Clinical trial NCT03487666
Conditions: Triple Negative Breast Cancer
Keywords: Triple Negative Breast Cancer Nivolumab Capecitabine
Sponsor: Georgetown University
Start date: 2018-05-21; Completion date: 2024-05-02
Enrollment: 45 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This pilot study will provide preliminary data regarding the role of PIS in predicting the benefit of immune checkpoint inhibition with or without chemotherapy for high risk patients with TNBC and residual disease after effective neoadjuvant chemotherapy.

Detailed description:

Arms: arm 1: Nivolumab 360 mg iv q3weeks for x 6 cycles arm 2: Capecitabine 1250mg/m2 bid D1-D14 q3 weeks x 6 cycles arm 3: Nivolumab 360mg iv q3weeks + Capecitabine 1250mg/m2 bid D1-D14 q3 weeks x 6 cycles
Interventions: intervention 1: Nivolumab intervention 2: Capecitabine
Intervention descriptions: intervention 1: Nivolumab is a human programmed death receptor-1 (PD-1) antibody currently approved in different diseases. intervention 2: Capecitabine was selected for Arm B given the recent results from CREATE-X trial and the increasing use by the community (feasibility). Importantly, available data from other scenarios indicates that capecitabine does not have immunosuppressive effects

Protocol documents:
Prot_SAP_000.pdf: 
 
 
 
OXEL: A pilot study of immune checkpoint or capecitabine or combination 
therapy as adjuvant therapy for triple negative breast cancer with residual 
disease following neoadjuvant chemotherapy 
 
Georgetown Protocol #:   
2017-1535 (CRC # 112017-01) BMS CA209-8CL 
 
Clinicaltrials.gov #: 
 
NCT03487666 
Protocol Version Date:   
Version 7.0, January 20, 2023 
 
Principal Investigator (PI): 
Candace Mainor, MD 
 
  
 
 
 
Lombardi Comprehensive Cancer Center 
 
  
 
 
 
Georgetown University Medical Center 
3800 Reservoir Road, NW 
Washington, DC 20057 
Telephone (202) 444-2223   
Fax (202) 444-9429 
Email: Candace.Mainor@gunet.georgetown.edu 
 
  
 
Correlative Science PI: 
 
Louis Weiner, MD, PhD 
 
  
 
 
 
Lombardi Comprehensive Cancer Center 
 
  
 
 
 
Georgetown University Medical Center 
3800 Reservoir Road, NW 
Washington, DC 20057 
Telephone (202) 687-2110   
Fax (202) 444-9429 
 
 
  
 
 
 
Jeffrey Schlom, PhD 
Center for Cancer Research 
National Cancer Institute (NCI) 
Building 10, Room 8B09 
Bethesda, MD 20892-1750 
Telephone 301-496-4343 
js141c@nih.gov 
 
Study Chair: 
 
 
Paula Pohlmann, MD, MSc, PhD 


 
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2 
 
Lombardi Comprehensive Cancer Center 
Georgetown University Medical Center 
 
    Co-Investigators: 
 
Claudine Isaacs, MD 
Lombardi Comprehensive Cancer Center 
Georgetown University Medical Center 
 
Sandra Swain, MD 
Georgetown University 
 
Corporate Collaborators: 
Bristol-Meyers Squibb 
 
Biostatistician:  
 
Hongkun Wang, PhD 
Lombardi Comprehensive Cancer Center 
Georgetown University Medical Center 
 
Study Drug: 
 
 
Nivolumab 
 
IND Number: 
 
 
137808 
 
Clinical Phase:  
 
Phase II 
 
Number of Subjects:  
45 
 
 
 
 
The study will be conducted according to the protocol and in compliance with Good Clinical 
Practice (GCP), with the Declaration of Helsinki, and with other applicable regulatory 
requirements including but not limited to Institutional Review Board/Ethics Committee (IRB/EC) 
approval. 
 
Confidentiality Statement 
 
All information contained in this document is privileged and confidential. Any distribution, 
copying, or disclosure is strictly prohibited without prior written approval by the Sponsor. 
 
 
 
 


 
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SPONSOR SIGNATURE PAGE 
 
Declaration of Sponsor or Responsible Medical Officer 
 
Title: OXEL study - A pilot study of immune checkpoint or capecitabine or combination therapy 
as adjuvant therapy for triple negative breast cancer with residual disease following 
neoadjuvant chemotherapy  
 
 
 
 
 
This study protocol was subjected to critical review and has been approved by the Sponsor. The 
information it contains is consistent with the current risk/benefit evaluation of the investigational 
product as well as with the moral, ethical, and scientific principles governing clinical research as 
set out in the Declaration of Helsinki and the guidelines on Good Clinical Practice. 
 
 
 
 
 
_____________________________________ _____________________ 
Candace Mainor, MD                                                 Date 
Lombardi Comprehensive Cancer Center 
Georgetown University Medical Center 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
Version 7.0, 20 January, 2023 
 
 
 
 
 
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INVESTIGATOR SIGNATURE PAGE 
 
Declaration of the Investigator 
 
Title: OXEL study - A pilot study of immune checkpoint or capecitabine or combination therapy 
as adjuvant therapy for triple negative breast cancer with residual disease following 
neoadjuvant chemotherapy 
 
 
 
I have read this study protocol, including all appendices. By signing this protocol, I agree to 
conduct the clinical study, following approval by an Independent Ethics Committee 
(IEC)/Institutional Review Board (IRB), in accordance with the study protocol, the current 
International Conference on Harmonisation (ICH) Guideline for Good Clinical Practice (GCP), 
and applicable regulatory requirements. I will ensure that all personnel involved in the study 
under my direction will be informed about the contents of this study protocol and will receive all 
necessary instructions for performing the study according to the study protocol. 
 
 
 
 
 
_____________________________________ _____________________ 
Candace Mainor, MD                                                 Date 
Lombardi Comprehensive Cancer Center 
Georgetown University Medical Center 
 
 


 
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Document History 
 
Document 
Version Date 
Summary of changes and rationale 
Version 3 
07MAY2018 
Administrative changes and the removal of 
EKG tests. 
 
Protocol Updates: 
 
Updated version date in footer. 
 
Page 1, Protocol version date: changed to 
v3, date 07MAY18 
 
Page 7, study synopsis: updated protocol 
number and NCT number 
 
Page 21, birth control: changed men must 
not donate sperm to seven months to be 
consistent with consent 
 
Page 28, 6.1 Table of events: removed 12 
lead EKG 
 
ICF Updates: 
 
Updated version date in footer. 
 
Page 3, "End of study": removed EKG 
 
Page 17: added Dr. Christopher Gallagher 
Version 4 
11JUL18 
Protocol Updates: 
 
Page 2: Added IND number 
 
Page 7, 16, 41: Made the distinction 
between secondary objectives and 
exploratory objectives. Note - no new 
objectives were added.   
 
Page 18 to 19: added additional information 
to clarify inclusion criteria after feedback 
received during the SIV: 
-Added RCB II or III 
-Added need to have tissue in the lead 
institution by C1D1 
-Added timeline for surgery and radiation 
completeness 
-Added info on radiation received 
-Limited PS to 0-1 
-Added need for normal thyroid function 


 
Version 7.0, 20 January, 2023 
 
 
 
 
 
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 
Page 19 to 20: added additional information 
to clarify exclusion criteria after feedback 
received during the SIV: 
-Added clarification on autoimmune 
diseases 
-Added clarification on definition of active 
hepatitis B and C 
 
Page 20: included endocrine therapy to anti-
cancer therapies excluded during study 
 
Page 26: added clarification on the dose of 
nivolumab (was already in the schema but 
was added to the text)   
 
Page 28: added clarification on the dose of 
capecitabine (was already in the schema but 
was added to the text). Added a table with 
dose modifications for capecitabine 
 
Page 30: table of events - added that 
pregnancy test is only required for women of 
child bearing potential only and clarification 
on type of hepatitis and thyroid function tests 
required 
 
ICF Updates: 
 
Added the option of research blood work (2 
tubes, 10ml each) on C1D2 or C1D3 of 
study. 
Version 5 
16JAN19 
Protocol Updates: 
 
Page 18: added clarification in terms of 
timing for one of the items of inclusion 
criteria to be consistent with other inclusion 
criteria. 
 
Page 27: added new information on 
preparation of nivolumab based on new IB 
 
Page 29: Table of events. Made changes for 
consistency with the text. Added clarification 
on time window for some labs and visits. 
Added clarification for correlative blood 
samples (at baseline and not screening) to 
be consistent with the text.  


 
Version 7.0, 20 January, 2023 
 
 
 
 
 
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 
Page 31: added that surveillance can be 
done by phone or review of medical records 
to be consistent with table of events 
 
Page 32: removed sentence that was left 
from the protocol template 
 
Page 33: changed from 30 to 100 days for 
participation of SAEs after discontinuation of 
dosing per BMS updated protocol 
guidelines. 
ICF Updates: 
 
Changes made to include Hackensack as a 
site  
Version 6 
16JUL2019 
Protocol Updates: 
 
Page 18, 20, Appendix E: Added Quality of 
Life Questionnaires 
 
Fixed minor administrative discrepancies 
throughout the protocol 
 
Page 34: Made clarifications regarding dose 
delays for correlative specimen collection 
 
Page 35: Clarifications on temporary 
suspension of treatment and dose 
interruptions 
 
Page 38: Updated the SAE reporting 
guidelines from BMS for subsites 
 
Page 48: Updated specimen labeling section 
to be consistent with the lab manual 
ICF Updates: 
 
Page 3-4: Added information on biopsy(ies) 
Version 6.1 
09Mar2020 
Protocol Updates: 
 
PI changed from Dr. Lynce to Dr. Mainor 
throughout protocol. 
 
Section 6.7 removed typo “atezolizumab or 
placebo” 
 
Other Administrative 
clarifications/corrections made throughout 
protocol to replace CRO with Multicenter 
Project Managers and SAE reporting 
 
Updates made to incorporate information 
from Protocol Clarification letters: 


 
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 
Inclusion Criteria 2 changed “must have” to 
“should be” and a Note Added for 
clarification “(Note: As long as tissue sample 
is confirmed shipped, the subject will be 
eligible)” 
 
Inclusion Criteria 5 typo correction made 
 
Inclusion Criteria 8 added clarification 
“(Patients that meet the definition of 
asymptomatic subclinical hypothyroidism will 
be eligible to participate)” 
 
Section 6.3 added clarification “Note: 
Assessments performed for clinical 
indications (not exclusively to determine 
study eligibility) may be used for 
screening/baseline values even if the studies 
were done before informed consent was 
obtained. 
Version 6.2 
06 OCT 2020 
 
Section 1.6.2 Administration of PRO 
questionnaires corrected to be consistent 
with table of events 
 
Section 5.2.1: 
corrected delay of treatment to >42 days to 
fix discrepancy between this section and 
Section 6.7. 
added the term “diarrhea” to be consistent 
with Appendix D 
clarified Permanently discontinue nivolumab 
“unless approved by the Sponsor/Medical 
Monitor” 
 
Appendix D: GI Adverse Events: updated to 
be consistent with section 5.2.1 and fixed 
typographical errors. 
 
Version 7 
20 Jan 2023 
 
Section 2.2 (Page 21) 
Change in the timeframe of one of the 
secondary endpoints. Given that this study is 
enriched for a high risk population 
considered to be relatively refractory to 
chemotherapy, a 2-year endpoint is 
considered appropriate. A recently published 
study that enrolled a similar patient 


 
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population elected 2-year time frame for 
their clinical endpoints (Schneider BP et al. 
JCO 2022).  
CURRENTLY STATES: To determine association 
between changes in PIS from baseline to week 6 
and week 12 and clinical outcome variables (DRFS 
and OS at 3-years).  
UPDATED TO: To determine association between 
changes in PIS from baseline to week 6 and week 
12 and clinical outcome variables (DRFS and OS at 
2-years). 
And added: To describe the following endpoints and 
compare them between arms: DRFS, OS   
 
 
Section 6.8 Surveillance (this was 
previously submitted as a protocol 
clarification letter on April 28,2021) 
CURRENTLY STATES: Participants will be 
monitored by their treating physicians for the 
development of either local (chest wall, axillary, or 
supraclavicular nodes) or distant recurrent disease 
at least once every 3 months for the first two years, 
then at least every 6 months during year 3.  
UPDATED TO: Participants will be monitored by 
their treating physicians for the development of 
either local (chest wall, axillary, or supraclavicular 
nodes) or distant recurrent disease, and survival, 
at least once every 3 months for the first two years, 
then at least every 6 months during year 3. 
 
 
 
 


 
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TABLE OF CONTENTS 
 
 
 
 
 
 
 
                   Page 
Table of Contents  
                                                                                                 8 
Study Synopsis 
 
 
 
 
 
 
 
 
 
 
10 
1.0   Background and Justification  
 
 
 
 
 
 
 
 
 
1.1 Triple negative breast cancer and residual disease 
 
 
 
12 
 
1.2 Immunotherapy as a treatment option for TNBC   
 
 
 
12 
 
1.3 The immune milieu in TNBC   
 
 
 
 
 
 
13 
 
1.4. Evaluating anti-tumor immunity in the absence of measurable disease  
13 
 
1.5 Nivolumab Activity and Pharmacokinetic Profile 
 
 
 
 
14 
 
1.6 Patient reported outcomes (PRO) 
 
 
 
 
 
 
18 
1.7 Rationale for the Current Study 
 
 
 
 
 
 
19 
 
2.0   Study Objectives  
 
 
 
 
 
 
 
 
 
 
2.1 Primary Objectives 
 
 
 
 
 
 
 
 
20 
 
2.2 Secondary Objectives  
 
 
 
 
 
 
 
20 
3.0   Study design 
 
 
 
 
 
 
 
 
 
21 
4.0 
Subject Population 
 
 
 
 
 
 
 
 
 
4.1 Subject Population, Number of Subjects, and Feasibility  
 
 
22 
 
4.2 Inclusion Criteria 
 
 
 
 
 
 
 
 
22 
 
4.3 Exclusion Criteria 
 
 
 
 
 
 
 
 
24 
 
4.4 Additional Study Restrictions  
 
 
 
 
 
 
24 
4.5 Other Prior and Concomitant Therapy 
 
 
 
 
 
26 
 
4.6 Removal/Replacement of Subjects from Therapy or Assessment 
 
27 
 
4.7 Multi-Institutional Trial Coordination  
 
 
 
 
 
27 
5.0 
Treatment Plan   
 
5.1 Dose modifications – General Guidelines 
 
 
 
 
 
29 
 
5.2 Nivolumab 
 
 
 
 
 
 
 
 
 
29 
 
5.3. Capecitabine 
 
 
 
 
 
 
 
 
 
32 
6.0  
Study Procedures  
 
 
6.1 Table of events   
 
 
 
 
 
 
 
 
33 
6.2 Pre-registration  
 
 
 
 
 
 
 
 
34 
6.3 Screening 
 
 
 
 
 
 
 
 
 
34 
6.4 Randomization                                                                                                    35 
6.5. On Study Day 1 
 
 
 
 
 
 
 
 
35 
6.6 On Treatment 
 
 
 
 
 
 
 
 
 
35 
6.7 Treatment discontinuation 
 
 
 
 
 
 
 
35 
 
6.8 Surveillance 
 
 
 
 
 
 
 
 
 
35 
7.0   Safety Variables and Toxicity Assessment  
 
 
 
 
 
7.1 Serious Adverse Events  
 
 
 
 
 
 
 
36 
 
7.2 Adverse Events  
 
 
 
 
 
 
 
 
39 
7.3. Adverse Events Associated with the Use of Immune Checkpoint Inhibitor 
40 


 
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7.4 Laboratory Test Abnormalities 
 
 
 
 
 
 
41 
7.5 Pregnancy 
 
 
 
 
 
 
 
 
 
42 
7.6 Overdose 
 
 
 
 
 
 
 
 
 
42 
7.7 Other Safety Considerations  
 
 
 
 
 
 
42 
 
7.8 Study Monitoring 
 
 
 
 
 
 
 
 
42 
 
7.9 Protocol Deviations and Violations 
 
 
 
 
 
 
44 
8.0   Statistical Considerations 
 
 
 
 
 
 
 
 
 
8.1 Objectives 
 
 
 
 
 
 
 
 
 
44 
 
8.2 Sample Size Considerations  
 
 
 
 
 
 
45 
 
8.3 Randomization and Stratification Factors 
 
 
 
 
 
45 
8.4 Endpoints 
 
 
 
 
 
 
 
 
 
45 
 
8.5 Analysis Plan 
 
 
 
 
 
 
 
 
 
46 
9.0   Correlative Research 
 
 
 
 
 
 
9.1 Peripheral immunoscore 
 
 
 
 
 
 
 
47 
 
9.2 Immune contexture in residual breast tumor  
 
 
 
 
47 
 
9.3 Sample labeling overview 
 
 
 
 
 
 
 
48 
 
10.0   Ethical Considerations 
 
 
 
 
 
 
 
 
 
10.1 Institutional Review Board (IRB) 
 
 
 
 
 
 
49 
10.2 Ethical Conduct of the Study  
 
 
 
 
 
 
49 
10.3 Subject Information and Consent 
 
 
 
 
 
 
49 
10.4 Ethical Consideration for Enrollment 
 
 
 
 
 
49 
 
10.5 Protection of Patient Confidentiality  
 
 
 
 
 
49 
11.0   References  
 
 
 
 
 
 
 
 
 
49 
12.0   Appendices  
 
 
 
 
 
 
 
 
 
51 
 
Appendix A: ECOG Performance Status Table)  
 
 
 
 
53 
 
Appendix B: Patient Registration Form  
 
 
 
 
 
54 
Appendix C: Data sharing Plan 
 
 
 
 
 
 
 
55 
Appendix D: Management Algorithms 
 
 
 
 
 
 
57 
Appendix E: Quality of Life Questionnaire (EORTC QLQ-C30 
 
 
66 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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STUDY SYNOPSIS 
 
Title 
OXEL: A pilot study of immune checkpoint or capecitabine or combination 
therapy as adjuvant therapy for triple negative breast cancer with residual 
disease following neoadjuvant chemotherapy 
Short Title 
OXEL study 
Protocol  
Number 
2017-1535 (Georgetown University Parent IRB); BMS CA209-8CL 
Clinicaltrials.go
v number: 
NCT03487666 
Phase 
Phase 2 
Investigational 
Agents 
Nivolumab, a PD-1 monoclonal antibody (BMS) 
Indication 
Advanced triple negative breast cancers  
Study Overview 
This is a pilot phase II trial for patients with triple negative breast cancer.  
 
Study Duration 
36 months 
Study Center(s) 
 Georgetown University, Lombardi Comprehensive Cancer Center  
Washington, DC 
 MedStar Washington Hospital Center, Washington DC 
 Hackensack University Medical Center, Hackensack, NJ 
 One additional participating center to be determined 
Objectives 
Primary objective: 
To assess the immunologic effects of capecitabine, nivolumab or the combo, 
post neoadjuvant and post-surgery, in the adjuvant setting, in patients with high 
risk TNBC as defined by presence of residual disease (breast and or LNs) at 
surgery, in terms of the change of PIS. 
Secondary objectives: 
1) To determine the incidence of toxicity graded using the National Cancer 
Institute CTCAE v. 4.0 until 30 days after last dose of treatment on trial. 
2) To determine association between changes in PIS from baseline to week 6 
and week 12 and clinical outcome variables (DRFS and OS at 2-years).  
3) To describe the following endpoints and compare them between arms: DRFS, 
OS   
4) Translational endpoints:  
a) circulating tumor DNA (ct-DNA) during treatment 
Exploratory objectives: 
a) To describe the immune contexture in residual tumors of patients with high 
risk TNBC after receiving neoadjuvant chemotherapy 
b) Tissue banking for future studies (NGS of initial biopsy and surgical 
specimen), plasma, PBMCs 
Number of 
Subjects 
The anticipated number of patients will be 45. 


 
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Diagnosis and 
Main Inclusion 
and Exclusion 
Criteria 
Key Inclusion Criteria: Biopsy proven TNBC (ER and PR defined as 5% cells 
stain positive), HER2 negativity defined as (IHC0, 1+ without in situ hybridization 
(ISH) HER2/neu chromosome 17 ratio OR IHC 2+ and ISH HER2/neu 
chromosome 17 ratio non-amplified with ratio <2.0 and if reported average HER2 
copy number <6 signals/cells); residual disease of 1.0 cm of the primary tumor 
and/or node positive disease measuring  0.5cm; receipt of neoadjuvant taxane 
+/- anthracycline; platinum use allowed; must have completed definitive resection 
of primary tumor; signed ICF; age ≥18. 
Key Exclusion Criteria: Stage IV disease; previous exposure to capecitabine, 
fluorouracil or immunotherapy with anti-PD1, anti PDL1 or anti-CTLA4; active 
autoimmune disease requiring systemic treatment in the past 2 years; 
tuberculosis, hepatitis B or C, HIV or other active infection; chronic use of 
systemic steroids or pregnancy. 
Study Design 
 
Pilot phase II open-label three arm randomized trial of nivolumab, capecitabine 
or combination as adjuvant therapy for 45 patients with residual TNBC after 
adequate neoadjuvant chemotherapy followed by definitive surgery. Patients are 
randomly assigned to 1 of 3 treatment arms: ARM A – Nivolumab 360 mg iv 
q3weeks for x 6 cycles; ARM B - Capecitabine 1250mg/m2 bid D1-D14 q3 weeks 
x 6 cycles; ARM C - Nivolumab 360mg iv q3weeks + Capecitabine 1250mg/m2 
bid D1-D14 q3 weeks x 6 cycles. We will enroll 15 patients per arm (45 totally for 
3 arms).  
Duration of 
therapy 
All drugs will be administered for 18 weeks, or until disease progression or 
unacceptable toxicity is observed.  
Sample size 
considerations  
The primary objective of the study is to assess the change in PIS, the Peripheral 
ImmunoScore, at 6 weeks (=2 cycles) from baseline, in each arm. The sample 
size of 15 per arm (45 totally for 3 arms) is mainly based on the feasibility of 
patient accrual. A sample size of 15 per arm will have about 85% power to 
detect an effect size of 1 (the difference of the change in PIS from baseline to 
week 6 between two arms divided by the standard deviation) at 5% significance 
level.  
 
 
 
 


 
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1.0 BACKGROUND AND JUSTIFICATION 
 
 
1.1. Triple negative breast cancer and residual disease 
Breast cancer (BC) is the most common cancer in women in the United States, with an estimated 
252,710 new cases of invasive BC anticipated in 20171. Overall, triple negative breast cancer 
(TNBC) accounts for 10-15% of invasive BC cases and it is associated with a worse prognosis 
and limited treatment options compared to the other subtypes2,3. Patients with TNBC and 
residual disease at the time of surgery after completing neoadjuvant chemotherapy constitute a 
group of patients at a high risk of recurrence. Long-term follow-up of neoadjuvant studies 
consistently demonstrates worse clinical outcomes in patients with TNBC who did not achieve 
pathologic complete response (pCR), with only 35-40% remaining free of recurrence at 2 years4-
6. Until recently, the standard of care for patients with early stage TNBC who do not achieve pCR 
was observation or participation in a clinical trial. More recently, adjuvant capecitabine became 
an option after the CREATE-X study revealed that the addition of adjuvant capecitabine 
prolonged disease-free survival (DFS) and overall survival (OS) among patients with HER2-
negative BC who had residual invasive disease on pathological testing7. This benefit was more 
striking in patients with TNBC (DFS 69.8% in the capecitabine group vs 56.1% in the control 
group, HR 0.58; 95% CI, 0.39 to 0.87; and OS 78.8% vs 70.3%, HR 0.52; 95% CI, 0.30 to 0.90). 
 
1.2. Immunotherapy as a treatment option for TNBC  
Immunotherapy has shifted the treatment paradigm for many malignancies, but not all cancer 
types have enjoyed a clinically meaningful response from checkpoint blockade. In BC, most work 
to date with immunotherapy has focused on TNBC given the greater frequency of tumor 
infiltrating lymphocytes (TILs)8. The overall response rate (ORR) in heavily pretreated patients 
with TNBC who received pembrolizumab single agent was 18.5%9. Other trials in TNBC either 
in the metastatic10 or neoadjuvant setting11, have 
shown that the combination of immune checkpoint 
inhibitors plus chemotherapy may be a more 
promising approach. In the phase I clinical trial of 
atezolizumab and nabpaclitaxel, in patients with 
metastatic disease those treated in first line 
derived the greatest benefit, when compared to 
patients treated in second or third line (ORR 67% 
vs 25-29% in 1st line versus 2nd/3rd line 
respectively)9. These findings confirm the overall 
impression that when chemoimmunotherapy is 
used earlier in TNBC, the outcome is better. They 
also support the notion that, in TNBC, the addition 
of chemotherapy to a checkpoint inhibitor is a 
promising strategy, contrary to what is observed in 
less chemosensitive diseases such as melanoma.  
Figure 1. Genome-wide shRNA library screen in 
EO771 TNBC tumors growing in WT or SCID 
C57Bl/6 mice reveals genes whose knockdown 
either reduces (left, upper) or increases (right, upper) 
the representation of the targeted tumor cells in 1 


 
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1.3. The immune milieu in TNBC  
It is unlikely that immunotherapy alone or in combination with chemotherapy will be effective in 
all patients with residual TNBC after neoadjuvant chemotherapy. Thus, we need to characterize 
the immune contexture of the residual tumors in order to select patients who will benefit 
additional therapy including immunotherapy. Many tools are available to describe the immune 
contexture in the tumor microenvironment, using powerful technologies such as multiplex 
immunohistochemistry (IHC), genome-wide association studies (GWAS) and mass cytometry12. 
Recently we employed a genome-wide shRNA screen to identify 709 genes that selectively 
regulated adaptive anti-tumor immunity in a syngeneic, functionally TNBC model and focused 
on five genes (CD47, TGFβ1, Sgpl1, Tex9 and Pex14) with the greatest impact as biomarkers 
of resistance13 (Fig. 1). We have used this same approach to identify genes that regulate 
resistance to PD-1 antibody directed immune attack in the same TNBC model (not shown). While 
work done using The Cancer Genome Atlas (TCGA) data to characterize immune cell infiltrates 
in TNBC is valuable and foundational14 it may not accurately reflect the immune milieu of tumors 
resistant to chemotherapy. This is the rationale to the evaluation of the immune contexture in 
tumors that are resistant to neoadjuvant chemotherapy, in order to guide future adjuvant therapy 
approaches for these patients at a high risk of recurrence.  
 
1.4. Evaluating anti-tumor immunity in the absence of measurable disease  
A significant challenge in evaluating the effects of experimental adjuvant therapies is the lack of 
measurable disease to assess therapeutic effects. In this setting, when tumor is not detectable 
such as in patients with early BC who have undergone surgical resection of their tumor, the 
identification of biomarkers in the peripheral blood – the most readily available tissue for 
sampling – to assess effects of the intervention is intuitively attractive. Immune cell subsets 
within peripheral blood mononuclear cells (PBMC) have been analyzed to determine if a 
peripheral immunoscore could have any prognostic significance for patients undergoing 
immunotherapy. Although to date there is no validated FDA-approved circulatory immunological 
biomarker for patients with breast cancer, the refined peripheral immunoscore (PIS) defined by 
Farsaci et al15 (Table 1) was 
validated in a group of patients 
with 
metastatic 
BC 
receiving 
docetaxel and immunotherapy, 
and shown to be predictive of 
progression free survival (PFS). 
When compared to predefined 
analyses of "classic" immune cell 
types (CD4, CD8, natural killer 
cells, regulatory T cells, myeloid-
derived suppressor cells, and ratios) that revealed no differences in PFS for either arm 
Table 1. Refined peripheral immunoscore 


 
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(docetaxel alone or docetaxel with vaccine), predefined analyses of refined immune cell subsets 
for which a biologic function had been previously reported revealed statistically significant 
improved PFS (P < 0.001) for those receiving docetaxel plus immunotherapy (Fig 2). Based on 
these results, we selected for our study the PIS as a surrogate of clinical benefit and a new 
strategy to identify patients with BC who may benefit from immunotherapy to eliminate residual 
micrometastasis. 
 
 
 
Figure 2.a Docetaxel alone 
 
 
Figure 2.b Docetaxel and vaccine 
 
 
 
1.5 Nivolumab Activity and Pharmacokinetic Profile 
1.5.1. Introduction 
Nivolumab (also referred to as BMS-936558, MDX1106, or ONO-4538) is a human monoclonal 
antibody (HuMAb; immunoglobulin G4 [IgG4]-S228P) that targets the programmed death-1 
(PD-1) cluster of differentiation 279 (CD279) cell surface membrane receptor. PD-1 is a 
negative regulatory molecule expressed by activated T and B lymphocytes16. Binding of PD-1 
to its ligands, programmed death–ligands 1 (PD-L1) and 2 (PD-L2), results in the down-
regulation of lymphocyte activation. Inhibition of the interaction between PD-1 and its ligands 
promotes immune responses and antigen-specific T-cell responses to both foreign antigens as 
well as self-antigens. Nivolumab is expressed in Chinese hamster ovary (CHO) cells and is 
produced using standard mammalian cell cultivation and chromatographic purification 
technologies. The clinical study product is a sterile solution for parenteral administration. 
OPDIVO (nivolumab) is approved for the treatment of several types of cancer in multiple 
regions including the United States (US, Dec-2014), the European Union (EU, Jun-2015), and 
Japan (Jul-2014). Nivolumab is also being investigated in various other types of cancer as 
monotherapy or in combination with other therapies, and as single-dose monotherapy for the 
treatment of sepsis. 
 
1.5.2. Nonclinical Studies 


 
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Nivolumab has been shown to bind specifically to the human PD-1 receptor and not to related 
members of the CD28 family17,18. Nivolumab inhibits the interaction of PD-1 with its ligands, 
PD-L1 and PD-L2, resulting in enhanced T-cell proliferation and interferon-gamma (IFN-γ) 
release in vitro19-21. Nivolumab binds with high affinity to activated human T-cells expressing 
cell surface PD-1 and to cynomolgus monkey PD-1.2 In a mixed lymphocyte reaction (MLR), 
nivolumab promoted a reproducible concentration-dependent enhancement of IFN- release22. 
In intravenous (IV) repeat-dose toxicology studies in cynomolgus monkeys, nivolumab was 
well tolerated at doses up to 50 mg/kg, administered weekly for 5 weeks, and at doses up to 
50 mg/kg, administered twice weekly for 27 doses. While nivolumab alone was well tolerated in 
cynomolgus monkeys, combination studies have highlighted the potential for enhanced toxicity 
when combined with other immunostimulatory agents23. 
In addition, an enhanced pre- and postnatal development (ePPND) study in pregnant 
cynomolgus monkeys with nivolumab was conducted24. Administration of nivolumab at up to 
50 mg/kg 2QW was well tolerated by pregnant monkeys; however, nivolumab was determined 
to be a selective developmental toxicant when administered from the period of organogenesis 
to parturition at  10 mg/kg (area under the concentration-time curve [AUC] from time zero to 
168 hours [AUC(0-168 h)] 117,000 gh/mL). Specifically, increased developmental mortality 
(including late gestational fetal losses and extreme prematurity with associated neonatal 
mortality) was noted in the absence of overt maternal toxicity. There were no nivolumab-
related changes in surviving infants tested throughout the 6-month postnatal period. Although 
the cause of these pregnancy failures was undetermined, nivolumab-related effects on 
pregnancy maintenance are consistent with the established role of PD-L1 in maintaining 
fetomaternal tolerance in mice25. 
 
1.5.3. Effects in Humans 
The pharmacokinetics (PK), clinical activity, and safety of nivolumab have been assessed in 
subjects with non-small cell lung cancer (NSCLC), melanoma, clear-cell renal cell carcinoma 
(RCC), classical Hodgkin Lymphoma (cHL), urothelial carcinoma (UC), squamous cell 
carcinoma of the head and neck (SCCHN), in addition to other tumor types. Nivolumab 
monotherapy is approved in multiple regions, including the US and EU, for unresectable or 
metastatic melanoma, previously treated metastatic NSCLC, previously treated 
advanced RCC, previously treated relapsed or refractory cHL, and previously treated 
advanced or metastatic UC; it is also approved for the treatment of previously treated recurrent 
or metastatic SCCHN in the US. In addition, nivolumab has been approved for use in 
combination with ipilimumab for unresectable melanoma in multiple countries, including the US 
and EU. Nivolumab is being investigated both as monotherapy and in combination with 
chemotherapy, targeted therapies, and other immunotherapies for the treatment of several 
types of cancer.  
 
1.5.4. Clinical Pharmacokinetics 


 
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The PK of nivolumab was studied in subjects with cancer over a dose range of 0.1 to 20 mg/kg 
administered as a single dose or as multiple doses of nivolumab every 2 or 3 weeks. 
Nivolumab clearance (CL) decreases over time, with a mean maximal reduction (% coefficient 
of variation [CV%]) from baseline values of approximately 24.5% (47.6%) resulting in a 
geometric mean steady state clearance (CLss) (CV%) of 8.2 mL/h (53.9%); the decrease in 
CLss is not considered clinically relevant. The geometric mean volume of distribution at steady 
state (Vss) was 6.8 L (27.3%), and geometric mean elimination half-life (t1/2) was 25 days 
(77.5%). Steady-state concentrations of nivolumab were reached by 12 weeks when 
administered at 3 mg/kg Q2W, and systemic accumulation was approximately 3.7-fold. The 
exposure to nivolumab increased dose proportionally over the dose range of 0.1 to 10 mg/kg 
administered every 2 weeks. Additionally, nivolumab has a low potential for drug-drug 
interactions. The clearance of nivolumab increased with increasing body weight. The PPK 
analysis suggested that the following factors had no clinically important effect on the CL of 
nivolumab: age (29 to 87 years), gender, race, baseline LDH, PD-L1 status, solid tumor type, 
baseline tumor size, and hepatic impairment. Although ECOG status, baseline glomerular 
filtration rate (GFR), albumin, and body weight had an effect on nivolumab CL, the effect was 
not clinically meaningful. PPK analysis suggest that nivolumab CL in subjects with cHL was 
approximately 32% lower relative to subjects with NSCLC; however, the lower CL in cHL 
subjects was not considered to be clinically relevant as nivolumab exposure was not a 
significant predictor for safety risks for these patients. When nivolumab is administered in 
combination with ipilimumab, the CL of nivolumab was increased by 29%, whereas there was 
no effect on the clearance of ipilimumab. PPK and exposure response analyses have been 
performed to support use of nivolumab 240 mg Q2W, 360 mg Q3W, and 480 mg Q4W dosing 
regimens in subjects with cancer in addition to the 3 mg/kg Q2W regimen. A flat dose of 
nivolumab 240 mg Q2W was selected since it is identical to a dose of 3 mg/kg for subjects 
weighing 80 kg, the observed median body weight in nivolumab treated cancer patients, while 
the nivolumab 360 mg Q3W and 480 mg Q4W regimens allow flexibility of dosing with less 
frequent visits and in combination with other agents using alternative dosing schedules to 
Q2W. Using a PPK model, the overall distributions of nivolumab exposures (Cavgss, Cminss, 
Cmaxss, and Cmin1) are comparable after treatment with either nivolumab 3 mg/kg or 240 mg 
Q2W. Following nivolumab 360 mg Q3W and 480 mg Q4W, Cavgss are expected to be similar 
to those following nivolumab 3 mg/kg or 240 mg Q2W, while Cminss are predicted to be 6% 
and ~16% lower, respectively, and are not considered to be clinically relevant. Following 
nivolumab 360 mg Q3W and 480 mg Q4W, Cmaxss are predicted to be approximately ~23% 
and ~43% greater, respectively, relative to that following nivolumab 3 mg/kg Q2W dosing. 
However, the range of nivolumab exposures (median and 90% prediction intervals) following 
administration of 240 mg flat Q2W, 360 mg Q3W, and 480 mg Q4W regimens across the 35 to 
160 kg weight range are predicted to be maintained well below the corresponding exposures 
observed with the well tolerated 10 mg/kg nivolumab Q2W dosing regimen. In this study we 
will use the flat dose of 360mg Q3W. Although this is a less frequent dosing regimen, it will 


 
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allow combination of nivolumab with the capecitabine schedule. This nivolumab dosing 
regimen was selected using several simulation models to provide approximately equivalent 
exposures following administration of nivo 3 mg/kg Q2W. The models predicted that following 
administration of nivo 360 mg Q3W exposures are expected to be similar to those following 
nivo 3 mg/kg or 240 mg Q2W. 
 
1.5.5. Clinical Efficacy 
Nivolumab has demonstrated durable responses exceeding 6 months as monotherapy and in 
combination with ipilimumab in several tumor types, including NSCLC, melanoma, RCC, cHL, 
SCLC, gastric cancer, SCCHN, urothelial cancer, HCC, and CRC. In confirmatory trials, 
nivolumab as monotherapy demonstrated a statistically significant improvement in OS as 
compared with the current standard of care in subjects with advanced or metastatic NSCLC, 
unresectable or metastatic melanoma, advanced RCC, or SCCHN. Nivolumab in combination 
with ipilimumab improved PFS and ORR over ipilimumab alone in subjects with unresectable 
or metastatic melanoma.  
 
1.5.6. Clinical Safety 
The overall safety experience with nivolumab, as a monotherapy or in combination with other 
therapeutics, is based on experience in approximately 16,900 subjects treated to date. For 
monotherapy, the safety profile is similar across tumor types. There is no pattern in the 
incidence, severity, or causality of AEs to nivolumab dose level. In Phase 3 controlled studies, 
the safety profile of nivolumab monotherapy is acceptable in the context of the observed 
clinical efficacy, and manageable using established safety guidelines. Clinically relevant AEs 
typical of stimulation of the immune system were infrequent and manageable by delaying or 
stopping nivolumab treatment and timely immunosuppressive therapy or other supportive care. 
Based on preliminary data from an ongoing Phase 1 study, there have been no unexpected 
safety findings to date in patients with sepsis who received a single dose of nivolumab 
monotherapy. In several ongoing clinical trials, the safety of nivolumab in combination with 
other therapeutics such as ipilimumab, cytotoxic chemotherapy, anti-angiogenics, and targeted 
therapies is being explored. Most studies are ongoing and, as such, the safety profile of 
nivolumab combinations continues to evolve. The most advanced combination under 
development is nivolumab + ipilimumab, which is approved in subjects with unresectable or 
metastatic melanoma, and being studied in multiple tumor types. Results to date suggest that 
the safety profile of nivolumab+ipilimumab combination therapy is consistent with the 
mechanisms of action of nivolumab and ipilimumab. The nature of the AEs is similar to that 
observed with either agent used as monotherapy; however, both frequency and severity of 
most AEs are increased with the combination. Nivolumab at 360mg q3w has been shown to be 
safe in combination with capecitabine and oxaliplatin in patients with G/GEJ cancers (Kang 
YK, et al. Annals of Oncology 2017). 


 
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There are other ongoing studies evaluating the combination of capecitabine and nivolumab 
(NCT02746796; NCT03006705). 
 
1.6 Patient reported outcomes (PRO) 
The assessment of patient-reported outcomes (PROs) in clinical research provides important 
insight into how therapies impact the daily lives of patients. Patient reports regarding health 
related quality of life have proven more comprehensive than provider-collected data in breast 
cancer patients (Oberguggenberger et al 2011).  
 
1.6.1 EORTC QLQ-C30 
In this study patient-reported disease related symptoms and health-related quality of life 
(HRQoL) will be evaluated using the validated EORTC QLQ-C30 questionnaire. The 
EORTC QLQ-C30 questionnaire was developed to assess HRQoL and is the most commonly 
used cancer-specific tool in oncology.  
The EORTC QLQ-C30 comprises 30 questions designed for all cancer types. Questions can 
be grouped into the following scales: 
 5 multi-item functional scales (physical, role, emotional, cognitive and social) 
 3 multi-item symptom scales (fatigue, pain, nausea vomiting) 
 A 2-item global QoL scale 
 5 single items assessing the following common cancer symptoms: dyspnea, loss of appetite, 
insomnia, constipation, diarrhea 
 1 item on the financial impact of the disease. 
 
All the EORTC scales range from 0 to 100 (through transformation of scores). A high scale 
score represents a higher response level. Thus a high score for a functional scale represents a 
high / healthy level of functioning, while a high score for a symptom scale / item represents a 
high level of symptomatology / problems. 
 
1.6.2 Administration of PRO questionnaires 
Paper-based EORTC QLQ-C30 will be administered at screening (prior to randomization), at 6 
weeks visit and at the end of treatment.   
Each center must allocate the responsibility for the administration of the questionnaires to a 
specific individual (e.g., a research nurse, study coordinator) and if possible assign a back-up 
person to cover if that individual is absent. The significance and relevance of the data need to 
be explained carefully to participating patients so that they are motivated to comply with data 
collection. 
The instructions for completion of the PRO questionnaires are as follows: 
 They must be completed prior to any other study procedures (following informed consent) 
and before discussion of disease progress to avoid biasing the patient’s responses to the 
questions. They must be completed in private by the patient 
 The patient should be given sufficient time to complete at their own speed 
 The patient should not receive help from relatives, friends or clinic staff to answer the 
questionnaire. 
 On completion of the questionnaire it should be handed back to the person responsible for 
questionnaires who should check for completeness 


 
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 
 Only one answer should be recorded for each question 
 
1.7. Rationale for Current Study 
Recent results presented at ASCO 2017 indicated that a subset of patients with early stage triple 
negative breast cancer benefit from immune checkpoint inhibitors11. It is of critical importance to 
develop tools to help identify which patients benefit from this strategy.  As discussed above, we 
currently don’t have any validated biomarker that allow us to detect this subset of patients. Tumor 
biopsies at different timepoints are not an option in this population when the only tumor available 
is the residual tissue removed at the time of surgery. The presence of circulating tumor cells 
after chemotherapy has been shown to have a negative impact on DFS and OS (Rack B, et al. 
JNCI 2014) but has not been used to predict benefit from immunotherapy. The presence of PD-
L1 expression on tumor cells has been associated with objective responses in metastatic cancer 
(Topalian, NEJM) but not been evaluated in patients who have completed adjuvant therapy. 
Presence of TILs has been associated with increased PD-L1 infiltrate, but the association 
between increased TILs and response to immune checkpoint therapy has not yet been 
established. For this pilot study, we selected the refined peripheral immunoscore (PIS)15 defined 
by Farsaci based on it’s being the closest to the particular scenario proposed on this study. His 
group demonstrated that an immunoscore of refined immune cell subsets showed significant 
prognostic value in PFS for metastatic breast cancer patients receiving docetaxel plus vaccine 
(P < 0.001) and for metastatic prostate cancer patients receiving radionuclide plus vaccine 
(p=0.004), but not on the same groups when treated with chemotherapy alone.  
 
This pilot study will provide preliminary data regarding the role of PIS in predicting the benefit of 
immune checkpoint inhibition with or without chemotherapy for high risk patients with TNBC and 
residual disease after effective neoadjuvant chemotherapy. If the peripheral immunoscore fails 
as a biomarker, this pilot study would still be very relevant as we will be collecting other 
exploratory biomarkers in this unique population.   
 
 


 
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2.0 STUDY OBJECTIVES 
2.1 Primary objective: 
1) To assess the immunologic effects of capecitabine, nivolumab or the combo, post 
neoadjuvant and post-surgery, in the adjuvant setting, in patients with high risk TNBC as 
defined by presence of residual disease (breast and or LNs) at surgery, in terms of the 
change of PIS. 
a) We hypothesized that among patients with TNBC and residual disease at the time of 
surgery, the change of the Peripheral ImmunoScore (PIS) from baseline to week 6 will 
be higher among those who receive post-surgery immunotherapy (ARM A and C), 
compared to those who receive post-surgery chemotherapy alone (ARM B).  
 
2.2 Secondary objectives: 
1). To determine the incidence of toxicity graded using the National Cancer Institute CTCAE v. 
4.0 until 30 days after last dose of treatment on trial. 
2). To determine association between changes in PIS from baseline to week 6 and week 12 and 
clinical outcome variables (DRFS and OS at 2-years)). After end of study visit, clinical follow up 
or telephone communication every 3months.3). To describe the following endpoints and 
compare them between arms: DRFS, OS   
4) Translational endpoints:  
a) Circulating-tumor DNA (ct-DNA) 
Exploratory objectives: 
c) To describe the immune contexture in residual tumors of patients with high risk TNBC 
after receiving neoadjuvant chemotherapy 
d) Tissue banking for future studies (NGS of initial biopsy and surgical specimen) 
e) To explore the impact of nivolumab on patient-reported outcomes (PROs) of health-related 
quality of life (HRQoL), as measured by the European Organization for Research and 
Treatment of Cancer (EORTC) EORTC Quality of Life Questionnaire Core 30 (QLQ-C30) 
disease related multi-item symptom and functional scales.  
 


 
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3.0 STUDY DESIGN 
 
 
 
 
Figure 3. Study design  
 
 
The OXEL “Opdivo, XELoda or combination therapy as adjuvant therapy for triple negative 
breast cancer with residual disease following neoadjuvant chemotherapy” is a pilot phase II 
open-label three arm randomized trial of nivolumab, capecitabine or combination as adjuvant 
therapy for 45 patients with residual TNBC after adequate neoadjuvant chemotherapy followed 
by definitive surgery. We will enroll 15 patients per arm (45 totally for 3 arms).  
 
Patients are randomly assigned to 1 of 3 treatment arms:  
 
ARM A – Nivolumab 360 mg iv q3weeks for x 6 cycles;  
 
ARM B - Capecitabine 1250mg/m2 bid D1-D14 q3 weeks x 6 cycles;  
 
ARM C - Nivolumab 360mg iv q3weeks + Capecitabine 1250mg/m2 bid D1-D14 q3 weeks x 6 
cycles.  
Nivolumab (Opdivo) is a human programmed death receptor-1 (PD-1) antibody currently 
approved in different diseases. Capecitabine (Xeloda) was selected for ARM B (as 
contemporary control arm) given the recent results from CREATE-X trial7 and the increasing 
use by the community (feasibility). Importantly, available data from other scenarios indicates 
that capecitabine does not have immunosuppressive effects27. Given capecitabine low 
myelosuppressive potential, it was felt to be a reasonable chemotherapy partner with the 
checkpoint inhibitor in this setting (ARM C). Finally, there is safety data regarding combination 
of nivolumab and capecitabine in patients with G/GEJ tumors (Kang YK, et al. Annals of 
Oncology 2017). 


 
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4.0 SUBJECT POPULATION 
4.1 Subject Population, Number of Subjects and Feasibility 
4.1.1 Subject Population 
Patients will have triple negative breast cancer. Enrolled patients will have completed standard 
neoadjuvant chemotherapy and will have residual disease at the time of definitive breast surgery. 
Patients will have completed adequate local therapy.  
 
4.1.2 Number of Subjects 
45 patients will be enrolled with advanced triple negative breast cancer. Patients who don’t have 
evaluable samples as per protocol will be replaced. 
 
 
4.2 Inclusion Criteria 
1. Biopsy proven TNBC:  
 ER- and PR- defined as 5% cells stain positive 
 HER2 negativity defined as: 
o IHC 0, 1+ without in situ hybridization (ISH) HER2/neu chromosome 17 ratio OR 
o IHC 2+ and ISH HER2/neu chromosome 17 ratio non-amplified with ratio less than 
2.0 and if reported average HER2 copy number < 6 signals/cells 
2. Residual disease of 1.0 cm at least of the primary tumor and/or node positive disease (at 
least ypN1) and/or Residual Cancer Burden (RBC) classification II or III. Tissue availability 
needs to be confirmed and should be received by the lead institution by day 1 of study 
treatment. (Note: As long as tissue sample is confirmed shipped, the subject will be eligible) 
3. Patients must have completed neoadjuvant chemotherapy; patients must NOT have 
received capecitabine as part of their neoadjuvant therapy regimen. Acceptable 
preoperative regimens include an anthracycline or a taxane, or both. Participants who 
received preoperative therapy as part of a clinical trial may enroll. Participants may not 
have received adjuvant chemotherapy after surgery prior to randomization. Carboplatin-
containing neoadjuvant chemotherapy is also allowed). Patients who cannot complete all 
planned neoadjuvant treatment cycles for any reason are considered high risk and 
therefore are eligible for the study if they have residual disease.  
4. Recovery of all toxicities from previous therapies to at least grade 1, except alopecia and 
≤ grade 2 neuropathy which are allowed. 
5. Must have completed definitive resection of primary tumor and have no evidence of 
unresected or metastatic disease at the time of study entry. For those who don’t require 
radiotherapy, the most recent surgery for breast cancer must have been completed at least 
14 days prior to day 1 of study treatment, but no more than 84 days prior to study 
registration. 
 Negative margins for both invasive and ductal carcinoma in situ (DCIS) are desirable, 


 
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however patients with positive margins may enroll if the treatment team believes no 
further surgery is possible and patient has received radiotherapy; patients with margins 
positive for lobular carcinoma in situ (LCIS) are eligible 
 Either mastectomy or breast conserving surgery (including lumpectomy or partial 
mastectomy) is acceptable 
 Sentinel node biopsy post neoadjuvant chemotherapy (i.e. at the time of definitive 
surgery) is allowed; axillary dissection is encouraged in patients with lymph node 
involvement, but is not mandatory 
 Whole breast radiotherapy is required for participants who underwent breast-conserving 
therapy, including lumpectomy or partial mastectomy. Participants must have completed 
radiotherapy at least 14 days prior (but no more than 84 days prior) to day 1 of study 
treatment. 
 Post-mastectomy radiotherapy is required for all participants with a primary tumor ≥ 5 
cm or involvement of ≥ 4 lymph nodes. For participants with primary tumors < 5 cm or 
with < 4 involved lymph nodes, provision of post-mastectomy radiotherapy is at the 
discretion of the treating physician.  
6. ECOG PS 0-1 
7. Patients must not be planning to receive concomitantly other biologic therapy, hormonal 
therapy, other chemotherapy, surgery, radiation therapy or other anti-cancer therapy while 
receiving treatment on this protocol.  
8. At the time of registration (randomization), patients must have the following laboratory 
results (obtained within 28 days prior to registration): 
a.  A serum TSH prior to registration to obtain a baseline value.  
b.  Patients must have adequate bone marrow function as evidenced by all of the 
following:  
 
- ANC ≥ 1,500 microliter (mcL);  
 
- Platelets ≥ 100,000/mcL;  
 
- Hemoglobin ≥ 9 g/dL.  
 c.  Patients must have adequate hepatic function as evidenced by the following:  
 
- Total bilirubin ≤ 1.5 x institutional upper limit of normal (IULN) (except Gilbert’s 
 
Syndrome, who must have a total bilirubin < 3.0 mg/dL), and  
 
- SGOT (AST) or SGPT (ALT) and alkaline phosphatase ≤ 2.5 x IULN.  
d.  Patients must have adequate renal function as evidenced by ONE of the following:  
 
- Serum creatinine ≤ IULN OR  
 
- Measured or calculated creatinine clearance ≥ 60 mL/min.  
e.  Normal thyroid function or stable on hormone supplementation (Patients that meet the 
definition of asymptomatic subclinical hypothyroidism will be eligible to participate) 
f.  Women of childbearing potential (WOCBP) must have a negative urine or serum 
pregnancy test within 28 days prior to registration and within 24h prior to the start of 
nivolumab. In addition, women of childbearing potential must agree to have a 
pregnancy test every 4 weeks while on nivolumab.  
9. Signed ICF 


 
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10. Age ≥18 
 
 
4.3 Exclusion criteria 
1. Stage IV disease 
2. Receipt of adjuvant chemotherapy 
3. Diagnosis of other invasive cancer except for adequately treated cervix cancer or skin cancer, 
or more than 5 years since other diagnosis of invasive cancer without current evidence of 
disease  
4. Previous exposure to capecitabine, fluorouracil or immunotherapy with anti-PD1, anti-PDL1, 
anti-CTLA4 or similar drugs.  
5. Active autoimmune disease that has required systemic treatment in the past 2 years; 
replacement therapy is not considered a form of systemic therapy. Autoimmune diseases 
include but are not limited to myasthenia gravis, myositis, autoimmune hepatitis, systemic 
lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular thrombosis 
associated with antiphospholipid syndrome, Wegener’s granulomatosis, Sjogren’s 
syndrome, Guillain-Barre syndrome, multiple sclerosis, vasculitis or glomerulonephritis.  
6. TB, active hepatitis B (defined as having a positive hepatitis B surface antigen [HBsAg]), 
active hepatitis C (defined as positive test for hepatitis C viral load by polymerase chain 
reaction [PCR]) or other active infection. Patients with past hepatitis B virus (HBV) infection 
or resolved HBV infection (defined as having a negative HBsAg test and a positive antibody 
to hepatitis B core antigen [anti-HBc] antibody test) are eligible. Patients with positive 
hepatitis C antibody and negative quantitative hepatitis C by PCR are eligible. Patients who 
have completed curative therapy for HCV are eligible. Patients with known HIV infection are 
eligible if they meet each of the following 3 criteria: CD4 counts ≥ 350 mm3; serum HIV viral 
load of < 25,000 IU/ml and treated on a stable antiretroviral regimen.  
7. History of (non-infectious) pneumonitis that required steroids or evidence of active pneumonia 
8. Uncontrolled disease 
9. Chronic use of systemic steroids 
10.  Live vaccine within 30 days prior to registration.  
11.  Incapacity to provide consent or to follow clinical trial procedures 
12.  Pregnancy, lactation, or planning to be pregnant 
 
Patients with microsatellite unstable tumors will not be excluded as immunotherapy as 
adjuvant therapy is not standard for these patients but we will prospective collect this data. 
 
 


 
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4.4 Additional Study Restrictions 
4.4.1 Other Anticancer Therapy 
For purposes of this protocol, anti-tumor treatment may be defined as, but is not limited to, 
anti-cancer agents (endocrine therapy, cytotoxic chemotherapy, immunotherapy, or biologic 
therapy), radiotherapy, and investigational agents. An investigational agent is any drug or 
therapy not currently approved for use in humans. No other anticancer therapy is permitted 
during the course of the study treatment for any patient (the patient can receive a stable dose 
of corticosteroids during the study as long as these were started at least 4 weeks prior to 
enrollment and the total daily dose does not exceed 10mg of prednisone, or the equivalent, per 
exclusion criteria above). If the patient discontinues study treatment, this restriction no longer 
applies, however the patient will remain enrolled in the study for the purpose of collecting 
subsequent outcomes. Radiotherapy is not allowed. 
 
4.4.2 Vaccines 
Live vaccine administration is not permitted within 30 days prior to the first dose of study 
treatment and while participating in the study. Examples of live vaccines include, but are not 
limited to, the following: measles, mumps, rubella, chicken pox, yellow fever, rabies, bacilli 
Calmette-Guerin (BCG), and typhoid (oral) vaccine. Seasonal influenza vaccines for injection 
are generally killed virus vaccines and are allowed. Intranasal influenza vaccines (eg, Flu-
Mist®) are live attenuated vaccines, however, and are not allowed.  
 
4.4.3 Birth Control 
Birth control should be used from the signing of the patient consent form and for 6 months 
following the last dose of nivolumab and capecitabine. Acceptable methods of birth control 
include:  
 At least one highly effective form of contraception, defined as a contraceptive method 
with a failure rate of less than 1% per year when used consistently and correctly. 
 Permanent sterilization, defined as hysterectomy, bilateral salpingectomy, bilateral 
oophorectomy, or bilateral orchiectomy 
 Postmenopausal, defined as a female patient or sexual partner >45 years of age who 
has not menstruated for at least 12 consecutive months 
 Total sexual abstinence  
In addition, men must not donate sperm during nivolumab and capecitabine therapy and for 
seven months after receiving the last dose of study therapy. 
 
4.4.4 Breast Feeding 
Patients must not breastfeed from the first dose and for 1 month following the final dose of 
nivolumab and capecitabine. 


 
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4.4.5 Blood Donation 
Patients must not donate blood during the study or for 90 days after the last dose of study 
treatment. 
 
4.4.6 Immunosuppressive Medication 
Immunosuppressive medications including, but not limited to systemic corticosteroids at doses 
exceeding 10 mg/day of prednisone or equivalent, methotrexate, azathioprine, and TNF-α 
blockers are not allowed. Use of immunosuppressive medications for the management of 
investigational product-related AEs or in subjects with contrast allergies is acceptable. In 
addition, use of inhaled, intranasal, ophthalmic and topical corticosteroids is permitted. A 
temporary period of steroids will be allowed for different indications, at the discretion of the 
principal investigator (e.g., chronic obstructive pulmonary disease, radiation, nausea, etc).    
 
 
4.5 Other Prior and Concomitant Therapy 
Any medication or vaccine (including over-the-counter or prescription medicines, vitamins 
and/or herbal supplements) that the subject is receiving at Screening up to the Final Visit must 
be recorded in source documents and the case report forms (CRFs). The reason for use, 
date(s) of administration (including start and end dates), and dosage information (including 
dose and frequency) must be recorded. Any change in concomitant therapy during the study 
period must be similarly recorded. Questions regarding prior or concomitant therapy should be 
directed to one of the investigators. 
 
4.5.1 Prior Surgery 
Patients must have fully recovered from all effects of surgery.  Patients must have had at least 
two weeks after minor surgery and four weeks after major surgery before starting therapy.  
Minor procedures requiring conscious sedation such as endoscopies or mediport placement 
may only require a 24-hour waiting period, but this must be discussed with an investigator. 
 
4.5.2 Supportive Care 
Subjects should receive best supportive care and treatment of symptoms during the study as 
appropriate, including transfusion of blood and blood products, oxygen therapy, nutritional 
support, intravenous fluids, and treatment with appropriate medications (antibiotics, 
antiemetics, antidiarrheals, and analgesics, etc.).  Medications that are given for supportive 
care, such as appetite stimulation, may be given concurrently. 
 
4.5.2.1 Bisphosphonates and denosumab 
Bisphosphonates and denosumab are permitted for the treatment of osteopenia or 
osteoporosis, or as adjuvant treatment to decrease risk of breast cancer recurrence. 


 
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4.5.2.2 Hematopoietic growth factors 
Hematopoietic growth factors may be used according to the American Society of Clinical 
Oncology (ASCO) guidelines, but not during the first cycle of the study. The patient must be 
referred to a hematologist for further evaluation (1) if frequent transfusions are required or (2) if 
the treatment-related hematologic toxicities have not recovered to CTCAE Grade 1 or less 
after 4 weeks. 
 
4.5.3 For patients randomized to capecitabine (arms B and C), the approved label of 
capecitabine should be followed when concomitantly using: 
a. Anticoagulants, monitor anticoagulant response (INR or prothrombin time) 
frequently to adjust the anticoagulant dose as needed. 
b. Phenytoin, monitor phenytoin levels in patients.  
c. CYP2C9 substrates, caution should be exercised. 
 
 
4.6 Removal/Replacement of Subjects from Therapy or Assessment 
An evaluable patient must meet all inclusion/exclusion criteria, have adequate tissue from 
definitive breast surgery for initial assessment, and be evaluable for the primary study 
endpoints of quantification of immune activation and immunomodulation, as well as the safety 
and tolerability of nivolumab and/or capecitabine.  
 
4.6.1 Screen Failures 
Patients will be identified and enrolled after completing definitive breast surgery. All patients 
must continue to meet the inclusion and exclusion criteria up to and including the first day of 
treatment. Reasons for patients who have enrolled, but become ineligible could include (but 
are not limited to): 
- The patient is no longer eligible based on laboratory parameters 
- The patient’s performance status has declined 
- The patient does not have adequate tissue for initial assessment  
Patients who become ineligible prior to initiation of therapy per protocol will be considered 
screen failures.  Screen failures must be replaced until 45 patients with advanced triple 
negative breast cancer are enrolled. 
 
 
4.6.2 Evaluable Patients 
4.6.2.1 Immune Response Evaluable 
For a patient to be evaluable for immunomodulation by assigned drugs, the patient must be on 
treatment for 6 weeks (when first assessment of peripheral immunoscore will be conducted). 
Any patient who is taken off study prior to completion of 2 cycles (=6 weeks) must be replaced. 


 
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4.7 Multi-Institutional Trial Coordination 
4.7.1 Personnel 
At each site, personnel dedicated to this protocol will be: 
 
- A study PI 
 
- A research coordinator 
 
- A data manager 
 
In addition, the Georgetown Multicenter Project management office will play the primary role in 
coordinating the trial between Lombardi-Georgetown and additional sites.  This Multicenter 
Project Managers will be the main point of contact for Dr. Mainor and the other site PIs for any 
study related concerns, and to confirm eligibility of each patient being considered for 
enrollment (Including “remote” confirmation of eligibility for the patients being screened at other 
sites).  The Project Manager(s) will also be the point of contact for the data managers for data 
entry questions.  Finally, the Project managers will play a major role in regulatory coordination 
of the study, specifically by: 1) Reviewing and confirming all study-related adverse events; 2) 
Ensuring that sites are submitting all severe adverse event (SAE) reports to the site IRB per 
local IRB policy ; 3) Gathering and preparing all necessary primary source data for 
review/audit. 
 
4.7.2 Patient Enrollment 
If a patient is being screened for enrollment, the local research coordinator must send an email 
within 24 hours containing the patient’s initials to the local PI, to Dr. Mainor, and to the Project 
Managers.  If a patient is successfully screened, the local research coordinator must send all 
supporting documentation to the Project Managers(by secure email).  Patients should not start 
therapy until Dr. Mainor and the Project Managers have reviewed the patient’s records and 
confirmed that the patient is indeed eligible for enrollment. 
 
4.7.3 Data Collection and Management  
Patient data will be entered into the on-line accessible database.  This database is housed at 
Lombardi-Georgetown, but is accessible anywhere there is internet access.  The data 
manager and research coordinator at each site will attend an on-line training session so that 
they may learn how to enroll data into the database.  All screening data should be entered 
prior to starting therapy, and all ongoing patient data should be entered within 10 business 
days of each patient visit.   
 
4.7.4 Conference Calls 
A biweekly conference call will be held between Lombardi-Georgetown and the other sites to 
review patient enrollment, toxicity, and response assessment.   


 
Version 7.0, 20 January, 2023 
 
 
 
 
 
31 
 
 
4.7.5 Trial Auditing 
The multicenter Project Manager will request primary source documents for the patients to be 
audited.  This will include collecting copies of the primary source data for any patients treated 
at other sites. 
 
 
5.0 TREATMENT PLAN 
 
If a subject randomizes to Arm A, nivolumab will be provided by the study. 
 
If a subject randomizes to Arm B, medication is not covered by the study and will be handled 
similarly to standard of care medication administration. Therapy will be based on the patient’s 
actual weight. Dose adjustments will be made according to the approved label and at the 
discretion of the treating physician.  
 
If a subject randomizes to Arm C, nivolumab will be provided by the study and capecitabine will 
be covered by patient’s insurance.  
 
Administration of nivolumab and/or capecitabine must be initiated within 2 weeks from 
enrollment in the study arm. 
 
5.1 Dose modifications - General Guidelines 
Participants will be monitored continuously for AEs while on study therapy. Participants will be 
instructed to notify their physician for any and all AEs. Modifications should be applied by the 
investigator’s judgment. In case of an AE relationship assignment to capecitabine alone, dose 
modifications for capecitabine alone are allowed. In case of doubt, both chemotherapy and 
nivolumab doses should be modified. Also, in case of assignment of AE relationship to 
nivolumab alone, dose reduction for chemotherapy is not mandated. Specific algorithms for the 
management of immune-related AEs are provided in Appendix D and are applicable to 
immune-related AEs for all immuno-oncology study treatment combinations. For capecitabine 
chemotherapy, the package insert and local standard of care rules for dose reduction should 
also be applied. 
 
5.2. Nivolumab 
Nivolumab will be given at flat dose of 360 mg iv every 3 weeks for 6 cycles. 
 
 
5.2.1. Dose Modifications 
Immuno-oncology (I-O) agents are associated with AEs that can differ in severity and duration 


 
Version 7.0, 20 January, 2023 
 
 
 
 
 
32 
 
from AEs caused by other therapeutic classes. Early recognition and management of AEs 
associated with I-O agents may mitigate severe toxicity. Management algorithms have been 
developed from extensive experience with nivolumab to assist investigators in assessing and 
managing the following groups of AEs: 
 Gastrointestinal 
 Renal 
 Pulmonary 
 Hepatic 
 Endocrinopathies 
 Skin 
 Neurological 
 
Specific algorithms for the management of immune-related AEs are provided in Appendix D 
and are applicable to immune-related AEs for all immuno-oncology study treatment 
combinations (Arm A and C). 
 
Nivolumab dose modifications do not apply. 
 
For an AE requiring dose modification, chemotherapy, and/or nivolumab should be 
interrupted to allow recovery from the AE. Re-initiation of study treatment cannot occur until 
the AE decreases to  Grade 1 or baseline assessment. In case of delayed recovery to  
Grade 1 or baseline from treatment-related AEs that result in a delay of treatment for > 42 
days, the participant will not receive additional protocol-related therapy and will be removed 
from study unless discussed and agreed upon by the Investigator and Sponsor/Medical 
Monitor that it is in the best interest of the participant to receive additional therapy with 
nivolumab.  
 
Withhold nivolumab for any of the following:  
- 
Grade 2 pneumonitis 
- 
Grade 2 or 3 diarrhea or colitis  
- 
Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) greater than 3 
and up to 5 times upper limit of normal (ULN) or total bilirubin greater than 1.5 and up to 
3 times ULN   
- 
Creatinine greater than 1.5 and up to 6 times ULN or greater than 1.5 times baseline 
- 
Any other severe or Grade 3 treatment-related adverse reactions  
- 
Grade 2 hypophysitis 
- 
Grade 2 adrenal insufficiency 
- 
New-onset moderate or severe neurologic signs or symptoms 
  


 
Version 7.0, 20 January, 2023 
 
 
 
 
 
33 
 
Resume nivolumab in patients whose adverse reactions recover to Grade 0-1.  
 
Permanently discontinue nivolumab for any of the following unless approved by the 
Sponsor/Medical Monitor:  
- 
Any life-threatening or Grade 4 adverse reaction  
- 
Grade 3 or 4 pneumonitis  
- 
Grade 4 diarrhea or colitis   
- 
AST or ALT greater than 5 times ULN or total bilirubin greater than 3 times ULN 
- 
Creatinine greater than 6 times ULN  
- 
Any severe or Grade 3 treatment-related adverse reaction that recurs  
- 
Inability to reduce corticosteroid dose to 10 mg or less of prednisone or equivalent per 
day within 12 weeks  
- 
Persistent Grade 2 or 3 treatment-related adverse reactions that do not recover to 
Grade 0-1 within 12 weeks after last dose of nivolumab 
- 
Grade 3 or 4 adrenal insufficiency 
- 
Immune-mediated encephalitis 
- 
Grade 3 myocarditis 
 
5.2.2. Preparation and Administration  
Visually inspect drug product solution for particulate matter and discoloration prior to 
administration. OPDIVO is a clear to opalescent, colorless to pale-yellow solution. Discard the 
vial if the solution is cloudy, is discolored, or contains extraneous particulate matter other than 
a few translucent-to-white, proteinaceous particles. Do not shake the vial.  
 
5.2.3. Preparation  
Vials of 100mg will be provided. There are 5 vials per carton. 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 of 1-10 mg/mL, with a maximum total volume of 160 mL for prepared 
infusions (including overfill). Mix diluted solution by gentle inversion. Do not shake. Discard 
partially used vials or empty vials of nivolumab. 
 
5.2.4. Storage of Infusion  
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.  


 
Version 7.0, 20 January, 2023 
 
 
 
 
 
34 
 
Do not freeze.  
 
5.2.5. Administration  
Administer the infusion over 60 minutes through an intravenous line containing a sterile, non 
pyrogenic, 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.  
 
5.3. Capecitabine 
 
Capecitabine will be given at 1250 mg/m2 PO BID for Days 1-14 only of a 21-day cycle for 6 
cycles. 
 
Commercially available capecitabine will be used.  Locally obtained commercial supplies of 
capecitabine will be used in accordance with local regulations. As capecitabine is an oral drug 
available in fixed doses, the dose administered may not exactly match the calculated dose. 
Determination of the rounding of capecitabine doses for administration should be made 
according to local institutional practices, with documentation of both the calculated and 
administered dose. Per package insert, it is recommended that capecitabine be administered 
with food. Capecitabine should be stored according to the package insert. For capecitabine, 
the package insert and local standard of care rules for dose reduction should also be applied. 
Dose modifications will be documented. 
 
5.3.1 Dose modifications for capecitabine for clinical adverse events considered related to 
capecitabine 
 
CTCAE Toxicity Grades 
During a course of therapy 
Dose adjustment for Next 
Treatment (% of starting 
dose) 
Grade 1 
Maintain dose level 
Maintain dose level 
Grade 2 
 
 
1st appearance 
Interrupt until resolved to Grade ≤ 
1 
100% 
2nd appearance 
Interrupt until resolved to Grade ≤ 
1 
75% 
3rd appearance 
Interrupt until resolved to Grade ≤ 
1 
50% 
4th appearance 
Discontinue permanently 
NA 
Grade 3 
 
 
1st appearance 
Interrupt until resolved to Grade ≤ 
1 
75% 
2nd appearance 
3rd appearance 
Interrupt until resolved to Grade ≤ 
1 
50% 
NA 


 
Version 7.0, 20 January, 2023 
 
 
 
 
 
35 
 
Discontinue permanently 
Grade 4 
1st appearance 
 
Discontinue permanently 
 
NA 
 
 
 
 
 
6.0 STUDY PROCEDURES AND TREATMENT ASSIGNMENT 
 
6.1. Table of events 
 
 
Pre-
registration 
Screening 
On Study  
(maximum 6 cycles; 
cycle is every 21 d) 
Treatment 
discontinuation 
Surveillance 
 
Post-
surgery 
-30 days 
D1 of each cycle +/- 
7 days. Each cycle 
is 21 days. 
30 days (+/-7 
days) after last 
dose 
 
Assessments 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
Medical history and height 
 
X 
 
 
 
Physical examination 
 
X 
X^ 
X 
 
Weight, BP 
 
X 
X^ 
X 
 
ECOG PS 
 
X 
X^ 
X 
 
CMP 
 
X 
X 
X 
 
Creatinine clearance 
 
X 
X 
X 
 
CBC with differential 
 
X 
X 
X 
 
Breast imaging (remaining 
tissue only) 
 
 
 
 
Yearly +/- 
30 days 
Adverse event and con 
meds assessment 
 
X 
X^ 
 
 
Urine pregnancy or serum 
HCG for WOCBP only 
 
X 
X^ (every 3 weeks) 
for Arm A and C 
 
 
ACTH and Thyroid 
Function Tests#  
 
X 
X^ (week 12) for  
Arm A and C 
X 
 
Hepatitis and HIV 
screening*  
 
X 
 
 
 
EORTC QLQ-C30& 
 
X 
X (week 6) 
X 
 
Telephone communication 
or focused physical exam+ 
 
 
 
 
Every 3-6 
months  
Treatment 
 
 
 
 
 
 
 
 
Nivolumab 360mg 
iv q3w; 
capecitabine 
1250mg/m2 D1-14 
 
 


 
Version 7.0, 20 January, 2023 
 
 
 
 
 
36 
 
Correlative Samples 
 
 
 
 
 
Tumor from initial 
diagnosis  
 
X (if 
available) 
 
 
 
Tumor from definitive 
surgery – with IHC testing 
for MSI 
X 
 
 
 
 
Serum for peripheral 
immunoscore 
 
 
X^ (baseline, week 
6 and 12) 
X (if 
recurrence) 
 
Blood for ct-DNA$ 
 
 
X^$ (baseline, 
week 6 and 12) 
X (if 
recurrence) 
 
Tumor from metastatic site 
 
 
 
X (if 
recurrence) 
 
# Thyroid-stimulating hormone (TSH); free T3 and free T4 at screening and reflex when TSH is 
abnormal at subsequent visits 
* hepatitis B surface antigen, anti-HBc, anti-HBs, hepatitis C antibody (if hep C Ab is positive, 
reflex to Hep C RNA) or hep C RNA, HIV-1 and -2 antibody (testing for HIV-1 and HIV-2 must 
be performed at sites where mandated by local requirements)  
$ there will be an optional draw for ct-DNA 24-48h after the first drug administration 
^ +/- 7 days. If a cycle is delayed due to blood counts, no need to repeat physical exam and 
correlative samples. The correlatives should follow C1D1 as baseline whenever possible and 
not be delayed in case of delays in treatment. 
+ Every 3 months +/- 30 days for the first 2 years, then every 6 months +/- 30 days in year 3 
& EORTC QLQ-C30 questionnaires to be completed at screening, week 6 and end of treatment 
 
6.2. Pre-registration 
Participants who sign informed consent will be pre-registered and tissue from surgery will be 
requested. Once confirmed availability and sufficient material, patients will undergo screening 
materials. 
 
6.3. Screening 
Within 30 days of study registration: 
- 
Complete medical history and complete physical examination including: height, weight, 
BP and ECOG performance status 
- 
Complete metabolic profile including serum chemistries and electrolytes 
- 
Calculated creatinine clearance 
- 
Complete blood count with differential 
- 
Urine pregnancy test or serum HCG (only in women of child bearing potential, WOCBP) 
within 24 hours prior to the start of nivolumab. Women should be counseled regarding 
acceptable birth control methods to utilize from the time of screening to start treatment. 
In addition, women of child bearing potential must accept to have a pregnancy test 
every 3 weeks if they are randomized to a nivolumab arm. 
- 
Adverse event and concomitant medication assessment 


 
Version 7.0, 20 January, 2023 
 
 
 
 
 
37 
 
- 
EORTC QLQ-C30 should be completed during screening  
- 
Obtain tumor from definitive breast surgery (mandatory) and from initial biopsy (if tissue is 
available) and send to the main site (Georgetown). See lab manual for more details. 
Note: Assessments performed for clinical indications (not exclusively to determine study 
eligibility) may be used for screening/baseline values even if the studies were done before 
informed consent was obtained.  
 
6.4. Randomization 
Eligible patients will be randomized to one of three arms (see 8.3.) 
 
6.5. On Study Day 1 
Cycle 1 Day 1 testing need not to be repeated if completed within 14 days of starting therapy. 
Will be obtained blood samples for correlative studies (see Correlative Laboratory Manual for 
more details). Cycle 1 Day 1 must occur within 2 weeks after receiving randomization results. 
 
6.6. On Treatment 
Blood samples will be obtained for correlative studies on week 6 and 12 (see Correlative 
Laboratory Manual for more details). 
 
6.7. Treatment discontinuation 
A participant will be discontinued from the protocol therapy under the following circumstances: 
- if there is evidence of progressive disease 
- if the treating physician thinks a chance of therapy would be in the best interest of the 
participant 
- if the participant withdraws consent to protocol treatment 
- if the drug exhibits unacceptable adverse events. Participants will be followed until the 
resolution of these adverse events. 
- if a participant becomes pregnant 
 
Patients may temporarily suspend study treatment if they experience an adverse event that 
requires a dose to be held. If study treatment is held because of adverse events for > 42 days 
beyond what was planned, then the patient will be discontinued from any study drug and be 
followed for safety. If, in the judgment of the investigator, the patient is likely to derive clinical 
benefit from resuming nivolumab and/or capecitabine after a hold > 42 days, study drug may 
be restarted with the approval of the Medical Monitor. 
 
Dose interruptions for reason(s) other than adverse events, such as surgical procedures, may 
be allowed with Medical Monitor approval. The acceptable length of interruption will depend on 
agreement between the investigator and the Medical Monitor. 
 


 
Version 7.0, 20 January, 2023 
 
 
 
 
 
38 
 
After treatment discontinuation, in the event of a continuing AE, patients must be followed up 
until resolution or stabilization of the AE. 
 
6.8. Surveillance 
Participants will be monitored by their treating physicians for the development of either local 
(chest wall, axillary, or supraclavicular nodes) or distant recurrent disease, and survival, at 
least once every 3 months for the first two years, then at least every 6 months during year 
3. Surveillance will be done through telephone communication, focused physical exam or 
review of medical records. Surveillance for immune-related adverse events will be included in 
these follow up visits or telephone calls. The Principal Investigator will notify the Data Safety 
Monitoring Board of any serious adverse events and immune related adverse events that are 
believed to be related to prior drug treatment or study procedures that occur at any time after a 
patient has discontinued treatment. 
 
For those patients that develop a recurrence while on active treatment or during the follow up 
period (i.e. 3 years), blood correlatives (ctDNA and PIS) and tissue biopsy will be obtained. 
Tissue for research will only be requested (one block or 13 unstained slides) if a biopsy is done 
as part of routine care, either to confirm metastatic disease and/or to repeat markers. 
 
7.0 SAFETY VARIABLES AND TOXICITY ASSESSMENT 
 
7.1. Serious Adverse Events 
A Serious Adverse Event (SAE) is any untoward medical occurrence that at any dose:  
 results in death 
 is life-threatening (defined as an event in which the participant was at risk of death at the 
time of the event; it does not refer to an event which hypothetically might have caused 
death if it were more severe) 
 requires inpatient hospitalization or causes prolongation of existing hospitalization (see 
NOTE below) 
 results in persistent or significant disability/incapacity 
 is a congenital anomaly/birth defect  
 is an important medical event (defined as a medical event(s) that may not be immediately 
life-threatening or result in death or hospitalization but, based upon appropriate medical 
and scientific judgment, may jeopardize the subject or may require intervention [eg, 
medical, surgical] to prevent one of the other serious outcomes listed in the definition 
above.) Examples of such events include, but are not limited to, intensive treatment in an 
emergency room or at home for allergic bronchospasm; blood dyscrasias or convulsions 
that do not result in hospitalization.)  


 
Version 7.0, 20 January, 2023 
 
 
 
 
 
39 
 
 Suspected transmission of an infectious agent (eg, pathogenic or nonpathogenic) via the 
study drug is an SAE.  
Although pregnancy, overdose, potential drug-induced liver injury (DILI), and cancer are not 
always serious by regulatory definition, these events must be handled as SAEs. 
Any component of a study endpoint that is considered related to study therapy should be 
reported as an SAE (eg, death is an endpoint, if death occurred due to anaphylaxis, 
anaphylaxis must be reported). 
NOTE:  
The following hospitalizations are not considered SAEs in BMS clinical studies:  
 a visit to the emergency room or other hospital department < 24 hours, that does not 
result in admission (unless considered an important medical or life-threatening event) 
 elective surgery, planned prior to signing consent 
 admissions as per protocol for a planned medical/surgical procedure 
 routine health assessment requiring admission for baseline/trending of health status (eg, 
routine colonoscopy) 
 Medical/surgical admission other than to remedy ill health and planned prior to entry into 
the study. Appropriate documentation is required in these cases. 
 Admission encountered for another life circumstance that carries no bearing on health 
status and requires no medical/surgical intervention (eg, lack of housing, economic 
inadequacy, caregiver respite, family circumstances, administrative reason). 
 Admission for administration of anticancer therapy in the absence of any other SAEs 
(applies to oncology protocols) 
 
All Serious Adverse Events (SAEs) that occur following the subject’s written consent to 
participate in the study through 100* days of discontinuation of dosing must be reported to 
BMS Worldwide Safety, whether related or not related to study drug. If applicable, SAEs must 
be collected that relate to any later protocol-specified procedure (eg, a follow-up skin biopsy). 
 
Following the subject’s written consent to participate in the study, all SAEs, whether related or 
not related to study drug, are collected, including those thought to be associated with protocol-
specified procedures. The investigator should report any SAE occurring after these 
aforementioned time periods, which is believed to be related to study drug or protocol-specified 
procedure. 


 
Version 7.0, 20 January, 2023 
 
 
 
 
 
40 
 
 
7.1.1 SAE reporting 
An SAE report should be completed for any event where doubt exists regarding its 
seriousness. If the investigator believes that an SAE is not related to study drug, but is 
potentially related to the conditions of the study (such as withdrawal of previous therapy or a 
complication of a study procedure), the relationship should be specified in the narrative section 
of the SAE Report Form. If the BMS safety address is not included in the protocol document 
(eg, multicenter studies where events are reported centrally), the procedure for safety reporting 
must be reviewed/approved by the BMS Protocol Manager. Procedures for such reporting 
must be reviewed and approved by BMS prior to study activation. 
 
An appropriate SAE form (USA = MedWatch form) should be used to report SAEs to BMS. The 
BMS protocol ID number must be included on whatever form is submitted by the 
Sponsor/Investigator.  
 
For studies with long-term follow-up periods in which safety data are being reported, include 
the timing of SAE collection.  
The Sponsor will reconcile the clinical database SAE cases (case level only) transmitted to 
BMS Global Pharmacovigilance (Worldwide.Safety@bms.com). Frequency of reconciliation 
should be every 3 months and prior to the database lock or final data summary. BMS GPV&E 
will email, upon request from the Investigator, the GPV&E reconciliation report. Requests for 
reconciliation should be sent to aepbusinessprocess@bms.com. The data elements listed on 
the GPV&E reconciliation report will be used for case identification purposes. If the Investigator 
determines a case was not transmitted to BMS GPV&E, the case should be sent immediately 
to BMS 
The MedWatch form is available at: 
https://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Forms/UCM048334.pdf  
In accordance with local regulations, BMS will notify investigators of all reported SAEs that are 
suspected (related to the investigational product) and unexpected (i.e., not previously 
described in the IB). An event meeting these criteria is termed a Suspected, Unexpected 
Serious Adverse Reaction (SUSAR). Investigator notification of these events will be in the form 
of a SUSAR Report.  
SAEs, whether related or not related to study drug, and pregnancies must be reported to BMS 
within 24 hours. SAEs must be recorded on either CIOMS or MedWatch form & pregnancies 
must be reported on a Pregnancy Surveillance Form or can be submitted on the 
aforementioned SAE form to BMS. 


 
Version 7.0, 20 January, 2023 
 
 
 
 
 
41 
 
Other important findings which may be reported by BMS as an Expedited Safety Report (ESR) 
include: increased frequency of a clinically significant expected SAE, an SAE considered 
associated with study procedures that could modify the conduct of the study, lack of efficacy 
that poses significant hazard to study subjects, clinically significant safety finding from a 
nonclinical (eg, animal) study, important safety recommendations from a study data monitoring 
committee, or sponsor decision to end or temporarily halt a clinical study for safety reasons. 
Upon receiving an ESR from BMS, the investigator must review and retain the ESR with the 
IB. Where required by local regulations or when there is a central IRB/IEC for the study, the 
sponsor will submit the ESR to the appropriate IRB/IEC. The investigator and IRB/IEC will 
determine if the informed consent requires revision. The investigator should also comply with 
the IRB/IEC procedures for reporting any other safety information.  
In addition to the Sponsor Investigator’s responsibility to report events to their local HA, 
suspected serious adverse reactions (whether expected or unexpected) shall be reported by 
BMS to the relevant competent health authorities in all concerned countries according to local 
regulations (either as expedited and/or in aggregate reports). 
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 to BMS (or 
designee) using the same procedure used for transmitting the initial SAE report.  
All SAEs should be followed to resolution or stabilization. 
 
SAE Reporting for Subsites: Subsites should report all SAEs to Georgetown using the 
MedWatch form within 24 hours. Georgetown will then forward SAE reports to BMS Safety 
within 24 hours through email or fax. 
 
7.2. Adverse Events 
An Adverse Event (AE) is defined as any new untoward medical occurrence or worsening of a 
preexisting medical condition in a clinical investigation participant administered study drug and 
that does not necessarily have a causal relationship with this treatment. An AE can therefore 
be any unfavorable and unintended sign (such as an abnormal laboratory finding), symptom, 
or disease temporally associated with the use of investigational product, whether or not 
considered related to the investigational product. 
 


 
Version 7.0, 20 January, 2023 
 
 
 
 
 
42 
 
The causal relationship to study drug is determined by a physician and should be used to 
assess all adverse events (AE). The casual relationship can be one of the following: 
a. Related: There is a reasonable causal relationship between study drug 
administration and the AE. 
b. Not related: There is not a reasonable causal relationship between study drug 
administration and the AE.  
 
The term "reasonable causal relationship" means there is evidence to suggest a causal 
relationship.  
Adverse events can be spontaneously reported or elicited during open-ended questioning, 
examination, or evaluation of a subject. (In order to prevent reporting bias, subjects should not 
be questioned regarding the specific occurrence of one or more AEs.) 
 
7.2.1. Nonserious Adverse Events  
Non-serious Adverse Events (AE) are to be provided to BMS in aggregate via interim or final 
study reports as specified in the agreement or, if a regulatory requirement [eg, IND US trial] as 
part of an annual reporting requirement.  
 
 Non-serious AE information should also be collected from the start of a placebo lead-in 
period or other observational period intended to establish a baseline status for the 
subjects.  
 
A non-serious adverse event is an AE not classified as serious.  
 
7.2.1.1. Non-serious Adverse Event Collection and Reporting 
The collection of non-serious AE information should begin at initiation of study drug. All 
non-serious adverse events (not only those deemed to be treatment-related) should be 
collected continuously during the treatment period and for a minimum of 30 days following the 
last dose of study treatment.  
 
Non-serious AEs should be followed to resolution or stabilization, or reported as SAEs if they 
become serious. Follow-up is also required for non-serious AEs that cause interruption or 
discontinuation of study drug and for those present at the end of study treatment as 
appropriate.  
 
7.3. Adverse Events Associated with the Use of Immune Checkpoint Inhibitor 
The immune-related AEs listed below have been reported as related to the use of Nivolumab. 
Each subject who receives Nivolumab (arms A and C) will be closely monitored by the 
Investigator and managed, as appropriate, per the respective product labels. In addition, all 


 
Version 7.0, 20 January, 2023 
 
 
 
 
 
43 
 
immune-related AEs will be evaluated by the Safety Review Committee throughout the 
conduct of this study. 
 
Subjects in treatment Arms A and C will be monitored for: 
 
 Pneumonitis 
 Colitis 
 Hepatitis 
 Hypophysitis  
 Thyroid disorders 
 Adrenal insufficiency 
 Diabetes mellitus 
 Nephritis and renal dysfunction 
 Rash 
 Encephalitis 
 
7.4. Laboratory Test Abnormalities 
All laboratory test results captured as part of the study should be recorded following 
institutional procedures. Test results that constitute SAEs should be documented and reported 
to BMS as such. 
 
The following laboratory abnormalities should be documented and reported appropriately: 
 any laboratory test result that is clinically significant or meets the definition of an SAE 
 any laboratory abnormality that required the participant to have study drug discontinued 
or interrupted 
 any laboratory abnormality that required the subject to receive specific corrective therapy.  
 
It is expected that wherever possible, the clinical rather than laboratory term would be used by 
the reporting investigator (eg, anemia versus low hemoglobin value). 
 
7.4.1. Potential Drug Induced Liver Injury (DILI)  
Specific criteria for identifying potential DILI have not been identified for this protocol. Standard 
medical practice in identifying and monitoring hepatic issues should be followed. 
Wherever possible, timely confirmation of initial liver-related laboratory abnormalities should 
occur prior to the reporting of a potential DILI event. All occurrences of potential DILIs, meeting 
the defined criteria, must be reported as SAEs. 
 
Potential drug induced liver injury is defined as:  
1) AT (ALT or AST) elevation > 3 times upper limit of normal (ULN) 


 
Version 7.0, 20 January, 2023 
 
 
 
 
 
44 
 
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. 
 
Wherever possible, timely confirmation of initial liver-related laboratory abnormalities should 
occur prior to the reporting of a potential DILI event. All occurrences of potential DILIs, meeting 
the defined criteria, must be reported as SAEs. 
 
7.5. 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).  
 
The investigator must immediately notify Worldwide.Safety@bms.com of this event via either 
the CIOMS, MedWatch or appropriate Pregnancy Surveillance Form in accordance with SAE 
reporting procedures. Protocol-required procedures for study discontinuation and follow-up 
must be performed on the participant. Follow-up information regarding the course of the 
pregnancy, including perinatal and neonatal outcome and, where applicable, offspring 
information must be reported on the CIOMS, MedWatch or appropriate Pregnancy 
Surveillance 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.  
 
7.6. Overdose 
An overdose is defined as the accidental or intentional administration of any dose of a product 
that is considered both excessive and medically important. All occurrences of overdose must 
be reported as an SAE. 
 
7.7. Other Safety Considerations 
Any significant worsening noted during interim or final physical examinations, 
electrocardiograms, X-rays, and any other potential safety assessments, whether or not these 


 
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procedures are required by the protocol, should also be recorded as a non-serious or serious 
AE, as appropriate, and reported accordingly.  
 
 
7.8. Study Monitoring 
7.8.1 Data Safety Monitoring Committee at Georgetown 
The Georgetown Lombardi Comprehensive Cancer Center (LCCC) will be responsible for the 
data and safety monitoring of this trial.  As this study is an investigator initiated study utilizing 
FDA-approved on label, and off label therapies, it is considered a high-risk study which requires 
real-time monitoring by the PI and study team and quarterly reviews by the LCCC Data and 
Safety Monitoring Committee (DSMC). 
 
The Principal Investigator, Dr. Mainor, and the Study Chair will review the data including safety 
monitoring at their monthly teleconferences with participating sites.   
 
All SAEs are required to be reported to Dr. Mainor and the Multicenter Project Manager(s). In 
additions, SAEs should be reported to the local and/or to the Georgetown IRB per local IRB 
policy.  Based on SAEs, the IRB retains the authority to suspend further accrual pending more 
detailed reporting and/or modifications to further reduce risk and maximize the safety of 
participating patients. 
 
Progress on the trial and the toxicities experienced will be reviewed by the LCCC Data and 
Safety Monitoring Committee every 3 months from the time the first patient is enrolled on the 
study. Results of the DSMC meetings will be forwarded to the IRB with recommendations 
regarding need for study closure. DSMC recommendations should be based not only on results 
for the trial being monitored as well as on data available to the DSMC from other studies.  It is 
the responsibility of the PI to ensure that the DSMC is kept apprised of non-confidential results 
from related studies that become available.  It is the responsibility of the DSMC to determine the 
extent to which this information is relevant to its decisions related to the specific trial being 
monitored. 
 
A written copy of the DSMC recommendations will be given to the trial PI and the IRB.  If the 
DSMC recommends a study change for patient safety or efficacy reasons the trial PI must act to 
implement the change as expeditiously as possible. In the unlikely event that the trial PI does 
not concur with the DSMC recommendations, then the LCCC Associate Director of Clinical 
Research must be informed of the reason for the disagreement. The trial PI, DSMC Chair, and 
the LCCC Associate Director for Clinical Research will be responsible for reaching a mutually 
acceptable decision about the study and providing details of that decision to the IRB.  
Confidentiality must be preserved during these discussions.  However, in some cases, relevant 
data may be shared with other selected trial investigators and staff to seek advice to assist in 


 
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reaching a mutually acceptable decision. If a recommendation is made to change a trial for 
reasons other than patient safety or efficacy the DSMC will provide an adequate rationale for its 
decision. If the DSMC recommends that the trial be closed for any reason, the recommendation 
will be reviewed by the Associate Director for Clinical Research at LCCC.  Authority to close a 
trial for safety reasons lies with the IRB, with the above described input from DSMC and the 
Associate Director for Clinical Research.   
 
Of note, the DSMC will also review the safety data of the patients enrolled outside of Georgetown 
University.  The Multicenter Project Manager will be tasked with the job of requesting and 
collecting primary source documentation for patients enrolled outside of Georgetown University.  
In addition, the data managers at each site will be entering data into the Georgetown database, 
so that all data will be available for the DSMC at Georgetown to review.  Records should be sent 
to the Multicenter Project Manager(s) and Dr. Mainor via email. 
 
 
7.9 Protocol Deviations and Violations 
Protocol deviations (including violations) are cases of drug administration, radiotherapy, clinical 
laboratory tests, toxicity evaluation, efficacy evaluation, etc., not being carried out in 
accordance with the study protocol. There are three categories of deviation, as detailed below. 
 
7.9.1 Violations 
In general, violations are deviations from the study protocol that meet any one of the following 
criteria: 
1. The deviation affects evaluation of the study endpoints 
2. The party responsible for the deviation is a responsible physician and/or medical institution 
3. The deviation was deliberate and/or long-term 
4. The deviation presented risks for the patients and/or was major 
5. As a result of the violation, the procedure followed was inappropriate for clinical use 
Violations must be described in detail in all published reports. 
 
7.9.2 Deviations 
This refers to deviations that belong to neither the “violation” nor “acceptable deviation” 
categories. If a particular deviation occurs numerous times, it is preferable for it to be included 
in published reports. 
 
7.8.3. Acceptable Deviations 
Acceptable deviations deviate from the protocol within a range that has been agreed upon, 
either beforehand or after the fact, by the study group and the Administrative Office. 
 
 
 
8.0. STATISTICAL CONSIDERATIONS 
8.1 Objectives 


 
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Primary objective: 
2) To assess the immunologic effects of capecitabine, nivolumab or the combo, post 
neoadjuvant and post-surgery, in the adjuvant setting, in patients with high risk TNBC as 
defined by presence of residual disease (breast and or LNs) at surgery, in terms of the 
change of PIS. 
a) We hypothesized that among patients with TNBC and residual disease at the time of 
surgery, the change of the Peripheral ImmunoScore (PIS) from baseline to week 6 will 
be higher among those who receive post-surgery immunotherapy (ARM A and C), 
compared to those who receive post-surgery chemotherapy alone (ARM B).  
Secondary objectives: 
1). To determine the incidence of toxicity graded using the National Cancer Institute CTCAE v. 
4.0 until 30 days after last dose of treatment on trial. 
2). To determine association between changes in PIS from baseline to week 6 and week 12 and 
clinical outcome variables (DRFS and OS at 2-years). After end of study visit, clinical follow up 
or telephone communication every 3months. 
3) To describe the following endpoints and compare them between arms: DRFS, OS   
4). Translational endpoints:  
a) To assess changes in  
b) circulating tumor DNA (ct-DNA) during treatment 
Exploratory objectives: 
a) To describe the immune contexture in residual tumors of patients with high risk TNBC 
after receiving neoadjuvant chemotherapy 
b) Tissue banking for future studies (NGS of initial biopsy and surgical specimen), plasma, 
PBMCs 
 
 
8.2 Sample Size Considerations 
The primary objective of the study is to assess the change in PIS, the Peripheral 
ImmunoScore, at 6 weeks (=2 cycles) from baseline, in each arm.      
 
The sample size of 15 per arm (45 totally for 3 arms) is mainly based on the feasibility of 
patient accrual. A sample size of 15 per arm will have about 85% power to detect an effect size 
of 1 (the difference of the change in PIS from baseline to week 6 between two arms divided by 
the standard deviation) at 5% significance level.  
 
8.3. Randomization and Stratification Factors 
Stratified randomization will be used to assign patients into the three arms. There will 
 be three strata: nivolumab (arm A), capecitabine (arm B) and nivolumab/capecitabine combo 
(arm C). Within each stratum, blocked randomization with randomly selected block sizes will 


 
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be used. The stratified randomization procedure will be carried out by the biostatistician(s) at 
the LCCC Biostatistics and Bioinformatics Shared Resource. They will implement the 
randomization, such as generate the randomization table and hold the randomization key.  
 
8.4 Endpoints 
8.4.1. Primary Endpoint 
 
a. Quantification of immune activation measured by changes of PIS from baseline to week 
6 in each arm.  
 
8.4.2 Secondary Endpoints 
a. Quantification of immune activation measured by changes of PIS from baseline to week 
12 in each arm.  
b. Quantification of grade 3 and 4 toxicities according to the National Cancer Institute 
Common Toxicity Criteria for Adverse Events Version 4.0 [NCI CTCAE v4.03] 
c. Association between changes in PIS from baseline to week 6 and week 12 and clinical 
outcome variables (DRFS and OS at 2-years). Distant recurrence free survival (DRFS) is 
defined by time from study enrollment to date of first invasive distant disease recurrence, 
second invasive primary cancer (breast or not), or death due to any cause. 
d. To describe the following endpoints and compare them between arms: DRFS, OS   
e. Quantification of ct-DNA at different time points 
 
8.4.3 Exploratory Endpoints 
f. Quantification of immune activation by IHC, flow cytometry and ELISA analysis 
g. Quantification of antigen-specific responses by intracellular cytokine staining and CD8+ 
T-cell clonal expansion 
 
8.5 Analysis Plan 
8.5.1. Analysis for the Primary Endpoint 
For the primary endpoint, the observed change of PIS from baseline to week 6 in each arm will 
be presented with its 95% confidence interval. The difference of the change of PIS between 
treatment arms will be compared using two-sample t-test. 
 
For a patient to be evaluable for immunomodulation, measured by the peripheral immunoscore, 
by nivolumab, capecitabine or the combo, the patient must complete the first 2 cycles. Any 
patient who is taken off study prior to completion of 2 cycles must be replaced. 
 
8.5.2. Analysis for the Secondary Endpoint 
The observed incidence of toxicity will be tabulated according to the grade level and the 
attribution using the National Cancer Institute CTCAE v. 4.0. Fisher’s Exact test will be used to 
compare the incidence rate of toxicity between treatment groups. We expect that among 


 
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patients with TNBC and residual disease at the time of surgery, those who receive post-
surgery immunotherapy (ARM A and C) will have longer invasive disease-free survival (DRFS) 
time compared to those who receive post-surgery chemotherapy alone (ARM B). Patients will 
be followed for DRFS and overall survival (OS) for 3 years. The Kaplan-Meier method will be 
used to analyze the DRFS and OS. The DRFS and OS at year 2 will be presented with their 
95% confidence intervals. Log-rank test will be used to compare the DRFS and OS between 
treatment groups.  
 
 
9.0 CORRELATIVE RESEARCH 
 
9.1 Peripheral Immunoscore 
We selected the refined PIS15 as a surrogate of clinical benefit and a new strategy to identify 
patients with TNBC and high-risk disease who may benefit from immunotherapy to eliminate 
residual micrometastasis. The peripheral immunoscore was calculated based on a predefined 
analyses of refined immune cell subsets for which a biologic function had been previously 
reported revealed statistically significant improved PFS (P < 0.001) in patients with metastatic 
breast cancer receiving docetaxel plus immunotherapy compared to docetaxel alone (Fig 2). 
To calculate the PIS, flow cytometry was performed on PBMC harvested at different time 
points. A multiparametric flow cytometry platform was applied to measure the frequency of 
PBMC. Patients' PBMCs by density gradient separation, and then 1 mL of PBMCs was 
cryopreserved in liquid nitrogen at a concentration of 107 cells/mL per vial. On the day of 
staining, one vial of cryopreserved PBMCs per patient was defrosted, cells were counted, and 
then stained with the appropriate monoclonal antibodies. Table 1 shows the classic immune 
cell types as well as those refined subsets with a phenotype reflecting immune function. 
Viability of all samples following thawing after cryopreservation was 80% to 95%. The 
frequency of individual subsets was calculated as a percentage of total PBMCs to help reduce 
the bias that could occur in the smaller subpopulations with fluctuations in parental leukocyte 
populations. The PIS defined by Farsaci et al was selected based on being the closest to the 
particular scenario proposed on the OXEL study. This has been validated in a group of 
patients with metastatic BC receiving docetaxel and immunotherapy, and shown to be 
predictive of PFS. While this (and other) immune biomarkers in the blood available today have 
not been validated in all clinical scenarios – including early BC – available data suggests that 
this immunoscore constitutes a promising surrogate marker of clinical outcome in this group of 
patients. The PIS will be performed 40) at Dr. Jeffrey Schlom’s lab at NIH, which developed 
this particular immunoscore. 
 
 
9.2 Immune contexture in residual tumors 
We will evaluate PD-L1 expression in the tumor, expression of other immune checkpoints that 
may be upregulated (e.g., LAG3, TIM3, ICOS) and expression of the cellular composition 
(CD8+, activated T cells, CD4+, T regs, MDSC and macrophages) using the Perkin Elmer 
Vectra 3.0 Automated Quantitative Pathology Imaging System, which is housed in the 
Lombardi Histopathology and Tissue Shared Resource (HTSR). We will also measure other 


 
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50 
 
cytokines and chemokines involved in the immune system activation by Nanostring, as 
described in Table 2. Based on preclinical studies of immune regulation of tumor growth13 we 
will specifically examine CD47, TGFF1, Sgpl1, Tex9 and Pex14 in the tumor specimens by 
PCR and IHC. All tissues will be processed in Dr. Louis Weiner’s laboratory and assays will be 
performed in the Lombardi HTSR (IHC) and the Lombardi Genomics and Epigenomics Shared 
Resource (Nanostring, PCR).  
 
 
 
 
 
Prioritized for Analysis 
Immunologic profile (Vectra 3.0 IHC) 
PDL1, LAG3, TIM3, ICOS, other checkpoints 
Cellular and molecular composition of 
residual tumor (Vectra 3.0) 
CD8+, CD4+, Tregs, MDSC, PD1, other 
checkpoints 
Other 
cytokines 
and 
chemokines 
(Nanostring)  
IL-2, 4, 6, 8, 10, 17; IFN-b, g; TNF-a; STING;  
Other candidate resistance biomarkers 
(qPCR, Vectra 3.0 IHC) 
CD47, TGFβ1, Sgpl1, Tex9 and Pex14 
 
Table 2. Immune Biomarkers to be Studied 
 
9.3. Sample Labeling Overview  
Patients will be de-identified and labeled with the following study label (XXX-XXXX-XX-OXEL): 
 
The first three letters will be the site name.  
o GUH = Georgetown 
o WHC = Washington Hospital Center  
o HCK = Hackensack 
o UOC = Univ of Chicago 
o UAB = Univ Alabama at Birmingham   
 
The four numbers will refer to the patient number preceded by the site number  
o 1 = Georgetown  
o 2 = Washington Hospital Center  
o 3 = Hackensack   
o 4 = Univ of Chicago 
o 5 = Univ Alabama at Birmingham   
 
This will be followed by 2 letters that will be the 2 patient initials (first name, last name)  
 
Finally, this will be followed by the study name OXEL 
 
 
Each sample (tissue) will be labeled with the procedure date in MM/DD/YR format and will have 
a number to indicate the type of collection. Options include: 
o Initial biopsy (tissue) - 1 
o Surgery (tissue) - 2 


 
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o Recurrence (tissue) - 3 
 
See Correlative Laboratory Manual for more details regarding sample handling and processing. 
 
 
 
 
 
10.0 ETHICAL CONSIDERATIONS 
 
10.1 Institutional Review Board (IRB) 
GCP requires that the clinical protocol, any protocol amendments, the Investigator's Brochure, 
the informed consent and all other forms of subject information related to the study (e.g., 
advertisements used to recruit subjects) and any other necessary documents be reviewed by an 
IRB. IRB approval of the protocol, informed consent and subject information and/or advertising, 
as relevant, will be obtained prior to the authorization of drug shipment to a study site.  Any 
amendments to the protocol will require IRB approval prior to implementation of any changes 
made to the study design.  Any serious adverse events that meet the reporting criteria, as 
dictated by local regulations, will be reported to the IRB. During the conduct of the study, the 
investigator should promptly provide written reports to the IRB of any changes that affect the 
conduct of the study and/or increase the risk to subjects.  
 
10.2 Ethical Conduct of the Study 
The study will be conducted in accordance with the protocol, ICH guidelines, applicable 
regulations and guidelines governing clinical study conduct and the ethical principles that have 
their origin in the Declaration of Helsinki.  
 
10.3 Subject Information and Consent 
Prior to the initiation of any screening or study-specific procedures, the investigator or his/her 
representative will explain the nature of the study to the subject and answer all questions 
regarding this study. Each informed consent will be reviewed, signed and dated by the subject 
and the person who administered the informed consent. A copy of each informed consent will 
be given to the subject and each original will be placed in the subject's medical record. An entry 
must also be made in the subject's dated source documents to confirm that informed consent 
was obtained prior to any study-related procedures and that the subject received a signed copy.  
Tissue sample collection for analysis will only be performed if the subject has voluntarily 
consented to participate after the nature of the testing has been explained and the subject has 
had the opportunity to ask questions.  
 
10.4 Ethical Consideration for Enrollment 


 
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Only patients with triple negative breast cancer and residual disease at the time of surgery, who 
have a high risk of recurrence, will be considered for enrollment. As described above, nivolumab 
alone or in combination with capecitabine is a rational and promising combination for such 
patients. 
 
10.5 Protection of Patient Confidentiality 
All patient records, questionnaires, and tissue specimens will be de-identified using a letter and 
number assigned to their case at the time of enrollment on study.  No record or specimen will 
contain information which could identify the patient.  The key which connects patient identifiable 
information with this assigned number will be held by the Principal investigator.  For computer 
records, the key will be protected by a double password protection system.  Any paper records 
will be contained in a locked cabinet within a locked office to ensure patient’s privacy is protected.  
 
 


 
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11.0 REFERENCES 
1. Howlader N, Noone AM, Krapcho M, et al (eds). SEER Cancer Statistics Review, 1975-2014, National 
Cancer Institute. Bethesda, MD, https://seer.cancer.gov/csr/1975_2014/, based on November 2016 
SEER data submission, posted to the SEER web site, April 2017. 
2. Dent RA, Mainwaring PN, Tan TJY, et al. Survival in triple-negative breast cancer (TNBC): Evidence 
from the SEER database 2010-2011. J Clin Oncol. 33:15_suppl, e12075-e12075, 2015. 
3. Stover DG, Winer EP. Tailoring adjuvant chemotherapy regimens for patients with triple negative 
breast cancer. Breast 2015;24 Suppl 2:S132-5. 
4. Carey LA, Dees EC, Sawyer L, et al: The triple negative paradox: primary tumor chemosensitivity of 
breast cancer subtypes. Clin Cancer Res 13:2329-34, 2007  
5. Von Minckwitz G, Untch M, Blohmer JU, et al: Definition and impact of pathologic complete response 
on prognosis after neoadjuvant chemotherapy in various intrinsic breast cancer subtypes. J Clin Oncol 
May 20, 2012:1796-1804 
6. Esserman LJ, Perou C, Cheang M, et al: Breast cancer molecular profiles and tumor response of 
neoadjuvant doxorubicin and paclitaxel: The I-SPY TRIAL. J Clin Oncol 27:(suppl; abstr LBA515), 2009  
7. Masuda N, Lee SJ, Ohtani S, et al. Adjuvant Capecitabine for Breast Cancer after Preoperative 
Chemotherapy. N Engl J Med 2017;376(22):2147-2159. 
8. Loi S, Sirtaine N, Piette F, et al. Prognostic and predictive value of tumor-infiltrating lymphocytes in a 
phase III randomized adjuvant breast cancer trial in node-positive breast cancer comparing the addition 
of docetaxel to doxorubicin with doxorubicin-based chemotherapy: BIG 02-98. J Clin Oncol. 31:860-7, 
2013. 
9. Nanda R, Chow LQ, Dees EC, et al. Pembrolizumab in patients with advanced triple negative breast 
cancer: phase Ib KEYNOTE-012 Study. J Clin Oncol. 34:2460-7, 2016. 
10. Adams S, Diamond JR, Hamilton EP, et al. Phase Ib trial of atezolizumab in combination with nab-
paclitaxel in patients with metastatic triple-negative breast cancer (mTNBC). J Clin Oncol. 2016;34 
(suppl); Abstract 1009. 
11. Nanda R, Liu MC, Yau C, et al. Pembrolizumab plus standard neoadjuvant therapy for high-risk 
breast cancer (BC): Results from I-SPY 2. J Clin Oncol 2017 (suppl); abstract 506. 
12. Gnjatic S, Bronte V, Brunet LR, et al. Identifying baseline immune-related biomarkers to predict 
clinical outcome of immunotherapy. J Immunother Cancer. 2017 May 16;5:44. doi: 10.1186/s40425-017-
0243-4. eCollection  2017 
13. Shuptrine CW, Ajina R, Feetig EJ, et al. An unbiased in vivo functional genomics screening approach 
in mice identifies novel tumor cell-based regulators of immune rejection. Cancer Immunol 
Immunother. 2017 Aug 2.  
14. Karn T, Jiang T, Hatzis C, et al. Association between Genomic Metrics and Immune Infiltration in 
Triple Negative Breast Cancer. JAMA Oncol 2017.   
15. Farsaci B, Donahue RN, Grenga I, et al. Analyses of Pretherapy Peripheral Immunoscore and 
Response to Vaccine Therapy. Cancer Immunol Res. 4:755-65, 2016. 
16. Sharpe AH, Wherry EJ, Ahmed R, et al. The function of programmed cell death 1 and its ligands in 
regulating autoimmunity and infection. Nat Immunol 2007;8(3):239-45. 
17. Nonclinical Study Report: Medarex Study No. MDX1106-025-R. In vitro characterization of a fully 
human anti-PD-1 monoclonal antibody. Bristol-Myers Squibb Company; 2007. Document Control No. 
930046580. 
18. Nonclinical Study Report: Medarex Study No. MDX1106-028-R. Binding and blocking 
characteristics of chimeric anti-mouse PD-1 antibody, 4H2. Bristol-Myers Squibb Company; 2007. 
Document Control No. 930046578. 
19. Velu V, Titanji K, Zhu B, et al. Enhancing SIV-specific immunity in vivo by PD-1 blockade. Nature 
2009;458:206-10. 
20. Nonclinical Study Report: Medarex Study No. MDX1106-023-R. Effect of anti-PD-1 monoclonal 
antibody administration on unstaged MC38 tumor growth rates in mice. Bristol-Myers Squibb Company; 


 
Version 7.0, 20 January, 2023 
 
 
 
 
 
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2006. Document Control No. 930046542. 
21. Nonclinical Study Report: Medarex Study No. MDX1106-032-R. Effects of anti-PD-1 administration 
on staged MC38 tumors in mice. Bristol-Myers Squibb Company; 2006. Document Control No. 
930046566. 
22. Wang C, Thudium KB, Han M, et al. In vitro characterization of the anit-PD-1 antibody nivolumab, 
BMS-936558, and in vivo toxicology in non-human primates. Cancer Immunol Res 2014;2:846-856. 
23. Nonclinical Study Report: Study No. DN12123; BMS-986016 and BMS-936558: Four-week 
intravenous combination toxicity study in monkeys with a 6-week recovery. Bristol-Myers Squibb 
Company; 2013. Document Control No. 930070016 
24. BMS-936558: Intravenous Study of pre- and postnatal development in cynomolgus monkeys with a 
6-month postnatal evaluation. Final report for Study DN12001. Bristol-Myers Squibb Company; 
Document Control No. 930073964. 
25. Habicht A, Dada S, Jurewicz M, et al. A link between PDL1 and T regulatory cells in fetomaternal 
tolerance. J Immunol 2007;179:5211-9. 
26. Johnson DB, Balko JM, Compton ML, et al. Fulminant Myocarditis with combination immune 
checkpoint blockage. N Eng J Med 2016;375:1749-1755. 
27. Middleton G, Greenhalf W, Costello E, et al. Immunobiological effects of gemcitabine and 
capecitabine combination chemotherapy in advanced pancreatic ductal adenocarcinoma. British Journal 
of Cancer (2016) 114, 510–518.  
 
 
 


 
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12.0 APPENDICES 
  
APPENDIX A 
 
Table 1: ECOG Performance Status Scale 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Completely disabled. Cannot carry on any self-care. Totally confined
to bed or chair.
4
Capable of only limited self care, confined to bed or chair more than
50% of waking hours.
3
Ambulatory and capable of all self-care but unable to carry out any
work activities. Up and about more than 50% of waking hours.
2
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.
1
Fully Active, able to carry on all pre-disease performance without 
restriction.
0
ECOG
Grade
Completely disabled. Cannot carry on any self-care. Totally confined
to bed or chair.
4
Capable of only limited self care, confined to bed or chair more than
50% of waking hours.
3
Ambulatory and capable of all self-care but unable to carry out any
work activities. Up and about more than 50% of waking hours.
2
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.
1
Fully Active, able to carry on all pre-disease performance without 
restriction.
0
ECOG
Grade


 
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56 
 
APPENDIX B: PATIENT REGISTRATION FORM 
 
OXEL: A pilot study of immune checkpoint or capecitabine or combination therapy as adjuvant 
therapy for triple negative breast cancer with residual disease following neoadjuvant 
chemotherapy 
 
Study ID: _________ 
Instructions: This form should be completed by the research staff before registering the patient 
into the trial. 
Completed form can be scanned/emailed to the Georgetown University Project Managers and 
cc: Candace.mainor@gunet.georgetown.edu. 
□ Georgetown University Medical Center 
 
   
  
□ Other Institution __________________________________________ 
 
□ Treating Physician ____________ ____________________________ 
 
 
1.  Date Informed Consent signed: ____/____/___ 
 
2.  Screening Date: ____/____/___ 
 
3.  Start date for treatment: ____/____/_______ 
 
4.  Prior therapies (date initiated/type): 
 
 
 
 
 
5.  Please fax the following documentation: 
□ 
Pathology Report 
□ 
Physicians Note validating: 
□ 
Previous treatments 
□ 
Laboratory Results 
□ 
Past Medical History 
 
 
 


 
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APPENDIX C: Data Sharing Plan 
Data sharing for this study will be conducted in compliance with the February 26, 2003 NIH 
Statement on Data Sharing (NOTICE: NOT-OD-03-032). The collaborating sites for this study 
generate a wide variety of scientific and clinical data and Data Sharing and Archiving will be 
handled by in accordance with NIH Statement on Data sharing, institutional internal document 
retention policies and all application rules, regulations and statutes.  
Subject to institutional policies, local IRB guidelines, and local, state and Federal laws and 
regulations including the Privacy Rule and the Bayh-Dole Act, we will make finished research 
data available through scientific presentations, publications (paper, web and other), depositing 
gene sequence, gene expression and other data in searchable electronic repositories, 
attendance at scientific meetings and extending invitations to scientists from other institutions 
for discussion. In accordance with the NIH policy, such data shall be made widely and freely 
available while safeguarding the privacy of participants and protecting Lombardi’s confidential 
and proprietary data.  
 
The participating sites will maintain awareness, and may participate in, discussions between 
members of multiple scientific and technical disciplines and their professional societies 
concerning data sharing, standards and best practices, and to create an environment that 
supports and develops data sharing tools. We will participate in or make ourselves aware of the 
outcome of any workshops the NIH or AACR will convene to address data sharing and which 
may address areas such as cleaning and formatting data, writing documentation, redacting data 
to protect subjects' identities and proprietary information, and estimating costs to prepare 
documentation and data for sharing.  
 
The NIH has recognized the need to protect patentable and other proprietary data and notes the 
restrictions on the sharing of data that may be imposed by agreements with third parties. Under 
the Bayh-Dole Act, grantees have the right to elect and retain title to subject inventions 
developed with Federal funding, and further, to commercialize any invention to which they retain 
title. Since its is not the stated intent of the NIH statement on Data Sharing to discourage, impede 
or prohibit the development of commercial products from federally funded research, our 
collaborating sites will continue to perform inventive activities, to seek patent protection for 
inventions that relate to data generated and may choose to defer publication or enter into 
agreements with third parties that may result in certain restrictions on data sharing. We note that 
seeking patent protection results in publication of the patent application into the public domain 
and, thus, may result in the data being broadly disseminated.  
 
All specimens submitted to any of the shared resource laboratories will be bar-coded upon 
receipt and assigned a unique identifier using a common software program. Tracking of 
specimens and their utilization will be carried out using a web-based system that will represent 
a modification of the systems presently in place at Georgetown (including but not limited to G-


 
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DOC, Georgetown Database of Cancer, Medidata Rave, REDCap), which will also give us the 
ability to track sample utilization. These systems have an “honest broker” interface which 
ensures HIPPA compliance and protection of any human subjects. As the same sample may 
well be used for genomic, proteomic, histopathological and clinical interrogation, assignment of 
a unique identifier as well as a common administrative structure ensures efficient cross-database 
interrogation.  
 
Data security 
The rights and privacy of people who participate in sponsored clinical research will be protected 
at all times. In the event that data is intended for broader use, it will be de-identified and would 
not permit linkages to individual research participants and variables that could lead to deductive 
disclosure of the identity of individual subjects. No efforts will be made to identify individual 
cases, and any shared archive data will not be linked to other identifiable data. The following de-
identification and security procedures will be followed to share information with collaborators part 
of the study: 
1) Deletion of 18 HIPAA identifiers 
a. Non-identifiable unique patient ID will be generated in G-DOC 
2) Secure netID-based single sign-on (netID is Georgetown’s LDAP based secure login 
system) 
3) Users will have to authenticate themselves prior to accessing controlled data 
4) Furthermore, based on their roles, users will require authorization to see specific studies 
5) Auditing and security assessments will be performed on a quarterly basis to ensure 
appropriate de-identification procedures and use of data. 
For future studies involving new data types that are not covered in the descriptions above, NIH 
policy on data sharing will be followed where applicable. For example, Genome Wide 
Association Studies, if conducted, will comply with NIH Guidelines NOT-OD-07-088 
(http://grants.nih.gov/grants/gwas/) for data release. Following these guidelines, GWAS data 
will be submitted to NCBI’s dbGAP (http://www.ncbi.nlm.nih.gov/sites/entrez?db=gap) or other 
tools as the NIH’s policy on GWAS evolves. 
 
Data Disclosure 
GUMC (Georgetown University Medical Center) has a Confidentiality and Non-Disclosure 
policy that pertains only to proprietary information belonging to GUMC. The disclosure of 
research information such as microarray analysis results is at the discretion of the faculty and 
staff. Notably, investigators with NIH funding are expected to make their data and results 
public in a reasonable time frame (Please see the University plan for sharing and distributing 
biomedical research resources at http://otc.georgetown.edu/documents/inventors/ 
NIHGrantLetter_ModelOrganismsUpdate_6-27-05.doc . To protect institutional intellectual 
property, the institution does have an internal review process prior to submission of journal 
manuscripts. This process will be propagated to other study sites as well. 


 
Version 7.0, 20 January, 2023 
 
 
 
 
 
59 
 
APPENDIX D: MANAGEMENT ALGORITHMS 
 
These general guidelines constitute guidance to the Investigator and may be supplemented by 
discussions with the Medical Monitor representing the Sponsor. The guidance applies to all 
immuno-oncology agents and regimens. 
 
A general principle is that differential diagnoses should be diligently evaluated according to 
standard medical practice. Non-inflammatory etiologies should be considered and 
appropriately treated. 
 
Corticosteroids are a primary therapy for immuno-oncology drug-related adverse events. The 
oral equivalent of the recommended IV doses may be considered for ambulatory patients with 
low grade toxicity. The lower bioavailability of oral corticosteroids should be taken into account 
when switching to the equivalent dose of oral corticosteroids. 
 
Consultation with a medical or surgical specialist, especially prior to an invasive diagnostic or 
therapeutic procedure, is recommended. 
 
The frequency and severity of the related adverse events covered by these algorithms will 
depend on the immuno-oncology agent or regimen being used. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
Version 7.0, 20 January, 2023 
 
 
 
 
 
60 
 
GI Adverse Event - Management Algorithm 
 
Rule out non-inflammatory causes. If non-inflammatory cause is identified, treat accordingly and 
continue I-O therapy. Opiates/narcotics may mask symptoms of perforation. Infliximab should not 
be used in cases of perforation or sepsis. 
 
 
 
 
Patients on IV steroids may be switched to an equivalent dose of oral corticosteroids (e.g. 
prednisone) at start of tapering or earlier, once sustained clinical improvement is observed. 
Lower bioavailability of oral corticosteroids should be taken into account when switching to 
the equivalent dose of oral corticosteroids. 
 
 
 
Grade of Diarrhea/ 
Colitis 
(NCI CTCAE v4) 
Grade 1 
Diarrhea:< 4 stools/day over baseline; 
Colitis: asymptomatic 
Grade 2 
Diarrhea: 4-6 stools per day over 
baseline; IV fluids indicated <24 hrs; 
not interfering with ADL 
Colitis: abdominal pain; blood in stool 
Grade 3-4 
Diarrhea (G3): >7 stools per day over 
baseline; incontinence; IV fluids >24 
hrs; interfering with ADL 
Colitis (G3): severe abdominal pain, 
medical intervention indicated, 
peritoneal signs 
G4: life-threatening, perforation 
Management 
• Continue I-O therapy per 
protocol 
• Symptomatic treatment 
• Delay I-O therapy per protocol 
• Symptomatic treatment 
• Hold I-O therapy per 
protocol1.0 to 2.0 mg/kg/day 
methylprednisolone IV or IV 
equivalent 
• Add prophylactic antibiotics for 
opportunistic infections 
• Consider lower endoscopy 
• Permanently discontinue I-O for 
Grade 4 Diarrhea or Colitis 
attributed to Nivolumab 
Follow-up 
• Close monitoring for worsening symptoms. 
• Educate patient to report worsening immediately 
If worsens: 
• Treat as Grade 2 or 3/4 
If improves to grade 1: 
• Resume I-O therapy per protocol If 
persists > 5-7 days or recur: 
• 0.5-1.0 mg/kg/day methylprednisolone or oral equivalent 
• When symptoms improve to grade 1, taper steroids over 
at least 1 month, consider prophylactic antibiotics for 
opportunistic infections, and resume I-O therapy per 
protocol. 
If worsens or persists > 3-5 days with oral steroids: 
• Treat as grade 3/4 
If improves: 
• Continue steroids until grade 1, then taper over at 
least 1 month 
If persists > 3-5 days, or recurs after improvement: 
• Add infliximab 5 mg/kg (if no contraindication). 
Note: Infliximab should not be used in cases of 
perforation or sepsis 
If Grade 3 Diarrhea/Colitis improves to grade < 1: 
Resume I-O therapy per protocol 


 
 
 
Renal Adverse Event - Management Algorithm 
 
 
Rule out non-inflammatory causes. If non-inflammatory cause, treat accordingly and continue I-O therapy 
 
 
 
 
Patients on IV steroids may be switched to an equivalent dose of oral corticosteroids (e.g. 
prednisone) at start of tapering or earlier, once sustained clinical improvement is observed. 
Lower bioavailability of oral corticosteroids should be taken into account when switching to 
the equivalent dose of oral corticosteroids
Grade of Creatinine 
Elevation 
(NCI CTCAE v4) 
Grade 1 
Creatinine > ULN and > 
than baseline but s 1.5x 
baseline 
Management 
• Continue I-O therapy per protocol 
• Monitor creatinine weekly 
Follow-up 
If returns to baseline: 
•Resume routine creatinine monitoring per protocol 
If worsens: 
•Treat as Grade 2 or 3/4 
Grade 2-3 
Creatinine > 1.5x baseline 
to s 6x ULN 
Grade 4 
Creatinine > 6x ULN 
• Delay I-O therapy per protocol 
• Monitor creatinine every 2-3 days 
• 0.5 to 1.0 mg/kg/day 
methylprednisolone IV or oral 
equivalent 
• Consider renal biopsy with 
nephrology consult 
• Discontinue I-O therapy per 
protocol 
• Monitor creatinine daily 
• 1.0-2.0 mg/kg/day 
methylprednisolone IV or IV 
equivalent 
• Consult nephrologist 
• Consider renal biopsy 
If returns to Grade 1: 
•Taper steroids over at least 1 month, consider prophylactic 
antibiotics for opportunistic infections, and resume I-O therapy 
and routine creatinine monitoring per protocol 
If elevations persist > 7  days or worsen: 
•Treat as Grade 4 
If returns to Grade 1 : Taper steroids over at least 1 month and 
add prophylactic antibiotics for opportunistic infections 


 
 
Pulmonary Adverse Event - Management Algorithm 
 
Rule out non-inflammatory causes. If non-inflammatory cause, treat accordingly and continue I-O 
therapy. Evaluate with imaging and pulmonary consultation. 
 
 
 
Patients on IV steroids may be switched to an equivalent dose of oral corticosteroids (e.g. prednisone) at start 
of tapering or earlier, once sustained clinical improvement is observed. Lower bioavailability of oral 
corticosteroids should be taken into account when switching to the equivalent dose of oral corticosteroids. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Grade of 
Pneumonitis 
(NCI CTCAE v4) 
Grade 1 
Radiographic changes only 
Management 
• Consider delay of I-O therapy 
• Monitor for symptoms every 2-3 
days 
• Consider Pulmonary and ID 
consults 
Follow-up 
• Re-image at least every 3 weeks 
If worsens: 
• Treat as Grade 2 or 3-4 
Grade 2 
Mild to moderate new 
symptoms 
• Re-image every 1-3 days 
If improves: 
• When symptoms return to near baseline, taper steroids over 
at least 1 month and then resume I-O therapy per protocol 
and consider prophylactic antibiotics 
If not improving after 2 weeks  or worsening: 
• Treat as Grade 3-4 
Grade 3-4 
Severe new symptoms; 
New/worsening hypoxia; 
Life-threatening 
If improves to baseline: 
• Taper steroids over at least 6 weeks 
If not improving after 48 hours or worsening: 
• Add additional immunosuppression 
• Delay I-O therapy per protocol 
• Pulmonary and ID consults 
• Monitor symptoms daily, consider 
hospitalization 
• 1.0 mg/kg/day methyl- 
prednisolone IV or oral equivalent 
• Consider bronchoscopy , lung 
biopsy 
• Discontinue I-O therapy per 
protocol 
• Hospitalize 
• Pulmonary and ID consults 
• 2-4 mg/kg/day 
methylprednisolone IV or IV 
equivalent 
• Add prophylactic antibiotics for 
opportunistic infections 
• Consider bronchoscopy, lung 
biopsy 


 
 
Hepatic Adverse Event - Management Algorithm 
 
 
Rule out non-inflammatory causes. If non-inflammatory cause, treat accordingly and continue I-O 
therapy. Consider imaging for obstruction. 
 
 
Patients on IV steroids may be switched to an equivalent dose of oral corticosteroids (e.g. 
prednisone) at start of tapering or earlier, once sustained clinical improvement is observed. 
Lower bioavailability of oral corticosteroids should be taken into account when switching to the 
equivalent dose of oral corticosteroids. 
*I-O therapy may be delayed rather than discontinued if AST/ALTs 8 x ULN or T.bilis 5 x ULN. 
**The recommended starting dose for grade 4 hepatitis is 2 mg/kg/day methylprednisolone IV. 
Grade of Liver 
Test Elevation 
(NCI CTCAE v4) 
Grade 1 
AST or ALT > ULN to 3.0 x 
ULN and/or T. bili > ULN 
to 1.5 x ULN 
Management 
• Continue I-O therapy per protocol 
Follow-up 
• Continue LFT monitoring per protocol 
If worsens: 
• Treat as Grade 2 or 3-4 
Grade 2 
AST or ALT > 3.0 to s 5 x 
ULN and/or T. bili > 1.5 
to s 3 x ULN 
Grade 3-4 
AST or ALT > 5 x ULN or 
T.bili >3 x ULN 
• Delay I-O therapy per protocol 
• Increase frequency of monitoring 
to every 3 days 
• Discontinue  I-O therapy* 
• Increase frequency of monitoring 
to every 1-2 days 
• 1.0 to 2.0 mg/kg/day 
methylprednisolone IV or IV 
equivalent** 
• Add prophylactic antibiotics for 
opportunistic infections 
• Consult  gastroenterologist 
If returns to baseline: 
•Resume routine monitoring, resume I-O therapy per protocol 
If elevations persist > 5-7 days or worsen : 
• 0.5-1 mg/kg/day methylprednisolone or oral equivalent and 
when LFT returns to grade 1 or baseline, taper steroids over at 
least 1 month, consider prophylactic antibiotics for 
opportunistic infections, and resume I-O therapy per protocol 
If returns to grade 2: 
• Taper steroids over at least 1 month 
If does not improve in >3-5 days, worsens or rebounds: 
• Add  mycophenolate mofetil 1 g BID 
• If no response within an additional 3-5 days, consider other 
immunosuppressants per local guidelines 


 
 
Endocrinopathy - Management Algorithm 
 
 
Rule out non-inflammatory causes. If non-inflammatory cause, treat accordingly and continue I-O therapy. 
Consider visual field testing, endocrinology consultation and imaging. 
 
 
Patients on IV steroids may be switched to an equivalent dose of oral corticosteroids (e.g. 
prednisone) at start of tapering or earlier, once sustained clinical improvement is observed. Lower 
bioavailability of oral corticosteroids should be taken into account when switching to the equivalent 
dose of oral corticosteroids. 
Asymptomatic 
TSH elevation 
• Continue I-O therapy per protocol 
• If TSH < 0.5 x LLN, or TSH > 2 x ULN, or consistently out of range in 2 subsequent measurements: include fT4 at 
subsequent cycles as clinically indicated; consider endocrinology consult 
Symptomatic 
endocrinopathy 
• Evaluate endocrine function 
• Consider pituitary scan 
Symptomatic with abnormal lab/pituitary scan: 
• Delay I-O therapy per protocol 
• 1-2 mg/kg/day methylprednisolone IV or PO equivalent 
• Initiate appropriate hormone therapy 
No abnormal lab/pituitary MRI scan but symptoms persist: 
• Repeat labs in 1-3 weeks / MRI in 1 month 
If improves (with or without 
hormone replacement): 
• Taper steroids over at least 1 
month and consider prophylactic 
antibiotics for opportunistic 
infections 
• Resume I-O therapy per protocol 
• Patients with adrenal 
insufficiency may need to 
continue steroids with 
mineralocorticoid component 
Suspicion of adrenal 
crisis (e.g. severe 
dehydration, 
hypotension, shock 
out of proportion to 
current illness 
• Delay or discontinue I-O therapy per protocol 
• Rule out sepsis 
• Stress dose of IV steroids with mineralocorticoid activity 
• IV fluids 
• Consult endocrinologist 
• If adrenal crisis ruled out, then treat as above for symptomatic 
endocrinopathy 


 
 
Grade of 
Rash 
(NCI CTCAE v4) 
Management 
 
 
Skin Adverse Event - Management Algorithm 
 
Rule out non-inflammatory causes. If non-inflammatory cause, treat accordingly and continue I-O therapy. 
 
 
Patients on IV steroids may be switched to an equivalent dose of oral corticosteroids (e.g. 
prednisone) at start of tapering or earlier, once sustained clinical improvement is observed. 
Lower bioavailability of oral corticosteroids should be taken into account when switching to the 
equivalent dose of oral corticosteroids. 
*Refer to NCI CTCAE v4 for term-specific grading criteria. 
^If SJS/TEN is suspected, withhold I-O therapy and refer patient for specialized care for 
assessment and treatment. If SJS or TEN is diagnosed, permanently discontinue I-O therapy. 
Grade 1-2 
Covering s 30% 
BSA* 
• Symptomatic therapy (e.g. antihistamines, 
topical steroids) 
• Continue I-O therapy per protocol 
Grade 3-4 
Covering >30% BSA; 
Life threatening 
consequences*^ 
• Delay or discontinue I-O therapy per 
protocol 
• Consider skin biopsy 
• Dermatology consult 
• 1.0-2.0 mg/kg/day IV methylprednisolone 
IV or IV equivalent 
Follow-up 
If persists > 1-2 weeks or recurs: 
• Consider skin biopsy 
• Delay I-O therapy per protocol 
• Consider 0.5-1.0 mg/kg/day methylprednisolone IV or 
oral equivalent. Once improving , taper steroids over 
at least 1 month, consider prophylactic antibiotics for 
opportunistic infections, and resume I-O therapy per 
protocol 
If worsens: 
• Treat as Grade 3-4 
If improves to Grade 1: 
• Taper steroids over at least 1 month and add 
prophylactic antibiotics for opportunistic infections 
• Resume I-O therapy per protocol 


 
 
Neurological Adverse Event Management Algorithm 
 
Rule out non-inflammatory causes. If non-inflammatory cause, treat accordingly and continue I-O therapy. 
 
 
 
 
Patients on IV steroids may be switched to an equivalent dose of oral corticosteroids (e.g. prednisone) 
at start of tapering or earlier, once sustained clinical improvement is observed. Lower bioavailability of 
oral corticosteroids should be taken into account when switching to the equivalent dose of oral 
corticosteroids 
 
 
 
 
 
 
 
 
 
Grade of 
Neurological 
Toxicity 
(NCI CTCAE v4) 
Management 
Follow-up 
Grade 1 
Asymptomatic or 
mild symptoms; 
Intervention not 
indicated 
• Continue I-O therapy per protocol 
Continue to monitor the patient. 
If worsens: 
• Treat as Grade 2 or 3-4 
Grade 2 
Moderate symptoms; 
Limiting instrumental 
ADL 
• Delay I-O therapy per protocol 
• Treat symptoms per local guidelines 
• Consider 0.5 to 1.0 mg/kg/day 
methylprednisolone IV or PO 
equivalent 
If improves to baseline: 
•Resume I-O therapy per protocol when improved to baseline 
If worsens: 
• Treat as Grade 3-4 
Grade 3-4 
Severe symptoms; 
Limiting self-care 
ADL; 
Life-threatening 
• Discontinue I-O therapy per protocol 
• Obtain neurology consult 
• Treat symptoms per local guidelines 
• 1.0-2.0 mg/kg/day IV 
methylprednisolone IV or IV equivalent 
• Add prophylactic antibiotics for 
opportunistic infections 
If improves to Grade 2: 
• Taper steroids over at least 1 month 
If worsens or atypical presentation: 
• Consider IVIG or other immunosuppressive therapies per 
local guidelines 


 
 
APPENDIX E: Quality of Life Questionnaire (EORTC QLQ-C30)  
 
 
EORTC QLQ-C30 (version 3) 
 
We are interested in some things about you and your health. Please answer all of the questions yourself by circling the 
number that best applies to you. There are no "right" or "wrong" answers. The information that you provide will 
remain strictly confidential. 
 
Please fill in your initials:                                    
 
Your birthdate (Day, Month, Year):                     
 
Today's date (Day, Month, Year):                31   
 
 
Not at 
All 
A 
Little 
Quite 
a Bit 
Very 
Much 
1. 
Do you have any trouble doing strenuous activities, 
like carrying a heavy shopping bag or a suitcase? 
1 
2 
3 
4 
2. 
Do you have any trouble taking a long walk? 
1 
2 
3 
4 
3. 
Do you have any trouble taking a short walk outside of the house? 
1 
2 
3 
4 
4. 
Do you need to stay in bed or a chair during the day? 
1 
2 
3 
4 
5. 
Do you need help with eating, dressing, washing 
yourself or using the toilet? 
1 
2 
3 
4 
 
During the past week: 
Not at 
All 
A 
Little 
Quite 
a Bit 
Very 
Much 
6. 
Were you limited in doing either your work or other daily activities? 
1 
2 
3 
4 
7. 
Were you limited in pursuing your hobbies or other 
leisure time activities? 
1 
2 
3 
4 
8. 
Were you short of breath? 
1 
2 
3 
4 
9. 
Have you had pain? 
1 
2 
3 
4 
10. Did you need to rest? 
1 
2 
3 
4 
11. Have you had trouble sleeping? 
1 
2 
3 
4 
12. Have you felt weak? 
1 
2 
3 
4 
13. Have you lacked appetite? 
1 
2 
3 
4 
14. Have you felt nauseated? 
1 
2 
3 
4 
15. Have you vomited? 
1 
2 
3 
4 
16. Have you been constipated? 
1 
2 
3 
4 
 
Please go on to the next page 


 
Version 6.0, 16JUL19 
 
 
 
 
 
68 
During the past week: 
Not at 
All 
A 
Little 
Quite 
a Bit 
Very 
Much 
17. Have you had diarrhea? 
1 
2 
3 
4 
18. Were you tired? 
1 
2 
3 
4 
19. Did pain interfere with your daily activities? 
1 
2 
3 
4 
20. Have you had difficulty in concentrating on things, 
like reading a newspaper or watching television? 
1 
2 
3 
4 
21. Did you feel tense? 
1 
2 
3 
4 
22. Did you worry? 
1 
2 
3 
4 
23. Did you feel irritable? 
1 
2 
3 
4 
24. Did you feel depressed? 
1 
2 
3 
4 
25. Have you had difficulty remembering things? 
1 
2 
3 
4 
26. Has your physical condition or medical treatment 
interfered with your family life? 
1 
2 
3 
4 
27. Has your physical condition or medical treatment 
interfered with your social activities? 
1 
2 
3 
4 
28. Has your physical condition or medical treatment 
caused you financial difficulties? 
1 
2 
3 
4 
 
 
For  the  following  questions  please  circle  the  number  between  1  and  7  
that best applies to you 
 
29. How would you rate your overall health during the past week? 
 
1 
2 
3 
4 
5 
6 
7 
 
Very poor 
Excellent 
 
 
 
30. How would you rate your overall quality of life during the past week? 
 
1 
2 
3 
4 
5 
6 
7 
 
Very poor 
Excellent 
 
© Copyright 1995 EORTC Quality of Life Group. All rights reserved. Version 3.0