzumab) 
s Clinical evaluation, with a bidimensional measurement of the tumor, will be performed every three weeks during Cycle 1-4 and every two weeks during Cycle 
5-8. The presence of erythema, edema, and/or peau d’orange should also be noted.  For subjects with no palpable mass, changes in clinically evaluable skin 
criteria (erythema, edema, peau d’orange), will be considered as response criteria. 
t Tumor assessments performed as standard of care and within 60 days prior to enrollment (Cycle 1 Day 1).  Initial imaging assessments must include bilateral 
mammogram and/or bilateral ultrasound. Bilateral breast MRI is optional. Imaging must also be performed at screening to rule out distant disease. CT scans 
(with IV contrast and oral contrast unless contraindicated) of the chest, abdomen, and pelvis or Positron emission tomography (PET)/CT may be used.  If a CT 
scan for tumor assessment is performed as part of a PET/CT, the CT acquisition must be consistent with the standards for a full-contrast diagnostic CT scan.  
MRI scans of the chest, abdomen, and pelvis may be used in subjects for whom CT scans with contrast are contraindicated (i.e., subjects with contrast allergy or 
impaired renal clearance). A bone scan or PET scan should also be performed to evaluate for bone metastases if there is clinical suspicion for osseous metastases. 
Re-evaluation of the primary tumor by imaging with either mammography, breast ultrasound, and/or breast MRI should be performed after the end of Cycle 8 
(prior to surgery).  
u FFPE archival tumor specimen or a fresh core biopsy (preferred) (optimally at least 2 cores) within 60 days prior to enrollment (Cycle 1 Day 1) is required. An 
optional core biopsy can be obtained at end of Cycle 4 (± 7 days) for correlatives. Tissue specimen will be obtained at the time of surgery if there is residual 
disease.  A tumor block is preferred, however if a block is not feasible, a minimum of 15-20 unstained slides from the resected tumor is allowed.    
v Correlative studies blood collection: Maximum of 40 cc collected per time point 
 
 
 


 
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6.2 Treatment discontinuation due to early progression or toxicity 
 
If a subject shows progressive disease (increase in tumor area by 25% or detection of new lesion) or treatment 
has to be discontinued due to toxicity, subjects wish, or other reasons, further treatment decisions have to be 
made individually by the Investigator.  
 
Immediate surgery (in the case of given operability), radiotherapy (in the case of inoperability) or continuation 
of systemic treatment have to be discussed with the subject. It is recommended to the investigator to follow 
as closely as possible protocol guidelines for surgical or radiation treatment as well as for postsurgical 
systemic treatment as the subject still remains a study participant and will be included in the intent-to-treat 
analysis.  Only a subject who has withdrawn her consent for data collection will be excluded from the analysis.  
 
With regard to continuation of neoadjuvant systemic therapy, the following recommendations are made:  
 
For HER2-negative disease, if tumor progression or intolerable toxicity occurs during the taxane-based cycles 
(paclitaxel or docetaxel), subjects may skip the remaining taxane cycles and continue with doxorubicin and 
cyclophosphamide), 
 
For HER2-positive disease, if tumor progression or intolerable toxicity occurs during the taxane-based cycles 
(paclitaxel or docetaxel), subjects may skip the remaining taxane cycles and continue with trastuzumab or 
pertuzumab. 
 
For HER2-positive disease, if tumor progression or intolerable toxicity occurs during treatment with 
trastuzumab and pertuzumab, subjects may skip the remaining cycles of trastuzumab and pertuzumab and 
continue with the taxane (paclitaxel or docetaxel). 
 
For both HER2-negative and HER2-positive disease, if tumor progression or intolerable toxicity occurs during 
the anthracycline-based cycles (doxorubicin and cyclophosphamide), systemic treatment should be 
discontinued and subjects should undergo immediate local treatment. 
 
The reason and date of chemotherapy discontinuation for all subjects will be documented on the Case Report  
 Form (e.g. progressive disease, death, adverse event, withdrawal of consent, lost to follow-up, etc.).   
6.3 Surgery and Post-operative Therapy 
 
After completion of neoadjuvant therapy, subjects will undergo surgery with mastectomy and axillary lymph 
node dissection, performed within 12 weeks after the last infusion of neoadjuvant therapy.  Surgery will not 
be done in case of metastatic progression.  
The third phase (adjuvant treatment) will include radiotherapy according to institutional practice.  Radiotherapy 
targets should include the chest wall and supraclavicular, infraclavicular, and internal mammary chain nodes. 
Subjects with HR-positive tumors should receive a minimum of 5 years of adjuvant endocrine therapy.  Choice of 
endocrine therapy is at the discretion of the investigator.   
 
For HER2-positive tumors, patients with residual disease after neoadjuvant therapy may receive ado-
trastuzumab emtansine (T-DM1) in the adjuvant setting for 14 cycles49.  Another option is to continue 
trastuzumab with or without pertuzumab to complete one year of HER2-directed therapy35.  For patients with 
pathologic complete response (no residual disease), adjuvant trastuzumab can be continued with or without 
pertuzumab to complete one year of HER2-directed therapy.  The choice of adjuvant therapy is at the 
discretion of the investigator. 
 
The use of adjuvant capecitabine for 6-8 cycles for subjects with TNBC with residual disease at the time of surgery is at 


 
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the discretion of the investigator50. 
6.4 Post-Treatment Follow-up/End of Treatment/End of Study Visits 
 
6.4.1  End of Treatment 
 
See the criteria in Section 4.4 for stopping treatment prematurely. 
 
6.4.2  Post-Treatment Follow-up and End of Study 
 
Post-Treatment Follow-up Assessment  
 
Adverse events will be collected for a minimum of 100 days following last dose of study treatment.  The study 
subject will be contacted by telephone call by a member of the study team (unless there is a clinic visit in the 
same time frame).   
 
After neoadjuvant treatment and surgery, all subjects will be followed up to two years for the occurrence of 
local or distant recurrence and death.  A visit at the trial site should be performed and documented every 
three months (±14 days) up to two years.  If an in-person visit is unable to be performed, a telemedicine (video 
or telephone) encounter is allowed.   
 
End of Study Visit 
 
Subject’s end of study visit is the last formal study visit or last formal contact or an unscheduled study visit in 
case of early withdrawal from the study for treatment and follow-up.  End of study (EOS) is defined as 24 
months after study treatment.    
Subjects will no longer be formally followed after completion of the end of study visit, unless adverse event(s) 
occur that require subsequent follow-up (i.e. unresolved AEs). All adverse events, both serious and non-
serious, and deaths that are encountered during the study and within 100 days of the last study intervention 
should be followed. 
 
6.4.3  Subjects Lost to Follow Up  
 
During the duration of the study, sites will be expected to continue efforts to contact all subjects as well as 
regularly consult publicly available information to ascertain vital status of the subject if permissible per local 
regulation. In cases where sites cannot successfully contact a subject and is not able to receive appropriate 
publicly available information for greater than two years, the subject will be noted as lost to follow up. 
 
Efforts will be made to contact the subject via phone calls and next of kin. If this approach is unsuccessful, 
then certified letters to the address on record will be sent requesting follow up via an in person visit.  After two 
unsuccessful calls and one certified letter with no response, a subject is considered lost to follow-up; survival 
data will be obtained by public record. 
 
6.4.4  Post-Study Access 
 
At the end of the study period, BMS will not continue to supply study drug to subjects/investigators unless the 
Sponsor-Investigator chooses to extend their study. The investigator is responsible to ensure that the subject 
receives appropriate standard of care or other appropriate treatment in the independent medical judgment of 
the Investigator to treat the condition under study. 
 


 
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6.5 Correlative Studies  
 
Associations of correlative biomarkers with pCR, other efficacy parameters, and sensitivity or resistance to 
therapy with the combination of nivolumab and chemotherapy will be studied. Changes in the tumor 
microenvironment will be evaluated62. This tumor tissue will be used to study possible mechanisms of 
resistance to study treatment.  Subsequent biopsies should be taken from the same lesion, if feasible.   
 
6.5.1 Tumor Tissue Samples 
 
Collection of pretreatment and on treatment tumor biopsies  
Archived FFPE specimens from the original diagnostic tumor biopsy may be utilized. If they do not provide 
sufficient material for study, then new biopsies will be performed.  Optimally, at least 2 core needle biopsies 
are preferred (prior to first dose of nivolumab and chemotherapy). Another optional core biopsy will be 
obtained during treatment at end of Cycle 4 (completion of nivolumab therapy).  A tumor block is preferred, 
however if a block is not feasible, a minimum of 15-20 unstained slides are allowed.  Slides should have a 
recommended tissue thickness of 5-10 microns. 
If only minute tissue is present (recuts listed in order of priority):  
1 USS 5 microns for H&E 
2 USS 5 microns for PD-L1 IHC (Charged slide) 
1 USS 5 microns for MP (Charged slide) 
6 USS 10 microns for BC360  
 
If optimal tissue is present, i.e. separate cores/separate blocks with good cellularity (recuts listed in order of 
priority):  
1 USS 5 microns for H&E 
2 USS 5 microns for PD-L1 IHC (Charged slide) 
1 USS 5 microns for MP (Charged slide) 
6 USS 10 microns for BC360  
4 USS 5 microns (back up IHC and MP Charged slide) 
 
For biopsies performed at NYULMC, the pathologist may verify the presence of leftover clinical recuts to be 
used for the study in case of limited samples. 
 
Operative specimens  
 
Tissue specimens will be obtained at the time of surgery if there is residual disease after neoadjuvant therapy.  
A tumor block is preferred, however if a block is not feasible, a minimum of 15-20 unstained slides from the 
resected tumor are allowed.  Slides should have a recommended tissue thickness of 5-10 microns. 
 
Select the area with highest tumor cellularity, (recuts listed in order of priority):  
1 USS 5 microns for H&E 
2 USS 5 microns for PD-L1 IHC (Charged slide) 
1 USS 5 microns for MP (Charged slide) 
6 USS 10 microns for BC360  
4 USS 5 microns (back up IHC and MP, Charged slide) 
 
For surgical resections performed at NYULMC, the pathologist may verify the presence of leftover clinical 
recuts to be used for the study in case of limited samples. 
 
6.5.2 Characterization of Tumor Immune Cells  
Immunohistochemistry (IHC) will be used to assess the number and composition of immune cells present 


 
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within FFPE tumor tissue before therapy, during treatment, and at the time of surgery19.  Expression of PD-
L1 will be measured on tumor and tumor-infiltrating immune cells. IHC analyses may include, but is not 
necessarily limited to, the following markers: MHC class I/II, CD8, CD-20 (active B-cells)63, CD4 (helper T 
cells, regulatory T cells), FoxP3 (regulatory T cells), CD86 (M1 macrophages), CD163 (M2 macrophages), 
IL8 (associated with IBC)64, and CD68 (total macrophages).  
6.5.3 Tumor Genomic Analysis  
RNA will be extracted from tumor samples for analysis with Nanostring assay (BC360 panel). The BC360 
panel includes 776 genes across 23 key breast cancer pathways and provides information about the breast 
tumor microenvironment and immune response. Analysis of data will provide information about 33 biological 
signatures including signatures based upon the validated PAM50 and Tumor Inflammation Signature (TIS) 
assays.  DNA will be extracted from tumor samples for analysis with a 580 genes NGS hybrid capture assay.  
Tumor mutational burden (TMB), defined as the number of somatic, coding base substitutions and short 
insertions and deletions per megabase of genome examined, will be evaluated.  Blockade of PD-1 by 
nivolumab from binding to its ligands PDL-1 and PDL-2 may result in expansion of tumor-specific T cells. TCR 
sequencing will be used to determine the effect of nivolumab on the T-cell repertoire in tumor specimens.  In 
addition, analyses of mTOR and JAK/STAT pathways, as well as inflammatory cytokines, and tumor-
associated macrophages (TAMs)65 will be performed. 
 
6.5.4 Peripheral Blood Samples 
 
Blood samples will be drawn at the time points identified in the Study Calendar (Section 6.1).   
  
Key immune biomarkers will be evaluated on circulating leukocytes to evaluate changes during PD-1 
blockade. In addition, the immune cell subset frequencies and expression of key receptors on PBMC will be 
studied to identify changes that occur after PD-1 blockade. Included in the analysis are CD4/CD8 and Th1/Th2 
profiles, immunosuppressive regulatory T cells (Tregs), the development of which is promoted by PD-1/PD-
L1 ligation, dendritic cells (DC), which are important APCs, and inhibitory receptors PD-1, CTLA4, TIM-3, and 
LAG-3, which can contribute to T cell exhaustion.  Flow cytometry will be used to quantify these biomarkers.  
Sequential samples of PBMCs will be analyzed from subjects before and during treatment with nivolumab.   
 
Liquid biopsy enables analysis of tumor cells and tumor DNA directly from blood. We will perform a 
comprehensive liquid biopsy evaluation in which whole tumor cells as well as cell-free tumor DNA are 
captured from blood and profiled. Genetic heterogeneity is analyzed on a single cell level and compared with 
the levels of cell-free tumor DNA to determine response to therapy and predict disease recurrence. DNA from 
circulating leukocytes is used as a control for DNA NGS and methylation. 
 
6.5.5  Banked Biospecimens 
 
To protect subject’s confidentiality, banked biospecimens and data generated from them will be coded with 
the subject’s study ID number.  Samples will be kept in the Center for Biospecimen Research and 
Development (CBRD) accessible only by badge-swipe. Data will be stored on password-protected computer 
systems. The key between the code and the subject’s personal identifiers will be held at the study site; the 
researchers using the biospecimens and data generated from them will not have access to the key nor any 
personally identifying information.  Biospecimens will only be used for the purposes described here and in the 
informed consent document/patient information sheet; any other uses require additional ethical approval.  
Unless a time limitation is required by local regulations or ethical requirements, biospecimens will be stored 
indefinitely to allow for future research on the topics described here, including research conducted during the 
lengthy drug development process and also post-marketing research.  Subjects can withdraw their consent 
for the use of their biospecimens at any time by making a request to the Investigator, in which event any 
remaining biospecimen will be destroyed; data already generated from the biospecimens will continue to be 
stored to protect the integrity of existing analyses. Subjects are notified in the informed consent 
document/patient information sheet that their results will not be given to them, unless required by local laws 
or regulations, in which case results will be returned via the Investigator.  


 
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6.5.6  Specimen Shipment 
 
See laboratory manual for full details on specimen shipment. 
 
7 Statistical Plan 
7.1 Primary Endpoint and Sample Size Determination 
 
The primary endpoint is pathological complete response (pCR).  pCR is defined as no histologic evidence of 
invasive tumor cells in the surgical breast specimen, axillary nodes, or sentinel node identified after 
neoadjuvant chemotherapy.  In a retrospective analysis of 527 patients with IBC at MDACC, the pCR rates 
after neoadjuvant chemotherapy by hormone receptor and HER2-defined subtypes were: 7.4% in HR-
positive/HER2-negative, 12.4% in TNBC, 15% in HR-positive/HER2-positive, and 30.5% in HR-
negative/HER2-positive15.  
 
For Cohort 1 (HER2-negative, including TNBC and HR-positive), a total sample size of 26 subjects with newly 
diagnosed IBC will be enrolled to evaluate the anti-tumor activity of the combination of nivolumab and 
chemotherapy in the neoadjuvant setting.  With a sample size of 26 for Cohort 1, we can detect a 20% 
increase in pCR in patients who will be treated with the combination of nivolumab and neoadjuvant 
chemotherapy compared to the 10% baseline pCR in patients treated with only neoadjuvant chemotherapy15 
with two-sided alpha of 0.05 and power of 80% based on Fisher’s exact test.  
 
For Cohort 2 (HER2-positive, independent of HR status), a total sample size of 26 subjects with newly 
diagnosed IBC will be enrolled to evaluate the anti-tumor activity of the combination of nivolumab and 
chemotherapy in the neoadjuvant setting. With a sample size of 26 for Cohort 2, we can detect a 25% increase 
in pCR in patients who will be treated with the combination of nivolumab and neoadjuvant chemotherapy 
compared to the 25% baseline pCR in patients treated with only neoadjuvant chemotherapy15 with two-sided 
alpha of 0.05 and power of 80% based on Fisher’s exact test.   
 
Descriptive statistics will be provided for efficacy endpoints. An estimated 70 subjects will be screened for 
eligibility to reach a goal of 52 participants.  
 
The two analysis populations will be defined as:  
• 
interim safety analysis population: all subjects in Cohort 2 who receive any amount of study drug (i.e. 
nivolumab).  
• 
efficacy evaluable population: all subjects in Cohorts 1 and 2 who receive any amount of study drug (i.e. 
nivolumab) (i.e. All-Treated Population (AT)). Analysis of efficacy endpoints will be performed on the 
efficacy evaluable population. Supportive and correlative analysis will be based on AT as well.  
7.2 Statistical Methods 
 
Definition of primary outcomes/endpoint:   
 
The primary endpoint will be pathological complete response (pCR).  pCR is defined as no histologic evidence 
of invasive tumor cells in the surgical breast specimen, axillary nodes, or sentinel node identified after 
neoadjuvant chemotherapy (ypT0/Tis ypN0). 
 
Definition of secondary outcomes/endpoints: 
 
Safety and tolerability of the combination of nivolumab and chemotherapy will be determined using the 


 
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Common Terminology Criteria for Adverse Events (CTCAE) v5.  Dose-limiting toxicity (DLT) is defined as any 
toxicity requiring discontinuation of nivolumab as defined in Section 5.3.2.   All on-study AEs, drug-related 
AEs, SAEs and drug-related SAEs, and/or AEs/SAEs leading to discontinuation will be tabulated as per NCI 
CTCAE v 5.0 criteria by system organ class and preferred term.   
 
Invasive recurrence-free interval (IRFI) will be assessed [time frame: up to 24 months after study entry]. This 
is defined as the time from study entry until diagnosis of the first invasive local, regional, or distant breast 
cancer recurrence during the 24 months after study entry.  If a subject has no event/death but the last known 
date alive is earlier than 24 months since study entry, then subject’s IRFI should be censored (at last known 
alive date or date of last assessment).   
 
Analytic plan for primary objective:   
 
The response rate and associated 95% confidence interval will be estimated using a uniformly minimum 
variance unbiased estimator as per Clopper-Pearson method. 
 
Analytic plan for secondary objectives: 
 
a) Safety monitoring will occur continuously in the study.  The safety endpoints are AEs graded using CTCAE 
(Version 5.0) criteria.  Safety will be assessed by quantifying the toxicities by type and grade experienced by 
subjects who have received therapy, including serious adverse events (SAEs). Summary statistics 
(percentage, mean, standard deviation, etc.) will be provided for the safety endpoints as appropriate.  
Sequential boundaries will be used to monitor dose-limiting toxicity rate. There will be an interim safety 
analysis in Cohort 2.  Monitoring for toxicity will follow a Bayesian-based rule for the probability that the rate 
of DLT exceeds a maximal tolerated level of 30%. We will assume a Beta(1,2) prior, which is prior information 
equivalent to one DLT observed in three treated subjects. Early termination for toxicity will be considered 
based on a posterior probability above 75% that the toxicity rate exceeds 30%. A formal dose-limiting toxicity 
(DLT) evaluation (assessed on day 21) will be done after the first 13 subjects for the interim safety analysis 
have completed treatment with combination of nivolumab and chemotherapy. If no more than 5 of the first 13 
subjects have DLT (clinically significant, pre-specified AEs), enrollment will continue (posterior probability that 
toxicity rate exceeds 30% is 72%).  If six or more of the first 13 have DLT, consideration would be given to 
modifying the dose of chemotherapy given in combination with nivolumab (posterior probability that toxicity 
rate exceeds 30% is 87%).  
 
b) Invasive recurrence-free interval (IRFI) will be evaluated using Kaplan-Meier analysis.  IRFI will be 
assessed as the time from study entry until diagnosis of the first invasive local, regional, or distant breast 
cancer recurrence during the 24 months after study entry.   
 
Analytic plan for exploratory/correlative objectives: 
 
The association between biomarkers and best overall response (responder versus non-responder primary) 
will be described by response rate in subgroups, and assessed using the mid-p adjustment to Fisher’s exact 
test. The association between biomarkers and response will be described by graphical summaries and 
assessed using a two-sample t-test with transformation as needed. 
7.3 Subject Population(s) for Analysis 
 
Intent-to-Treat Population (ITT) 
 
The ITT population will include all participants who are enrolled onto the study. The ITT population will be the 
primary population for evaluating all efficacy endpoints and participant characteristics. 
 
All-Treated Population (AT) 
 


 
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The AT population will include all participants who receive at least one dose of study treatment (i.e. 
nivolumab), with treatment assignments designated according to actual study treatment received. The AT 
population will be the primary population for evaluating treatment administration/compliance, safety, and 
efficacy.  
 
8 Safety and Adverse Events 
8.1 Definitions 
 
Unanticipated Problems Involving Risk to Subjects or Others 
 
Any incident, experience, or outcome that meets all of the following criteria:  
• Unexpected in nature, severity, or frequency (i.e. not described in study-related documents such as 
the IRB-approved protocol or consent form, the Investigator’s Brochure (IB), etc.) 
• Related or possibly related to participation in the research (i.e. possibly related means there is a 
reasonable possibility that the incident experience, or outcome may have been caused by the 
procedures involved in the research) 
• Suggests that the research places subjects or others at greater risk of harm (including physical, 
psychological, economic, or social harm) 
SERIOUS ADVERSE EVENTS 
A Serious Adverse Event (SAE) is 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) 
• 
results in persistent or significant disability/incapacity 
• 
is a congenital anomaly/birth defect  
• 
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 subject 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.)  
• 
Suspected transmission of an infectious agent (eg, pathogenic or nonpathogenic) via the study drug is 
an SAE.  
Although pregnancy, overdose, potential drug-induced liver injury (DILI), and cancer are not always serious 
by regulatory definition, these events must be handled as SAEs. 
Any component of a study endpoint that is considered related to study therapy should be reported as an SAE 
(eg, death is an endpoint, if death occurred due to anaphylaxis, anaphylaxis must be reported). 
NOTE: (PI determines if this information regarding hospitalizations are considered SAEs and should be 
included in the protocol. This is supplemental information that is included in BMS-sponsored trials) 


 
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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) 
ADVERSE EVENTS 
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 drug 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 
investigational product, whether or not considered related to the investigational product. 
The causal relationship to study drug is determined by a physician and should be used to assess all adverse 
events (AE). The casual relationship can be one of the following: 
Related: There is a reasonable causal relationship between study drug administration and the AE. 
Not related: There is not a reasonable causal relationship between study drug administration and the AE.  
The term "reasonable causal relationship" means there is evidence to suggest a causal relationship.  
Adverse events can be spontaneously reported or elicited during open-ended questioning, examination, or 
evaluation of a subject. (In order to prevent reporting bias, subjects should not be questioned regarding the 
specific occurrence of one or more AEs.) 
NONSERIOUS ADVERSE EVENT 
• 
Non-serious Adverse Events (AE) are to be provided to BMS in aggregate via interim or final study 
reports as specified in the agreement or, if a regulatory requirement [eg, IND US trial] as part of an 
annual reporting requirement.  
• 
Non-serious AE information should also be collected following the subject’s written consent to 
participate in the study to establish a baseline status for the subjects.  
A non-serious adverse event is an AE not classified as serious.  
Non-serious Adverse Event Collection and Reporting 


 
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The collection of non-serious AE information should begin following the subject’s written consent to participate 
in the study. All non-serious adverse events (not only those deemed to be treatment-related) should be 
collected continuously during the treatment period and for a minimum of 100 days following the last dose of 
study treatment.  
Non-serious AEs should be followed to resolution or stabilization, or reported as SAEs if they become serious. 
Follow-up is also required for non-serious AEs that cause interruption or discontinuation of study drug and for 
those present at the end of study treatment as appropriate.  
Laboratory Test Abnormalities 
All laboratory test results captured as part of the study should be recorded following institutional procedures. 
Test results that constitute SAEs should be documented and reported to BMS as such. 
The following laboratory abnormalities should be documented and reported appropriately: 
• 
any laboratory test result that is clinically significant or meets the definition of an SAE 
• 
any laboratory abnormality that required the participant to have study drug discontinued or interrupted 
• 
any laboratory abnormality that required the subject to receive specific corrective therapy.  
It is expected that wherever possible, the clinical rather than laboratory term would be used by the reporting 
investigator (e.g., anemia versus low hemoglobin value). 
8.2 Recording of Adverse Events 
 
At each contact with the subject, the Investigator must seek information on adverse events by specific 
questioning and, as appropriate, by examination.  Information on all adverse events should be recorded 
immediately in the source document, and also in the appropriate adverse event module of the CRF.  All clearly 
related signs, symptoms, and abnormal diagnostic procedures results should be recorded in the source 
document, though should be grouped under one diagnosis. 
 
All adverse events occurring during the study period must be recorded.  The clinical course of each event 
should be followed until resolution, stabilization, or until it has been determined that the study treatment or 
participation is not the cause.  Serious adverse events that are still ongoing at the end of the study period 
must be followed up to determine the final outcome.  Any serious adverse event that occurs after the study 
period and is considered to be possibly related to the study treatment or study participation should be recorded 
and reported immediately. 
8.3 Reporting of Serious Adverse Events and Unanticipated Problems 
 
Investigators and the Study Sponsor must conform to the adverse event reporting timelines, formats and 
requirements of the various entities to which they are responsible, but at a minimum those events that must 
be reported are those that are: 
 
• related to study participation, 
• unexpected, and  
• serious or involve risks to subjects or others  
(see definitions, Section 8.1)   
 
Events should be reported using the NYU CTO Medical Events Form. Please email all SAEs to 
NYUPCCsafety@nyumc.org, Dr. Maryann Kwa, the NYULMC PCC regulatory specialist, and the Medical 
Monitor Dr. Elaine Shum within 24 hours of learning of the SAE.   
 


 
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Adverse events that do not fit the above immediately reportable criteria must still be reported to the IRB at 
each annual review, either in a summary or tabular format. 
 
8.3.1 Investigator Reporting: Notifying the Study Sponsor 
 
Since multiple sites will be participating, the following describes events that must be reported to the 
study sponsor (NYU Langone Health PCC) and the study sponsor reports to BMS in an expedited fashion. 
 
Initial Report: within 24 hours: 
The following events must be reported to the study sponsor (NYULH PCC) by email within 24 hours of 
awareness of the event using the NYU CTO Medical Events Form: 
 
• Unanticipated problems related to study participation, 
• Serious adverse events, regardless of whether they are unexpected. 
 
The investigator shall maintain a copy of the Medical Events Form on file at the study site. All report 
forms 
must be signed and dated by the Principal Investigator. If the Principal Investigator is not 
available at the time of the initial report, then the form can be submitted by a Sub-Investigator. This 
form should be reviewed by the Principal Investigator, whom sign/date initial report upon return. 
 
Report to: 
NYUPCCsafetyreports@nyulangone.org 
 
AND 
 
                                                      Maryann Kwa, MD 
                                                      Assistant Professor of Medicine 
 
 
 
 
  NYU Perlmutter Cancer Center  
  160 East 34th Street, Fourth Floor 
  New York, NY 10016 
  Tel: (212) 731-6364 
  Email: maryann.kwa@nyulangone.org  
 
Events of Clinical Interest (any medical event that is deemed significant via Principal Investigator’s 
expertise, but does not apply to SAE categories) will be reported within 2-5 days, or as per study 
Sponsor specifications. 
 
Follow-up report:  
As a follow-up to the initial report, the investigator shall provide further information, as applicable, on 
the unanticipated event or the unanticipated problem in the form of a written narrative. This should 
include a copy of the completed Unanticipated 
Problem form, and any other diagnostic information 
that will assist the understanding of the event. 
 
Other Reportable events: 
 
• 
Deviations from the study protocol 
Deviations from the protocol must receive both Sponsor and the investigator’s IRB approval 
before they are initiated. Any protocol deviations initiated without Sponsor and the 
investigator’s IRB approval that may affect the scientific soundness of the study, or affect 
the rights, safety, or welfare of study subjects, must be reported to the Sponsor and to the 
investigator’s IRB as soon as a possible, but no later than 5 working days of the protocol 
deviation. 
• 
Withdrawal of IRB approval 


 
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An investigator shall report to the sponsor a withdrawal of approval by the investigator’s 
reviewing 
IRB as soon as a possible, but no later than 5 working days of the IRB 
notification of withdrawal of approval 
• 
All Serious Adverse Events (SAEs) that occur following the subject’s written consent to participate in 
the study through 100 days of discontinuation of dosing must be reported to BMS Worldwide Safety, 
whether related or not related to study drug. If applicable, SAEs must be collected that relate to any 
later protocol-specified procedure (eg, a follow-up skin biopsy). 
• 
Following the subject’s written consent to participate in the study, all SAEs, whether related or not 
related to study drug, are collected, including those thought to be associated with protocol-specified 
procedures. The investigator should report any SAE occurring after these aforementioned time periods, 
which is believed to be related to study drug or protocol-specified procedure. 
• 
An SAE report should be completed for any event where doubt exists regarding its seriousness;  
• 
If the investigator believes that an SAE is not related to study drug, but is potentially related to the 
conditions of the study (such as withdrawal of previous therapy or a complication of a study procedure), 
the relationship should be specified in the narrative section of the SAE Report Form. 
• 
If the BMS safety address is not included in the protocol document (eg, multicenter studies where events 
are reported centrally), the procedure for safety reporting must be reviewed/approved by the BMS 
Protocol Manager. Procedures for such reporting must be reviewed and approved by BMS prior to study 
activation. 
An appropriate SAE form (e.g. ex-US = CIOMS form or USA = Medwatch form) should be used to report 
SAEs to BMS.  If you prefer to use your own Institutional form, it must be reviewed by BMS prior to study 
initiation.  Note:  Please include the BMS Protocol number on the SAE form or on the cover sheet with the 
SAE form transmission.   
o 
The CIOMS form is available at: http://www.cioms.ch/index.php/cioms-form-i  
o 
The MedWatch form is available at: MedWatch 3500 Form  
 
• 
For studies with long-term follow-up periods in which safety data are being reported, include the timing 
of SAE collection.  
 
• 
The Sponsor will reconcile the clinical database SAE cases (case level only) transmitted to BMS 
Global Pharmacovigilance (Worldwide.Safety@bms.com). Frequency of reconciliation should be 
every 3 months and prior to the database lock or final data summary. BMS GPV&E will email, upon 
request from the Investigator, the GPV&E reconciliation report. Requests for reconciliation should be 
sent to aepbusinessprocess@bms.com. The data elements listed on the GPV&E reconciliation report 
will be used for case identification purposes. If the Investigator determines a case was not transmitted 
to BMS GPV&E, the case should be sent immediately to BMS.  
 
• 
In accordance with local regulations, BMS will notify investigators of all reported SAEs that are 
suspected (related to the investigational product) and unexpected (ie, not previously described in the 
IB). An event meeting these criteria is termed a Suspected, Unexpected Serious Adverse Reaction 
(SUSAR). Investigator notification of these events will be in the form of a SUSAR Report.  
 
o 
Other important findings which may be reported by BMS as an Expedited Safety Report (ESR) 
include: increased frequency of a clinically significant expected SAE, an SAE considered 
associated with study procedures that could modify the conduct of the study, lack of efficacy that 
poses significant hazard to study subjects, clinically significant safety finding from a nonclinical 
(eg, animal) study, important safety recommendations from a study data monitoring committee, or 
sponsor decision to end or temporarily halt a clinical study for safety reasons. 


 
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o 
Upon receiving an ESR from BMS, the investigator must review and retain the ESR with the IB. 
Where required by local regulations or when there is a central IRB/IEC for the study, the sponsor 
will submit the ESR to the appropriate IRB/IEC. The investigator and IRB/IEC will determine if the 
informed consent requires revision. The investigator should also comply with the IRB/IEC 
procedures for reporting any other safety information.  
o 
In addition to the Sponsor Investigator’s responsibility to report events to their local HA, suspected 
serious adverse reactions (whether expected or unexpected) shall be reported by BMS to the 
relevant competent health authorities in all concerned countries according to local regulations 
(either as expedited and/or in aggregate reports). 
SAEs, whether related or not related to study drug, and pregnancies must be reported to BMS within 24 hours\ 
1 Business Day of becoming aware of the event. SAEs must be recorded on either CIOMS, MedWatch, or 
approved site SAE form.   
Pregnancies must be reported and submitted to BMS on any of the following form(s): 
1. MedWatch or, CIOMS or 
2. BMS Pregnancy Surveillance Form or,  
3. Approved site SAE form  
* Note: Reporting requirements will vary by product.  Please check with your ISR Lead for applicable reporting 
timeframe. 
SAE Email Address:  Worldwide.Safety@BMS.com 
SAE Facsimile Number:  +1 609-818-3804 
If only limited information is initially available, follow-up reports are required. (Note: Follow-up SAE reports 
should include the same investigator term(s) initially reported.)  
If an ongoing SAE changes in its intensity or relationship to study drug or if new information becomes 
available, a follow-up SAE report should be sent within 24 hours \ 1 Business Day to BMS using the same 
procedure used for transmitting the initial SAE report.  
All SAEs should be followed to resolution or stabilization. 
 
8.3.2 Pregnancy 
 
If, following initiation of the investigational product, it is subsequently discovered that a study participant is 
pregnant or may have been pregnant at the time of investigational product exposure, including during at least 
5 half-lives after product administration, the investigational product will be permanently discontinued in an 
appropriate manner (e.g., dose tapering if necessary for participant).  
The investigator must immediately notify Worldwide.Safety@bms.com of this event via either the CIOMS, 
MedWatch or appropriate Pregnancy Surveillance Form in accordance with SAE reporting procedures.  
Protocol-required procedures for study discontinuation and follow-up must be performed on the participant. 
Follow-up information regarding the course of the pregnancy, including perinatal and neonatal outcome and, 
where applicable, offspring information must be reported on the CIOMS, MedWatch, BMS Pregnancy 
Surveillance Form, or approved site SAE form.  A BMS Pregnancy Surveillance Form may be provided upon 
request. 
Any pregnancy that occurs in a female partner of a male study participant should be reported to BMS. 
Information on this pregnancy will be collected on the Pregnancy Surveillance Form. 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.  


 
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Chemotherapy with docetaxel, paclitaxel, doxorubicin, cyclophosphamide, trastuzumab, or pertuzumab is 
considered Non-IP as it represents routine or standard of care treatment for the respective patient population.  
• Docetaxel injection can cause fetal harm when administered to a pregnant woman. Female subjects 
/female partners of male subjects should not become pregnant during treatment with docetaxel. Females 
must not breast-feed while being treated with docetaxel. Males being treated with docetaxel are advised 
not to father a child during and up to 6 months after treatment and to seek advice on conservation of 
sperm prior to treatment because docetaxel may alter male fertility. Use of highly effective contraception 
during treatment is recommended. This drug is classified as FDA Category D, there is positive evidence 
of human fetal risk based on adverse reaction data from investigational or marketing experience or studies 
in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks. 
• Paclitaxel can cause fetal harm when administered to a pregnant woman. Female subjects /female 
partners of male subjects should not become pregnant during treatment with paclitaxel. Females must 
not breast-feed while being treated with paclitaxel. Males being treated with paclitaxel, are advised not to 
father a child during treatment and to seek advice on conservation of sperm prior to treatment because 
paclitaxel may impair fertility. Use of highly effective contraception during treatment is recommended. 
This drug is classified as FDA Category D, there is positive evidence of human fetal risk based on adverse 
reaction data from investigational or marketing experience or studies in humans, but potential benefits 
may warrant use of the drug in pregnant women despite potential risks. 
• Doxorubicin can cause fetal harm when administered to a pregnant woman. Female subjects /female 
partners of male subjects should not become pregnant during treatment with doxorubicin. Females must 
not breast-feed while being treated with doxorubicin. Doxorubicin may cause infertility in males and 
females. Use of highly effective contraception during treatment and for 6 months after treatment is 
recommended. This drug is classified as FDA Category D, there is positive evidence of human fetal risk 
based on adverse reaction data from investigational or marketing experience or studies in humans, but 
potential benefits may warrant use of the drug in pregnant women despite potential risks. 
• Cyclophosphamide can cause fetal harm when administered to pregnant women. Female subjects /female 
partners of male subjects should not become pregnant during treatment with cyclophosphamide. Females 
must not breast-feed while being treated with cyclophosphamide. Male and female reproductive function 
and fertility may be impaired in patients being treated with cyclophosphamide. Use of highly effective 
contraception during treatment and for up to 1 year after treatment is recommended. This drug is classified 
as FDA Category D, there is positive evidence of human fetal risk based on adverse reaction data from 
investigational or marketing experience or studies in humans, but potential benefits may warrant use of the 
drug in pregnant women despite potential risks. 
• Trastuzumab can cause fetal harm when administered to pregnant women. Female subjects /female 
partners of male subjects should not become pregnant during treatment with trastuzumab. There is no 
information regarding the presence of trastuzumab in human milk, the effects on the breastfed infant, or 
the effects on milk production. Developmental and health benefits of breastfeeding along with the mother's 
clinical need for treatment and any potential adverse effects on the breastfed child from treatment or from 
the underlying maternal condition will be considered by the treating physician. This consideration will also 
take into account the trastuzumab wash out period of 7 months. Use of highly effective contraception 
during treatment and for up to 7 months after treatment is recommended. This drug is classified as FDA 
Category D, there is positive evidence of human fetal risk based on adverse reaction data from 
investigational or marketing experience or studies in humans, but potential benefits may warrant use of 
the drug in pregnant women despite potential risks. 
• Pertuzumab can cause fetal harm when administered to pregnant women. Female subjects /female 
partners of male subjects should not become pregnant during treatment with pertuzumab. There is no 
information regarding the presence of pertuzumab in human milk, the effects on the breastfed infant, or 
the effects on milk production. Developmental and health benefits of breastfeeding along with the mother's 
clinical need for treatment and any potential adverse effects on the breastfed child from treatment or from 
the underlying maternal condition will be considered by the treating physician. This consideration will also 
take into account the pertuzumab wash out period of 7 months. Use of highly effective contraception 
during treatment and for up to 7 months after treatment is recommended. This drug is classified as FDA 


 
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Category D, there is positive evidence of human fetal risk based on adverse reaction data from 
investigational or marketing experience or studies in humans, but potential benefits may warrant use of 
the drug in pregnant women despite potential risks. 
8.3.3 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. All occurrences of overdose must be reported as an SAE. 
 
8.3.4 Other Safety Considerations 
 
Any significant worsening noted during interim or final physical examinations, electrocardiograms, imaging 
tests, and any other potential safety assessments, whether or not these procedures are required by the 
protocol, should also be recorded as a non-serious or serious AE, as appropriate, and reported accordingly.  
 
8.3.5 Investigator Reporting: Notifying the IRB 
 
Federal regulations require timely reporting by Investigators to their local IRB of unanticipated problems 
posing risks to subjects or others.  The following describes the NYULMC IRB reporting requirements, though 
Investigators at participating sites are responsible for meeting the specific requirements of their local IRB of 
record.  The NYULMC IRB address is: 
 
NYU School of Medicine IRB 
 
 
 
One Park Avenue, 6th Floor 
 
 
 
New York, NY 10016 
 
Report Promptly, but no later than 5 working days: 
 
Researchers are required to submit reports of the following problems promptly but no later than 5 working 
days from the time the Investigator becomes aware of the event: 
 
• 
Unanticipated problems including adverse events that are unexpected and related 
– Unexpected: An event is “unexpected” when its specificity and severity are not accurately reflected 
in the protocol-related documents, such as the IRB-approved research protocol, any applicable 
Investigator Brochure, and the current IRB-approved informed consent document and other 
relevant sources of information, such as product labeling and package inserts.  
– Related to the research procedures: An event is related to the research procedures if in the opinion 
of the Principal Investigator or Sponsor, the event was more likely than not to be caused by the 
research procedures.  
– Harmful: either caused harm to subjects or others, or placed them at increased risk 
 
Other Reportable events: 
 
The following events also require prompt reporting to the IRB, though no later than 5 working days: 
• Complaint of a research subject when the complaint indicates unexpected risks or the complaint 
cannot be resolved by the research team. 
• Protocol deviations or violations (includes intentional and accidental/unintentional deviations from 
the IRB approved protocol) for any of the following situations:  
– one or more participants were placed at increased risk of harm  
– the event has the potential to occur again 
– the deviation was necessary to protect a subject from immediate harm 
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• Incarceration of a participant when the research was not previously approved under Subpart C and 
the Investigator believes it is in the best interest of the subject to remain on the study. 
• New Information indicating a change to the risks or potential benefits of the research, in terms 
of severity or frequency. (e.g. analysis indicates lower-than-expected response rate or a more severe 
or frequent side effect; Other research finds arm of study has no therapeutic value; FDA labeling 
change or withdrawal from market) 
 
Reporting Process 
 
The reportable events noted above will be reported to the IRB using the form: “Reportable Event Form” or as 
a written report of the event (including a description of the event with information regarding its fulfillment of 
the above criteria, follow-up/resolution and need for revision to consent form and/or other study 
documentation). 
 
Copies of each report and documentation of IRB notification and receipt will be kept in the Investigator’s study 
file. 
 
8.3.6 Sponsor Reporting: Notifying the FDA 
 
The Study Sponsor is required to report certain study events in an expedited fashion to the FDA.  These 
written notifications of adverse events are referred to as IND safety reports. The following describes the safety 
reporting requirements by timeline for reporting and associated type of event: 
 
• Within 7 calendar days (via telephone or facsimile report) 
 
Any study event that is: 
– associated with the use of the study drug 
– unexpected,  
– fatal or life-threatening 
 
• Within 15 calendar days (via written report) 
 
Any study event that is: 
– associated with the use of the study drug, 
– unexpected, and 
– serious, but not fatal or life-threatening 
-or- 
– a previous adverse event that was not initially deemed reportable but is later found to fit the criteria 
for reporting (reporting within 15 calendar days from when event was deemed reportable). 
 
Additional reporting requirements 
Sponsors are also required to identify in IND safety reports all previous reports concerning similar adverse 
events and to analyze the significance of the current event in light of the previous reports. 
 
Reporting Process 
Adverse events may be submitted on FDA Form 3500A or in a narrative format. If supplied as in a narrative 
format, the minimum information to be supplied is noted above at the beginning of Section 8.3. The contact 
information for submitting IND safety reports is noted below: 
NYU Langone Health Contacts: 
 
NYUPCCsafetyreports@nyulangone.org 
 
AND 
 
Maryann Kwa, MD 
NYU Perlmutter Cancer Center 


 
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160 East 34th Street 
New York, NY 10016 
Tel: (212) 731-6364 
Email: maryann.kwa@nyulangone.org 
 
8.3.7    Sponsor Reporting: Notifying Participating Investigators 
 
For multi-center trials, it is the responsibility of the Study Sponsor to notify all participating Investigators of 
any adverse event that meets the FDA 15-day reporting requirement criteria. The same materials and timeline 
used to report to the FDA are used for notifying participating Investigators. 
8.4 Medical Monitoring 
 
It is the responsibility of the Principal Investigator to oversee the safety of the study at his/her site.  This safety 
monitoring will include careful assessment and appropriate reporting of adverse events as noted above, as 
well as the construction and implementation of a site data and safety-monitoring plan detailed below.  Serious 
adverse events are evaluated regularly by the principal investigator in conjugation with the 
research 
team, the DSMC is notified of serious adverse events via email initially, reviewed offline by the designated 
medical monitor, and presented at the next DSMC monthly meeting. The Data Safety and Monitoring 
Committee (DSMC) will review the study at least quarterly. Medical monitoring will include a 
regular 
assessment of the number and type of serious adverse events.  
 
8.4.1 Data Safety Monitoring Committee (DSMC) 
 
This investigator-initiated study will be monitored by the Data Safety Monitoring Committee (DSMC) of the 
NYU Perlmutter Cancer Center. The DSMC operates based on the National Cancer Institute approved 
Charter. It is an existing multidisciplinary committee (consisting of clinical investigators/oncologists, 
biostatisticians, nurses, and research administration staff knowledgeable of research methodology and design 
and in proper conduct of clinical trials) that is responsible for monitoring safety, conduct and compliance in 
accordance with protocol data monitoring plans for clinical trials conducted at the NYU Perlmutter Cancer 
Center that are not monitored by another institution or agency. The DSMC reports to the Director of the NYU 
Perlmutter Cancer Center (Benjamin Neel, MD, PhD).  
 
Per the NYU Institutional Data Safety and Monitoring Plan, this phase II trial will be monitored by the DSMC 
quarterly (from the date the first subject is enrolled), at protocol-specified interim time points, and at the 
completion of the study prior to study closure. This review includes accrual data, subject demographics and 
adverse events. Principal Investigators are required to attend the review of their studies. Additional reviews 
can be scheduled based on SAE reports, investigator identified issues, external information, etc.  The DSMC 
will review safety data every 3 months.  DSMC summary reports are available to facilitate the review and 
monitoring of this study.    These reports include the following:  subject listings and summary reports that 
describe study enrollment and accrual, eligibility, demographic characteristics, dose modifications, 
adverse experiences, subject’s death and additional external published data if applicable to the study.  
Cumulative toxicities, SAEs, and AEs are reviewed, to identify possible adverse events with elevated 
frequency that is unexpected.  Once a recommendation is made if further action is required, the 
Investigator’s must respond within 10 business days of receipt of DSMC letter. 
 
9 Data Handling and Record Keeping 
 
9.1 Confidentiality 
 
The NYU Perlmutter Cancer Center Clinical Trials Office (CTO) together with the PI will oversee the data 
management of this trial.  TrialMaster, an electronic database capture system will be created to 
record the data for this trial. Research coordinators will input clinical trial data into the database. This 
database is password protected and only the PI, assigned study team members, and CTO staff 


 
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will have access to the database. DataCore, a core resource of the institution, will provide the 
primary data collection instrument for the study. All data requested in the system must be reported. 
All missing data must be explained. The quality assurance specialists will monitor this trial every 4-6 
weeks for data entry accuracy. 
 
Source documentation should be consistent with data entered into any electronic medical record or 
Trial 
master.  Relevant source documentation to be reviewed by the DSMC throughout the study 
includes: 
1. Baseline measures to assess pre-protocol disease status 
2. Concurrent medications 
3. Treatment records 
4. Adverse events 
 
The study team will maintain clinical and laboratory data in a designed manner to ensure patient 
confidentiality. All study personnel have passed human subject protection courses. If applicable, tissue 
samples sent to collaborators outside of NYU will only be labeled with an assigned protocol-patient 
identification number without patient identifiers. Systems used for electronic data capture are compliant with 
FDA regulations in 21 CFR Part 11 and applicable local regulatory agency guidelines. All documents are kept 
in strictly confidential files and are only made accessible for review of sponsors, monitors and authorized 
representatives of regulatory agencies as described in the informed consent document. 
9.2 Confidentiality and HIPAA 
 
Information about study subjects will be kept confidential and managed according to the requirements of the 
Health Insurance Portability and Accountability Act of 1996 (HIPAA).  Those regulations require a signed 
subject authorization informing the subject of the following:  
 
• What protected health information (PHI) will be collected from subjects in this study 
• Who will have access to that information and why 
• Who will use or disclose that information  
• The rights of a research subject to revoke their authorization for use of their PHI 
 
In the event that a subject revokes authorization to collect or use PHI, the Investigator, by regulation, retains 
the ability to use all information collected prior to the revocation of subject authorization.  For subjects that 
have revoked authorization to collect or use PHI, attempts should be made to obtain permission to collect at 
least vital status (i.e. that the subject is alive) at the end of their scheduled study period. 
9.3 Source Documents 
 
Source data is all information, original records of clinical findings, observations, or other activities in a clinical 
trial necessary for the reconstruction and evaluation of the trial.  Source data are contained in source 
documents.  Examples of these original documents, and data records include: hospital records, clinical and 
office charts, laboratory notes, memoranda, subjects’ diaries or evaluation checklists, pharmacy dispensing 
records, recorded data from automated instruments, copies or transcriptions certified after verification as 
being accurate and complete, microfiches, photographic negatives, microfilm or magnetic media, x-rays, 
subject files, and records kept at the pharmacy, at the laboratories, and at medico-technical departments 
involved in the clinical trial. 
9.4 Records Retention 
 
It is the Investigator’s responsibility to retain study essential documents for at least 2 years after the last 
approval of a marketing application in their country and until there are no pending or contemplated marketing 
applications in their country or at least 2 years have elapsed since the formal discontinuation of clinical 
development of the investigational product.  These documents should be retained for a longer period if 


 
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61 
required by an agreement with the Sponsor.  In such an instance, it is the responsibility of the Sponsor to 
inform the Investigator/Institution as to when these documents no longer need to be retained.   
 
10 Study Monitoring, Auditing, and Inspecting 
10.1 Study Monitoring Plan 
 
This study will be monitored according to the monitoring plan detailed below, subsite monitoring follows 
parameters detailed in Appendix 1. The Investigator will also ensure that the monitor, other compliance 
or quality assurance reviewer is given access to all the above noted study-related documents.  A risk-
based, data-driven monitoring approach will be used to verify data for this trial which will also include a 
centralized review of data for quality, trends, 
consistency and general safety review. A quality 
assurance specialist will review various aspects of the trial including, but not limited to: screening and 
enrollment logs; compliance with the protocol and with the principles of 
Good Clinical Practice; 
completion of case report forms; source data verification; study drug accountability and storage. 
 
During scheduled monitoring visits, the investigator and the investigational site staff must be available 
to meet with the quality assurance specialist in order to discuss the progress of the trial, make necessary 
corrections to case report form entries, respond to data clarification requests and respond to any other 
trial-related inquiries of the monitor. In addition to on-site monitoring visits, the Sponsor and/or 
representatives will also be routinely reviewing data. Any queries identified through this review will be 
managed within the systems established for query resolution and tracking. Inquiries related to study 
conduct, which require further information or action will be discussed within the study team for 
appropriate and documented escalation plans. It is expected that response to data clarification requests 
and other 
trial-related inquiries will occur throughout the course of the study through regular 
communication with the site monitor, the Sponsor or representatives, and review/entry of data into the 
electronic study database. 
 
At any time during the course of the study, representatives of the FDA and/or local regulatory agencies 
may review the conduct or results of the study at the investigational site. The investigator must promptly 
inform NYU PCC CTO and BMS of any audit requests by health authorities, and will provide BMS with 
the results of any such audits and with copies of any regulatory documents related to such audits. 
 
In accordance with HIPAA and associated privacy regulations, a patient’s authorization to use personal 
identifiable health information may be required from each patient before commencement of research 
activities. This authorization document must clearly specify what parties will have access to a patient’s 
personal health information, for what purpose and for what duration. 
 
At the NYU Perlmutter Cancer Center, all investigator-initiated protocols are subject to a standardized   
data and safety monitoring, which includes scientific peer review, IRB review and DSMC review as well 
as internal auditing. 
 
The review of AEs and trial conduct for this trial occurs at several levels: 
 
(1) Principal Investigator: Adverse events are evaluated monthly by the principal 
investigator in conjunction with the research nurses, data manager and research team. 
 
(2) DSMC, quarterly 
 
(3) Institutional Review Board (IRB): An annual report to the IRB is submitted by the trial PI 
for continuation of the protocol. It includes a summary of all AEs, total enrollment with 
demographics, protocol violations, and current status of subjects as well as available 
research data. 
 


 
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In addition, the quality assurance unit will monitor this trial every 4-6 weeks, this includes real-time review 
of all eCRFs to ensure completeness and to verify adherence to the protocol; the 
completeness, 
accuracy and consistency of the data; and adherence to ICH Good Clinical 
Practice guidelines. 
Additionally, a first subject audit is to be conducted within four weeks of enrollment. 
10.2 Auditing and Inspecting 
 
The Investigator will permit study-related monitoring, audits, and inspections by the IRB/Ethics Committee 
(EC), the Sponsor, government regulatory bodies, and University compliance and quality assurance groups 
of all study related documents (e.g. source documents, regulatory documents, data collection instruments, 
study data etc.).  The Investigator will ensure the capability for inspections of applicable study-related facilities 
(e.g. pharmacy, diagnostic laboratory, etc.). 
 
Participation as an Investigator in this study implies acceptance of potential inspection by government 
regulatory authorities and applicable University compliance and quality assurance offices. 
 
 
11 Ethical Considerations 
 
This study is to be conducted accordance with applicable US government regulations and international 
standards of Good Clinical Practice, and applicable institutional research policies and procedures. 
 
This protocol and any amendments will be submitted to a properly constituted Institutional Review Board (IRB) 
or independent Ethics Committee (EC) in agreement with local legal prescriptions, for formal approval of the 
study conduct.  The decision of the IRB/EC concerning the conduct of the study will be made in writing to the 
Investigator and a copy of this decision will be provided to the Sponsor before commencement of this study.  
The Investigator should provide a list of IRB/EC members and their affiliate to the Sponsor. 
 
All subjects for this study will be provided a consent form describing this study and providing sufficient 
information for subjects to make an informed decision about their participation in this study.  This consent 
form will be submitted with the protocol for review and approval by the IRB/EC for the study.  The formal 
consent of a subject, using the IRB/EC-approved consent form, must be obtained before that subject 
undergoes any study procedure.  The consent form must be signed by the subject or legally acceptable 
surrogate, and the investigator-designated research professional obtaining the consent.  
 
12 Study Finances 
12.1 Funding Source 
 
This investigator-initiated trial is supported by Bristol-Myers Squibb, Inc.  Subjects will not be paid for their 
participation in this research study.  
 
12.2 Conflict of Interest 
 
Any Investigator who has a conflict of interest with this study (patent ownership, royalties, or financial gain 
greater than the minimum allowable by their institution, etc.) must have the conflict reviewed by a properly 
constituted Conflict of Interest Committee with a Committee-sanctioned conflict management plan that has 
been reviewed and approved by the Study Sponsor prior to participation in this study.  All NYULH investigators 
will follow the applicable University conflict of interest policies. 
 
13 Publication Plan 
 


 
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Neither the complete nor any part of the results of the study carried out under this protocol, nor any of the 
information provided by the sponsor for the purposes of performing the study, will be published or passed on 
to any third party without the consent of the Study Sponsor.  Any Investigator involved with this study is 
obligated to provide the Sponsor with complete test results and all data derived from the study. 
 
The study PI holds the primary responsibility for publication of the results of the study.  Any publications or 
abstracts arising from this study require approval by BMS prior to publication or presentation. All draft 
publications must be submitted to BMS at the earliest practicable time for review, but at any event not less 
than 30 days before submission.  


 
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14 References 
 
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Adams S, Gray RJ, Demaria S, et al. Prognostic value of tumor-infiltrating lymphocytes in triple-
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Loi S, Michiels S, Salgado R, et al. Tumor infiltrating lymphocytes are prognostic in triple negative 
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21. 
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recurrence: understanding the biology of a unique disease. Cancer 2007;110:1436-44. 
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Sharpe AH, Wherry EJ, Ahmed R, Freeman GJ. The function of programmed cell death 1 and its 
ligands in regulating autoimmunity and infection. Nat Immunol 2007;8:239-45. 
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of chimeric anti-mouse PD-1 antibody, 4H2.  Bristol-Myers Squibb Company; 2007.  Document Control No: 
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month postnatal evaluation. Final report for Study DN12001. Bristol-Myers Squibb Company; Document 
Control No: 930073964. 
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carcinoma: twenty years of experience at M. D. Anderson Cancer Center. Cancer Chemother Pharmacol 
1997;40:321-9. 
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Kim T, Lau J, Erban J. Lack of uniform diagnostic criteria for inflammatory breast cancer limits 
interpretation of treatment outcomes: a systematic review. Clin Breast Cancer 2006;7:386-95. 
32. 
Gianni L, Eiermann W, Semiglazov V, et al. Neoadjuvant and adjuvant trastuzumab in patients with 
HER2-positive locally advanced breast cancer (NOAH): follow-up of a randomised controlled superiority trial 
with a parallel HER2-negative cohort. Lancet Oncol 2014;15:640-7. 
33. 
Schneeweiss A, Chia S, Hickish T, et al. Pertuzumab plus trastuzumab in combination with standard 
neoadjuvant anthracycline-containing and anthracycline-free chemotherapy regimens in patients with HER2-
positive early breast cancer: a randomized phase II cardiac safety study (TRYPHAENA). Ann Oncol 
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Schneeweiss A, Chia S, Hickish T, et al. Long-term efficacy analysis of the randomised, phase II 
TRYPHAENA cardiac safety study: Evaluating pertuzumab and trastuzumab plus standard neoadjuvant 
anthracycline-containing and anthracycline-free chemotherapy regimens in patients with HER2-positive early 
breast cancer. Eur J Cancer 2018;89:27-35. 
35. 
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HER2-Positive Breast Cancer. N Engl J Med 2017;377:122-31. 
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breast cancer. Semin Oncol 2008;35:41-50. 
37. 
Bertucci F, Fekih M, Autret A, et al. Bevacizumab plus neoadjuvant chemotherapy in patients with 
HER2-negative inflammatory breast cancer (BEVERLY-1): a multicentre, single-arm, phase 2 study. Lancet 
Oncol 2016;17:600-11. 
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Pierga JY, Petit T, Delozier T, et al. Neoadjuvant bevacizumab, trastuzumab, and chemotherapy for 
primary inflammatory HER2-positive breast cancer (BEVERLY-2): an open-label, single-arm phase 2 study. 
Lancet Oncol 2012;13:375-84. 
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Pierga JY, Bidard FC, Autret A, et al. Circulating tumour cells and pathological complete response: 
independent prognostic factors in inflammatory breast cancer in a pooled analysis of two multicentre phase II 
trials (BEVERLY-1 and -2) of neoadjuvant chemotherapy combined with bevacizumab. Ann Oncol 
2017;28:103-9. 
40. 
Palazzo A, Dellapasqua S, Munzone E, et al. Phase II Trial of Bevacizumab Plus Weekly Paclitaxel, 
Carboplatin, and Metronomic Cyclophosphamide With or Without Trastuzumab and Endocrine Therapy as 
Preoperative Treatment of Inflammatory Breast Cancer. Clin Breast Cancer 2018. 


 
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41. 
von Minckwitz G, Schneeweiss A, Loibl S, et al. Neoadjuvant carboplatin in patients with triple-
negative and HER2-positive early breast cancer (GeparSixto; GBG 66): a randomised phase 2 trial. Lancet 
Oncol 2014;15:747-56. 
42. 
Sikov WM, Berry DA, Perou CM, et al. Impact of the addition of carboplatin and/or bevacizumab to 
neoadjuvant once-per-week paclitaxel followed by dose-dense doxorubicin and cyclophosphamide on 
pathologic complete response rates in stage II to III triple-negative breast cancer: CALGB 40603 (Alliance). J 
Clin Oncol 2015;33:13-21. 
43. 
Nanda R, Liu, MC, Yau, C, et al. Pembrolizumab plus standard neoadjuvant therapy for high-risk 
breast cancer (BC): Results from I-SPY 2. J Clin Oncol 35, 2017 (suppl; abstr 506). 
44. 
Schmid P, Park, YH, Munoz-Couselo, E, et al. Pembrolizumab + chemotherapy as neoadjuvant 
treatment for triple negative breast cancer (TNBC): Preliminary results from KEYNOTE-173. J Clin Oncol 35, 
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45. 
Loibl S, Untch, M, Burchardi, N, et al. A randomized phase II neoadjuvant study (GeparNuevo) to 
investigate the addition of durvalumab, a PD-L1 antibody, to a taxane-anthracycline containing chemotherapy 
in triple negative breast cancer (TNBC). J Clin Oncol 35, 2017 (suppl; abstr 3062)  
46. 
Loibl S, Untch, M, Burchardi, N, et al. Randomized phase II neoadjuvant study (GeparNuevo) to 
investigate the addition of durvalumab to a taxane-anthracycline containing chemotherapy in triple negative 
breast cancer (TNBC).  . J Clin Oncol 36, 2018 (suppl; abstr 104). 
47. 
Pusztai L, Silber, A, Wysong Hofstatter, E, et al. Safety of MEDI4736 (anti-PD-L1 antibody) 
administered concomitant with weekly nab-paclitaxel and dose dense doxorubicin/cyclophosphamide (ddAC) 
as neoadjuvant chemotherapy for stage I-III triple negative breast cancer (TNBC): A Phase I/II trial. J Clin 
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Loi S, Giobbe-Hurder, A, Gombos, A, et al. Phase Ib/II study evaluating safety and efficacy of 
pembrolizumab and trastuzumab in patients with trastuzumab-resistant HER2-positive metastatic breast 
cancer: Results from the PANACEA (IBCSG 45-13/BIG 4-13/KEYNOTE-014) study. 2018 San Antonio Breast 
Cancer Symposium (SABCS). Abstract GS2-06. 
49. 
von Minckwitz G, Huang CS, Mano MS, et al. Trastuzumab Emtansine for Residual Invasive HER2-
Positive Breast Cancer. N Engl J Med 2019;380:617-28. 
50. 
Masuda N, Lee SJ, Ohtani S, et al. Adjuvant Capecitabine for Breast Cancer after Preoperative 
Chemotherapy. N Engl J Med 2017;376:2147-59. 
51. 
Hellmann MD, Ciuleanu TE, Pluzanski A, et al. Nivolumab plus Ipilimumab in Lung Cancer with a 
High Tumor Mutational Burden. N Engl J Med 2018. 
52. 
Hellmann MD, Rizvi NA, Goldman JW, et al. Nivolumab plus ipilimumab as first-line treatment for 
advanced non-small-cell lung cancer (CheckMate 012): results of an open-label, phase 1, multicohort study. 
Lancet Oncol 2017;18:31-41. 
53. 
Adams S, Diamond, JR, Hamilton, EP, et al. Phase Ib trial of atezolizumab in combination with nab-
paclitaxel in patients with metastatic triple-negative breast cancer (mTNBC). J Clin Oncol 34, 2016 (suppl; 
abstr 1009). 
54. 
Early Breast Cancer Trialists' Collaborative G, Peto R, Davies C, et al. Comparisons between 
different polychemotherapy regimens for early breast cancer: meta-analyses of long-term outcome among 
100,000 women in 123 randomised trials. Lancet 2012;379:432-44. 
55. 
Rastogi P, Anderson SJ, Bear HD, et al. Preoperative chemotherapy: updates of National Surgical 
Adjuvant Breast and Bowel Project Protocols B-18 and B-27. J Clin Oncol 2008;26:778-85. 
56. 
Bear HD, Anderson S, Smith RE, et al. Sequential preoperative or postoperative docetaxel added to 
preoperative doxorubicin plus cyclophosphamide for operable breast cancer:National Surgical Adjuvant 
Breast and Bowel Project Protocol B-27. J Clin Oncol 2006;24:2019-27. 
57. 
Dieras V, Fumoleau P, Romieu G, et al. Randomized parallel study of doxorubicin plus paclitaxel and 
doxorubicin plus cyclophosphamide as neoadjuvant treatment of patients with breast cancer. J Clin Oncol 
2004;22:4958-65. 
58. 
von Minckwitz G, Raab G, Caputo A, et al. Doxorubicin with cyclophosphamide followed by docetaxel 
every 21 days compared with doxorubicin and docetaxel every 14 days as preoperative treatment in operable 
breast cancer: the GEPARDUO study of the German Breast Group. J Clin Oncol 2005;23:2676-85. 
59. 
Earl HM, Vallier AL, Hiller L, et al. Effects of the addition of gemcitabine, and paclitaxel-first 
sequencing, in neoadjuvant sequential epirubicin, cyclophosphamide, and paclitaxel for women with high-risk 
early breast cancer (Neo-tAnGo): an open-label, 2x2 factorial randomised phase 3 trial. Lancet Oncol 
2014;15:201-12. 


 
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60. 
Hammond ME, Hayes DF, Dowsett M, et al. American Society of Clinical Oncology/College of 
American Pathologists guideline recommendations for immunohistochemical testing of estrogen and 
progesterone receptors in breast cancer. Arch Pathol Lab Med 2010;134:907-22. 
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Wolff AC, Hammond ME, Hicks DG, et al. Recommendations for human epidermal growth factor 
receptor 2 testing in breast cancer: American Society of Clinical Oncology/College of American Pathologists 
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Lim B, Woodward WA, Wang X, Reuben JM, Ueno NT. Inflammatory breast cancer biology: the 
tumour microenvironment is key. Nat Rev Cancer 2018. 
63. 
Arias-Pulido H, Cimino-Mathews A, Chaher N, et al. The combined presence of CD20 + B cells and 
PD-L1 + tumor-infiltrating lymphocytes in inflammatory breast cancer is prognostic of improved patient 
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64. 
Valeta-Magara A, Gadi A, Volta V, et al. Inflammatory Breast Cancer Promotes Development of M2 
Tumor-associated Macrophages and Cancer Mesenchymal Cells Through a Complex Cytokine Network. 
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65. 
Jhaveri K, Teplinsky E, Silvera D, et al. Hyperactivated mTOR and JAK2/STAT3 Pathways: Molecular 
Drivers and Potential Therapeutic Targets of Inflammatory and Invasive Ductal Breast Cancers After 
Neoadjuvant Chemotherapy. Clin Breast Cancer 2016;16:113-22 e1. 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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16   Appendices 
 
Appendix 1: Guidelines for Sub-site Institutions in Multi-Center Studies  
 
1. Multi-site Communication 
 
The Clinical Trials Office (CTO) at NYU Permutter Cancer Center (PCC) provides administration, data 
management, and organizational support for the affiliate sites in the conduct of a multicenter clinical trial. The 
CTO 
office 
will 
coordinate 
regularly 
scheduled 
conference 
calls 
with 
affiliate 
sites.  
 
2. Regulatory Documents 
 
Prior to Site Initiation:  
 
Regulatory documents may be sent to: PCC-QAU@nyulangone.org 
 
3. Central Registration Procedures: Sub-site Institution Research Participant Registration 
Process 
 
All sub-site Institutions must register subjects with the coordinating center (NYULH) prior to any 
administration of study drug/intervention/local institution registration.  Please see instructions below:  
 
Enrollment at additional sites can begin once each site’s IRB has approved this protocol, a copy of each site’s 
IRB approval, Citi training certificates, Medical Licenses and signed CVs are provided to NYU Langone Health 
Perlmutter Cancer Center (PCC) Clinical Trials Office.  Once, all required documents are provided to NYU 
Clinical Trials Office an activation notification will be sent to the PI and research coordinator of that site.  Central 
registration for this study will take place at NYU Langone Health PCC Quality Assurance Unit (PCC-
QAU@nyulangone.org).  
 
Each patient must sign and date an informed consent form before undergoing any study specific 
procedures unless a procedure is being performed as part of the patient’s standard of care. Once a 
patient has signed consent, each site must notify the NYU Langone Health PCC Quality Assurance Unit 
and forward a copy of the signed consent to NYU Langone Health PCC Clinical Trials Office within 24 
hours. 
 
1.  Within 24 hours of obtaining consent (excluding holidays and weekends), the sub-site Institution CRN and/or 
CRC is required to submit the following documents via email (PCC-QAU@nyulangone.org), with a request to 
register the patient “pending eligibility” to the NYULH’s Clinical Trials Office, Quality Assurance Unit.. The 
documents will be reviewed for accurateness, and subsequently the patient will be registered.   
 
2.  Registration will occur once the Senior Research Nurse for Quality Assurance conducts a central 
review 
of the submitted materials. Once eligibility is verified, a unique subject study number will be 
issued within 
24 hours of receiving all required registration material. This number is unique to the 
participant and must be written on all data and correspondence for the participant. The NYU Langone 
Health PCC CTO will return a signed eligibility confirmation worksheet email with the subject’s unique 
study number. 
  
3.  The subject will not be identified by name. This is the point, at which, the patient is considered 
accrued on study. Protocol treatment should  begin within  designated timeframe; issues  that would 
cause 
treatment delays should be discussed with the overall PI, Dr. K w a . All screen 
failures/ineligible subjects, as well as subject’s who withdraw consent prior to initiation of protocol 
therapy must be submitted to the CTO in a manner analogous to the procedures noted above. 
Applicable source documentation will be required within the corresponding submissions. 
 


 
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4.   Each site is responsible for reporting all unexpected problems involving risks to participants or others 
to NYU Langone PCC Clinical Trials Office and to their IRB as per site institutional policy. 
 
5.  Please email all SAEs to NYUPCCsafetyreports@nyulangone.org, Dr. Kwa, and the NYU Langone 
Health QA Unit (PCC-QAU@nyulangone.org) . 
 
4.  Protocol Deviation/Subject Waiver Request for Sub-sites 
 
The sub-site MUST submit a prospective deviation request to the NYULH lead PI and NYU DSMC for review 
and submission. Approvals must be obtained from all entities prior to implementation at the Sub-site. If a 
prospective protocol deviation request is submitted for review (from a sub-site), the PI/site memo(s), NYU 
DSMC approval(s) and correspondence and NYU IRB eligibility deviation approval letter(s) should be forwarded 
to the sub-site for documentation. The sub-site is also required to obtain prospective local IRB approval as per 
institutional policies/procedures prior to implementing the proposed deviation and registering/enrolling the 
subject via NYULH Central Registration. All documents and determinations must be clearly documented in the 
study subject’s medical record, research chart and regulatory binder, as described.  
 
5.  Guidelines for Monitoring  
 
An SIV (or) teleconference will be scheduled and conducted prior to study drug being made available (if 
applicable) and before any subjects are enrolled on a study at the external site.  
 
Monitoring visits are done remotely unless otherwise specified, via remote EMR access. If not possible, 
secure email exchange will be utilized. The quality assurance specialist will confirm an upcoming 
monitoring visit with a sub-site Investigator and staff. If remote EMR access is not available, then the sub-
site Coordinator will ensure that all source documents for subjects are de-identified and labeled only with 
the subject ID number(s), and emails all requested documents to the quality assurance specialist by the 
specified visit date. All documents are reviewed and a monitoring report is submitted within 5 business 
days from the date of the visit. Any outstanding documents will be listed in the report as a high- priority 
request for the next monitoring visit. It is expected that response to data clarification requests and other 
trial-related inquiries will occur throughout the course of the study through regular communication with the 
site monitor, the Sponsor or representatives, and review/entry of data into the electronic study database. 
Continued non-compliance and failure to submit documentation will result in the suspension of 
subject 
enrollment at the site, until the documents have been received. 
 
1. External sites will be monitored by the QA Specialist on both a regulatory level, as well as a clinical 
data/source documentation review level.  
2. Redacted source documents (applicable to supporting the protocol specific CRF data requirements) will be 
sent to the designated QA Specialist via secure email for all subjects enrolled at external sites. Timelines for 
submission procedures will be defined on a case-by-case basis.  
3. The QA Specialist will review all submitted redacted source documents against the data entered on the 
protocol specific CRFs. The QA Specialist will issue queries when/if necessary.  
4. The external site research staff will respond to queries within the designated time frame (response times vary 
based on trial risk). If queries remain outstanding, the QA Specialist will send a delinquent query reminder for 
the outstanding items.  
5. The remote monitoring procedures will include review of applicable redacted source documentation and 
supporting applicable documents to determine compliance regarding:  
 
• 
Informed consent procedures  
• 
Eligibility criteria  
• 
Protocol specific treatment compliance  
• 
Protocol specific toxicity/outcome documentation/compliance  
• 
Protocol specific schedule of events (e.g., baseline visits, pre-treatment, on study, follow-up)  
• 
Participating site IRB documents (e.g., IRB amendment approvals, annual renewals, SAE/UP 
submissions, violation/deviation submissions, INDSR submissions, etc.).  


 
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• 
Required specimen submissions (e.g., tissue specimens, research blood specimens, etc.)  
• 
Pharmacy accountability records  
• 
Adherence to the CRF submission timeframes to NYULH (within the protocol specified timeframes)  
 
6. External site remote monitoring reports will be sent to the lead PI, NYULH DSMC, and sub-sites after each 
remote monitoring review. Reports will include information regarding data submission timeliness/accuracy, 
protocol adherence items, query resolution status, regulatory status, and overall site performance. These 
reports will be generated by the QA Specialist and reviewed with the QA Manager prior to dissemination.  
 
6. Dose Level Determinations 
 
The Sponsor-Investigator/Statistician will review enrollment for each dose level cohort during the regularly 
scheduled conference call with the sub-sites.  
 
The dose level for newly enrolled subjects will be determined by the study statistician upon notification that a 
subject has signed informed consent to participate in the study. The assigned dose level for any subject to 
begin study treatment will be communicated to the affiliate site along with the determination by Central 
Registration that the subject is eligible for enrollment in the study.  
 
If a Dose Limiting Toxicity (DLT) is identified in a subject, the affiliate site must notify the Sponsor-Investigator 
via email at the study specific email address within 1 business day of identification. The lead site will 
communicate that a DLT has been experienced within 1 business day. 
  
7. Confidentiality  
 
Each external site will be assigned a site number. Each subject that signs consent should be assigned a unique 
code number consisting of site number followed by a number with each new subject being assigned the next 
sequential number (e.g. 04-10). All sites will be required to enter their data in the designated electronic data 
capture Clinical Trial Management System used for all cancer-related clinical research at NYULH. All users 
must login with their own application username and password. Users off campus must first access the NYULMC 
Portal with their assigned campus username and password and then use their application credentials.  
 
Subject confidentiality must be maintained according to HIPAA regulations and GCP recommendations.  
Except when required by law, study information shared with persons and organizations outside of NYULH must 
not identify the patient by name, social security number, address, telephone number, or any other direct 
personal identifier.  
 
If the results of this research project are published or presented at a scientific or medical meeting, the patient 
not be identified. Otherwise, all results will be kept confidential and will not be divulged (except as required by 
law) without permission.  
 
8.  Data Reporting Plan  
 
NYULH is deeply committed to research integrity and strong credibility when it comes to the discovery of new 
treatment concepts, implementation of new clinical research techniques, and acceptance of its researcher's 
findings by the medical establishment. In accord with these ethics, NYULH encourages and supports its 
investigators in the sharing of final research data and/or details of newly developed clinical treatments.  
 
NYULH's policies that pertain to patient data sharing conform to NYU IRB rules, local and state laws, and HIPAA 
privacy regulations. The primary reason for this is to protect the privacy of patients who participate in clinical 
trials. The data can be made available for continuing review by federal agencies upon request and for ongoing 
study safety reviews by the Principal Investigator, Statistician, Data Safety and Monitoring Board (DSMC), and, 
in other instances, the NYU IRB. 
 


 
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Data collected during the course of this clinical trial will primarily be shared with other investigators and 
University staff, the IRB, FDA, and other reporting agencies, and/or transferred to other collaborators. Prior to 
transfer, the data collected must comply with, and must be limited by, the NYULMC's guidelines for Protecting 
the Rights and Privacy of Human Subjects.  
 
9.  Data Acquisition and Submission  
 
Informed consent, including HIPPA authorization, must be obtained on all subjects prior to their participation. 
Always keep the original signed and dated consent form, with the redacted source documents and eligibility 
checklist. A designated electronic data capture system will be used as the electronic clinical trials and data 
management system. Affiliate sites will enter data directly into the system via customized case report forms for 
the study. The research staff will generate reports from the designated electronic data capture system to ensure 
timely submission of data by affiliate sites. This resource allows for the timely analysis of particular data sets 
for safety analysis.  
 
 
 
 


 
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Appendix 2: Eastern Cooperative Oncology Group (ECOG) Performance Status 
Criteria 
 
 
Description 
Grade 
Fully active, able to carry on all pre-disease 
performance without restriction 
 
0 
Restricted in physically strenuous activity, but 
ambulatory and able to carry out work of a light or 
sedentary nature (i.e., light house work, office 
work)  
 
1 
Ambulatory and capable of all self-care but unable 
to carry out any work activities. Up and about more 
than 50% of waking hours.  
 
2 
Capable of only limited self-care, confined to bed or 
chair more than 50% of waking hours 
 
3 
Completely disabled. Cannot carry on any self-
care. Totally confined to bed or chair.  
4 
Dead 
 
5 
 
 
 
 


 
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Appendix 3: Management Algorithms for Investigational Agent, Nivolumab  
 
These general guidelines constitute guidance to the Investigator and may be supplemented by discussions with 
the Principal Investigator.  The guidance applies to all immuno-oncology agents and regimens. 
 
A general principle is that different 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 4: Asymptomatic Decline in LVEF: Algorithm for Continuation and 
Discontinuation of Treatment with Trastuzumab, and/or Pertuzumab 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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Appendix 5: 
 
NYU/Bellevue Clinical Co-Investigators:  
Sylvia Adams, MD 
Yelena Novik, MD 
James Speyer, MD 
Ruth Oratz, MD 
Marleen Meyers, MD 
Franco Muggia, MD 
Jennifer Wu, MD 
Arjun Iyengar, MD 
MaryLynn Nierodzik, MD 
Amber Guth, MD 
Deborah Axelrod, MD 
Freya Schnabel, MD 
Karen Hiotis, MD 
Richard Shapiro, MD 
Kathie-Ann Joseph, MD 
 
NYU Laboratory Co-Investigators: 
Robert Schneider, PhD 
Paolo Cotzia, MD 
Matija Snuderl, MD 
Pratip Chattopadhyay, PhD 
 
NYU Biostatistician Co-Investigator:  
Andrea B. Troxel, ScD 
 
Indiana University Clinical Co-Investigator: 
Kathy Miller, MD