Phase Ib/II Study to Evaluate Safety and Tolerability of Neoadjuvant Nivolumab and Chemotherapy in Patients With Localized Triple-negative Breast Cancer
Phase: PHASE1
Conditions: Triple Negative Breast Cancer
Sponsor: Washington University School of Medicine

Protocol Version: 07/27/22 
 
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Phase Ib/II study to evaluate safety and tolerability of neoadjuvant nivolumab and chemotherapy 
in patients with localized triple-negative breast cancer 
 
Washington University School of Medicine, Division of Oncology 
660 South Euclid Avenue, Campus Box 8056 // St. Louis, MO  63110 
 
Protocol #: 202007016 
Version Date: 27 July 2022 
 
Principal Investigator: 
Andrew Davis, M.D. 
Phone:  (314) 273-3581 
E-mail:  aadavis@wustl.edu 
 
Sub-Investigators 
 
 
 
 
Modality 
Katherine Weilbaecher, M.D.   
 
 
Medical Oncology 
Rebecca Aft, M.D., Ph.D. 
 
 
 
Surgical Oncology 
Mark A. Watson, MD, PhD 
 
 
 
Pathology and Immunology 
David DeNardo, Ph.D.  
 
 
 
Molecular Oncology 
Jingqin (Rosy) Luo, Ph.D. 
 
 
 
Biostatistics 
Foluso Ademuyiwa, M.D. 
 
 
 
Medical Oncology 
Nusayba Bagegni, M.D.  
 
 
 
Medical Oncology 
Ron Bose, M.D.  
 
 
 
 
Medical Oncology 
Katherine Clifton, M.D.  
 
 
 
Medical Oncology 
Ashley Frith, M.D.  
 
 
 
 
Medical Oncology 
Cynthia Ma, M.D., Ph.D.  
 
 
 
Medical Oncology 
Peter Oppelt, M.D.  
 
 
 
 
Medical Oncology 
 
Lindsay Peterson, M.D.  
 
 
 
Medical Oncology 
Caron Rigden, M.D.  
 
 
 
 
Medical Oncology 
Rama Suresh, M.D.  
 
 
 
 
Medical Oncology 
 
Study Drugs:  
 
Cabiralizumab (safety lead-in only) 
Nivolumab 
SOC neoadjuvant chemotherapy 
IND#: 
150891 
IND Sponsor: 
Andrew Davis, M.D. 
NCT#: 
NCT04331067 
Funded by: 
Bristol Myers Squibb 
 
CONFIDENTIAL 
The information contained in this document is regarded as confidential and, except to the extent necessary to obtain 
informed consent, may not be disclosed to another party unless law or regulations require such disclosure.  Persons to 
whom the information is disclosed must be informed that the information is confidential and may not be further disclosed 
by them. 
 

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Phase Ib/II study to evaluate safety and tolerability of cabiralizumab in combination with 
nivolumab and neoadjuvant chemotherapy in patients with localized triple-negative breast 
cancer 
 
Protocol Revision History 
 
Initial Approval Version 
 
 
 
 
 
 
29 June 2020 
Amendment #1 Version 
 
 
 
 
 
 
18 September 2020 
Amendment #2 Version 
 
 
 
 
 
 
14 January 2021 
Amendment #3 Version 
 
 
 
 
 
 
25 May 2021 
Amendment #4 Version 
 
 
 
 
 
 
20 July 2021 
Amendment #5 Version 
 
 
 
 
 
 
28 October 2021 
Amendment #6 Version 
 
 
 
 
 
 
02 December 2021 
Amendment #7 Version 
 
 
 
 
 
 
27 July 2022 
 
 
 

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STATEMENT OF COMPLIANCE 
The trial will be carried out in accordance with International Conference on Harmonisation Good 
Clinical Practice (ICH GCP) and the following:  
 
• United States (US) Code of Federal Regulations (CFR) applicable to clinical studies (45 
CFR Part 46, 21 CFR Part 50, 21 CFR Part 56, 21 CFR Part 312, and/or 21 CFR Part 812)  
 
National Institutes of Health (NIH)-funded investigators and clinical trial site staff who are 
responsible for the conduct, management, or oversight of NIH-funded clinical trials have 
completed Human Subjects Protection and ICH GCP Training. 
 
The protocol, informed consent form(s), recruitment materials, and all participant materials will 
be submitted to the Institutional Review Board (IRB) for review and approval.  Approval of both 
the protocol and the consent form must be obtained before any participant is enrolled.  Any 
amendment to the protocol will require review and approval by the IRB before the changes are 
implemented to the study.  In addition, all changes to the consent form will be IRB-approved; a 
determination will be made regarding whether a new consent needs to be obtained from 
participants who provided consent, using a previously approved consent form. 
 
 
 
 
 
 
 
 

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Table of Contents 
PROTOCOL SUMMARY .............................................................................................................. 6 
SCHEMA ........................................................................................................................................ 8 
SCHEDULE OF ACTIVITIES....................................................................................................... 9 
1.0 
INTRODUCTION ............................................................................................................. 11 
1.1 
Rationale to conduct a study in patients with localized Triple negative breast cancers .11 
1.2 
Rationale for immunotherapy in TNBC ..........................................................................12 
1.3 
Rationale to target tumor-associated macrophages (TAMs) in breast cancer .................12 
1.4 
Rationale to combine checkpoint inhibitors with CSF-1R inhibitor and chemotherapy 13 
1.5 
Cabiralizumab .................................................................................................................15 
1.6 
Rationale to conduct this study in the neoadjuvant setting .............................................19 
1.7 
Rationale for tumor infiltrating lymphocytes (TILs) and pathologic complete response 
as endpoints ................................................................................................................................20 
1.8 
Rationale to study the effects of immunotherapy on disseminated tumor cells in the 
bone marrow ...............................................................................................................................20 
1.9 
Rationale for Amendment 7 (Removal of Cabiralizumab) .............................................21 
2.0 
OBJECTIVES AND ENDPOINTS ................................................................................... 22 
3.0 
STUDY POPULATION .................................................................................................... 24 
3.1 
Inclusion Criteria .............................................................................................................24 
3.2 
Exclusion Criteria ............................................................................................................26 
3.3 
Inclusion of Women and Minorities................................................................................28 
4.0 
REGISTRATION PROCEDURES ................................................................................... 28 
4.1 
Confirmation of Patient Eligibility ..................................................................................28 
4.2 
Patient Registration in the Siteman Cancer Center OnCore Database ............................29 
4.3 
Assignment of UPN ........................................................................................................29 
4.4 
Screen Failures ................................................................................................................29 
4.5 
Randomization ................................................................................................................29 
4.6 
Strategies for Recruitment and Retention .......................................................................29 
5.0 
TREATMENT PLAN ........................................................................................................ 30 
5.1 
Premedication Administration.........................................................................................30 
5.2 
Study Intervention Description .......................................................................................30 
5.3 
Study Intervention Administration ..................................................................................30 
5.4 
Definitions of Evaluability ..............................................................................................31 
5.5 
Concomitant Therapy and Supportive Care Guidelines ..................................................31 
5.6 
Women of Childbearing Potential ...................................................................................34 
5.7 
Duration of Therapy ........................................................................................................34 
5.8 
Duration of Follow-up .....................................................................................................35 
5.9 
Lost to Follow-Up ...........................................................................................................35 
6.0 
DOSE DELAYS/DOSE MODIFICATIONS .................................................................... 35 
6.1 
Dosing Adjustments for Standard of Care Chemotherapy ..............................................36 
6.2 
Dosing Adjustments for Nivolumab ...............................................................................41 
6.3 
Dose discontinuation criteria for cabiralizumab and nivolumab ....................................47 
7.0 
REGULATORY AND REPORTING REQUIREMENTS ............................................... 47 
7.1 
Sponsor-Investigator Reporting Requirements ...............................................................48 
7.2 
Exceptions to Expedited Reporting .................................................................................51 
8.0 
PHARMACEUTICAL INFORMATION .......................................................................... 51 

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8.1 
Paclitaxel .........................................................................................................................52 
8.2 
Carboplatin ......................................................................................................................53 
8.3 
Nivolumab .......................................................................................................................54 
8.4 
Cabiralizumab .................................................................................................................57 
9.0 
CORRELATIVE STUDIES .............................................................................................. 59 
9.1 
Tumor Biopsy ..................................................................................................................60 
9.2 
Bone Marrow...................................................................................................................61 
9.3 
Blood Draw .....................................................................................................................62 
10.0 DATA SUBMISSION SCHEDULE ................................................................................. 63 
10.1 Adverse Event Collection in the Case Report Forms ......................................................64 
10.2 Concomitant Medication Collection in the Case Report Forms .....................................64 
11.0 MEASUREMENT OF EFFECT........................................................................................ 64 
11.1 Surgery ............................................................................................................................64 
11.2 Post-surgery .....................................................................................................................64 
12.0 DATA AND SAFETY MONITORING ............................................................................ 65 
13.0 STATISTICAL CONSIDERATIONS............................................................................... 65 
13.1 Study Design ...................................................................................................................65 
13.2 Objectives ........................................................................................................................66 
13.3 Endpoints .........................................................................................................................66 
13.4 Statistical hypothesis .......................................................................................................66 
13.5 Sample size for the primary endpoint .............................................................................67 
13.6 Sample size for the secondary endpoint pCR rate...........................................................68 
13.7 Sample size for comparing TAM and TILs percentage change by pCR status ..............68 
13.8 Data analysis ...................................................................................................................68 
13.9 Futility monitoring plan ..................................................................................................70 
13.10 
Safety stopping rule .....................................................................................................70 
13.11 
Definitions of Study Populations for Analysis ............................................................70 
14.0 REFERENCES .................................................................................................................. 72 
APPENDIX A: ECOG Performance Status Scale ........................................................................ 76 
APPENDIX B: Management Algorithms for Endocrinopathy, Gastrointestinal, Hepatic, 
Neurological, Pulmonary, Renal, and Skin Adverse Events ........................................................ 77 
APPENDIX C: Definitions for Adverse Event Reporting ............................................................ 84 
APPENDIX D: Reporting Timelines ............................................................................................ 86 
 
 

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PROTOCOL SUMMARY 
 
Title: 
Phase Ib/II study to evaluate safety and tolerability of neoadjuvant 
nivolumab and chemotherapy in patients with localized triple-negative 
breast cancer 
Study Description: 
The hypothesis of this study is that on-treatment tumor associated 
macrophages (TAMs) and tumor infiltrating lymphocytes (TILs) will 
improve (reduced TAMs, increased TILs) following neoadjuvant 
nivolumab with chemotherapy. 
 
In this study, a safety lead-in of 12 eligible patients with clinical stage 
II/III TNBC will be randomized on a 1:1 ratio to receive neoadjuvant 
chemotherapy and nivolumab with or without cabiralizumab.  Following 
the activation of Amendment 7, an additional 19 patients will be enrolled 
who will all receive neoadjuvant chemotherapy and nivolumab 
(cabiralizumab will not be given). 
Objectives: 
Primary Objective:  
1. Safety lead-in: To investigate if the combination of neoadjuvant 
chemotherapy with nivolumab +/- cabiralizumab is safe in 
patients with TNBC. 
2. To compare on-treatment TAMs and TILs against their baseline 
levels in patients with newly diagnosed stage II/III TNBC treated 
with neoadjuvant nivolumab + chemotherapy. 
 
Secondary Objectives: 
1. To estimate the pathological complete response (pCR) rate in 
patients with newly diagnosed stage II/III TNBC treated with 
neoadjuvant nivolumab + chemotherapy. 
2. To determine recurrence-free survival (RFS). 
3. To estimate grade 3 or higher treatment-related adverse event 
rate. 
4. To compare the percent change of TAMs and TILs between 
patients who achieve pCR vs. those who do not.  
 
Exploratory Objectives: 
1. To evaluate disseminated tumor cell (DTC) gene signature 
elimination in the bone marrow after neoadjuvant treatment and 
correlation with pCR and prognosis. 
2. To evaluate potential biomarkers of response to NAC + 
nivolumab +/- combination with cabiralizumab in patients with 
newly diagnosed TNBC. Potential biomarkers include baseline 
TAMs and/or TILs percentage, baseline PD-L1 expression in the 
tumor and tumor infiltrating immune cells, CSF-1R+. These 
biomarkers will be correlated with pathologic complete response. 
3. To compare the difference in the immune cell infiltration and 
cytokine expression in the biopsied tumors of patients with 

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TNBC before and after treatment with the combination of NAC 
plus nivolumab. 
4. To correlate changes in the immune infiltrate with clinical 
responses to treatment with the combination of NAC plus 
nivolumab and clinical outcomes (pCR, RFS) following 
treatment. 
5. To compare the difference in ctDNA response in patients who 
achieve pCR vs. patients who do not achieve pCR. 
Endpoints: 
Primary Endpoints:  
The primary endpoint for the safety lead-in is toxicity by CTCAE v 5.0. 
 
The co-primary endpoints are percent change of on-treatment TAMs 
from baseline and percent change of on-treatment TILs from baseline 
(stromal TIL score is defined as the percentage of tumor stroma area that 
was occupied by mononuclear inflammatory cells). 
  
Secondary Endpoints: 
- 
pCR rate 
- 
AEs, especially grade 3 or higher treatment-related AE rate 
- 
Recurrence-free survival defined from time of surgery to the 
earliest of time of recurrence, time to development of a 2nd 
cancer, time of death from any cause. 
Study Population: 
31 women of any race and ethnicity newly diagnosed with clinical stage 
II or III triple-negative breast cancer will be enrolled to this study 
Phase: 
Ib/II 
Description of Sites / 
Facilities Enrolling: 
This study will be open at Siteman Cancer Center at Washington 
University School of Medicine. 
Description 
of 
Study 
Intervention: 
The neoadjuvant chemotherapy (NAC) being given on this study is 
paclitaxel 80 mg/m2 IV weekly with carboplatin AUC 5 IV every 3 
weeks for a total of 12 weeks.  Nivolumab will be given with the 
chemotherapy at a dose of 240 mg IV every 2 weeks for 12 weeks.  
Patients who are randomized to the cabiralizumab arm will receive it 
with NAC plus nivolumab at a dose of 4 mg/kg IV every 2 weeks for 12 
weeks. 
Study Duration: 
88 months (24 months for accrual + 4 months for participation + 60 
months for follow-up) 
Participant Duration: 
Neoadjuvant treatment will take place over the course of 12 weeks.  The 
standard of care surgery and possible standard of care adjuvant therapy 
will occur as part of the patient’s routine care and not as part of 
enrollment to this study. Follow-up will continue for 5 years after 
surgery.  Total expected participant duration is approximately 64 
months. 
 
 
 
 
 
 
 
 

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SCHEMA 
 
 
 
 
 
 
The first six patients randomized to each arm will be part of a safety run-in.  The allocation to an 
arm will pause after enrollment of the sixth patient to that arm until all six patients in that arm have 
completed all 12 weeks of treatment and have passed the toxicity monitoring period (4 weeks after 
last dose or until surgery whichever occurs first. 
 
With the conclusion of the safety run-in and the activation of Amendment 7, randomization is 
discontinued and all patients will enroll in Arm A (SOC chemo + nivolumab).  

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SCHEDULE OF ACTIVITIES 
 
There is a 21-day window for screening and +/- 1-day window for all assessments and procedures. 
 
1. Women of childbearing potential only 
2. If randomized to Arm B; note that after completion of the safety run-in and with the activation of Amendment 7, all patients enrolled thereafter will be treated in Arm A. 
3. Prior to treatment 
 
Screening 
W1 
W2 
W3 
W4 
W5 
W6 
W7 
W8 
W9 
W10 
W11 
W12 
Surgery10 
Post- 
Op 
F/U 
F/U6 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Height14 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
H&P, ECOG PS 
X11 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
X 
 
CBC 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
CMP 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
TSH, T3, T4 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
 
INR, aPTT 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
TB test13 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cortisol 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
 
Lipase 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
 
Urinalysis 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X8 
 
 
Pregnancy test1 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X8 
 
 
12-lead EKG 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X8 
 
 
CT scan (chest) 
X12 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
X9 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Carboplatin 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
 
 
 
Paclitaxel 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Nivolumab 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
 
Carbiralizumab2 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
 
Research breast biopsy15 
X9 
 
 
 
 
X3 
 
 
 
 
 
 
 
X4 
 
X7 
Research bone marrow biopsy15 
X9 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X7 
Research blood draw15 
X9 
 
X3 
X3 
 
X3 
 
 
 
 
X3 
 
 
X16 
X 
X7 
AE assessment 
 
X -------------------------------------------------------------------------------------------------------- X5 
 
Concomitant medications 
 
X -------------------------------------------------------------------------------------------------------X 
 
 
Progression and survival 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 

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4. From surgical specimen 
5. Until 100 days after last treatment or day of surgery, whichever is first 
6. Follow-up will be at 6 months and 1 year post-surgery, and then on a yearly basis thereafter for an additional 2 years (3 years total). Patients who do not undergo surgery will be 
followed for survival only. 
7. At time of recurrence only – OPTIONAL  
8. Within 2 weeks prior to day of surgery 
9. To occur after consent 
10. Within 4-8 weeks after last dose of study treatment (but may be delayed depending on the availability of the surgeon) 
11. Includes 2D measurements of breast tumor 
12. Within 4 weeks prior to the start of therapy 
13. 21 day screening window applies to when TB test is read, not placed 
14. Use for dosing  
15. Refer to Section 9.1.1 for exception to specimen collection  
16. Collect up to 7 days prior to day of surgery

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1.0 
INTRODUCTION 
 
1.1 
Rationale to conduct a study in patients with localized Triple negative breast 
cancers 
 
Breast cancer is a major public health problem. In the United States (US), 1 out of 8 women 
will be diagnosed with breast cancer in their life time 1. A total of 268,670 new breast 
cancer cases and 41,400 deaths are expected to be attributed to BC in the year 2018 2. Since 
the majority of breast cancer cases are diagnosed at an early stage (I – III), relapse of early 
stage disease accounts for the majority of breast cancer deaths 1. The neoadjuvant setting 
has become an important research tool in drug development and in studying mechanisms 
of resistance. Response to neoadjuvant chemotherapy measured by pathologic complete 
response (pCR) rate, and post-chemotherapy residual disease burden has been shown to 
correlate with long-term outcomes 3-5. Triple negative breast cancer (TNBC) is 
immunohistochemically defined by the lack of estrogen receptor (ER), and progesterone 
receptor (PR) expression, as well as lack of overexpression/amplification of human 
epidermal growth factor receptor 2 (HER2). Given the lack of clinically meaningful 
therapeutic targets in TNBC, limited treatment options are available for TNBC, and patient 
outcomes are typically poor. Pathological complete response (pCR) after neoadjuvant 
chemotherapy (NACT) is associated with improved outcomes in TNBC 5,6. Standard 
anthracycline-taxane containing NACT leads to pCR in 25% to 40% of TNBC 7,8. 
Platinum-based neoadjuvant regimens have yielded superior pCR rates (about 50%) 8-10. 
The optimal chemotherapy regimen remains unclear and chemo-resistant disease is a 
clinical challenge. The majority of patients with TNBC still suffer from dismal clinical 
outcomes including early relapse and metastatic spread. Therefore, developing optimal 
therapeutic strategies for the treatment of TNBC is an unmet need.  
 
Tumor infiltrating myeloid cells including tumor-associated macrophages (TAMs) are 
linked to immune checkpoint inhibitor resistance. Reducing TAMs number is a promising 
strategy to enhance PD-1 inhibitors effectiveness due to its marked effect on tumor 
microenvironment. The evidence that TAMs result crucial in modulating the expression 
and activity of immune checkpoints suggest that combined TAM-centered strategies could 
maximize the efficacy of anti-PD-1 agents in breast cancer 11.  
 
We propose a study to investigate the safety and preliminary clinical activity of 
cabiralizumab, a CSF1R inhibitor, in combination with nivolumab and neoadjuvant 
chemotherapy in patients with triple-negative BC. The effect of CSF1R targeting in 
combination with nivolumab and chemotherapy on the tumor immune microenvironment, 
peripheral blood immune cell and cytokine profile, and bone marrow microenvironment of 
breast cancer patients is unknown, as is the aim of our correlative studies in this proposed 
study.  
 
We aim to prove that cabiralizumab will induce a significant reduction of TAMs 
(CD68+/CD163+) and CSF-1R+ cells in on-treatment biopsies analyzed after 4 weeks 

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of therapy and this change is correlated with increasing TILs and better clinical 
outcomes.  
 
1.2 
Rationale for immunotherapy in TNBC 
 
Accumulating evidence is supporting the study of immunotherapy in combination with 
chemotherapy in breast cancer. TNBC is characterized by high genomic instability and 
high mutational burden with abundant infiltrating immune cells 12. Multiple studies are 
focusing on combining programmed cell death-1/programmed death ligand-1 (PD-1/PD-
L1) antagonists with chemotherapy in different settings and early data are encouraging. 
The recently published Impassion130 phase 3 trial demonstrated that atezolizumab plus 
nab-paclitaxel, compared to nab-paclitaxel alone, prolonged progression-free survival (7.2 
months v 5.5 months, respectively) in patients with metastatic TNBC. Importantly, this 
benefit is driven by the patients with positive PD-L1 expression in immune cell infiltrates 
13. In early TNBC, phase I/II studies have reported increased pCR rates with PD-1/L1 
blockade in combination with neoadjuvant chemotherapy. The I-SPY 2 trial demonstrated 
that pCR rates increased from 22.3% to 62.4% by adding neoadjuvant pembrolizumab to 
paclitaxel followed by anthracycline-based chemotherapy, which represents an 
approximately 40% improvement in pCR compared with standard chemo- therapy alone 
14. The KEYNOTE-173 trial showed a remarkably increased pCR rate from 60% to 90% 
in high-risk patients by combining pembrolizumab with paclitaxel or conventional 
chemotherapy according to the physician’s discretion 15. More recently, the GeparNuevo 
study presented at ASCO 2018 showed that the addition of durvalumab to neoadjuvant 
chemotherapy increases the pCR rate numerically in primary TNBC patients (53% vs 44%; 
p=0.287) 16. The encouraging results from these early studies have led to launch several 
phase 3 clinical trials of PD-1/L1 checkpoint inhibition plus neoadjuvant chemotherapy in 
TNBC (KEYNOTE-522, NSABP B-59, IMPassion 030). These results are encouraging 
and ongoing efforts are to improve the effectiveness of immunotherapy by overcoming the 
molecular mechanisms that drive resistance to checkpoint blockade in breast cancer. 
 
1.3 
Rationale to target tumor-associated macrophages (TAMs) in breast cancer 
 
The tumor microenvironment plays an important role in breast cancer progression. Among 
the many cell types associated with the tumor microenvironment, macrophages are among 
the most influential for breast cancer progression by promoting angiogenesis, tumor growth 
and metastasis 17-19. Tumor-associated macrophages (TAMs) are elevated in many tumors 
including breast cancer. Macrophages are an important component of the mammary gland 
stroma and facilitate normal mammary gland development. Resident macrophages in the 
adult mammary gland play crucial roles in homeostasis and modulation of inflammation. 
In the breast cancer microenvironment, TAMs are among the most important regulators of 
tumor progression.  
 
Immune cells represent a major component of TNBC microenvironment 20 and have been 
identified as potential prognostic factors in these patients 21. TAMs constitute a major 
leukocyte population infiltrating tumors that originate from circulating blood monocytes 
differentiating into macrophages after their extravasation into tissues. TAMs are recruited 

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into the BC microenvironment and, in response to several stimuli, undergo M1 (classical) 
or M2 (alternative) activation 22,23. Breast cancer cells have been shown to secrete factors 
that promote macrophage polarization towards M2 status. High number of CD163+ M2-
macrophages was strongly correlated with higher proliferation, poorer differentiation, HR 
negativity and histological ductal type 24. Several mediators are involved in M2 
polarization, including IL-4, IL-10, Transforming Growth Factor-β (TGF-β) and 
Macrophage-Colony Stimulating Factor (M-CSF) 25. TNBC secretes more Granulocyte-
Colony Stimulating Factor (G-CSF) than other BC histologies, thus promoting M1 cell 
skewing to M2 status 26. Medrek et al. stained M2 macrophages for CD163 and reported 
that these cells were more present in TNBC and basal-like BC 27.  Furthermore, CD163+ 
cells were directly associated with HR negativity and TNBC histology and inversely 
correlated with Luminal A subtype. More recently, Klingen et al. have confirmed these 
data reporting a strong correlation between high CD163 count and aggressive features such 
as vessel invasion in nonluminal breast cancer 28. Moreover, CD204 is emerging as a 
marker to identify TAMs in breast cancer and a high number of CD204+ TAMs correlates 
with worse prognoses in this setting 29. Interestingly, patients with TNBC after surgery 
showed augmented number of TAMs and expression levels of IL-6, which is directly 
implicated in TNBC angiogenesis and cell migration 30, and Chemokine (C-C motif) 
Ligand 5 (CCL5), which is involved in TNBC cell invasiveness and dissemination 31{Wang, 
2016 #105}. In TNBC, TAMs exert their immunosuppressive functions by several 
mechanisms that include: (1) the secretion of inhibitory cytokines; (2) the reduction of 
effector functions of TILs; (3) the promotion of Regulatory T cell (Treg) development; (4) 
the production of reactive oxygen species. 
 
Colony-stimulating factor-1 (CSF-1) is required to recruit macrophages into the mammary 
gland and tumor microenvironment. The bone marrow releases monocytes and other 
myeloid derived suppressor cells (MDSCs, the precursors of granulocytes, macrophages 
and dendritic cells) into the peripheral blood. Monocytes are ultimately recruited to the 
breast cancer microenvironment, by the influence CSF-1, where they become TAMs 27. 
Multiple studies have demonstrated that TAM infiltration is associated with poor 
chemotherapy response and prognosis in breast cancer 32,33. Treatment with neoadjuvant 
paclitaxel has been demonstrated to increase CSF-1 expression and elevate TAM 
infiltration in the breast cancer microenvironment 32. Furthermore, high levels of TAM 
infiltration were associated with high histologic grade and high Ki-67 proliferation index 
in both hormone receptor-positive and hormone receptor-negative groups, and was an 
independent prognostic factor for poor disease-free survival in hormone-receptor positive 
breast cancer 34. All the above, provides a rationale to target TAMs with CSF-1 receptor 
inhibition in breast cancer 
 
1.4 
Rationale to combine checkpoint inhibitors with CSF-1R inhibitor and 
chemotherapy 
 
It is well accepted that checkpoint blockade alone is an insufficient therapeutic approach 
in most breast cancers. Therefore, current efforts are focused on developing 
immunotherapy combinations that convert nonresponders to responders, deepen those 
responses that do occur and overcome resistance to immunotherapy 12. In metastatic 

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TNBC, the combination of atezolizumab with chemotherapy led to improved outcomes 
and demonstrated that combining checkpoint inhibitors with chemotherapy is feasible and 
effective in this subgroup of breast cancers. However, the clinical benefit was mostly 
limited to tumors that had a pre-existing immune response evident by the PD-L1 positive 
immune cells 13. One explanation for the modest response rates to immunotherapy in breast 
cancer is that PD-1/L1 blockade requires pre-existing immune "recognition" of the tumor 
and that some tumor types are less naturally recognizable by the immune system due to 
either low antigenicity related to mutational load and/or a hostile tumor microenvironment 
35.  
 
TAMs have been shown to directly and indirectly modulate PD-1/PD-L1 expression in 
tumor environment 36,37. TAMs are able to secrete several cytokines that mediate their 
immunosuppressive and pro-tumor activity in the tumor microenvironment. Among them, 
Interferon (IFN)-γ, IL-1β, TNF-α, TGF-β, IL-6 and IL-18 present key mediators of TAM 
functions38. Indeed, TAMs can induce the expression of PD-L1 by the secretion of IFN-γ 
via Janus kinase/signal transducer and activator of transcription 3 (JAK/STAT3) and the 
phosphatidylinositol 3-kinase (PI3K)/AKT signaling pathways 39. Recently, IFN-γ-related 
mRNA profile has been proposed as a predictor of clinical response to PD-1 blockade40. 
TGF-β is a multifunctional cytokine that is involved in generating Tregs and supporting 
their suppressive activity against cytotoxic T cell (CTL) effector function in the tumor 
microenvironment in mouse models41,42. TGF-β can also increase the suppressive activity 
of TAMs by inducing their polarization to M2 phenotype and induce the upregulation of 
PD-L1, leading to tumor escape 43. Furthermore, TAMs have been shown to reduce the 
effector activity of TILs. In TNBC patients, the presence of high levels of TILs has been 
significantly correlated with a better prognosis 44. Patients with TNBCs with combined 
low-TILs and high-PD-L1 expression showed poor prognosis in the preoperative systemic 
therapy setting 45. TAMs are implicated in promoting the activity of Tregs. PD-L1 and 
FOXP3 +Tregs seems to work synergistically and their overexpressions induce cancer 
immune evasion in BC 46. Based on these findings, combined strategies aimed at blocking 
PD-1 and depleting Tregs should be investigated in these patients. 
 
Colony-stimulating factor 1 (CSF1) play a key role in monocyte recruitment and TAM 
generation. Ding et al. revealed that in vivo inhibition of CSF1 reduced TAM infiltration 
and tumor growth and progression47. These results indicate that CSF1 pathway inhibition 
may represent effective strategies to reduce TAM accumulation and, as a consequence, to 
modulate PD-1/PD-L1 expression in BC. Breast cancer mouse models with high levels of 
infiltrating myeloid cells, had lower infiltration of cancer-killing T-cells and, for this 
reason, were resistant to anti-PD-1 or anti-CTLA4 therapy. Cabiralizumab, a humanized 
IgG4 monoclonal antibody, binds to CSF‐1 receptor (CSF-1R) and blocks cytokine 
signaling that is needed for TAM activation and survival, leading to TAM depletion. 
Targeting 
immunosuppressive 
TAMs 
within 
tumors 
with 
cabiralizumab may 
prevent immune evasion by cytotoxic T-cells. Tumor infiltrating myeloid cells including 
TAMs are linked to immune checkpoint inhibitor resistance, suggesting that cabiralizumab 
treatment may improve the efficacy of immune checkpoint blocking therapies in patients 
with high levels of TAMs infiltration.  In addition, De Nardo et al, highlighted the 
importance of the CSF1/CSF1R signaling in the recruitment of TAMs in breast cancer and 

Protocol Version: 07/27/22 
 
Page 15 of 88 
 
 
further showed that CSF1R blockade can inhibit TAMs and enhance the activity of 
chemotherapy. Therefore, inhibiting the CSF1R with cabiralizumab to deplete 
immunosuppressive TAMs may be synergistic to PD-1 blockade.  
 
The initial purpose of this study was to investigate the safety and preliminary clinical 
activity of cabiralizumab in combination with nivolumab and neoadjuvant chemotherapy 
in TNBC patients.  However, with Amendment 7, the purpose of this study became 
investigating the safety and clinical activity of neoadjuvant nivolumab and chemotherapy 
in TNBC patients. 
 
1.5 
Cabiralizumab  
 
(Note: following the conclusion of the safety lead-in and beginning with the 
implementation of Amendment 7, cabiralizumab is no longer given to patients enrolled to 
this study.) 
 
CSF1R signaling plays a fundamental role in the differentiation, maintenance, trafficking, 
and function of monocytic lineage cells, including monocytes, macrophages, and 
osteoclasts. Cabiralizumab blocks the binding of CSF1 and IL34 to CSF1R, thus inhibiting 
downstream functions such as development and survival of monocytic lineage cells. 
Immunosuppressive TAMs are dependent on CSF1 for survival; a drug that inhibits CSF1R 
could limit the influence of TAMs on the tumor microenvironment and could be 
complementary 
and 
augment 
current 
cancer 
therapies 
(eg, 
checkpoint-based 
immunotherapies such as antibodies that target the programmed cell death protein 1 [PD1].  
 
Cabiralizumab also referred to as BMS-986227-01, BMS-986227, or FPA008 is a 
recombinant, humanized IgG4 mAb that binds to human CSF1R. Binding of cabiralizumab 
to CSF1R antagonizes binding of CSF1 and IL34, the 2 ligands to CSF1R, thereby 
preventing activation of CSF1R. Cabiralizumab contains a single amino acid substitution 
in the hinge region to prevent hemi-dimer exchange. Cabiralizumab, is composed of 2 
heavy chains and 2 light chains that targets human CSF1R. Cabiralizumab is produced 
from cell culture using a Chinese Hamster Ovary (CHO) cell line. The physical and 
chemical properties of cabiralizumab drug substance are summarized below: 
 
Physical and Chemical Properties of Cabiralizumab Drug Substance 
 
BMS Number  
BMS-986227-01 
Other names  
BMS-986227; Cabiralizumab, Anti-CSF1R mAb, FPA008 
Molecular Weight  
148,910 Daltons 
Appearance  
Colorless to yellow liquid, clear to very opalescent 
Solution  
pH 6.2 to 7.0 
 
Cabiralizumab Clinical Safety: 
 
Cabiralizumab was evaluated in 1 completed study (Study FPA008001) and is currently 
being evaluated in 5 ongoing studies (Study FPA008002, Study FPA008003, Study 

Pr ot oc ol Versi o n:  0 7/ 2 7/ 2 2  
 
P a ge 1 6  of 8 8  
 
 
C A 0 2 5 0 0 1, St u d y C A 0 2 5 0 0 6, a n d St u d y C A 0 2 8 0 0 1). T his secti o n prese nts s u m marize d 
a n d pr eli mi nar y dat a f r o m s o me of t hese st u dies. Acr oss all st u dies, a t otal of 1 5 1 s u bjects 
were  treate d  wit h  ca bir aliz u ma b  m o n ot hera p y,  a n d  4 2 9  s u bjects  were  treate d  wit h  
ca biraliz u ma b i n c o m bi nati o n wit h ni v ol u ma b, wit h or wit h o ut c he m ot hera p y. 
 
O verall, ca biraliz u m ab as m o n ot hera p y de m o nstrates a t olera ble safet y pr ofile i n s u bjects 
wit h  mali g na ncies a n d h ealt h y v ol u nteers. T his is base d o n safet y data fr o m 1 5 1 s u bjects. 
T he m ost fre q ue nt A Es ( A S T i ncrease d a n d bl o o d creati ne p h os p h o ki nas e  i ncrease d) are 
res ults f or t he s pecific M O A of ca biraliz u ma b. T he o verall i nci de nce of treat me nt relate d 
S A Es are i nfre q u e nt.  T he c o m bi nati o n of ca biraliz u ma b a n d ni v ol u ma b a p pears t o be 
t olerate d base d o n dat a fr o m 4 2 9 s u bjects. T he safet y pr ofile a p pears si milar t o t hat of t he 
i n di vi d ual c o m p o ne nts a n d t he fre q u e nc y a n d t y pes of i m m u ne-me diate d A Es a p pear 
si milar acr oss m ulti ple t y p es of t u m ors. A d diti o nall y, t he c o m bi nati o n of ca biraliz u ma b 
a n d ni v ol u ma b wit h or wit h o ut c he m ot hera p y as e val uate d i n St u d y C A 0 2 5 0 0 6 a p pears t o 
be t olerate d . 
 
Alterati o n i n e nz y mes ( e g, A S T, A L T, a n d C K) i n t he a bse nce of c h a n ges i n bilir u bi n a n d 
peri or bital e d e ma  h a ve  bee n  o bs er ve d  acr oss  m ulti ple  trials  as  a  c o ns e q ue nce  of  t he  
de pleti o n of tiss ue-i nfiltrati n g m acr o p h a ges me diate d b y ca biraliz u ma b. S ki n dis o ders 
ha ve occ urre d acr oss  m ulti ple trials. T he s pecific al g orit h ms de vel o pe d f or ca biraliz u ma b 
pr o vi de e xte nsi ve g ui da n ce t o ma na ge t hese e v e nts.  
 
o  St u d y  F P A 0 0 8 0 0 2  ( P h ase  1 -D ose  es c al ati o n):  I n  P hase  1  d ose- escalati o n 
m o n ot hera p y, A Es c o nsi dere d b y t he i n v esti gat or as rel ate d t o ca biraliz u ma b were 
e x perie nce d b y 9 of 9 ( 1 0 0 %) s u bjects. T here were n o Gra d e 5  treat me nt-relate d 
A Es e x perie nce d b y a n y s u bject i n P hase 1 m o n ot hera p y.  t h ose e x perie nce d b y > 1 
s u bject i ncl u de d p eri or bit al e de ma a n d fati g ue ( 6 [ 6 6. 7 %] s u bjects eac h); peri p heral 
oe de ma ( 5 [ 5 5. 6 %] s u bjects); bl o o d creati ne  p h os p h o ki nase i ncrease d ( 4 [ 4 4. 4 %] 
s u bjects); dr y s ki n, facial e de ma, a n d pr urit us ge n eralize d  ( 3 [ 3 3. 3 %] s u bjects 
eac h); a n d A L T i ncr ease d, A S T i ncrease d, d er matitis, ras h, a n d s ki n dis or der  ( 2 
[ 2 2. 2 %]  s u bjects  eac h). I n  P hase  1  d os e-es cal ati o n  m o n ot hera p y,  S A Es  were  
e x perie nce d  b y  2  of  9  ( 2 2. 2 %)  s u bjects.  O ne  s u bject  e x perie nce d  Gra de  3  
e n d ocar ditis, Gr a de 3 i nt er vert e bral discitis, a n d Gra de 3  stre pt oc occal se psis. T he 
ot her s u bject e x perie n ce d Gra de 2 h y perte nsi o n a n d Gra de 2 u p per  a b d o mi nal pai n. 
All S A Es were deter mi ne d t o be n ot treat me nt relate d . I n P hase 1 d ose-es calati o n 
m o n ot hera p y,  3  of  9  ( 3 3. 3 %)  s u bjects  disc o nti n ue d  s t u d y  treat me nt  d ue  t o 
treat me nt-r elate d  A Es  i ncl u di n g  s ki n  dis or der,  bl o o d  creati ne  p h os p h o ki nase  
i ncreas e d,  a n d p eri or bital  oe de ma  ( 1  [ 1 1. 1 %]  s u bject  eac h).  N o  d eat hs  were  
re p orte d i n P hase 1 of t his st u d y. 
o  St u d y F P A 0 0 8 0 0 3  ( P h ase 1 a c o m bi n ati o n t her a p y): As of 1 5 -J ul-2 0 1 9, i n t he 
P hase 1a c o m bi nati o n t hera p y d ose -escalati o n c o h orts, A Es were  e x perie nce d b y 
1 5 of 1 6 ( 9 3. 8 %) s u bjects treate d. I n t he P hase 1a c o m bi nati o n t hera p y   d ose-
escalati o n  c o h orts,  2  ( 1 2. 5 %)  s u bjects  ha d  Gra de  5  e ve nts,  w hic h  i ncl u de d  
res pirat or y fail ure a n d treat me nt -relate d p ne u m o nitis ( 1 s u bject eac h). treat me nt-
relate d A Es were e x perie nce d b y 1 3 of 1 6 ( 8 1. 3 %) s u bjects. T he m ost c o m m o nl y 
re p orte d ( 3 s u bjects)  treat me nt-relate d A Es i ncl u de d fati g u e ( 8 [ 5 0 %] s u bjects); 

Protocol Version: 07/27/22 
 
Page 17 of 88 
 
 
periorbital oedema (7 [43.8%] subjects); and rash, blood creatine phosphokinase 
increased, AST increased, rash maculopapular, pruritus, and pneumonitis (3 
[18.8%] subjects each). There was 1 (25%) subject that experienced a Grade 5 
treatment-related AE of pneumonitis. In the Phase 1a combination therapy dose-
escalation cohorts, 7 of 16 (43.8%) subjects experienced at least 1 SAE. Treatment 
related SAEs occurred in 2 of 16 (12.5%) subjects and included Grade 5 
pneumonitis (1 [6.3%] subject) and Grade 3 colitis (1 [6.3%] subject). No DLTs 
were reported in the Phase 1a dose-escalation combination therapy arm of this 
study. In the Phase 1a combination therapy dose-escalation cohorts, 3 of 16 (18.8%) 
subjects discontinued study treatment due to a treatment-related AE and included 
Grade 4 pneumonitis (1 [6.3%] subject), Grade 3 colitis (1 [6.3%] subject), and 
Grade 2 urticaria (1 [6.3%] subject). 
o Study CA025001: A Phase 1 Study of Cabiralizumab Administered Alone or 
in Combination with Nivolumab in Advanced Malignancies. The administration 
of 4 mg/kg cabiralizumab + 3 mg/kg nivolumab with a Q2W interval presents a 
tolerable safety profile. Treatment-related AEs in the 4 mg/kg cabiralizumab + 3 
mg/kg nivolumab Q2W cohort C1 were experienced by 7 of 7 (100.0%) subjects. 
The most commonly reported treatment-related AEs included AST increased (7 of 
7 [100.0%] subjects), blood creatine phosphokinase increased (6 [85.7%] subjects), 
amylase increased and lipase increased (4 [57.1%] subjects), and blood ALP 
increased (3 [42.9%] subjects each). Treatment-related AEs in the 4 mg/kg 
cabiralizumab + 3 mg/kg nivolumab Q2W cohort C2 were experienced by 4 of 5 
(80.0%) subjects. The most commonly reported treatment-related AEs included 
blood creatine phosphokinase increased (3 [60.0%] subjects) and amylase increased 
and AST increased (2 [40.0%] subjects each). There were no Grade 5 AEs 
experienced by any subject in monotherapy and combination therapy. Of the 
subjects treated with 4 mg/kg cabiralizumab + 3 mg/kg nivolumab Q2W, 5 of 12 
(41.7%) subjects experienced at least 1 SAE. Treatment-related SAEs occurred in 
1 of 12 (8.33%) subjects. The subject experienced Grade 3 gastritis bacterial. None 
of the subjects treated in this study discontinued treatment due to a drug-related 
AE. One of 7 (14.3%) subjects treated with cabiralizumab monotherapy 
discontinued treatment due to an AE of Grade 2 deep vein thrombosis, which was 
not related to treatment. Two of 12 (16.7%) subjects treated with 4 mg/kg 
cabiralizumab + 3 mg/kg nivolumab Q2W due to Grade 5 AEs of cholangitis 
infective (C1) and plasma cell myeloma (C2), which were not related to treatment. 
No deaths due to treatment-related AEs were reported.  
o Study CA025006: A Phase 2 Study of Cabiralizumab Administered in 
Combination with Nivolumab with and without Chemotherapy in Subjects 
with Advanced Pancreatic Cancer. The treatment of 4 mg/kg cabiralizumab 
Q2W and 480 mg nivolumab Q4W with or without gemcitabine and nab-paclitaxel 
or FOLFOX demonstrate a tolerable and manageable safety profile. Arm C of this 
study investigated cabiralizumab in combination with nivolumab and 
gemcitabine/Abraxane. Treatment-related AEs were experienced by 34 of 40 
(85.0%) subjects in Arm C. The most commonly reported treatment-related AEs 
included AST increased and fatigue (16 [40.0%] subjects each); blood creatine 
phosphokinase increased and anemia (13 [32.5% subjects); ALT increased, 

Protocol Version: 07/27/22 
 
Page 18 of 88 
 
 
thrombocytopenia, and periorbital oedema (11 [27.5%] subjects each); platelet 
count decreased (9 [22.5%] subjects); nausea and neutropenia (8 [20.0%] subjects 
each); blood ALP increased, WBC count decreased, vomiting, rash, and decreased 
appetite (7 [17.5%] subjects each); and pruritus, rash maculo-papuloar, blood 
lactate dehydrogenase decreased, pyrexia, and diarrhea (6 [15.0%] subjects each). 
Treatment- related SAEs occurred in 9 of 40 (22.5%) subjects in Arm C. One 
subject experienced Grade 2 pneumonitis; 1 subject experienced Grade 3 acute 
kidney injury; 1 subject experienced Grade 3 thrombocytopenia; 1 subject 
experienced Grade 2 facial edema and Grade 2 peripheral edema; 1 subject 
experienced Grade 2 myositis and Grade 4 neutropenia; 1 subject experienced 
Grade 4 liver abscess; 1 subject experienced Grade 2 pneumonitis; 1 subject 
experienced Grade 1 pyrexia; and 1 subject experienced Grade 2 pyrexia. Fifty-six 
of 157 (35.7%) subjects died during the course of the study due to disease 
progression, 1 (0.6%) subject due to study drug toxicity, 2 (1.3%) subjects due to 
AE/SAE indicated death, 5 (3.2%) subjects due to “other,” and 1 (0.6%) subject 
due to “unknown.” Forty-one of 157 (26.1%) subjects died during the course of the 
study within 100 days of the last dose due to disease progression. 
o Unexpected Life-threatening and/or Fatal Serious Adverse Reactions There were 
no unexpected life-threatening and/or fatal serious adverse reactions (SARs) 
experienced by subjects following cabiralizumab monotherapy exposure. The 
unexpected life-threatening and/or fatal SARs experienced by subjects following 
cabiralizumab plus nivolumab combination therapy with or without chemotherapy 
are shown in the following table obtained from the investigator brochure (version 
no. 07) :  
 
 
 

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1.6 
Rationale to conduct this study in the neoadjuvant setting  
 
Most early-phase drug development trials are conducted in patients with metastatic disease; 
however, this population may be the least amenable to response to immunotherapy because 
of larger tumor burden and/or treatment-related immune suppression. The following are 
additional points to support the conduction of this study in this population: 
 
1. TNBC carries a poor prognosis with high risk of relapse and early time course of 
metastasis. Therefore, investigating novel agents/combinations in this setting is 
feasible. 
2. Pathologic complete response to NACT and TILs are emerging as surrogates of 
prognosis in TNBC. Pre-surgical treatment allows for serial assessment of TILs, 
which may be useful for demonstrating favorable on-target treatment effects such 
as decreasing TAMs and expansion of effector T cells and within the tumor 
microenvironment by cabiralizumab.  
3. The neoadjuvant setting allows evaluating if facilitating antitumor immunity will 
also target disseminated tumor cells (DTCs) in the bone marrow and increase the 
likelihood of long-term disease control. This study will collect pre-treatment blood, 
tumor and bone marrow to test for DTCs and evaluate the effects of immunotherapy 
on the microenvironment of DTCs which is novel. Our research team has developed 
methods to enrich, detect, and classify DTCs in breast cancer patients correlating 
the presence of DTCs with prognosis and response to anti-cancer treatments. The 
correlative work in this trial is heavily focused on exploring the biological and 
immunological basis for DTC dormancy, to understand the molecular heterogeneity 
of DTCs and to investigate the effects of immunotherapy on DTCs and their 
microenvironment.    
4. Correlative studies will be conducted on serially collected blood, tumor and bone 
marrow specimens to explore the local and systemic impact of the intervention, 
with a goal of directly informing future studies.  
5. During the study we will incorporate a safety lead in phase in which we will assess 
the safety of administering the combination of nivolumab, cabiralizumab and 
chemotherapy in early-stage TNBC.  
 
Thus, we have chosen weekly paclitaxel plus carboplatin as the chemotherapy backbone to 
combine with immunotherapy for the patients with TNBC based on the results from the 
KEYNOTE-173 study (NCT02622074), a six-cohort phase Ib study of neoadjuvant 
platinum/taxane chemotherapy in combination with pembrolizumab in patients with 
locally advanced TNBC. In this study, six-cohorts were evaluated with different doses and 
schedules of taxanes and platinum in combination with pembrolizumab. The study sought 
to determine the safety and tolerability as well as establish a recommended phase II dose 
for further evaluation. The patients treated with the combination of paclitaxel 80 mg/m2 
weekly with carboplatin (AUC 5 every 3 weeks) plus pembrolizumab had an ORR of 70% 
and there were no DTLs reported. The findings support the ongoing phase 3 KEYNOTE-
522 trial, which is comparing this combination with placebo in this patient population. The 
ADAPT-TN trial demonstrated that an anthracycline-free regimen of nab-paclitaxel plus 

Protocol Version: 07/27/22 
 
Page 20 of 88 
 
 
carboplatin for 12-weeks had high efficacy and tolerability. Furthermore, those patients 
that achieved a pCR did not seem to benefit from additional anthracycline therapy in the 
adjuvant setting. 
 
1.7 
Rationale for tumor infiltrating lymphocytes (TILs) and pathologic complete 
response as endpoints 
 
Tumor infiltrating lymphocytes (TILs), mainly the CD8 +T cells, have been identified and 
validated as a predictive and prognostic biomarker of long-term survival in TNBC treated 
with neoadjuvant chemotherapy 48,49. In metastatic TNBC patients treated with 
atezolizumab, response rate and overall survival significantly correlated with the level of 
TILs 50. Several retrospective studies of early TNBC demonstrated significantly worse 
survival outcomes in patients with high PD-L1 expression and a low number of TILs or a 
high ratio of PD-L1/CD8 expression 45,51,52. On the contrary, immunogenic factors 
potentially involved in the expression of neoantigens positively correlated with higher TILs 
and a more favorable prognosis 53,54. All the above supports the use of TILs as a predictive 
and prognostic immune biomarker 55,56. Pathological complete response (pCR)- defined as 
complete absence of disease in the breast and lymph nodes- after neoadjuvant 
chemotherapy (NACT) is associated with improved outcomes in TNBC 5,6. Therefore, pCR 
has been used as a primary endpoint in most neoadjuvant trials in TNBC. It is important to 
acknowledge that even though there is a clear correlation between pCR with chemotherapy 
and long-term outcomes in TNBC, there is uncertainty on how clear the correlation is with 
immune therapy combinations. Early data from the Keynote-173 study of pembrolizumab 
plus chemotherapy reported 12-month event free survival rates of 100% among patients 
who achieved pCR and 88% (90% CI, 71-95) among those who did not (Schmid P, et al. 
Abstract PD5-01. Presented at: San Antonio Breast Cancer Symposium; Dec. 4-8, 2018; 
San Antonio.)  
 
1.8 
Rationale to study the effects of immunotherapy on disseminated tumor cells 
in the bone marrow  
 
Disseminated tumor cells (DTCs) are tumor cells that escape the environment of a primary 
breast tumor, and seed distant niches, such as bone marrow (BM), where they can serve as 
a source for future, metastatic spread 57. DTCs can be detected in the BM of up to 40% of 
patients with early stage BC without any clinical signs of metastasis. The presence of DTCs 
is associated with an increased rate of distant recurrence in breast cancer patients 58. 
Interestingly, the molecular phenotype of DTCs, particularly with regard to targeted 
therapeutic sensitivities, is often distinct from the primary breast tumor from which they 
originate 59. Tumor cells evoke a number of molecular mechanisms to avoid immune 
recognition and destruction, and these pathways may be critical for establishing DTC 
dormancy in the BM of breast cancer patients 60. The molecular characterization of DTCs 
based upon specific gene mutations or gene expression profiles is feasible. Multi-marker, 
gene expression-based panels can provide a sensitive, specific, and technically streamlined 
approach to the detection and classification of BM DTCs 61-63. Our research team (Aft, 
Watson) has developed methods to enrich, detect, and classify DTCs in breast cancer 
patients correlating the presence of DTCs with prognosis and response to anti-cancer 

Protocol Version: 07/27/22 
 
Page 21 of 88 
 
 
treatments. The correlative work in this trial is heavily focused on exploring the biological 
and immunological basis for DTC dormancy, to understand the molecular heterogeneity of 
DTCs and to investigate the effects of immunotherapy on DTCs and their 
microenvironment. 
 
We have defined an 8-gene BM DTC expression panel, assayed prior to neoadjuvant 
therapy, that is associated with incomplete response to neoadjuvant chemotherapy and 
early distant metastasis in ‘triple negative’ (TN) breast cancer patients. 
 
 
 
1.9 
Rationale for Amendment 7 (Removal of Cabiralizumab) 
 
After completion of the 12-patient safety run-in and with the activation of Amendment 7, 
this study has been changed to a single-arm, non-randomized study because cabiralizumab 
has an expiry date prior to the planned completion of enrollment of the two-arm 
randomized trial. The initial signal from the safety run-in of the non-cabiralizumab trial 
arm that includes carboplatin, paclitaxel, and nivolumab (Arm A) demonstrated early 
evidence of safety and preliminary evidence of efficacy that warranted further evaluation 
with additional patients.  
 
Notably, in July 2021, neoadjuvant chemotherapy in combination with pembrolizumab was 
approved by the FDA based on KEYNOTE-522 (NCT03036488), a randomized, double-
blind, placebo-controlled trial of 1174 patients. The regimen includes four chemotherapy 

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Page 22 of 88 
 
 
drugs (carboplatin, paclitaxel, cyclophosphamide, and an anthracycline) combined with 
both neoadjuvant and adjuvant pembrolizumab. This study demonstrated an improved 
pathological complete response rate and event-free survival of chemotherapy regimen with 
pembrolizumab compared to the control arm. However, there are ongoing questions 
regarding chemotherapy and immune-related toxicities of the regimen, the necessity of an 
anthracycline, and the need for adjuvant immune checkpoint inhibition for all patients. The 
median age of the patients included in the trial was less than 50 with nearly 90% of patients 
less than 65 years of age. Therefore, alternative neoadjuvant treatment options that include 
both chemotherapy and immune checkpoint inhibition are needed for patients that have 
lower toxicity and better tolerance. 
 
In this single-arm study, all patients enrolled will receive 12 weeks of neoadjuvant 
carboplatin, paclitaxel, and nivolumab. Adjuvant therapy is per investigator’s choice. For 
patients who have a pathological complete response after neoadjuvant therapy, 
anthracycline therapy can likely be avoided, and adjuvant immune checkpoint inhibition 
can be considered. In contrast, for patients without a pathological complete response, 
adjuvant anthracycline with cyclophosphamide and immune checkpoint inhibition can be 
given with similar therapies split between neoadjuvant and adjuvant therapy as given in 
KEYNOTE-522. The current single-arm study, which includes robust biomarker analysis 
including tissue, peripheral blood, and bone marrow analyses, may permit a precision 
medicine approach by allowing the utilization of a de-escalated regimen for some patients, 
while still permitting anthracycline therapy for other patients who require additional 
therapy after surgery. Both chemotherapy and immune-related adverse events are 
anticipated to be lower than KEYNOTE-522 based on the shorter duration of therapy and 
fewer drugs incorporated into the treatment regimen.   
 
 
 
2.0 
OBJECTIVES AND ENDPOINTS 
 
Objectives 
Endpoints 
Justification for 
Endpoints 
Primary 
Safety Lead-In: To investigate if 
the combination of neoadjuvant 
chemotherapy with nivolumab 
and cabiralizumab is safe in 
patients with TNBC. 
Toxicity by CTCAE v 5.0. 
The study includes a safety 
lead-in part that will assess 
safety of the combination 
of nivolumab +/- 
cabiralizumab with NAC. 
To compare on-treatment TAMs 
and TILs against their baseline 
levels in patients with newly 
diagnosed stage II/III TNBC 
treated with neoadjuvant 
nivolumab + chemotherapy. 
Percent change of on-
treatment TAMs from 
baseline and percent change 
of on-treatment TILs from 
baseline (stromal TIL score 
is defined as the percentage 
of tumor stroma area that was 
TILs, mainly the CD8 +T 
cells, have been identified 
and validated as a 
predictive and prognostic 
biomarker of long-term 
survival in TNBC treated 
with neoadjuvant 
chemotherapy. In 

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Page 23 of 88 
 
 
occupied by mononuclear 
inflammatory cells). 
metastatic TNBC patients 
treated with a PD-L1 
inhibitor, response rate and 
overall survival 
significantly correlated 
with the level of TILs 
Secondary 
To estimate the pathological 
complete response (pCR) rate in 
patients with newly diagnosed 
stage II/III TNBC treated with 
neoadjuvant nivolumab + 
chemotherapy. 
pCR rate 
pCR defined as complete 
absence of disease in the 
breast and lymph nodes- 
after NAC is associated 
with improved outcomes in 
TNBC. Therefore, pCR has 
been used as a primary 
endpoint in most 
neoadjuvant trials in 
TNBC. It is important to 
acknowledge that even 
though there is a clear 
correlation between pCR 
with chemotherapy and 
long-term outcomes in 
TNBC, there is uncertainty 
on how clear the 
correlation is with immune 
therapy combinations. We 
will also evaluate residual 
cancer burden (RCB) status 
in all patients.  
To estimate the grade 3 or higher 
treatment-related adverse event 
rate. 
Grade 3 or higher treatment-
related AE rate. 
Observed grade 3+ toxicity 
events in prior studies are 
high and can lead to 
impaired quality of life, 
long-term toxicity, 
treatment delays and, at 
times, early treatment 
discontinuation. 
To compare the percent change of 
TAMs and TILs between who 
achieve a pCR after treatment 
with neoadjuvant nivolumab and 
chemotherapy versus those who 
do not. 
TILs and TAMs percentage 
will be measured at baseline 
and after initiation of 
therapy. 
TILs, mainly the CD8 +T 
cells, have been identified 
and validated as a 
predictive and prognostic 
biomarker of long-term 
survival in TNBC treated 
with neoadjuvant 
chemotherapy. In 
metastatic TNBC patients 

Protocol Version: 07/27/22 
 
Page 24 of 88 
 
 
treated with a PD-L1 
inhibitor, response rate and 
overall survival 
significantly correlated 
with the level of TILs 
To determine recurrence-free 
survival (RFS)  
Recurrence-free survival 
(RFS) defined from time of 
surgery to the earliest time 
of recurrence, time to 
development of a second 
cancer, or time to death 
from any cause. 
RFS is a widely accepted 
end point to assess clinical 
benefit of a new treatment. 
In this study, we will 
investigate the effect of 
adding a novel 
immunotherapy 
combination to NAC in 
TNBC patients.  
  
Exploratory 
To evaluate disseminated tumor cell (DTC) gene signature elimination in the bone marrow 
after neoadjuvant treatment and correlation with pCR and prognosis. 
To evaluate potential biomarkers of response to NAC + nivolumab +/- combination with 
cabiralizumab in patients with newly diagnosed TNBC. Potential biomarkers include baseline 
TAMs and/or TILs percentage, baseline PD-L1 expression in the tumor and tumor infiltrating 
immune cells, CSF-1R+.  These biomarkers will be correlated with pathologic complete 
response. 
To compare the difference in the immune cell infiltration and cytokine expression in the 
biopsied tumors of patients with TNBC before and after treatment with the combination of 
NAC plus nivolumab. 
To correlate changes in the immune infiltrate with clinical responses to treatment with the 
combination of NAC plus nivolumab and clinical outcomes (pCR, RFS) following treatment.  
To compare the difference in ctDNA response in patients who achieve pCR vs. patients who 
do not achieve pCR. 
 
 
3.0 
STUDY POPULATION 
 
3.1 
Inclusion Criteria 
 
1. Histologically or cytologically confirmed newly diagnosed ER-/HER2- breast cancer.  
ER and PR < Allred score of 3 or < 1% positive staining cells in the invasive component 
of the tumor. HER2 negative by FISH or IHC staining 0 or 1+ according to ASCO/CAP 
guidelines.  
 
2. Clinical stage II or III (by AJCC 8th edition – at least T2, any N, M0 or if N+ then any 
T) breast cancer eligible for neoadjuvant chemotherapy with complete surgical excision 
of the breast cancer after neoadjuvant therapy as the treatment goal. 
 

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3. Tumor size at least 2 cm in one dimension by clinical or radiographic exam (WHO 
criteria).  Patients with histologically confirmed or clinically palpable lymph nodes 
may be enrolled regardless of tumor size.  A palpable mass is not required as long as 
the mass is at least 2 cm in one dimension by radiographic exam. 2D measurements 
should be completed during screening if available. 
 
4. No prior therapy for this disease 
 
5. At least 18 years of age. 
 
6. ECOG performance status ≤ 1 (see Appendix A) 
 
7. Normal bone marrow and organ function as defined below: 
a. Leukocytes ≥ 2,000/mcL (stable off any growth factor within 4 weeks of first study 
treatment administration) 
b. Absolute neutrophil count ≥ 1,500/mcL (stable off any growth factor within 4 
weeks of first study treatment administration) 
c. Platelets ≥ 100,000/mcL (stable off any growth factor within 4 weeks of first study 
treatment administration) 
d. Hemoglobin ≥8.5 g/dl (transfusion to achieve this level is not permitted within 2 
weeks of first study treatment administration) 
e. Total bilirubin ≤ 1.5 x institutional upper limit of normal (IULN) (except 
participants with Gilbert’s Syndrome who must have normal direct bilirubin) 
f. AST(SGOT)/ALT(SGPT) ≤ 2.0 x IULN 
g. Alkaline phosphatase <2.5 x ULN 
h. Serum creatinine < 1.5 x ULN or creatinine clearance > 40 mL/min by Cockcroft-
Gault 
i. Albumin ≥ 3 g/dL 
j. INR and aPTT <1.5 x IULN (This applies only to patients who do not receive 
therapeutic anticoagulation; patients receiving therapeutic anticoagulation, such as 
low-molecular-weight heparin or warfarin, should be on a stable dose).  
 
8. Women of childbearing potential (WOCBP) 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. 
 
9. Women must not be breastfeeding. 
 
10. WOCBP must agree to follow instructions for method(s) of contraception for the 
duration of treatment with study treatment(s) and for a total of 5 months post-treatment 
completion. 
 
11. Ability to understand and willingness to sign an IRB approved written informed 
consent document (or that of legally authorized representative, if applicable). 
 

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12. Consent for fresh pre-treatment, on-treatment, biopsy samples at acceptable clinical 
risk, as judged by the investigator. 
 
13.  Participants must be willing and able to comply with scheduled visits, treatment 
schedule, and laboratory testing 
 
3.2 
Exclusion Criteria 
 
1. Prior treatment with immunotherapy for cancer 
 
2. Known metastatic disease 
 
3. Known invasive cancer in contralateral breast 
 
4. Patients with a previous history of non-breast malignancy are eligible only if they meet 
the following criteria for a cancer survivor: 
• 
Has undergone potentially curative therapy for all prior malignancies AND 
• 
Has been considered disease-free for at least 1 year (with the exception of basal cell 
or squamous cell carcinoma of the skin or carcinoma-in-situ of the cervix). 
 
5. Currently receiving any other investigational agents. 
 
6. A history of allergic reactions attributed to compounds of similar chemical or biologic 
composition to paclitaxel, carboplatin, nivolumab, or other agents used in the study. 
Patients who have received multiple blood transfusions. 
 
7. Evidence of uncontrolled ongoing or active infection, requiring parenteral anti-
bacterial, anti-viral, or anti-fungal therapy ≤ 7 days prior to administration of study 
treatment. Patients receiving prophylactic antibiotics (e.g., for prevention of a urinary 
tract infection or chronic obstructive pulmonary disease) are eligible. 
 
8. Patients with prior allogeneic bone marrow transplantation or prior solid organ 
transplantation. 
 
9. History or risk of autoimmune disease, including, but not limited to, systemic lupus 
erythematosus, rheumatoid arthritis, inflammatory bowel disease (Crohn’s disease and 
ulcerative colitis), vascular thrombosis associated with antiphospholipid syndrome, 
Wegener’s granulomatosis, Sjögren’s syndrome, Bell’s palsy, Guillain-Barré 
syndrome, 
multiple 
sclerosis, 
autoimmune 
thyroid 
disease, 
vasculitis, 
or 
glomerulonephritis.  
 
• 
Patients with a history of autoimmune hypothyroidism on a stable dose of thyroid 
replacement hormone may be eligible. 
• 
Patients with controlled Type 1 diabetes mellitus on a stable insulin regimen may 
be eligible. 

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• 
Patients with eczema, psoriasis, lichen simplex chronicus of vitiligo with 
dermatologic manifestations only (e.g., patients with psoriatic arthritis would be 
excluded) are permitted provided that they meet the following conditions: 
o Patients with psoriasis must have a baseline ophthalmologic exam to rule out 
ocular manifestations 
o Rash must cover less than 10% of body surface area (BSA) 
o Disease is well controlled at baseline and only requiring low potency topical 
steroids (e.g., hydrocortisone 2.5%, hydrocortisone butyrate 0.1%, flucinolone 
0.01%, desonide 0.05%, aclometasone dipropionate 0.05%) 
o No acute exacerbations of underlying condition within the last 12 months (not 
requiring psoralen plus ultraviolet A radiation [PUVA], methotrexate, retinoids, 
biologic agents, oral calcineurin inhibitors; high potency or oral steroids) 
 
10. History of idiopathic pulmonary fibrosis, pneumonitis (including drug induced), 
organizing pneumonia (i.e., bronchiolitis obliterans, cryptogenic organizing 
pneumonia, etc.), or evidence of active pneumonitis on screening chest computed 
tomography (CT) scan.  
 
11. Uncontrolled or significant cardiovascular disease 
 
12. History of any chronic hepatitis as evidenced by the following: 
• 
i) Positive test for hepatitis B surface antigen 
• 
ii) Positive test for qualitative hepatitis C viral load (by polymerase chain reaction 
[PCR]). 
 
13. Positive test for latent tuberculosis (TB) at screening (e.g. T-SPOT or Quantiferon test) 
or evidence of active TB. 
 
14. Major surgical procedure within 28 days prior to Cycle 1, Day 1 or anticipation of need 
for a major surgical procedure during the course of the study with the exception of the 
planned breast cancer surgery that is part of the trial design.  Participants must have 
recovered from the effects of major surgery or significant traumatic injury at least 14 
days before the first dose of study treatment. 
  
15. Any uncontrolled medical condition which, in the opinion of the Investigator, would 
pose a risk to participant safety or interfere with study participation or interpretation of 
individual participant results. 
 
16. Treatment with systemic immunosuppressive medications (including, but not limited 
to, prednisone, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-
tumor necrosis factor [anti-TNF] agents) within 2 weeks prior to Cycle 1, Day 1. 
• 
Patients who have received acute, low dose, systemic immunosuppressant 
medications (e.g., a one-time dose of dexamethasone for nausea) may be enrolled. 
• 
The use of inhaled corticosteroids and mineralocorticoids (e.g., fludrocortisone) for 
patients with orthostatic hypotension or adrenocortical insufficiency is allowed. 

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The use of replacement doses of prednisone or other corticosteroid for 
adrenocortical insufficiency is allowed 
• 
Participants with a condition requiring systemic treatment with either 
corticosteroids (> 10 mg daily prednisone equivalents) or other immunosuppressive 
medications within 14 days of start of study treatment. Inhaled or topical steroids 
and adrenal replacement steroid doses > 10 mg daily prednisone equivalent are 
permitted in the absence of active autoimmune disease. 
 
17. Evidence of coagulopathy or bleeding diathesis. 
 
18. Ascites needing paracentesis or medical management. 
 
19. Patients positive for human immunodeficiency virus (HIV) are NOT excluded from 
this study, but HIV-positive patients must have:  
• 
A stable regimen of highly active anti-retroviral therapy (HAART)  
• 
No requirement for concurrent antibiotics or antifungal agents for the prevention of 
opportunistic infections  
• 
A CD4 count above 250 cells/mcL and an undetectable HIV viral load on standard 
PCR-based tests  
 
3.3 
Inclusion of Women and Minorities 
 
Men and women and members of all races and ethnic groups are eligible for this trial. 
 
 
4.0 
REGISTRATION PROCEDURES 
 
Patients must not start any protocol intervention prior to registration through the Siteman 
Cancer Center. 
 
The following steps must be taken before registering patients to this study: 
 
1. Confirmation of patient eligibility 
2. Registration of patient in the Siteman Cancer Center database 
3. Assignment of unique patient number (UPN) 
 
4.1 
Confirmation of Patient Eligibility 
 
Confirm patient eligibility by collecting the information listed below: 
 
1. Registering MD’s name 
2. Patient’s race, sex, and DOB 
3. Three letters (or two letters and a dash) for the patient’s initials 
4. Copy of signed consent form 
5. Completed eligibility checklist, signed and dated by a member of the study team 
6. Copy of appropriate source documentation confirming patient eligibility 

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4.2 
Patient Registration in the Siteman Cancer Center OnCore Database 
 
All patients must be registered through the Siteman Cancer Center OnCore database. 
 
4.3 
Assignment of UPN 
 
Each patient will be identified with a unique patient number (UPN) for this study.  All data 
will be recorded with this identification number on the appropriate CRFs. 
 
4.4 
Screen Failures 
 
Screen failures are defined as participants who consent to participate in the clinical trial 
but are not subsequently randomized to the study intervention or entered in the study.  A 
minimal set of screen failure information is required to ensure transparent reporting of 
screen failure participants, to meet the Consolidated Standards of Reporting Trials 
(CONSORT) publishing requirements and to respond to queries from regulatory 
authorities.  Minimal information includes demography, screen failure details, eligibility 
criteria, and any serious adverse event (if applicable).   
 
4.5 
Randomization 
 
Patients will be randomized at a 1:1 ratio between Arm A (neoadjuvant chemotherapy + 
nivolumab) and Arm B (neoadjuvant chemotherapy + nivolumab + cabiralizumab) and will 
be stratified by clinical stage (stage II vs stage III).  A stratified block randomization will 
be used with varying block size of 2 to 4. The randomization scheme will be produced by 
a computer software program that incorporates a standard procedure for generating 
randomization numbers.  
 
After the conclusion of the safety run-in and with the activation of Amendment 7, 
randomization is discontinued.  All patients enrolled thereafter will be treated on Arm A. 
 
4.6 
Strategies for Recruitment and Retention 
 
Triple negative breast cancer (TNBC) lacks specific therapeutic targets. Therefore, 
treatment options are limited to chemotherapy in the neoadjuvant setting. If patients relapse 
after NAC and definitive surgery, outcomes are typically poor. Of importance, our 
institution is becoming a national leader in developing personalized vaccines and other 
novel approaches to treat breast cancer with many patients being referred to our institution 
for treatment. Based on the current trend, we estimate 4 new patients per month with TNBC 
to be treated at our institution at the time of study opening. 
 
We believe that this trial will have excellent patient accrual. The primary source of patients 
who are eligible for this study is via the surgical and medical oncologists specializing in 
breast cancer treatments. Dr. Rebecca Aft from the surgical oncology team is a collaborator 
and sub-investigator of this study and is very supportive of this clinical trial. The fact that 

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the current treatment strategy for TNBC at this institution is similar to this study protocol 
should lend further reassurance that this study ought to have excellent patient accrual.  
 
With the current rate of TNBC patients presenting at our institution, we anticipate 
approximately 60 patients per year who will be treated at our institution. A conservative 
estimate is that 50% of these patients will consent to participate in this study. This yields 
an estimated accrual of 30 patients per year. We anticipate that we will enroll 51 adult 
patients (>18 years of age) of all genders, races, and ethnicities. We anticipate that 60 
patients will be screened to reach target enrollment. We anticipate that we will accrue 
approximately 2 patients per month, therefore completing accrual in approximately 2 years. 
Patients will be accrued from the outpatient clinics and inpatient hospitals of one U.S. site. 
Potential participants will be identified by our multidisciplinary team physicians and 
discussed in tumor board. 
 
 
5.0 
TREATMENT PLAN 
 
5.1 
Premedication Administration 
 
Premedications in order to avoid the occurrence of sever hypersensitivity reactions to 
paclitaxel and carboplatin will be administered per institutional standard.   
 
See Section 10.2 for instructions on data collection on concomitant medication. 
 
5.2 
Study Intervention Description 
 
During the safety run-in, consenting and eligible patients will be randomized to Arm A or 
Arm B.  After the conclusion of the safety run-in and with the activation of Amendment 7, 
randomization is discontinued and all patients will be enrolled to Arm A. 
 
Arm A is paclitaxel + carboplatin + nivolumab.  Arm B is paclitaxel + carboplatin + 
nivolumab + cabiralizumab.  Paclitaxel and carboplatin are chemotherapies approved for 
administration to patients with breast cancer.  Nivolumab is an anti-PD-1 monoclonal 
antibody which works as a checkpoint inhibitor.  It is approved for several indications, 
including melanoma, metastatic non-small cell and small-cell lung cancers, advanced renal 
cell carcinoma, relapsed classical Hodgkin lymphoma, recurrent or metastatic head and 
neck cancer, advanced or metastatic urothelial carcinoma, metastatic colorectal cancer, and 
hepatocellular cancer, but is not approved for breast cancer and is therefore considered 
investigational in the context of this study. Cabiralizumab is an investigational agent and 
is not approved by the FDA. 
 
5.3 
Study Intervention Administration 
 
All patients enrolled to this study must receive neoadjuvant paclitaxel + carboplatin for 
their neoadjuvant chemotherapy.  Paclitaxel will be given intravenously at a dose of 80 
mg/m2 IV over 1 hour (+/- 15 min) on a weekly basis for 12 weeks (Weeks 1, 2, 3, 4, 5, 6, 

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7, 8, 9, 10, 11, and 12).  Carboplatin will be given intravenously at a dose of AUC 5 IV 
over 30 min (+/- 10 min) every 3 weeks for 12 weeks (Weeks 1, 4, 7, and 10). 
 
All patients enrolled to this study will also receive nivolumab as part of their neoadjuvant 
therapy. Nivolumab will be given intravenously at a dose of 240 mg over 30 minutes (+/- 
5 min) every 2 weeks for 12 weeks (Weeks 1, 3, 5, 7, 9, and 11). In patients randomized to 
Arm A, nivolumab will be administered first, starting 30 min (+/- 5 min) after treatment 
start time), followed by paclitaxel starting 60 min (+/- 15 min) after treatment start time, 
followed by carboplatin starting 2 hours (+/- 15 min) after treatment start time.  
 
Patients randomized to Arm B will also receive cabiralizumab as part of their neoadjuvant 
therapy.  Cabiralizumab will be given intravenously at a dose of 4 mg/kg over 30 minutes 
every 2 weeks for 12 weeks (Weeks 1, 3, 5, 7, 9, and 11). In patients randomized to Arm 
B, nivolumab will be administered first, starting 30 min (+/- 5 min) after treatment start 
time), followed by cabiralizumab starting 60 min (+/- 15 min) after treatment start time, 
followed by paclitaxel starting 90 min (+/- 15 min) after treatment start time, followed by 
carboplatin starting 2.5 hours (+/- 15 min) after treatment start time. 
 
Definitive surgery will be performed 4 to 8 weeks after the end of neoadjuvant treatment 
per treating surgeon discretion.  Adjuvant therapy following definitive surgery will be at 
the discretion of the treating oncologist. 
 
The first six patients randomized to each arm will be part of a safety run-in.  The allocation 
to an arm will pause after enrollment of the sixth patient to that arm until all six patients in 
that arm have completed all 12 weeks of treatment and have passed the toxicity monitoring 
period (4 weeks after last infusion of nivolumab and/or cabiralizumab or surgery whichever 
occurs first). Refer to Section 13.6 for early stopping rules.   
 
5.4 
Definitions of Evaluability 
 
All patients who receive any study treatment are evaluable for toxicity.  Patients are 
evaluated from first receiving study treatment until a 30-day follow up after the conclusion 
of treatment, day of surgery, or death, whichever comes first. 
 
Patients are considered evaluable for the primary objective if they satisfy eligibility criteria, 
have received at least 2 doses of the total immunotherapeutic drug dosage, and have valid 
baseline and on-treatment TAMs and TILs measurements for a percent change evaluation 
of TAMs and TILs. Patients who cannot have the on-treatment biopsy may continue to 
receive treatment on study but must be replaced.   
 
In order to be evaluable for pCR and RFS, patients must meet the eligibility requirements 
and have been assessed for pCR (undergone surgery or have documented disease 
progression prior to surgery). 
 
5.5 
Concomitant Therapy and Supportive Care Guidelines 
 

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See Section 10.2 for instructions regarding collection of concomitant medications. 
 
Growth factor support (GFS) is permitted when patients are on study per discretion of the 
treating physician.  GFS is not allowed during screening due to lab requirements.  
 
5.5.1 Treatment of Nivolumab-Related Infusion Reactions 
 
Since nivolumab contains only human immunoglobulin protein sequences, it is 
unlikely to be immunogenic and induce infusion or hypersensitivity reactions.  
However, if such a reaction were to occur, it might manifest with fever, chills, 
rigors, headache, rash, urticaria, angioedema, pruritus, arthralgias, hypo- or 
hypertension, bronchospasm, or other symptoms.  
 
All Grade 3 or 4 infusion reactions should be reported as an SAE if criteria are met.  
Infusion reactions should be graded according to NCI CTCAE version 5.0 
guidelines. 
 
Treatment recommendations are provided below and may be modified based on 
local treatment standards and guidelines as medically appropriate: 
 
Remain at bedside and monitor subject until recovery from symptoms  
 
For Grade 1 symptoms: (Mild reaction; infusion interruption not indicated; 
intervention not indicated)  
 
Infusion rate may be slowed or interrupted and restarted at 50% of the original 
infusion rate when symptoms resolve; if no further complications ensue after 30 
minutes, the rate may be increased to 100% of the original infusion rate.  Monitor 
patient closely.   
 
The following prophylactic premedications are recommended for future infusions:  
diphenhydramine 50 mg (or equivalent) and/or paracetamol 325 to 1000 mg 
(acetaminophen) at least 30 minutes before additional nivolumab administrations, 
slowing infusion rate as above. 
 
For Grade 2 symptoms: (Moderate reaction requires therapy or infusion 
interruption but responds promptly to symptomatic treatment [e.g., antihistamines, 
non-steroidal anti-inflammatory drugs, narcotics, corticosteroids, bronchodilators, 
IV fluids]; close observation for recurrence and treatment medications may need to 
be continued for 24-48 hours, and no further nivolumab will be administered at that 
visit.)   
 
Stop the nivolumab infusion, begin an IV infusion of normal saline, and treat the 
subject with diphenhydramine 50 mg IV (or equivalent) and/or paracetamol 325 to 
1000 mg (acetaminophen); remain at bedside and monitor patient until resolution 
of symptoms.  Corticosteroid or bronchodilator therapy may also be administered 

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as appropriate.  If the infusion is interrupted, then restart the infusion at 50% of the 
original infusion rate when symptoms resolve; if no further complications ensue 
after 30 minutes, the rate may be increased to 100% of the original infusion rate.  
Monitor patient closely.  If symptoms recur, re administer diphenhydramine 50 mg 
IV, and remain at bedside and monitor the patient until resolution of symptoms.  
The amount of study drug infused must be recorded on the electronic case report 
form (eCRF). 
 
The following prophylactic premedications are recommended for future infusions: 
diphenhydramine 50 mg (or equivalent) and (acetaminophen) (or paracetamol) 325 
to 1000 mg should be administered at least 30 minutes before additional nivolumab 
administrations.  If necessary, corticosteroids (recommended dose: up to 25 mg of 
IV hydrocortisone or equivalent) may be used. 
 
For Grade 3 or Grade 4 symptoms: (Severe reaction), 
 
Grade 3 symptoms: prolonged [i.e., not rapidly responsive to symptomatic 
medication and/or brief interruption of infusion]; recurrence of symptoms 
following initial improvement; hospitalization indicated for other clinical 
sequelae [e.g., renal impairment, pulmonary infiltrates]).   
 
Grade 4 symptoms: (life threatening; pressor or ventilatory support indicated).  
 
Nivolumab will be permanently discontinued. 
 
Immediately discontinue infusion of nivolumab.  Begin an IV infusion of normal 
saline, and bronchodilators, epinephrine 0.2 to 1 mg of a 1:1,000 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.  Patient should be 
monitored until the investigator is comfortable that the symptoms will not recur.   
 
Investigators should follow their institutional guidelines for the treatment of 
anaphylaxis.  Remain at bedside and monitor patient until recovery from symptoms.  
 
In the case of late-occurring hypersensitivity symptoms (e.g., appearance of a 
localized or generalized pruritus within 1 week after treatment), symptomatic 
treatment may be given (e.g., oral antihistamine, or corticosteroids).  Additional 
treatment prior to next dose as per guidelines above.  
 
Please note that late occurring events including isolated fever and fatigue may 
represent the presentation of systemic inflammation.  Please evaluate accordingly. 
  
5.5.2 Restricted Concomitant Therapies 
 
The following therapies are restricted: 

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• Concomitant use of statins while on study. However, a participant using statins 
for over 3 months prior to study drug administration and in stable status without 
CK rise may be permitted to enroll. 
• Receipt of a live/attenuated vaccine within 30 days of first treatment. The 
inactivated seasonal influenza vaccine can be given to participants before 
treatment and while on therapy without restriction. 
 
5.6 
Women of Childbearing Potential 
 
Women of childbearing potential (defined as women with regular menses, women with 
amenorrhea, women with irregular cycles, women using a contraceptive method that 
precludes withdrawal bleeding, and women who have had a tubal ligation) are required to 
have a negative pregnancy test within 14 days prior to the first dose of study treatment.   
 
Heterosexually active patients are required to use two forms of acceptable contraception, 
including one barrier method, during participation in the study and for 5 months following 
the last dose of any study treatment.  
 
If a patient is suspected to be pregnant, all study treatment should be immediately 
discontinued.  In addition a positive urine test must be confirmed by a serum pregnancy 
test.  If it is confirmed that the patient is not pregnant, the patient may resume dosing. 
 
If a patient becomes pregnant during therapy or within 5 months after the last dose of any 
study treatment, the investigator must be notified in order to facilitate outcome follow-up. 
 
5.7 
Duration of Therapy 
 
If at any time the constraints of this protocol are considered to be detrimental to the 
patient’s health and/or the patient no longer wishes to continue protocol therapy, the 
protocol therapy should be discontinued and the reason(s) for discontinuation documented 
in the case report forms. 
 
In the absence of treatment delays due to adverse events, treatment may continue for 12 
weeks or until one of the following criteria applies: 
 
• Documented and confirmed disease progression 
• Death 
• Adverse event(s) that, in the judgment of the investigator, may cause severe or 
permanent harm or which rule out continuation of study drug 
• General or specific changes in the patient’s condition render the patient unable to 
receive further treatment in the judgment of the investigator 
• Suspected pregnancy 
• Serious noncompliance with the study protocol 
• Lost to follow-up 
• Patient withdraws consent 

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• Investigator removes the patient from study 
• The Siteman Cancer Center decides to close the study 
 
Patients who prematurely discontinue treatment for any reason will still be followed as 
indicated in the study calendar. 
 
5.8 
Duration of Follow-up 
 
Patients will be followed for 3 years after discontinuation of treatment or until death, 
whichever occurs first.  Follow-up will be at 6 months and one year post-surgery and on 
an annual basis thereafter for an additional 2 years (3 years total).  Patients who come off 
study treatment prior to surgery will be followed for 100 days for adverse events and will 
continue to be followed for survival only.  Patients unable to complete all of the prescribed 
treatments due to an adverse event will be followed until resolution or stabilization of the 
adverse event and after will enter the follow up period as above. 
 
5.9 
Lost to Follow-Up 
 
A participant will be considered lost to follow-up if he or she fails to return for 3 scheduled 
visits and is unable to be contacted by the study team. 
 
The following actions must be taken if the participant fails to return to clinic for a required 
study visit: 
o The study team will attempt to contact the participant and reschedule the missed 
visit within 1 week and counsel the participant on the importance of maintaining 
the assigned visit schedule and ascertain if the participant wishes to and/or should 
continue in the study. 
o Before a participant is deemed lost to follow-up, the investigator or designee will 
make every effort to regain contact with the participant (where possible, 3 telephone 
calls and, if necessary, a certified letter to the participant’s last known mailing 
address).  These contact attempts should be documented in the participant’s medical 
record or study file. 
o Should the participant continue to be unreachable, he or she will be considered to 
have withdrawn from the study with a primary reason of lost to follow-up. 
 
 
6.0 
DOSE DELAYS/DOSE MODIFICATIONS 
 
Recommended dose holds and modifications for the standard of care neoadjuvant chemotherapy 
are described in Section 6.1, but additional modifications may be made at the discretion of the 
treating physician. 
 
If the AE requiring hold and/or discontinuation was due to one of the study drugs, the non-
offending drug(s) may be continued, at the discretion of the treating physician and PI. 
 

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Dose holds and modifications for paclitaxel, carboplatin, nivolumab and cabiralizumab (for the 
safety lead-in patients; cabiralizumab is not given to any patients enrolled after the safety lead-in) 
are specified in Sections 6.2 and 6.3.  Other holds and modifications may be made at the discretion 
of the treating physician and PI. 
 
Nivolumab and cabiralizumab will be held when paclitaxel and/or carboplatin are held.  If 
cabiralizumab is held, nivolumab and paclitaxel and/or carboplatin can continue. If there is a need 
to discontinue chemotherapy (such as due to severe hypersensitivity reaction), patients should 
continue to surgery. 
 
6.1 
Dosing Adjustments for Standard of Care Chemotherapy 
 
Paclitaxel Dose Levels 
Level 
Dose 
Starting Dose 
80 mg/m2 
Dose Level -1 
65 mg/m2 
Dose Level -2 
50 mg/m2 
Dose Level -3 
Discontinue 
 
Carboplatin Dose Levels 
Level 
Dose 
Starting Dose 
AUC 5 
Dose Level -1 
AUC 4 
Dose Level -2 
AUC 3 
Dose Level -3 
Discontinue 
 
Dose modifications must be based on the AE requiring the greatest modification.  
Chemotherapy doses that have been reduced may not be escalated.  Chemotherapy should 
be held for at least 1 week until any chemotherapy-related AE requiring dose modification 
returns to ≤ grade 1 unless indicated otherwise below.  If recovery to ≤ grade 1 (or to other 
level specified) has not occurred after 3 weeks of delay, therapy must be discontinued. 
 
CTCAE v 5.0 
grade 
Modifications for AEs that 
occurred between treatments but 
did NOT require a delay in 
treatment (for paclitaxel) or 
resolve prior to the next 
treatment cycle (for carboplatin); 
treatment may NOT proceed 
until clinically significant AEs are 
≤ grade 1 (except neutrophils, 
which must be ≥ 1000/mm3 and 
bilirubin, which must be ≤ the 
baseline grade) (in between 
treatments) 
Day of treatment: Modifications for 
AEs that require a delay in the next 
treatment; hold and check weekly, 
and resume treatment when toxicity 
is ≤ grade 1 (with the exception of 
neutrophils and bilirubin); if 
toxicity has not resolved to ≤ grade 
1 after 3 weeks of delay, 
DISCONTINUE PACLITAXEL 
AND CARBOPLATIN 
Neutrophil count decreased 

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Grade 2 
Maintain doses 
Maintain dose of paclitaxel.  
2nd occurrence – consider adding G-
CSF) 
 
 
Grades 3, 4 
• Hold paclitaxel until ANC ≥ 
1000/mm3.  Maintain dose of 
paclitaxel and add G-CSF (if 
already receiving G-CSF, reduce 
paclitaxel by one dose level). 
• Hold carboplatin until ANC ≥ 
1000/mm3. 
• If recovery takes 1 week, maintain 
dose of carboplatin and add G-
CSF. 
• If recovery takes 2 weeks, reduce 
carboplatin by one dose level and 
add G-CSF. 
• If recovery takes 3 weeks, 
discontinue carboplatin. 
• If already receiving G-CSF and 
recovery takes 1 week, reduce 
carboplatin by one dose level. 
• If already receiving G-CSF and 
recovery takes > 1 week, 
discontinue carboplatin. 
• For grade 4 toxicity. Resuming 
treatment after discussion with the 
research team 
Platelet count decreased 
Grades 2, 3 
Maintain doses 
• Hold both until platelets ≥ 
75,000/mm3. 
• If recovery takes 1 week, maintain 
dose of paclitaxel and reduce 
carboplatin by one dose level. 
• If recovery takes > 1 week, reduce 
paclitaxel by one dose level and 
reduce carboplatin by two dose 
levels or discontinue. 
Grade 4 
Discontinue treatment 
Discontinue treatment 
Anemia 
Grade 3, 4 
Hold until > or equal to grade 2.  Transfusion is acceptable for improving the 
hemoglobin value to allow therapy to continue without delay. The patient 
should be assessed to rule out other causes of anemia. Use of erythropoiesis-
stimulating agents is prohibited. 

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For grade 4 toxicity. Resuming treatment after discussion with the research 
team 
Diarrhea (if related to chemotherapy) 
Grade 2 
 
(despite full 
anti-diarrhea 
therapy) 
Maintain doses 
Maintain paclitaxel dose or reduce by 
one dose level.  Reduce carboplatin by 
one dose level. 
(Consider stool leukocytes and 
infectious workup). 
Grade 3 
(despite full 
anti-diarrhea 
therapy) 
Reduce both by one dose level 
Grade 4 
Hold, initiate workup. If not due to autoimmune component – treat as per 
standard of care and resume when equal to or better than grade 3. Reduce 
paclitaxel by one dose level or discontinue.  Reduce carboplatin by two dose 
levels or discontinue. Resuming treatment after discussion with the research 
team 
Mucositis – oral (if related to chemotherapy) 
Grade 2 
Maintain doses 
Maintain paclitaxel dose or reduce by 
one dose level.  Reduce carboplatin by 
one dose level. 
Grade 3 
Hold until equal to or better than grade 2. Reduce both by one dose level 
Grade 4 
Hold until equal to or better than grade 2. Reduce paclitaxel by one dose 
level or discontinue.  Reduce carboplatin by two dose levels or discontinue. 
Resuming treatment after discussion with the research team 
Vomiting (if related to chemotherapy and despite antiemetics) 
Grade 2 
Maintain doses or reduce both by one dose level  (preferred modification is 
to add anti-nausea medications to pre-treatment) 
Grades 3, 4 
Reduce both by one dose level or 
discontinue 
For grade 4 toxicity. Resuming 
treatment after discussion with the 
research team 
Hold until equal to or better than grade 
2. Modify pre-treatment anti-nausea 
medications as per standard of care. 
Reduce paclitaxel by one dose level or 
discontinue.  Reduce carboplatin by 
two dose levels or discontinue. 
For grade 4 toxicity. Resuming 
treatment after discussion with the 
research team 
Elevation in AST/alkaline phosphatase and/or bilirubin 
Grade 2 
Maintain doses or reduce both by 
one dose level. 
Hold until bilirubin returns to the 
baseline grade and AST and alk phos 
have returned to ≤ grade 1, consider 
reducing either paclitaxel and/or 
carboplatin by one dose level 
Grade 3 
Consider reducing paclitaxel by one 
dose level or discontinue.  
Hold until bilirubin returns to the 
baseline grade and AST and alk phos 
have returned to ≤ grade 1, then 

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Reducing carboplatin by one dose 
level or discontinue. 
reduce paclitaxel by one dose level or 
discontinue and reduce carboplatin by 
two dose levels or discontinue. 
Grade 4 
Discontinue both. 
Infection or febrile neutropenia 
Grade 2 
Consider hold if clinically indicated. Maintain doses and add G-CSF 
prophylaxis for subsequent chemotherapy cycles if neutropenia was present.  
(If grade 2 criteria for infection include topical antibiotics or other local 
treatment, use of G-CSF is at the investigator’s discretion.) 
Grade 3 
Hold until resolves to grade 2 or better. Maintain doses and add G-CSF 
prophylaxis for subsequent chemotherapy cycles.  If receiving prophylactic 
G-CSF, reduce both by one dose level. 
Grade 4 
Hold until resolves to grade 2 or better. Maintain doses or reduce both by 
one dose level and add G-CSF prophylaxis for subsequent chemotherapy 
cycles.  If receiving prophylactic G-CSF, reduce both by one dose level or 
discontinue. 
Creatinine increased 
Grades 2, 3 
Hold until creatinine ≤ grade 1 or less than or equal 1.5 X baseline. Resume 
paclitaxel at same dose level. 
Hold carboplatin until serum creatinine is ≤ grade 1 equal 1.5 X baseline 
AND measured or calculated creatinine clearance is ≥ 30 mL/min. If 
creatinine clearance is > 50 mL/min, maintain dose of carboplatin.  If 
creatinine clearance is 30-50 mL/min, reduce carboplatin by one dose level. 
If measured or calculated creatinine clearance is < 30 mL/min but all other 
non-renal function AEs have resolved to ≤ grade 1 on the scheduled Day 1, 
carboplatin must be held.  If measured or calculated creatinine clearance 
subsequently improves to ≥ 30 mL/min, carboplatin may be resumed.  The 
missed carboplatin dose will not be made up. 
Grade 4 
Hold until creatinine ≤ grade 1 or less than or equal 1.5 X baseline. 
Resuming treatment after discussion with the research team. Maintain 
paclitaxel.  Discontinue carboplatin. 
Other clinically significant AEs related to chemotherapy (at the discretion of the 
investigator)*** for CK elevations please refer to CK table  
Grade 2 
Hold until grade 1 or better. Maintain doses or reduce both by one dose level 
Grade 3 
Hold until grade 1 or better. Reduce both by one dose level 
Grade 4 
Hold until grade 1 or better. Reduce paclitaxel by one dose level or 
discontinue.  Reduce carboplatin by two dose levels or discontinue.  
Resuming treatment after discussion with the research team and safety 
committee. 
 
Treatment management for paclitaxel-related neuropathy 
Nervous System 
Disorders 
(Paresthesias, 
peripheral sensory 
neuropathy) 
1-7 days duration 
Persistent for > 7 days OR caused the 
next treatment to be delayed 

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Grade 1 
Maintain dose 
Grade 2 
Maintain dose (must be 
resolved to ≤ grade 1 on 
the next treatment day) 
Continue treatment. Consider reducing by 
one dose level treatment with dose 
modification for paclitaxel. Stop therapy as 
clinically indicated.  
Grade 3 
First episode: 
Reduce by one dose 
level (must be resolved 
to ≤ grade 1 on the next 
treatment day) 
Second episode: 
Discontinue paclitaxel 
Discontinue paclitaxel 
Grade 4 
Discontinue paclitaxel 
 
Treatment management for paclitaxel-related musculoskeletal pain 
Musculoskeletal and 
Connective Tissue 
Disorders 
(Arthralgia, 
myalgia) 
1-7 days duration 
Persistent for > 7 days OR caused the next 
treatment to be delayed 
Grade 1 
Maintain dose 
 
Grade 2 
Maintain dose 
Maintain dose or reduce by one dose level 
(hold paclitaxel and carboplatin for persistent 
grade 2 musculoskeletal pain (despite opioid 
therapy); Persistent pain – consider workup for 
myositis. When ≤ grade 1, resume treatment 
with dose modification for paclitaxel but no 
dose modification for carboplatin. If grade 2 
toxicity persists after 3 weeks of delay, 
discontinue all chemotherapy) 
Grade 3  (despite 
opioid therapy) 
First episode: 
Reduce by one dose 
level 
Second episode: 
Reduce by 1 dose 
level or Consider 
discontinuing 
paclitaxel 
First episode 
Reduce by one dose level or discontinue (hold 
paclitaxel and carboplatin for persistent grade 
3 musculoskeletal pain; when ≤ grade 1, 
resume treatment with dose modification for 
paclitaxel but no dose modification for 
carboplatin. If grade 3 toxicity persists after 3 
weeks of delay, discontinue all chemotherapy) 
Second episode 
Discontinue paclitaxel 
Note: these instructions only apply to patients with musculoskeletal pain not controlled by 
analgesics.  Use of narcotics and NSAIDs is encouraged to maintain the paclitaxel dose if 
possible. 
 
Other treatment management instructions 

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• If a paclitaxel-related hypersensitivity reaction occurs despite premedication, treatment as 
medically indicated will be instituted.  For ≤ grade 3 allergic reaction or grade 3 
anaphylaxis, continuation of paclitaxel is at the investigator’s discretion.  Following a 
grade 4 allergic reaction or grade 4 anaphylaxis, paclitaxel must be permanently 
discontinued. Can be changed to nab-paclitaxel as per institutional standards. 
• Carboplatin must be permanently discontinued if a grade 3 or 4 hypersensitivity reaction 
occurs that the investigator attributes to carboplatin. 
• Paclitaxel and carboplatin must be completed within 18 weeks.  Any of the 12 paclitaxel 
doses or 4 carboplatin doses remaining after 18 weeks following the first paclitaxel and 
carboplatin doses should not be administered. 
 
6.2 
Dosing Adjustments for Nivolumab 
 
Please refer to Appendix B for toxicity management algorithms which include specific 
treatment guidelines.  However, there are algorithms in this section that may be different 
from Appendix B.  In these cases, please follow the protocol specific dose modification 
guidelines in this section unless there are specific clinical circumstances for which the 
treating physician decides an alternative treatment approach is clinically appropriate. These 
treatment guidelines apply to adverse events that are attributed to nivolumab per treating 
physician. Laboratory abnormalities or adverse events that per treating physician are 
related to chemotherapy and/or cabiralizumab do not require modification in nivolumab 
dosing or schedule.  Consultation with the study PI is recommended.  
 
Generally, we strongly encourage early evaluation while withholding drug, and appropriate 
treatment as indicated in the management tables and event specific guidelines. 
 
Cardiac *   
Management/Next Dose for Nivolumab Cardiac Toxicities  
Less than 
grade 2 
Hold all treatments pending evaluation and observation.**  Evaluate for 
signs and symptoms of CHF, ischemia, arrhythmia or myositis.  Obtain 
history EKG, CK (for concomitant myositis), CK-MB.  Repeat troponin, 
CK and EKG 2-3 days.  If troponin and labs normalize without evidence 
of myocarditis may resume therapy.   If labs worsen or symptoms 
develop then treat as below.   
Grade >2  
Hold all treatements.**  Admit to hospital.  Cardiology consult.  Rule out 
MI and other causes of cardiac disease.  Cardiac Monitoring.  Cardiac 
Echo.  Consider cardiac MRI and cardiac biopsy.  Initiate high dose 
methylprednisolone and immune suppression as clinically indicated. If no 
improvement within 24 hours consider adding either infliximab, ATG or 
tacrolimus. May resume therapy if it was asymptomatic troponin raise 
and there is a return to baseline and myocarditis is excluded or considered 
unlikely. Other asymptomatic abnormalities can also be considered for 
resumption of therapy after consultation with research team. 

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Cardiac *   
Management/Next Dose for Nivolumab Cardiac Toxicities  
Grade >2 
with 
confirmed 
myocarditis  
Off protocol therapy.  Admit to CCU (consider transfer to nearest Cardiac 
Transplant Unit).  Treat as above.  Consider high dose 
methylprednisolone   
Add ATG or tacrolimus if no improvement.   Off protocol treatment. 
*Including CHF, LV systolic dysfunction, Myocarditis, , and troponin **Patients with 
evidence of myositis without myocarditis may be treated according as “other event”   
Note:  The optimal treatment regimen for immune mediated myocarditis has not been 
established.  Since this toxicity has caused patient deaths, an aggressive approach is 
recommended.   
   
 
ALL OTHER 
EVENTS NOT 
OTHERWISE 
NOTED 
Management/Next Dose for Nivolumab  
Grade 1 
No change in dose  
Grade 2 
Hold until ≤ Grade 1 OR baseline (exceptions as noted below)     
Grade 3 
 Off protocol therapy (exceptions as noted below)   
Grade 4 
Off protocol therapy 
Recommended management:  As clinically indicated  
 
o Any grade 2 drug-related uveitis or 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 should go off protocol treatment  
o Any Grade 3 or 4 drug-related laboratory abnormality or electrolyte abnormality, 
that can be managed independently from underlying organ pathology with 
electrolyte replacement, hormone replacement, insulin or that does not require 
treatment does not require discontinuation.   
o Any AE, laboratory abnormality, or intercurrent illness which, in the judgment of 
the investigator, presents a substantial clinical risk to the subject with continued 
study drug dosing should go off protocol treatment.  
 
Skin Rash and Oral 
Lesions 
Management/Next Dose for Nivolumab 
Grade 1 
No change in dose * 
Grade 2 
Hold* until ≤ Grade 1 .  Resume at same dose.  
Grade 3 
Hold* until ≤ Grade 1.  Resume at investigator discretion  
Grade 4 
Off protocol therapy 
*Patients with purpuric or bullous lesions must be evaluated for vasculitis, Steven-Johnson 
syndrome, toxic epidermal necrolysis (TEN), and autoimmune bullous disease including oral 
lesions of bullous pemphigus/pemphagoid.  Pruritus may occur with or without skin rash and 
should be treated symptomatically if there is no associated liver or GI toxicity.  Note skin rash 
typically occurs early and may be followed by additional events particularly during steroids 
tapering.   

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Recommended management:  AE management guidelines 
 
 
Liver Function 
AST, ALT, and 
Bilirubin elevation   
Management/Next Dose for Nivolumab 
Grade 1 
Consider holding if rapid raise and no alternative explanation 
likely until ULN or baseline.   Resume at same dose. 
Grade 2 
Hold until grade 1 (ULN – 3x ULN) or baseline and resume at 
same dose at investigator discretion.  
Grade 3 
Hold until grade 1 or baseline.  Resume therapy at investigator 
discretion with return to grade 1 or baseline within 7 days 
without steroids. If determined it was due to nivolumab and 
AST/ALT were > 8 X ULN and/or bilirubin was > 3 X ULN 
permanently discontinue.  If persistent or steroids are required, 
off protocol therapy. 
Grade 4 
Off protocol therapy 
Continued treatment of active immune mediated hepatitis may exacerbate ongoing 
inflammation.  Holding drug to evaluate liver function test (LFT) changes and early treatment 
are recommended.   
LFT changes may occur during steroid tapers from other events and may occur together with 
other GI events including cholecystitis/pancreatitis.  
Please note: grades for liver function follow ULN rather than multiples of baseline. 
Recommended management:  see Hepatic AE management algorithm 
 
 
Diarrhea/ Colitis  
Management/Next Dose for Nivolumab 
Grade 1 
May continue – close monitoring of symptoms recommended. 
Consider workup for infectious causes. 
Grade 2 
Hold until baseline. Resume at investigator discretion if resolved 
to grade 1 within 7 days without steroids and no evidence of 
colitis.  
Grade 3 
Resume treatment at investigator discretion if resolved to grade 
1 within 7 days without steroids and no evidence of colitis.  If 
persistent or steroids are required, may consider resuming if 
symptoms resolve and steroids equivalent to < or equal to 10 mg 
of prednisone a day. 
Grade 4 
Off protocol therapy 
See GI AE Algorithm for management of symptomatic colitis.  
Patients with grade 2 symptoms but normal colonoscopy and biopsies may be retreated.  
Patients who require systemic steroids may consider resuming if all symptoms have resolved 
after steroid taper.  
 Please evaluate pituitary function prior to starting steroids if possible without compromising 
acute care.   
Evaluation for all patients for additional causes includes C. diff, acute and self-limited infectious 
and foodborne illness, ischemic bowel, diverticulitis, and IBD.  
Recommended management:  see GI AE management Algorithm 

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Pancreatitis 
Amylase/Lipase  
Management/Next Dose for Nivolumab 
Grade 1 
Continue treatment if asymptomatic at investigator discretion 
Grade 2 
Continue treatment if asymptomatic at investigator discretion.  If 
symptomatic, resume treatment when resolved. 
Grade 3 
Continue treatment if asymptomatic at investigator discretion. 
Patients should have imaging study when clinically indicated (if 
grade 3 symptomatic pancreatitis is confirmed – stop nivolumab 
permanently) before resuming treatment.  Workup for diabetes 
indicated. 
Grade 4 
Hold until grade 2.  Resume if asymptomatic. Patients who are 
symptomatic should have imaging study prior to resuming 
treatment and when clinically indicated.  Patients who develop 
grade 3 or 4 symptomatic pancreatitis stop nivolumab 
permanently. 
Patients may develop symptomatic and radiologic evidence of pancreatitis as well as diabetes 
mellitus and diabetes ketoacidosis.  Lipase elevation may occur during the period of steroid 
withdrawal and with other immune mediated events or associated with colitis, hepatitis, and 
patients who have asymptomatic lipase elevation typically have self-limited course and may be 
retreated.  
For treatment management of symptomatic pancreatitis please follow the Hepatic AE 
Management Algorithm  
 
 
Pneumonitis 
Management/Next Dose for Nivolumab 
Grade 1 
Hold dose pending evaluation, consider pulmonary consult. 
Continue treatment as clinically indicated.  
Grade 2 
Hold dose pending evaluation. Resume no change in dose after 
pulmonary and/or ID consultation excludes lymphocytic 
pneumonitis as the cause of the pneumonitis. Stop nivolumab 
permanently if prolonged (> 4 weeks) steroids are required. 
Grade 3 
Hold dose pending evaluation. Resume no change in dose after 
pulmonary and/or ID consultation excludes lymphocytic 
pneumonitis as the cause of the pneumonitis. If cause is likely 
autoimmune pneumonitis stop nivolumab permanently. 
Grade 4 
Off protocol therapy 
Distinguishing inflammatory pneumonitis is often a diagnosis of exclusion for patients who do 
not respond to antibiotics and have no causal organism identified including influenza. All 
patients should have COVID testing. Most patients with respiratory failure or hypoxia will be 
treated with steroids.  Bronchoscopy may be required and analysis of lavage fluid for 
lymphocytic predominance may be helpful.  Patients with new lung nodules should be evaluated 
for sarcoid like granuloma.  Please consider recommending seasonal influenza killed vaccine 
for all patients. 
Recommended management:  See Pulmonary AE Management Algorithm  

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Fatigue  
Management/Next Dose for Nivolumab 
Grade 2 
No change in dose 
Grade 3 
Hold until ≤ Grade 2.  Resume treatment at discretion of 
investigator.  
Grade 4 
Nivolumab permanently discontinued 
Fatigue is the most common AE associated with immune checkpoint therapy.  Grade 2 
or greater fatigue should be evaluated for associated or underlying organ involvement 
including pituitary, thyroid, and hepatic, or muscle (CPK) inflammation  
 
 
Neurologic events  
Management/Next Dose for Nivolumab 
Grade 1 
Hold dose pending evaluation and observation. Resume with no 
change in dose when resolved to baseline. .  
Grade 2 
Hold dose pending evaluation and observation. Hold until ≤ 
Grade 1. Nivolumab to be permanently discontinued if 
prolonged (>4 weeks) treatment with steroids is required.  
Resume at same dose level for peripheral isolated n. VII (Bell’s 
palsy) 
Grade 3 
Off protocol therapy  
Grade 4 
Off protocol therapy  
Patients with any CNS events including aseptic meningitis, encephalitis, symptomatic 
hypophysitis, or myopathy, peripheral demyelinating neuropathy, cranial neuropathy 
(other than peripheral n. VII), GB syndrome, myasthenia gravis should be off study.   
Recommended management:  See Neurologic AE Management Algorithm  
 
 
Endocrine 
Hypophysitis 
Adrenal 
Insufficiency  
Management/Next Dose for Nivolumab 
Grade 1 
*Hold pending evaluation for evidence of adrenal insufficiency 
or hypophysitis.  Asymptomatic thyroid stimulating hormone 
(TSH) elevation may continue treatment while evaluating the 
need for thyroid replacement. 
Grade 2 
Hold pending evaluation and may resume while on replacement 
hormone regimen.  Asymptomatic thyroid stimulating hormone 
(TSH) elevation may continue treatment with initiation of 
replacement therapy. If treated with steroids patients must be 
stable off steroids prior to resumption of therapy. Resume 
treatment.   
Grade 3 
Hold until patients are on a stable replacement hormone 
regimen.  If treated with steroids, patients must be stable off 
steroids.  

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Endocrine 
Hypophysitis 
Adrenal 
Insufficiency  
Management/Next Dose for Nivolumab 
Resume treatment. 
Grade 4 
Hold until patients are on a stable replacement hormone 
regimen.  If treated with steroids, patients must be stable off 
steroids.  
Consider resuming treatment. 
Note all patients with symptomatic pituitary enlargement, exclusive of hormone deficiency, but 
including severe headache or enlarged pituitary on MRI should be considered grade 3 events.  
Isolated thyroid or testosterone deficiency may be treated as grade 2 if there are no other 
associated deficiencies and adrenal function is monitored.  
Please evaluate pituitary function before beginning steroid therapy or replacement therapy of 
any kind.  
*Note patients with thyroiditis may be retreated on replacement therapy.  Patients must be 
evaluated to rule out pituitary disease prior to initiating thyroid replacement. 
Recommended management: See Endocrine Management Algorithm  
 
 
Renal   
Management/Next Dose for Nivolumab 
Grade 1 
Monitor closely and continue therapy. 
Grade 2 
Hold until ≤ Grade 1.  Resume treatment. 
Grade 3 
Hold until ≤ Grade 1.  Resume at discretion of investigator.  
Grade 4 
Off treatment 
 
 
 
Infusion reaction  
Management/Next Dose for Nivolumab 
Grade 1 
Monitor closely and continue therapy. 
Grade 2 
Hold until ≤ Grade 1.  Resume treatment  
Grade 3 
Hold until ≤ Grade 1.  Resume treatment at discretion of 
investigator.  
Grade 4 
Off treatment 
See Treatment of Nivolumab-Related Infusion 
 
 
Fever  
Management/Next Dose for Nivolumab 
Grade 1 
Evaluate and continue at same dose level 
Grade 2 
Hold until ≤ Grade 1.  Resume treatment.  
Grade 3 
Hold until ≤ Grade 1.  Resume treatment. 
Grade 4 
Off treatment 
Patients with fever should be evaluated as clinically appropriate.  Patients may experience 
isolated fever during infusion reactions or up to several days after infusion.  Evaluation over the 
course of 1-2 weeks should be done for other autoimmune events that may present as fever  
 

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o Any patients who require additional immune suppressive treatment beyond steroids 
should go off study treatment.  
o Prior to starting corticosteroids or hormone replacement for any reason, 
appropriate endocrine testing including cortisol, Cortrosyn® adrenocorticotrophic 
hormone (ACTH), thyroid stimulating hormone (TSH), and thyroxine (T4) must 
be obtained to document baseline.   
o Please note that in some cases the treatment algorithms recommend steroids if 
symptoms do not resolve in 7 days.  However, this recommendation is not meant to 
delay steroid treatment at any time it is clinically indicated. 
o Any patient started on corticosteroids initially, who is determined to not require steroid 
treatment for an autoimmune AE, may resume therapy after a 2-week observation 
period without further symptoms at the discretion of the PI or investigator.  
 
6.3 
Dose discontinuation criteria for nivolumab 
 
Treatment with nivolumab should be discontinued in the 
following cases unless otherwise specified: 
 
• Any Grade 3 or higher infusion-related reactions. Any re-initiation of therapy in this 
circumstance would require consultation with the PI. 
 
• Any Grade 4 drug-related AE 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 < 7 days 
o Isolated Grade 4 amylase or lipase abnormalities that are not associated with 
symptoms or clinical manifestations of pancreatitis.  
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 
 
• Any drug-related clinically significant adverse event that leads to delay in dosing 
lasting > 6 weeks from the previous dose requires discontinuation.  
 
• Any AE, laboratory abnormality, or intercurrent illness which, in the opinion of the 
investigator, presents a substantial clinical risk to the participant with continued 
cabiralizumab and/or nivolumab dosing 
 
 
7.0 
REGULATORY AND REPORTING REQUIREMENTS 
 
The entities providing oversight of safety and compliance with the protocol require reporting as 
outlined below.  Please refer to Appendix C for definitions and Appendix D for a grid of reporting 
timelines. 
 

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Adverse events will be tracked from date of consent through 100 days after the last day of study 
treatment or until time of surgery, whichever occurs first.  All adverse events must be recorded on 
the toxicity tracking case report form (CRF) with the exception of: 
• Baseline adverse events, which shall be recorded on the medical history CRF 
• AEs related to surgery 
• Grade 1 and 2 hypertension 
 
Refer to the data submission schedule in Section 11 for instructions on the collection of AEs in the 
EDC. 
 
Reporting requirements for Washington University study team may be found in Section 8.1.   
 
7.1 
Sponsor-Investigator Reporting Requirements 
 
7.1.1 Reporting to the Human Research Protection Office (HRPO) at 
Washington University 
 
Reporting will be conducted in accordance with Washington University IRB 
Policies. 
 
Pre-approval of all protocol exceptions must be obtained prior to implementing the 
change. 
 
7.1.2 Reporting to the Quality Assurance and Safety Monitoring 
Committee (QASMC) at Washington University 
 
The Sponsor Investigator (or designee) is required to notify the QASMC of any 
unanticipated problems involving risks to participants or others occurring at WU or 
any BJH or SLCH institution that has been reported to and acknowledged by 
HRPO.  (Unanticipated problems reported to HRPO and withdrawn during the 
review process need not be reported to QASMC.) 
 
QASMC must be notified within 10 days of receipt of IRB acknowledgment via 
email to qasmc@wustl.edu.  Submission to QASMC must include the myIRB form 
and any supporting documentation sent with the form. 
 
7.1.3 Reporting to Bristol Myers Squibb 
 
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 the BMS Protocol Manager prior to study initiation to 
ensure that at a minimum all of the data elements on the CIOMS form are present.  
Note:  Please include the BMS Protocol number on the SAE form or on the  cover 
sheet with the SAE form transmission.   
• The CIOMS form is available at: http://www.cioms.ch/index.php/cioms-
form-i  

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• The MedWatch form is available at: MedWatch 3500 Form  
 
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.  BMS will perform due 
diligence follow-up using the BMS Pregnancy Form which the investigator must 
complete.  
 
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. 
 
The causal relationship to study drug is determined by a physician and should be 
used to assess all adverse events (AE). 
 
Adverse Events that are routinely collected according to GCP shall be submitted to 
BMS every three (3) months by the last working day of the third month. 
   
The Adverse Event information required to be sent to BMS is noted in Appendix 
D.  It should be sent to MG-RD-GPVE-PHARMACOVIGILANCE@bms.com. 
 
When the file is submitted to BMS, it must be noted the file contains all non-serious 
adverse events (only adverse events not previously submitted to BMS within the 3 
months). 
 
7.1.3.1 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 (eg, dose tapering if 
necessary for participant).  
 

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The investigator must immediately notify Worldwide.Safety@bms.com of 
this event and complete one of the following forms within 24 hours of 
awareness of the 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. 
 
7.1.4 Reporting to the FDA 
 
The conduct of the study will comply with all FDA safety reporting requirements.  
PLEASE NOTE THAT REPORTING REQUIREMENTS FOR THE FDA 
DIFFER FROM REPORTING REQUIREMENTS FOR HRPO/QASMC.  It 
is the responsibility of the Sponsor-Investigator to report to the FDA as follows: 
 
• Report any unexpected fatal or life-threatening suspected adverse reaction 
(refer to Appendix C for definitions) no later than 7 calendar days after 
initial receipt of the information.   
• Report a suspected adverse reaction that is both serious and unexpected 
(SUSAR, refer to Appendix C) no later than 15 calendar days after it is 
determined that the information qualifies for reporting.  Report an adverse 
event (refer to Appendix C) as a suspected adverse reaction only if there is 
evidence to suggest a causal relationship between the drug and the adverse 
event, such as: 
o A single occurrence of an event that is uncommon and known to be 
strongly associated with drug exposure 
o One or more occurrences of an event that is not commonly associated 
with drug exposure but is otherwise uncommon in the population 
exposed to the drug 
o An aggregate analysis of specific events observed in a clinical trial that 
indicates those events occur more frequently in the drug treatment 
group than in a concurrent or historical control group 

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• Report any findings from epidemiological studies, pooled analysis of 
multiple studies, or clinical studies that suggest a significant risk in humans 
exposed to the drug no later than 15 calendar days after it is determined 
that the information qualifies for reporting. 
• Report any findings from animal or in vitro testing that suggest significant 
risk in humans exposed to the drug no later than 15 calendar days after it 
is determined that the information qualifies for reporting.  
• Report any clinically important increase in the rate of a serious suspected 
adverse reaction of that listed in the protocol or IB within 15 calendar days 
after it is determined that the information qualifies for reporting. 
 
Submit each report as an IND safety report in a narrative format or on FDA Form 
3500A or in an electronic format that FDA can process, review, and archive.  Study 
teams must notify the Siteman Cancer Center Protocol Development team of each 
potentially reportable event within 1 business day after initial receipt of the 
information, and must bring the signed 1571 and FDA Form 3500A to the Siteman 
Cancer Center Protocol Development team no later than 1 business day prior to the 
due date for reporting to the FDA. 
 
Each notification to FDA must bear prominent identification of its contents (“IND 
Safety Report”) and must be transmitted to the review division in the Center for 
Drug Evaluation and Research (CDER) or in the Center for Biologics Evaluation 
and Research (CBER) that has responsibility for review of the IND.  Relevant 
follow-up information to an IND safety report must be submitted as soon as the 
information is available and must be identified as such (“Follow-up IND Safety 
Report”). 
 
7.2 
Exceptions to Expedited Reporting 
 
Events that do not require expedited reporting as described in Section 8.1 include: 
• planned hospitalizations 
• hospitalizations < 24 hours 
• respite care 
• events related to disease progression 
 
Events that do not require expedited reporting must still be captured in the EDC. 
 
 
8.0 
PHARMACEUTICAL INFORMATION 
 
Table 9 
CA025-018 Study treatments  
Product 
Description / 
Class and 
Dosage Form 
Potency/Route of 
Administration 
Blinded or 
Open Label 
IMP or non-
IMP 
Packaging / 
Appearance 
Storage 
Conditions 
(Per Label) * 

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Table 9 
CA025-018 Study treatments  
Nivolumab 
(BMS-936558-
01) 
Solution for 
Injection 
100 mg 
(10 mg/mL) 
Open label 
IMP 
Vial 
Refer to the 
label on 
container 
Nivolumab  
(BMS-936558-
01) Solution for 
Injection 
40 mg 
(10 mg/mL) 
Open label 
IMP 
Vial 
Refer to the 
label on 
container 
Cabiralizumab 
(BMS-986227) 
Solution for 
Injection 
100 mg 
(20 mg/mL) 
Open label 
IMP 
Vial 
Refer to the 
label on 
container 
Cabiralizumab 
(BMS-986227) 
Solution for 
Injection 
140 mg 
(20 mg/mL) 
Open label 
IMP 
Vial 
Refer to the 
label on 
container 
Paclitaxel 
 
 
Non-IMP ** 
 
 
Carboplatin 
 
 
Non_IMP ** 
 
 
 
* Please refer to the current version of the Investigator Brochures for complete preparation, 
storage, and handling information. 
 
** Paclitaxel and Carboplatin should   be obtained by the investigating site’s standard prescribing 
procedures. 
 
8.1 
Paclitaxel 
 
8.1.1 Product Description 
 
Paclitaxel is obtained via a semi-synthetic process from Taxus baccata. The 
chemical name for paclitaxel is 5β,20-Epoxy-1,2α,4,7β,10β,13α-hexahydroxytax-
11-en-9-one 4,10-diacetate 2-benzoate 13-ester with (2R,3S)-N-benzoyl-3-
phenylisoserine. Paclitaxel Injection, USP is a clear, colorless to slightly yellow 
viscous solution. It is supplied as a nonaqueous solution intended for dilution with 
a suitable parenteral fluid prior to intravenous infusion. Paclitaxel Injection, USP 
is available in 30 mg (5 mL), 100 mg (16.7 mL), and 300 mg (50 mL) multidose 
vials. Each mL of sterile nonpyrogenic solution contains 6 mg paclitaxel, USP, 527 
mg of purified polyoxyl 35 castor oil, and 49.7% (v/v) dehydrated alcohol, USP. 
 
8.1.2 Solution Preparation 
 
Please refer to the package insert for standard preparation instructions. 

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8.1.3 Route of administration 
 
Contact of the undiluted concentrate with plasticized PVC equipment or devices 
used to prepare solutions for infusion is not recommended. In order to minimize 
patient exposure to the plasticizer DEHP [di-(2-ethylhexyl)phthalate], which may 
be leached from PVC infusion bags or sets, diluted paclitaxel solutions should be 
stored in bottles (glass, polypropylene) or plastic bags (polypropylene, polyolefin) 
and administered through polyethylene-lined administration sets. 
 
Administer paclitaxel as an IV infusion over 1 hour. 
 
8.1.4 Agent ordering 
 
Paclitaxel is commercially available. 
 
8.1.5 Prescribing Information 
 
Please refer to the package insert for full prescribing information on paclitaxel. 
 
8.2 
Carboplatin 
 
8.2.1 Formulation 
 
Carboplatin Injection is supplied as a sterile, pyrogen-free, 10 mg/mL aqueous 
solution of carboplatin, USP. Carboplatin, USP is a platinum coordination 
compound. The chemical name for carboplatin, USP is platinum diamine [1,1-
cyclobutanedicarboxylato(2-)-0,0’]-,(SP-4-2). Carboplatin, USP is a crystalline 
powder. It is soluble in water at a rate of approximately 14 mg/mL, and the pH of 
a 1% solution is 5 to 7. It is virtually insoluble in ethanol, acetone, and 
dimethylacetamide. 
 
Each mL of carboplatin injection contains 10 mg of carboplatin, USP in water for 
injection and is available as a 60 mL multidose vial. 
 
8.2.2 Storage 
 
Unopened vials of carboplatin injection are stable to the date indicated on the 
package when stored at 20° to 25°C (68° to 77°F). 
 
PROTECT FROM LIGHT. 
 
Carboplatin injection multidose vials maintain microbial, chemical, and physical 
stability for up to 14 days at 25°C following multiple needle entries. 
 

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Parenteral drug products should be inspected visually for particulate matter and 
discoloration prior to administration. Solutions for infusion should be discarded 8 
hours after preparation. 
 
8.2.3 Preparation 
 
Carboplatin Injection is a premixed aqueous solution of 10 mg/mL carboplatin. 
 
Carboplatin aqueous solution can be further diluted to concentrations as low as 0.5 
mg/mL with 5% Dextrose in Water (D5W) or 0.9% Sodium Chloride Injection, 
USP. 
 
When prepared as directed, carboplatin aqueous solutions are stable for 8 hours at 
room temperature. Since no antibacterial preservative is contained in the 
formulation, it is recommended that carboplatin aqueous solutions be discarded 8 
hours after dilution. 
 
8.2.4 Route of Administration 
 
Contact of the undiluted concentrate with plasticized PVC equipment or devices 
used to prepare solutions for infusion is not recommended. In order to minimize 
patient exposure to the plasticizer DEHP [di-(2-ethylhexyl)phthalate], which may 
be leached from PVC infusion bags or sets, diluted paclitaxel solutions should be 
stored in bottles (glass, polypropylene) or plastic bags (polypropylene, polyolefin) 
and administered through polyethylene-lined administration sets. 
 
Administer paclitaxel as an IV infusion over 1 hour. 
 
8.2.5 Agent ordering 
 
Carboplatin is commercially available. 
 
8.2.6 Prescribing Information 
 
Please refer to the package insert for full prescribing information on carboplatin. 
 
8.3 
Nivolumab 
 
8.3.1 Nivolumab Description 
 
Nivolumab is a programmed death receptor-1 (PD-1) blocking antibody indicated 
for the treatment of: 
 
• patients with unresectable or metastatic melanoma, as a single agent or in 
combination with ipilimumab 

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• patients with melanoma with lymph node involvement or metastatic disease 
who have undergone complete resection, in the adjuvant setting 
• patients with metastatic non-small cell lung cancer and progression on or 
after platinum-based chemotherapy  
• patients with metastatic small cell lung cancer with progression after 
platinum-based chemotherapy and at least one other line of therapy 
• patients with advanced renal cell carcinoma who have received prior 
antiangiogenic therapy 
• patients with intermediate or poor risk, previously untreated advanced renal 
cell carcinoma, in combination with ipilimumab 
• adult patients with classical Hodgkin lymphoma that has relapsed or 
progressed after:  
 autologous hematopoietic stem cell transplantation (HSCT) and 
brentuximab vedotin, or  
 3 or more lines of systemic therapy that includes autologous HSCT  
• patients with recurrent or metastatic squamous cell carcinoma of the head 
and neck with disease progression on or after a platinum-based therapy 
• patients with locally advanced or metastatic urothelial carcinoma who:  
 have disease progression during or following platinum-containing 
chemotherapy  
 have disease progression within 12 months of neoadjuvant or adjuvant 
treatment with platinum-containing chemotherapy 
• adult and pediatric (12 years and older) patients with microsatellite 
instability-high (MSI-H) or mismatch repair deficient (dMMR) metastatic 
colorectal cancer that has progressed following treatment with a 
fluoropyrimidine, oxaliplatin, and irinotecan, as a single agent or in 
combination with ipilimumab 
• patients with hepatocellular carcinoma who have been previously treated 
• with sorafenib 
 
It is a human monoclonal antibody that blocks the interaction between PD-1 and its 
ligands, PD-L1 and PD-L2.  Nivolumab is an IgG4 kappa immunoglobulin that has 
a calculated molecular mass of 146 kDa. 
 
8.3.2 Clinical Pharmacology 
 
Binding of the PD-1 ligands, PD-L1 and PD-L2, to the PD-1 receptor found on T 
cells, inhibits T-cell proliferation and cytokine production. Upregulation of PD-1 
ligands occurs in some tumors and signaling through this pathway can contribute 
to inhibition of active T-cell immune surveillance of tumors. Nivolumab is a human 
immunoglobulin G4 (IgG4) monoclonal antibody that binds to the PD-1 receptor 
and blocks its interaction with PD-L1 and PD-L2, releasing PD-1 pathway-
mediated inhibition of the immune response, including the anti-tumor immune 
response. In syngeneic mouse tumor models, blocking PD-1 activity resulted in 
decreased tumor growth. 
 

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8.3.3 Pharmacokinetics and Drug Metabolism 
 
The pharmacokinetics (PK) of nivolumab was studied in patients 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 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) 
(CV%) is 6.8 L (27.3%), and geometric mean elimination half-life is 25 days 
(77.5%).  Steady-state concentrations of nivolumab were reached by 12 weeks 
when administered at 3 mg/kg every 2 weeks, and systemic accumulation was 
approximately 3-fold. The exposure to nivolumab increased dose proportionally 
over the dose range of 0.1 to 10 mg/kg administered every 2 weeks. 
 
8.3.4 Supplier 
 
Nivolumab will be supplied by Bristol Myers Squibb. 
 
8.3.5 Dosage Form and Preparation 
 
Nivolumab will be provided either as a 100 mg/10 mL (10 mg/mL) solution in a 
single-use vial or a 40 mg/4 mL solution in a single-use vial. 
 
• Withdraw the required volume of nivolumab and transfer into an 
intravenous container. 
• Dilute nivolumab with either 0.9% Sodium Chloride Injection, USP or 5% 
Dextrose Injection, USP, to prepare an infusion with a final concentration 
ranging from 1 mg/mL to 10 mg/mL. 
• Mix diluted solution by gentle inversion. Do not shake. 
• Discard partially used vials or empty vials of nivolumab. 
 
8.3.6 Storage and Stability 
 
The product does not contain a preservative. 
 
After preparation, store the nivolumab infusion either: 
• at room temperature for no more than 8 hours from the time of preparation. 
This includes room temperature storage of the infusion in the IV container 
and time for administration of the infusion or 
• under refrigeration at 2°C to 8°C (36°F-46°F) for no more than 24 hours 
from the time of infusion preparation. 
 
Do not freeze. 
 

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8.3.7 Administration 
 
Administer the infusion over 30 minutes through an intravenous line containing a 
sterile, nonpyrogenic, low protein binding in-line filter (pore size of 0.2 micrometer 
to 1.2 micrometer). 
 
Do not coadminister other drugs through the same intravenous line. 
 
Flush the intravenous line at end of infusion. 
 
8.4 
Cabiralizumab 
 
Note that no patients enrolled after implementation of Amendment 7 (following the 
conclusion of the safety lead-in) will receive cabiralizumab. 
 
8.4.1 Cabiralizumab Description 
 
Cabiralizumab is a polypeptide that comprises of 2 heavy chains and 2 light chains 
and is a recombinant, humanized IgG4 monoclonal antibody that targets human 
CSF1R. Cabiralizumab is produced from cell culture using a Chinese Hamster 
Ovary (CHO) cell line. 
 
8.4.2 Clinical Pharmacology 
 
Cabiralizumab is a recombinant, humanized IgG4 mAb that binds to human 
CSF1R. Binding of cabiralizumab to CSF1R antagonizes binding of CSF1 and 
IL34, the 2 ligands to CSF1R, thereby preventing activation of CSF1R. 
Cabiralizumab contains a single amino acid substitution in the hinge region to 
prevent hemi-dimer exchange. 
 
8.4.3 Pharmacokinetics and Drug Metabolism 
 
No in vitro or in vivo metabolism studies have been conducted using cabiralizumab. 
In accordance with the regulatory guidelines for biotechnology-derived 
pharmaceuticals, the expected in vivo degradation of mAbs is to small peptides and 
amino acids via biochemical pathways that are generally understood and 
independent of typical small-molecule drug-metabolizing enzymes. 
 
8.4.4 Supplier(s) 
 
Cabiralizumab will be provided by Bristol Myers Squibb. 
 
8.4.5 Dosage Form and Preparation 
 
The 2 formulations of cabiralizumab injection available for clinical use are as 
described below. 

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Cabiralizumab Injection, 100 mg/Vial (20 mg/mL) (Formulation 2) 
Cabiralizumab injection is a colorless to pale yellow liquid, clear to slightly 
opalescent, light (few) particulates (consistent in appearance to protein particulates) 
may be present. The drug product is a sterile, nonpyrogenic, single-use, isotonic 
aqueous solution formulated at 20 mg/mL in L-histidine, L-histidine hydrochloride 
monohydrate, sucrose, edetate disodium dihydrate, polysorbate 80, and water for 
injection at pH 6.5. Diluted solutions of hydrochloric acid and/or sodium hydroxide 
maybe used for pH adjustment. The drug product includes a 0.58-mL overfill to 
account for vial, needle, and syringe holdup. It is supplied in a 5-cc Type I flint 
glass vial, stoppered with a fluoropolymer film-laminated rubber stopper, and 
sealed with aluminum seal. 
 
Cabiralizumab Injection, 140 mg/Vial (20 mg/mL) 
Cabiralizumab injection is a colorless to pale yellow liquid, clear to slightly 
opalescent, light (few) particulates (consistent in appearance to protein particulates) 
may be present. The drug product is a sterile, nonpyrogenic, single-use, isotonic 
aqueous solution formulated at 20 mg/mL in L-histidine, L-histidine hydrochloride 
monohydrate, sucrose, edetate disodium dihydrate, polysorbate 80, and water for 
injection at pH 6.2-7.0. Diluted solutions of hydrochloric acid and/or sodium 
hydroxide maybe used for pH adjustment. The drug product includes a 0.6-mL 
overfill to account for vial, needle, and syringe holdup. It is supplied in a 10-cc 
Type I flint glass vial, stoppered with a fluoropolymer film-laminated rubber 
stopper, and sealed with aluminum seal. 
 
Cabiralizumab injection is to be administered as an IV infusion through a low-
protein-binding polyethersulfone membrane, 0.2-µm in-line filter at the protocol-
specified doses and infusion times. Cabiralizumab injection can be infused 
undiluted (20 mg/mL) or diluted with 0.9% sodium chloride injection or 5% 
dextrose injection to protein concentrations as low as 1.0 mg/mL. During drug 
product preparation and handling, vigorous mixing or shaking is to be avoided. 
Detailed instructions for drug product dilution and administration are provided in 
the pharmacy manual for the clinical study. 
 
For both formulations, care must be taken to ensure sterility of the prepared solution 
because the product does not contain any antimicrobial preservative or 
bacteriostatic agent. No incompatibilities between cabiralizumab injection and 
PVC or polyolefin infusion bags with DEHP-free infusion sets have been observed. 
 
8.4.6 Storage and Stability 
 
Cabiralizumab Injections 
Vials of cabiralizumab injections must be stored at 2°C to 8°C (36°F to 46°F), 
protected from light, and must not be frozen. 
 

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Undiluted Cabiralizumab Injections and Diluted Cabiralizumab Injections in the IV 
Bag 
The administration of cabiralizumab 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, protected 
from light and a maximum of 4 hours of the total 24 hours can be at room 
temperature (20°C to 25°C, 68°F to 77°F) and room light. The maximum 4-hour 
period under room temperature and room light conditions includes the product 
administration period. 
 
8.4.7 Administration 
 
Refer to Section 6.3. 
 
 
9.0 
CORRELATIVE STUDIES 
 
To assess the effects of cabiralizumab in combination with chemotherapy and nivolumab on the 
tumor, blood and bone marrow microenvironment of patients with triple-negative breast cancer as 
measured by: 
a. Correlation of TILs (CD8+), TAMs (CD163+), CSF-1R+ cells content with clinical 
activity (CSF-1R+ biomarker, CXCR-1 expression, and other M1 and M2 CD206, 
Iba1 biomarkers to assess target engagement of cabiralizumab for patients who 
participated in the safety lead-in only).  
b. Tumor infiltrating lymphocytes (TILs) pre, during and post therapy. Intra tumoral T cell 
composition (CD8/CD4 ratio) pretreatment and on-treatment (4-weeks of therapy). We 
expect the CD8/CD4 ratio to increase with treatment.  
c. Tumor associated macrophages (TAMs) pre, during and post therapy.  
d. Correlation of immunosuppressive cytokine levels secreted by TAMs with TAM content, 
TILs and response to therapy.  
e. Correlation of other tumor associated immune cells with treatment response 
f. Analysis of nonclassical and classical monocyte content in peripheral blood  
          
From the breast tumor, bone marrow and peripheral blood samples, we will determine: 
 
• Breast Tumor Tissue:  
o M2 TAM content (CD68+/CD163+, CSF1R+) by IHC (CSF-1R+ biomarker for 
patients who participated in the safety lead-in only) 
o TILs and PD-L1 levels by IHC 
o CD4+ and CD8+ TIL content by histology.  
o FoxP3+ T regulatory cells and dendritic cell (DC) content by IHC.  
o Detailed tumor, immune cell and stromal cell characteristics could be obtained at each 
time point using sophisticated imaging analysis.  Multiplexed fluorescence microscopy 
(MxIF) system developed for quantitative, single-cell, and subcellular characterization 
of multiple analytes in single FFPE tissue. MxIF will address tumor-microenvironment 

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heterogeneity while the integration of MxIF with clinical data will provide a 
comprehensive picture on treatment responses. 
 
• Bone Marrow Aspirate:  
o MDSC and DC content by flow cytometry 
o Disseminated tumor cell (DTC) gene signature   
 
• Peripheral Blood: 
o CSF1, IL-34, IL-8, other cytokines (ELISA). Plasma CSF-1 and IL-34 concentrations 
are expected to increase with cabiralizumab treatment. (CSF-1R+ biomarker for 
patients who participated in the safety lead-in only) 
o Non-classical monocytes (CD14+ CD16++) by flow cytometry. Nonclassical 
monocytes are expected to decrease after cabiralizumab treatment. Classical 
CD14+CD16- monocytes are not expected to change substantially. (CSF-1R+ 
biomarker for patients who participated in the safety lead-in only) 
o Circulating T lymphocytes, MDSC and DC by flow cytometry 
o Circulating tumor cells 
o Circulating tumor DNA 
o Bone turnover biomarkers 
o Storage for future studies 
 
Expression profiling correlative endpoints 
1. 
Cryopreserved bone marrow and tissue biopsies will be subjected to bulk DNA/RNA 
sequencing to access cell composition and mutational burden. 
2. 
Cryo-preserved bone marrow and fresh biopsies will be subjected to single cell RNAseq to 
determine immune cell compositions. 
 
9.1 
Tumor Biopsy 
 
9.1.1 Collection of Specimens 
 
Research biopsies will be performed at baseline, Week 5, definitive surgery, and at 
time of relapse (optional). If a patient discontinues protocol therapy and receives 
SOC neoadjuvant therapy prior to surgery, the bone marrow, tissue and blood 
should not be collected.  If a patient discontinues protocol therapy due to toxicity 
and/or other reasons and does not receive SOC neoadjuvant therapy, the bone 
marrow, tissue and blood should be collected.  Guidelines are below. 
 
9.1.2 Tumor Biopsies 
 
Four cores (with a 14-gauge needle) of tumor tissue will be collected at pre-
treatment (preferable at the time of port-a-cath placement), on-treatment at week 5 
and at the time of surgery.  Biopsies will be performed at pre-treatment and on-
treatment (week 5). At surgery, the cores will be collected from the surgical 
specimen. At time of recurrence a biopsy will be collected (optional).  
 

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Baseline 
During screening, preferably at same time as port-a-cath 
placement 
Week 5 
On-treatment biopsy after 2 cycles of nivolumab +/- 
cabiralizumab. 
Surgery 
At the time of definitive surgery. Cores will be collected 
from the surgical specimen. 
Disease 
Progression  
Optional 
 
9.1.3 Handling of Specimens  
 
Four cores will be collected at each time point and processed as described below: 
 
1) First Core—in 10% formalin and TPC creates FFPE block for IHC analysis of 
immune cells 
2) Second Core— placedin media and put on wet ice  and transported to 
investigators lab (DeNardo)   
3) Third Core—in saline for snap freezing at the TPC for possible use in 
proteomics 
4) Fourth Core—in saline for cell dissociation and cryopreservation of cells for 
banking/future use at by TPC.  
     
All samples should be taken to the Siteman Cancer Center Tissue Procurement Core 
(TPC) for processing, assignment of accession number and storage until time of 
analysis:  
 
Siteman Cancer Center Tissue Procurement Facility 
425 S. Euclid Ave., Rm 5120 
St. Louis, MO 63110 
Phone: 314-454-7615 
Fax: 314-454-5525 
Email: tbank@pathology.wustl.edu 
 
9.1.4 Specimen Storage 
 
After processing, FFPE, fresh and frozen cores will be stored at the TPC until time 
of analysis.  
 
9.2 
Bone Marrow 
 
9.2.1 Collection of Specimens 
 
Two EDTA tubes (10 mL each) of bone marrow aspirate will be collected, 1 tube 
from each iliac crest at the following time points:  
 
• Time of port placement (baseline) 

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• Time of surgery 
• Disease progression (optional) 
 
9.2.2 Handling of Specimens 
 
Specimens will be handled per instructions on the TPC submission forms using the 
TPC SOP or per the Aft lab SOPs. 
 
9.2.3 Specimen Storage 
 
Specimen storage will be addressed per instructions in the TPC submission forms 
using the TPC SOP or per the Aft lab SOPs. 
 
9.3 
Blood Draw 
 
9.3.1 Collection of Specimens 
 
Four EDTA tubes each containing 8-10 mL of blood and 1 red/tiger top tube 
(without additive or gel) containing 5-10 mL of blood will be collected at the 
following time points: 
 
Time point 
Instructions 
Tube type(s) 
Blood volumes 
Baseline 
Prior to Week 1 treatment 
4 EDTA tubes 
 
 
1 red/tiger top 
tube (without 
additive or gel) 
8-10 mL blood 
each 
 
5-10 mL blood 
each 
Week 2 
Prior to Week 2 treatment 
3 EDTA tubes 
8-10 mL blood 
each 
Week 3 
Prior to Week 3 treatment 
3 EDTA tubes 
8-10 mL blood 
each 
Week 5 
After 4 weeks of chemo + 
nivolumab +/- 
cabiralizumab +/- 3 days 
of mandatory tumor 
biopsy 
4 EDTA tubes 
 
 
1 red/tiger top 
tube (without 
additive or gel) 
8-10 mL blood 
each 
 
5-10 mL blood 
each 
Week 10 
Prior to Week 10 
treatment 
3 EDTA tubes 
8-10 mL blood 
each 
Prior to 
surgery 
After completion of 
treatment prior to surgery 
(no more than 7 days prior 
to time of surgery) 
4 EDTA tubes 
 
 
1 red/tiger top 
tube (without 
additive or gel) 
8-10 mL blood 
each 
 
5-10 mL blood 
each 

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Post-surgery 
follow-up 
At standard of care post- 
surgery follow-up 
appointment typically 3-4 
weeks post-surgery but 
may be shorter or longer. 
4 EDTA tubes 
 
 
1 red/tiger top 
tube (without 
additive or gel) 
8-10 mL blood 
each 
 
5-10 mL blood 
each 
Disease 
progression  
Optional 
4 EDTA tubes 
 
 
1 red/tiger top 
tube (without 
additive or gel) 
8-10 mL blood 
each 
 
5-10 mL blood 
each 
 
9.3.2 Handling of Specimens 
 
Specimens will be handled per instructions TPC or Aft lab SOPs. 
  
 
10.0 
DATA SUBMISSION SCHEDULE 
 
Case report forms with appropriate source documentation will be completed according to the 
schedule listed in this section. 
 
 
Case Report Form 
Submission Schedule 
Original Consent Form 
Prior to registration 
On-Study Form 
Medical History Form 
Prior to starting treatment 
Treatment Form 
Weekly 
Toxicity Form 
Continuous 
Treatment Summary Form 
Completion of treatment 
Surgery Form 
Time of surgery 
Correlatives Form 
Baseline, Week 2, Week 3, Week 5, Week 10, time of 
surgery, post-surgery follow-up (blood draw only),time 
of recurrence 
Follow Up Form 
6 months and 12 months after surgery, Year 2, Year 3, 
Year 4, Year 5 
MedWatch Form 
See Section 7.0 for reporting requirements 
Progression Form 
Time of progression 
Death Form 
Time of death 
 

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10.1 
Adverse Event Collection in the Case Report Forms 
 
All adverse events that occur beginning with start of treatment (minus exceptions defined 
in Section 7.0) must be captured in the Toxicity Form.  Baseline AEs should be captured 
on the Medical History Form. 
 
Participant death due to disease progression should be reported on the Toxicity Form as 
grade 5 disease progression.  If death is due to an AE (e.g. cardiac disorders: cardiac arrest), 
report as a grade 5 event under that AE.  Participant death must also be recorded on the 
Death Form. 
 
10.2 
Concomitant Medication Collection in the Case Report Forms 
 
All concomitant medications should be recorded for the first six patients enrolled to each 
arm. Beginning with enrollment with the seventh patient of each arm only medications 
taken regularly are required to be collected.  
 
 
11.0 
MEASUREMENT OF EFFECT 
 
11.1 
Surgery 
 
A pathologic complete response (pCR) is defined as no histology evidence of invasive 
tumor cells in the surgical breast specimen and sentinel or axillary lymph nodes. 
 
11.2 
Post-surgery 
 
Local recurrence is defined as histologic evidence of ductal carcinoma in situ or invasive 
breast cancer in the ipsilateral breast or chest wall. 
 
Regional recurrence is defined as the cytologic or histologic evidence of disease in the 
ipsilateral internal mammary, ipsilateral supraclavicular, ipsilateral infraclavicular and/or 
ipsilateral axillary nodes or soft tissue of the ipsilateral axilla. 
 
Distant recurrence is defined as the cytologic, histologic, and/or radiographic evidence of 
disease in the skin, subcutaneous tissue, lymph nodes (other than local or regional 
metastasis), lung, bone narrow, central nervous system or histologic and/or radiographic 
evidence of skeletal or liver metastasis. 
 
Second primary breast cancer is defined histologic evidence of ductal carcinoma in situ or 
invasive breast cancer in the contralateral breast or chest wall. 
 
Second primary cancer (non-breast) is defined as any non-breast second primary cancer 
other than squamous or basal cell carcinoma of the skin, melanoma in situ, or carcinoma 
in situ of the cervix is to be reported and should be confirmed histologically whenever 
possible. 

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12.0 
DATA AND SAFETY MONITORING 
 
In compliance with the Washington University Institutional Data and Safety Monitoring Plan, the 
Principal Investigator will provide a Data and Safety Monitoring (DSM) report to the Washington 
University Quality Assurance and Safety Monitoring Committee (QASMC) semi-annually 
beginning six months after accrual has opened (if at least one patient has been enrolled) or one 
year after accrual has opened (if no patients have been enrolled at the six-month mark). 
 
The Principal Investigator will review all patient data at least every six months, and provide a 
semi-annual report to the QASMC. This report will include: 
• HRPO protocol number, protocol title, Principal Investigator name, data coordinator 
name, regulatory coordinator name, and statistician 
• Date of initial HRPO approval, date of most recent consent HRPO approval/revision, 
date of HRPO expiration, date of most recent QA audit, study status, and phase of study 
• History of study including summary of substantive amendments; summary of accrual 
suspensions including start/stop dates and reason; and summary of protocol exceptions, 
error, or breach of confidentiality including start/stop dates and reason 
• Study-wide target accrual and study-wide actual accrual 
• Protocol activation date 
• Average rate of accrual observed in year 1, year 2, and subsequent years 
• Expected accrual end date and accrual by cohort 
• Objectives of protocol with supporting data and list the number of participants who 
have met each objective 
• Measures of efficacy 
• Early stopping rules with supporting data and list the number of participants who have 
met the early stopping rules 
• Summary of toxicities separated by cohorts 
• Abstract submissions/publications 
• Summary of any recent literature that may affect the safety or ethics of the study  
 
The study principal investigator and Research Patient Coordinator will monitor for serious 
toxicities on an ongoing basis. Once the principal investigator or Research Patient Coordinator 
becomes aware of an adverse event, the AE will be reported to the HRPO and QASMC according 
to institutional guidelines. 
 
 
13.0 
STATISTICAL CONSIDERATIONS 
 
13.1 
Study Design 
 
As of July 1, 2022, 12 patients have been enrolled to the study in the safety lead-in. Due to 
the expiration of cabiralizumab, Amendment 7 was activated to remove the cabiralizumab 

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arm. Accordingly, the statistical considerations of the protocol have been changed as 
follows: 
 
The original design of a phase II randomized two-arm study has been updated to a 
phase II single arm study where a total of N=25 eligible and primary-endpoint 
evaluable patients with clinical stage II/III TNBC will receive SOC chemo + 
nivolumab.  The primary endpoint remains the same (percent change of on-treatment 
TAMs from baseline and percent change of on-treatment TILs from baseline), but there 
will no longer be a comparison between TAM and TIL percent change between patients 
who receive cabiralizumab and patients who don’t.  
 
As of July 1, 2022, 6 evaluable patients have been enrolled to the SOC chemo + 
nivolumab arm (and 6 patients were enrolled to the now-discontinued cabiralizumab 
arm).  Following the approval and activation of Amendment 7, we will continue to 
recruit an additional 19 evaluable patients (for a total of N=25 evaluable patients) 
to the SOC chemo + nivolumab arm in this study.  
 
13.2 
Objectives 
 
The primary objective is to compare on-treatment TAMs and TILs (Week 5) against their 
baseline levels. It is hypothesized that the on-treatment TAMs and TILs will improve 
compared with baseline levels with reduced TAMs and increased TILs post treatment. 
 
The secondary objectives are: 
• to estimate the pCR rate in this study 
• to determine recurrence-free survival 
• to estimate the grade 3 or higher treatment related adverse event (AE) rate 
• to compare TAM and TILs percent change between patients who achieve pCR vs. 
those who didn’t.  It is hypothesized that patients who do not achieve pCR may 
have increasing TAMs or/and reduced TILs.  
 
13.3 
Endpoints 
 
The co-primary endpoints are percent (%) change of on-treatment TAMs from baseline and 
percent (%) change of on-treatment TILs from baseline. Stromal TIL score is defined as 
the percentage of tumor stroma area that was occupied by mononuclear inflammatory cells. 
 
The secondary endpoints include: 
• pathological complete response (pCR) rate 
• adverse events, especially grade 3 or higher treatment related AE rate 
• recurrence-free survival (RFS), defined from date of surgery to the earliest time of 
recurrence, time to development of a second cancer, or time of death from any 
cause. 
  
13.4 
Statistical hypothesis 
 

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The overall alpha level is set at 5% and we evenly split the alpha level on TAM and TILs, 
each with alpha=2.5%. 
 
We will simultaneously test the following hypotheses for the primary endpoint TAM. 
 
H1: reduction in % change of on-treatment TAMs ≠ 0 
 
vs.  
 
H0: reduction in % change of on-treatment TAMs = 0  
 
  
and for TILs,  
 
H1: increase in % change of on-treatment TILs ≠ 0 
 
vs.  
 
H0: increase in % change of on-treatment TILs = 0  
 
  
13.5 
Sample size for the primary endpoint 
 
A one-stage design based on one-sample normal test was used to achieve 80% power at 
alpha=2.5% for each of the two co-primary endpoints for the phase II single arm study to 
test the on-treatment vs. baseline TAM and TIL percentage change against a null value of 
0.   
 
 
According to Loi (2019 JCO), the average (SD) of stromal TILs and intratumor TILs at 
diagnosis is 0.23 (0.2) and 0.053 (0.1), respectively, for TNBC patients at time of diagnosis. 
Chemotherapy has been reported to decrease TILs. We assume that on-treatment stromal 
TILs in Arm A has a mean (SD) of 0.2 (0.3).  
 
According to Ries et al (Figure 6B top panel on TAM marker CD68+/CD163+, 2019 
Cancer Cell), the % change from BL of TAM was estimated at around -0.57 with a standard 
deviation (SD) around 0.28, under the treatment of chemo plus anti-CSF-1R inhibitor.   
 
We conservatively assume an averaged percent change of on treatment TAM from baseline 
is about -20% with a SD of 0.3. Similarly, the TILs % change from baseline is expected at 
least 20% with a SD of 0.3. N=25 patients allows 81.98% power to test an averaged percent 
change of on treatment TAMs from baseline estimated about -20% and an averaged percent 
change of on treatment TILs from baseline estimated about 20%,  assuming a standard 
deviation of 0.3, based on simultaneous 2-sided 1-sample normal test at alpha=2.5%.   
 
The 6 patients enrolled in Arm A (chemo + nivolumab) during the safety lead-in are 
included towards the total N=25 evaluable patients enrolled to this study and thus we need 
to enroll an additional 19 patients after approval and activation of Amendment 7. 

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13.6 
Sample size for the secondary endpoint pCR rate 
 
The total sample size of N=25 allows to estimate a hypothesized pCR rate of 0.55 for this 
study with a 95% CI of 0.362~0.725. 
 
13.7 
Sample size for comparing TAM and TILs percentage change by pCR status 
 
For the secondary objective of comparing % change of TAMs and TILs between patients 
with pCR versus non-pCR, we hypothesize that patients with non-pCR have higher % 
change of TAMs or/and lower % change of TILs at on-treatment relative to baseline, when 
compared with patients with pCR. We expect among N=25, 12/13 patients with/without 
pCR, allowing 80% power to detect a mean difference effect size of 1.17 for either TAM 
or TILS between the two patient groups, based on 2-sided 2-sample normal test at 
alpha=5%. 
 
13.8 
Data analysis 
 
All data on the chemo+nivolumab treatment group will be analyzed as recorded and no 
data imputation will be performed. Baseline demographic, clinical-pathological and lab 
tests will be summarized using summary statistics. For summary statistics, continuous 
variables will be summarized with mean/median and standard deviation/inter-quartile 
range at each time point. Qualitative variables will be summarized by counts and 
percentages.  
 
Data from the 6 patients enrolled in the discontinued Arm B (chemo + nivolumab + 
cabiralizumab) during the safety lead-in will be analyzed as described in Section 13.8.9. 
 
13.8.1 Baseline Characteristics and Demographic Variables 
 
Demographic data (e.g., age, gender, race, height, weight and ethnicity), medical 
history, prior treatments, and baseline disease characteristics, including primary 
tumor location, stage of disease and performance status, will be summarized among 
all or by patient subsets (e.g.,pCR vs. non-pCR). 
 
13.8.2 Data Analysis for TAMs and TILs 
 
TAM and TILs at baseline and post treatment will be separately summarized by 
descriptive statistics including mean, median, interquartile range, standard 
deviation, overall and by pCR status. For testing the percent change of on-treatment 
TAMs and on-treatment TILs from baseline, the paired sample t-test or Wilcoxon 
signed rank sum will be used as proper. For TAM and TILs percent change 
difference between pCR vs. non-pCR, two sample t-test or Wilcoxon rank sum test 
will be used as proper. 
 
13.8.3 Data Analysis for grade 3 or higher treatment related AE rate 

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The toxicity profiles will be graded according to CTCAE v5 and listed by organ 
class. Worst grade toxicity will be tabulated as counts and frequencies, overall, by 
grades and by patient characteristics. Rate of grade 3 or higher all type and immune-
related toxicities relevant to the study drugs will be calculated with 95% exact 
Clopper-Pearson confidence interval (CI) overall and by patient subset and will be 
compared between patients subset by Fisher’s exact test. The grade 3 or higher 
treatment related AE rate (or equivalently, the grade 3 or higher treatment related 
AE free rate) will be estimated with 95% Wilson-type CI and tested against the null 
rate of 75% by 1-sample proportion test based on normal approximation.  
 
13.8.4 Data Analysis for pCR 
 
The pCR rate will be estimated with 95% Wilson-type CI.  
 
 
 
13.8.5 Data Analysis for the DTC elimination and BM status 
 
DTC elimination rate at time point from BL will be calculated as the percentage of 
BL DTC+ patients who achieved DTC- on or after neoadjuvant treatment at 
surgery. BM test positive rate will be calculated as % of patients whose bone 
marrow sample tested positive. DTC elimination rate and BM rate will be 
calculated at each post-treatment time point, overall and by patient subset 
separately, accompanied with 95% exact Clopper-Pearson CI. Fisher’s exact test 
will be used to compare the rate difference.   
 
13.8.6 Data Analysis for the RFS 
 
RFS will be analyzed by the Kaplan-Meier method to estimate empirical survival 
probability overall and median PFS with 95% Brookmeyer and Crowley confidence 
intervals. The survival difference between patient subsets will be compared by log 
rank test. The covariate-adjusted Cox proportional hazard model will be applied to 
estimate the hazard ratio between patient groups when other covariates (classical 
demographic and clinic-pathological variables for breast cancer) are considered.  
 
13.8.7 Correlative study data analysis 
 
Median curve with 95% CI will be derived for the pre, during and post-treatment 
TAMs and TILs. TILs and  TAMs at pre, during and post-treatment will be each 
summarized by descriptive statistics and each, as well % change, will be compared 
between patient subsets (e.g., pCR vs. residual disease) by two sample t-test or 
Wilcoxon rank sum test as appropriate. TILs and TAMs between time points will 
be compared by paired sample t-test or Wilcoxon signed rank test as appropriate. 
Inflammatory gene expression data will be compared by two sample t-test or 
Wilcoxon rank sum test as appropriate. Across time points, TILs and TAMs will 

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each be integratively analyzed by linear mixed effects model fitting TILs or TAMs 
on patient characteristics, treatment response and potentially their interactions. 
Multiple testing will be controlled for false discovery rate. TIL/TAM ratios will be 
derived and similarly analyzed. 
 
13.8.8 Analysis of TAMs and TILs on Arm B patients 
 
For the 6 patients already enrolled to the discontinued SOC chemo + nivolumab + 
cabiralizumab arm, we will summarize the toxicity data as previously described for 
the SOC + nivolumab treatment patients. TAMs and TILs will be summarized by 
descriptive statistics as appropriate.  
 
13.9 
Futility monitoring plan  
 
There is no futility stopping rule due to the initial signal of efficacy for the first 6 patients 
enrolled in the nivolumab + chemotherapy arm and recent pCR data with a similar neoadjuvant 
regimen65. 
13.10 Safety stopping rule  
 
Given the safety results from KEYNOTE-522, safety concerns mandating early stopping 
of the trial are not expected, as this study will only use two chemotherapeutic drugs while 
KEYNOTE-522 used four chemotherapeutic drugs.  
 
Further, all grade 2 and 3 immune-related adverse events in addition to all grade 4 and 5 
adverse events will be reviewed at each regularly scheduled study conference call. In the 
event of any concerns related to excessive treatment-related adverse events, enrollment 
will be temporarily discontinued and all available data on adverse events will be assessed 
by a review committee in order to make a recommendation of continuation of accrual, 
suspension followed by formal amendment and reactivation, or study closure. 
 
13.11 Definitions of Study Populations for Analysis 
 
13.11.1Safety Population 
 
The safety population will consist of all subjects who receive any amount of study 
immunotherapy drug. Analyses based on safety population will be performed 
according to the actual treatment received for the length of the study. Data handling 
rules for subjects in the experimental/control arm who received incorrect study 
treatment will be described in the SAP. 
 
13.11.2 pCR evaluable patients 
 
Patients are evaluable if patients satisfy inclusion criteria and have pCR results 
(either had surgery or have documented disease progression prior to surgery). 
 
13.11.3 TAM and TILs evaluable patients 

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Patients are considered evaluable for the primary objective if they satisfy eligibility 
criteria, have received at least 2 doses of the total immunotherapeutic drug dosage, 
and have valid baseline and on-treatment TAMs and TILs measurements for a 
percent change evaluation of TAMs and TILs.  
 
 

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We would like to thank the Alvin J. Siteman Cancer Center at Washington University School of 
Medicine and Barnes-Jewish Hospital in St. Louis, Missouri, for the use of the Clinical Trials Core 
which provided protocol development services. The Siteman Cancer Center is supported in part 
by an NCI Cancer Center Support Grant #P30 CA91842. 
 
 

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APPENDIX A: ECOG Performance Status Scale 
 
 
Grade 
 
 
Description 
0 
Normal activity.  Fully active, able to carry on all pre-disease 
performance without restriction. 
1 
Symptoms, but ambulatory.  Restricted in physically strenuous 
activity, but ambulatory and able to carry out work of a light or 
sedentary nature (e.g., light housework, office work). 
2 
In bed <50% of the time.  Ambulatory and capable of all self-care, but 
unable to carry out any work activities.  Up and about more than 50% 
of waking hours. 
3 
 
In bed >50% of the time.  Capable of only limited self-care, confined 
to bed or chair more than 50% of waking hours. 
 
4 
100% bedridden.  Completely disabled.  Cannot carry on any self-care.  
Totally confined to bed or chair. 
5 
 
Dead. 
 
 
 
 

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APPENDIX B: Management Algorithms for Endocrinopathy, Gastrointestinal, Hepatic, 
Neurological, Pulmonary, Renal, and Skin Adverse Events 
 
 
 
 

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APPENDIX C: Definitions for Adverse Event Reporting 
 
A. Adverse Events (AEs) 
 
As defined in 21 CFR 312.32: 
 
Definition: any untoward medical occurrence associated with the use of a drug in humans, 
whether or not considered drug-related. 
 
Grading: the descriptions and grading scales found in the revised NCI Common Terminology 
Criteria for Adverse Events (CTCAE) version 5.0 will be utilized for all toxicity reporting.  A 
copy of the CTCAE version 5.0 can be downloaded from the CTEP website. 
 
Attribution (relatedness), Expectedness, and Seriousness: the definitions for the terms 
listed that should be used are those provided by the Department of Health and Human Services’ 
Office for Human Research Protections (OHRP).  A copy of this guidance can be found on 
OHRP’s website: 
http://www.hhs.gov/ohrp/policy/advevntguid.html 
 
B. Suspected Adverse Reaction (SAR) 
 
As defined in 21 CFR 312.32: 
 
Definition: any adverse event for which there is a reasonable possibility that the drug caused 
the adverse event.  “Reasonable possibility” means there is evidence to suggest a causal 
relationship between the drug and the adverse event.  “Suspected adverse reaction” implies a 
lesser degree of certainty about causality than adverse reaction, which means any adverse event 
caused by a drug. 
 
C. Life-Threatening Adverse Event / Life Threatening Suspected Adverse Reaction  
 
As defined in 21 CFR 312.32: 
 
Definition: any adverse drug event or suspected adverse reaction is considered “life-
threatening” if, in the view of the investigator, its occurrence places the patient at immediate 
risk of death. It does not include an adverse event or suspected adverse reaction that, had it 
occurred in a more severe form, might have caused death. 
 
D.  Serious Adverse Event (SAE) or Serious Suspected Adverse Reaction 
 
As defined in 21 CFR 312.32: 
 
Definition:  an adverse event or suspected adverse reaction is considered “serious” if, in the 
view of the investigator, it results in any of the following outcomes: 
o Death 
o A life-threatening adverse event 

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o Inpatient hospitalization or prolongation of existing hospitalization 
o A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions 
o A congenital anomaly/birth defect 
o Any other important medical event that does not fit the criteria above but, based upon 
appropriate medical judgment, may jeopardize the subject and may require medical or 
surgical intervention to prevent one of the outcomes listed above 
 
E. Protocol Exceptions 
 
Definition: A planned change in the conduct of the research for one participant. 
 
F. Deviation 
 
Definition: Any alteration or modification to the IRB-approved research without prospective 
IRB approval.  The term “research” encompasses all IRB-approved materials and documents 
including the detailed protocol, IRB application, consent form, recruitment materials, 
questionnaires/data collection forms, and any other information relating to the research study. 
 
A minor or administrative deviation is one that does not have the potential to negatively impact 
the rights, safety, or welfare of participants or others or the scientific validity of the study. 
 
A major deviation is one that does have the potential to negatively impact the rights, safety, 
or welfare of participants or others or the scientific validity of the study. 
 
G. Potential Drug-Induced Liver Injury 
 
Definition: Potential drug induced liver injury is defined as:  
1. AT (ALT or AST) elevation > 3 times upper limit of normal (ULN) 
AND 
2. Total bilirubin > 2 times ULN, without initial findings of cholestasis (elevated serum 
alkaline phosphatase) 
AND 
3. No other immediately apparent possible causes of AT elevation and 
hyperbilirubinemia, including, but not limited to, viral hepatitis, pre-existing chronic 
or acute liver disease, or the administration of other drug(s) known to be hepatotoxic. 
 
 

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APPENDIX D: Reporting Timelines 
 
Expedited Reporting Timelines 
Event 
HRPO 
QASMC 
FDA 
Bristol Myers Squibb 
Serious AND unexpected 
suspected adverse reaction 
 
 
Report no later than 15 calendar 
days after it is determined that 
the information qualifies for 
reporting 
 
Serious adverse events 
(regardless of relatedness) 
and all occurrences of 
potential DILIs 
 
 
 
Report within 24 hours/1 business 
day of becoming aware of the event 
Unexpected fatal or life-
threatening suspected adverse 
reaction 
 
 
Report no later than 7 calendar 
days after initial receipt of the 
information 
 
Unanticipated problem 
involving risk to participants 
or others 
Report within 10 working days.  If 
the event results in the death of a 
participant enrolled at 
WU/BJH/SLCH, report within 1 
working day. 
Report via email after 
IRB acknowledgment 
 
 
Pregnancy 
 
 
 
Report within 24 hours/1 business 
day of becoming aware of the event 
Major deviation 
Report within 10 working days.  If 
the event results in the death of a 
participant enrolled at 
WU/BJH/SLCH, report within 1 
working day. 
 
 
 
A series of minor deviations 
that are being reported as a 
continuing noncompliance 
Report within 10 working days.   
 
 
 
Protocol exception 
Approval must be obtained prior to 
implementing the change 
 
 
 
 
 
Clinically important increase 
in the rate of a serious 
 
 
Report no later than 15 calendar 
days after it is determined that 
 

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Expedited Reporting Timelines 
Event 
HRPO 
QASMC 
FDA 
Bristol Myers Squibb 
suspected adverse reaction of 
that list in the protocol or IB 
the information qualifies for 
reporting 
Complaints 
If the complaint reveals an 
unanticipated problem involving 
risks to participants or others OR 
noncompliance, report within 10 
working days.  If the event results 
in the death of a participant 
enrolled at WU/BJH/SLCH, report 
within 1 working day.  Otherwise, 
report at the time of continuing 
review. 
 
 
 
Breach of confidentiality 
Within 10 working days. 
 
 
 
Incarceration 
If withdrawing the participant 
poses a safety issue, report within 
10 working days.   
 
If withdrawing the participant does 
not represent a safety issue and the 
patient will be withdrawn, report 
at continuing review. 
 
 
 
 
Routine Reporting Timelines 
Event 
HRPO 
QASMC 
FDA 
Bristol Myers Squibb 
Adverse event or SAE 
that does not require 
expedited reporting 
If they do not meet the definition 
of an unanticipated problem 
involving risks to participants or 
others, report summary 
information at the time of 
continuing review 
Adverse events will 
be reported in the 
toxicity table in the 
DSM report which is 
typically due every 6 
months. 
The most current 
toxicity table 
from the DSM 
report is provided 
to the FDA with 
the IND’s annual 
report. 
SAE Reconciliation: the clinical database AE cases 
transmitted to BMS Global Pharmacovigilance will be 
reconciled every 3 months to verify and confirm all SAEs 
have been transmitted. 
 
AEs that are routinely collected according to GCP shall be 
submitted to BMS every 3 months by the last working day 
of the third month.  Data points to be sent include date 
entered, BMS study number, subject ID, site subject, 
gender, age, race, drug name, visit, study day, days on drug 

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Routine Reporting Timelines 
Event 
HRPO 
QASMC 
FDA 
Bristol Myers Squibb 
at AE start, MedDRA preferred term, investigator verbatim 
term, AE start date, AE stop date, event duration, intensity, 
relationship, action taken, outcome, concomitant 
medications, and medical history. 
 
The AE information is required to be sent in an Excel file 
named BMS CA025-018_DD-MMM-YYYY.xls.  When the 
file is submitted to BMS, it must be noted the file contains 
all non-serious adverse events (only AEs not previously 
submitted to BMS within the previous 3 months). 
Minor deviation 
Report summary information at 
the time of continuing review. 
 
 
 
Complaints 
If the complaint reveals an 
unanticipated problem involving 
risks to participants or others OR 
noncompliance, report within 10 
working days.  If the event 
results in the death of a 
participant enrolled at 
WU/BJH/SLCH, report within 1 
working day.  Otherwise, report 
at the time of continuing review. 
 
 
 
Incarceration 
If withdrawing the participant 
poses a safety issue, report 
within 10 working days.   
 
If withdrawing the participant 
does not represent a safety issue 
and the patient will be 
withdrawn, report at continuing 
review.