Randomized, Double-Blind, Parallel Group Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of BMS-936558 (Nivolumab) in Participants With Severe Sepsis or Septic Shock.
Phase: PHASE1
Conditions: Severe Sepsis
Sponsor: Bristol-Myers Squibb



Clinical Protocol
CA209923
BMS-936558
nivolumab
Revised Protocol No.: 01
Date: 03-Mar-2017
2
to BMS or promptly destroy it. All other rights reserved. References to BMS in this 
protocol may apply to partners to which BMS has transferred obligations, e.g., a Contract 
Research Organization (CRO).
Replace all previous version(s) of the protocol with this revised protocol and please provide a 
copy of this revised protocol to all study personnel under your supervision, and archive the 
previous versions.
2.0
Approved
930105656
2.0
v

Clinical Protocol
CA209923
BMS-936558
nivolumab
Revised Protocol No.: 01
Date: 03-Mar-2017
3
DOCUMENT HISTORY
Document
Date of Issue
Summary of Change
Revised Protocol 01
03-Mar-2017
Incorporates Amendment 01
Amendment 01
03-Mar-2017
The number of participants in the study was clarified as 
being “up to approximately 30” to reflect the fact that 30 
participants is the maximum number planned. A key 
objective of this study is to characterize the 
pharmacokinetics (PK) of nivolumab in participants with 
sepsis, with the goal to obtain a PK profile from at least 6 
subjects per dose level.
The body weight eligibility criteria was revised to (1) 
remove the word “ideal,” which was inadvertently included 
in the original protocol, and (2) align the upper limit of 
body weight with that studied in the nivolumab oncology 
development program. 
In the original protocol, members of BMS Research and 
Development are blinded; in the amended protocol, they 
will be unblinded to study treatment in order to facilitate 
real-time analyses of PK, RO, and safety data in support of 
dose selection for future studies. The unblinded data and 
the corresponding analysis/report will be included in 
documents for communication with regulatory authorities. 
The investigators, all study personnel with the exception of 
the pharmacist, and patients will remain blinded until the 
end of the study. 
The discrepancy between textual description of the 
schedule for thyroid function testing in Section 9.4.4 and 
the tabular presentation in Table 2-2 was corrected.
A typographical error relating to time relative to dosing in 
hours at the Day 28 time point was corrected.
The potential interim analysis was removed because, in the 
amended protocol, the BMS team is fully unblinded thus 
the interim analysis becomes unnecessary.
The amendment applies to all subjects.
Original Protocol
01-Sep-2016
Not Applicable
2.0
Approved
930105656
2.0
v

9. STUDY ASSESSMENTS AND PROCEDURES .................................................... 
9.1 Efficacy Assessments ........................................................................................ 
9.1.1 Imaging Assessment for the Study............................................................ 
9.2 Adverse Events ................................................................................................. 
9.2.1 Immune-mediated Adverse Events ........................................................... 
9.2.2 Time Period and Frequency for Collecting AE and SAE Information .... 
9.2.3 Method of Detecting AEs and SAEs ......................................................... 
9.2.4 Follow-up of AEs and SAEs ..................................................................... 
9.2.5 Regulatory Reporting Requirements for SAEs ......................................... 
9.2.6 Pregnancy ................................................................................................ 
9.2.7 Laboratory Test Result Abnormalities ..................................................... 
9.2.8 Potential Drug Induced Liver Injury (DILI) ............................................ 
9.2.9 Other Safety Considerations .................................................................... 
9.3 Overdose ........................................................................................................... 
9.4 Safety ................................................................................................................ 
9.4.1 Physical Examinations ............................................................................. 
9.4.2 Vital signs................................................................................................. 
9.4.3 Electrocardiograms ................................................................................. 
9.4.4 Clinical Safety Laboratory Assessments .................................................. 
9.4.5 Suicidal Risk Monitoring ......................................................................... 
9.4.6 Imaging Safety Assessment ...................................................................... 
9.5 Pharmacokinetic ................................................................................................ 
9.6 Pharmacodynamics ........................................................................................... 
9.7 Pharmacogenomics ........................................................................................... 
9.7.1 ADME Sampling ...................................................................................... 
9.8 Biomarkers ........................................................................................................ 
9.8.1 Additional Research Collection ............................................................... 
9.8.2 Immunogenicity Assessments ................................................................... 
9.8.3 RNA Transcriptome Research.................................................................. 
9.8.4 RNA Expression Research of a Subset of RNA Species ........................... 
9.8.5 Proteome Research .................................................................................. 
9.8.6 Metabolomic Research............................................................................. 
9.8.7 Other Assessments ................................................................................... 
9.8.8 Receptor Occupancy ................................................................................ 
9.8.9 mHLA-DR ................................................................................................ 
9.9 Health Economics OR Medical Resource Utilization and Health Economics . 
10. STATISTICAL CONSIDERATIONS ................................................................... 
10.1 Sample Size Determination ............................................................................. 
10.2 Populations for Analyses ................................................................................ 
10.3 Statistical Analyses ......................................................................................... 
10.3.1 Safety Analyses....................................................................................... 
10.3.2 Pharmacokinetic Analyses ..................................................................... 
 
10.3.4 Secondary Biomarker Analyses ............................................................. 
 
10.3.6 Other Analyses ....................................................................................... 
37
37
38
38
38
38
39
39
39
40
40
41
41
41
41
42
42
42
42
43
43
43
45
45
45
45
46
47
47
47
47
47
47
48
48
48
48
48
48
49
49
49
49
50
50
50
Clinical Protocol
BMS-936558
CA209923
nivolumab
Revised Protocol No.: 01
Date: 03-Mar-2017
5
2.0
Approved
930105656
2.0
v

10.3.7 Interim Analyses ..................................................................................... 
 
12. APPENDICES ........................................................................................................ 
APPENDIX 1 ABBREVIATIONS AND TRADEMARKS ........................................ 
APPENDIX 2 STUDY GOVERNANCE CONSIDERATIONS ................................. 
APPENDIX 3 ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS: 
DEFINITIONS AND PROCEDURES FOR RECORDING, EVALUATING, 
FOLLOW UP AND REPORTING ......................................................................... 
APPENDIX 4 WOMEN OF CHILDBEARING POTENTIAL DEFINITIONS AND 
METHODS OF CONTRACEPTION ..................................................................... 
51
52
57
58
62
70
74
Clinical Protocol
BMS-936558
CA209923
nivolumab
Revised Protocol No.: 01
Date: 03-Mar-2017
6
2.0
Approved
930105656
2.0
v

Clinical Protocol
CA209923
BMS-936558
nivolumab
1.
SYNOPSIS
Protocol Title: Randomized, Double-Blind, Parallel Group Study to Evaluate the Safety, 
Tolerability, Pharmacokinetics and Pharmacodynamics of BMS-936558 (nivolumab) in 
Participants with Severe Sepsis or Septic Shock.
Study Phase:
1b
 
 
 
 
 
 
Study Population:
Men and women ages ≥ 18 years old with severe sepsis or septic shock and sepsis-associated
immunosuppression.
Objectives and Endpoints:
Objective
Endpoint
Primary

To assess the safety and tolerability of a single dose 
of nivolumab 480 mg or 960 mg in participants 
with severe sepsis or septic shock 

To assess the pharmacokinetics of BMS-936558 in 
participants with severe sepsis  or septic shock

Incidence rates of SAEs, AEs, immune-mediated
AEs, AEs leading to discontinuation, deaths, and 
vital signs, ECG, or clinical laboratory 
abnormalities.  

Cmax, Cmin, Cavg, Tmax, AUC(0-T), CLT, Vd, 
T1/2.
Secondary

To assess receptor occupancy of
nivolumab
following single dose administration

To assess the effect of a single dose of nivolumab
on monocyte HLA-DR expression and absolute 
lymphocyte count

To assess the immunogenicity
of nivolumab
following single dose administration

Receptor occupancy on T cells at baseline and 
after study treatment administration at planned 
sampling time points

Baseline and post-dosing assessments of mHLA-
DR expression on monocytes, of absolute 
lymphocyte count

Number and percentage of participants with 
detectable anti-nivolumab antibodies at baseline 
and following single dose administration of 
nivolumab and the relationship with other 
outcome measures
Revised Protocol No.: 01
Date: 03-Mar-2017
7
2.0
Approved
930105656
2.0
v

Clinical Protocol
CA209923
BMS-936558
nivolumab
Overall Design:
Phase 1b, randomized, double-blind, multi-center study to evaluate the safety, tolerability, 
pharmacokinetics and pharmacodynamics of a single dose of nivolumab in participants with 
severe sepsis or septic shock.
Number of Participants: 
Up to approximately 30 participants will be randomized and treated, in order to obtain a PK 
profile from at least 6 subjects per dose level.
Treatment Arms and Duration:
The total duration of study for each participant is approximately 100 Days, comprised of a 
screening period of up to 10 days, plus a single dose of nivolumab on Day 1, followed by clinical 
study assessments up to Day 90.  AEs and SAEs will be collected up to Day 90.
Screening
Baseline
Treatment
On-Treatment 
Assessments
Day -10 to -1
Day -1
Day 1
Day 1 to Day 90
Determine 
eligibility
Randomize 
eligible 
participants 
(1:1 ratio)
Single dose 
nivolumab    
480 mg (n=15)
OR
Single dose 
nivolumab
960 mg (n=15)
Hospital discharge 
may occur prior to 
Day 90
Study treatment: 
Study Drug for CA209923
Medication 
Potency 
IP/Non-IP 
Nivolumab Solution for Injection
10 mg/mL
IP
Revised Protocol No.: 01
Date: 03-Mar-2017
8
2.0
Approved
930105656
2.0
v

Clinical Protocol
CA209923
BMS-936558
nivolumab
2.
SCHEDULE OF ACTIVITIES
Table 2.-1:
Screening Procedural Outline (CA209923)
Procedure
Screening a
Visit
Baseline b
Visit
Notes
Eligibility Assessments
Informed Consent
X
A participant is considered enrolled only when a protocol specific 
informed consent is signed.  Participants unable to give their written 
consent may only be enrolled in the study with the consent of a legally 
acceptable representative. The participant must also be informed about the 
nature of the study to the extent compatible with his or her understanding, 
and should this participant become capable, he or she should personally 
sign and date the consent form as soon as possible.
Inclusion/Exclusion Criteria
X
X
Medical History
X
Include any toxicities or allergy related to previous treatments. Include 
any chronic medical conditions (for example, hypertension, diabetes) and 
past surgeries.
Safety Assessments
Physical Examination (PE)
X
X
If the screening PE is performed within 24 hours prior to dosing on Day 1 
then a single exam may count as both the screening and predose 
evaluation.
Physical Measurements
X
Includes height, weight, and BMI.
Vital Signs
X
X
Includes body temperature, respiratory rate, blood pressure and heart rate. 
Blood pressure and heart rate should be measured after the participant has 
been resting quietly for at least 5 minutes. 
Electrocardiogram (ECGs)
X
X
ECGs should be recorded after the participant has been supine for at least 
5 minutes. 
Laboratory Tests
Clinical safety laboratory tests
X
X
Includes blood and urine samples. See Section 9.4.4
Pregnancy Test
X
X
WOCBP only. See note in Section 9.4.4
Revised Protocol No.: 01
Date: 03-Mar-2017
9
2.0
Approved
930105656
2.0
v

Clinical Protocol
CA209923
BMS-936558
nivolumab
Table 2.-1:
Screening Procedural Outline (CA209923)
Procedure
Screening a
Visit
Baseline b
Visit
Notes
Follicle Stimulating Hormone (FSH)
X
Women only. Refer to Appendix 4 for applicability.
Thyroid function testing
X
See note in Section 9.4.4
Adverse Event Reporting
Monitor for Serious Adverse Events
(SAEs)
X
X
Collection of SAEs begins when the informed consent form is signed.
Clinical Drug Supplies
Randomize
X
Randomization can occur either on Day -1 or Day 1.
Clinical Assessments
SOFA Score
X
Pre-dose, after participant is admitted to the ICU
Ventilator Usage
X
Record Start date, if applicable
Vasopressor Usage
X
Record Start date, if applicable
Dialysis Usage
X
Record Start date, if applicable
a Screening assessments must be performed within 10 days prior to Day 1 administration of randomized study treatment. If screening assessments other than 
labs are within 24 hours of dosing, then assessments performed for screening can be counted as both screening and baseline. Screening labs within 48 hours 
prior to dosing can be counted as both screening and baseline.
b Baseline assessments excluding labs must be within 24 hours prior to dosing. Baseline labs can be within 48 hours prior to dosing.
Revised Protocol No.: 01
Date: 03-Mar-2017
10
2.0
Approved
930105656
2.0
v

Clinical Protocol
CA209923
BMS-936558
nivolumab
Table 2.-2:
On Treatment Procedural Outline (CA209923)
Procedure
WK 1
D1-7
WK2 
D10    
WK2
D14
WK3
D21
WK4
D28
WK6 
D42
WK8
D56
WK10
D70
Indexa
Hospitaliza
tion 
Discharge
Studyb
Discharge
D90
Notes
Visit window
+/- 1 
day
+/- 1 
day
+/- 2 
days
+/- 3 
days
+/- 4 
days
+/- 5 
days
+/- 7 
days
+/- 9    
days
Clinical Drug 
Supplies
Randomize
X
Randomization can 
occur either on Day -1 
or Day 1.
Study Drug 
Administration
X
Day 1.
Safety Assessments
Physical 
Examination (PE)
X
X
X
X
X
X
Perform daily in Week 
1, at Index 
Hospitalization 
Discharge, and at 
Study Discharge; 
Perform at other time 
points only if still 
hospitalized.
Physical 
Measurements 
X
X
Weight only.
Vital Signs
X
X
X
X
X
X
Perform daily in Week 
1, at Index 
Hospitalization 
Discharge, and at 
Study Discharge; 
Perform at other time 
points only if still 
hospitalized. See note 
in screening 
Revised Protocol No.: 01
Date: 03-Mar-2017
11
2.0
Approved
930105656
2.0
v

Clinical Protocol
CA209923
BMS-936558
nivolumab
Table 2.-2:
On Treatment Procedural Outline (CA209923)
Procedure
WK 1
D1-7
WK2 
D10    
WK2
D14
WK3
D21
WK4
D28
WK6 
D42
WK8
D56
WK10
D70
Indexa
Hospitaliza
tion 
Discharge
Studyb
Discharge
D90
Notes
procedures.
Electrocardiogram 
(ECGs)
X
X
X
X
X
X
Perform at end of 
infusion on Day 1, at 
Index Hospitalization 
Discharge, and at 
Study Discharge; 
Perform at other time 
points only if still 
hospitalized.
Clinical safety 
laboratory tests
X
X
X
X
X
X
X
X
Days 1, 4 and 7 of 
week 1.  See note in 
screening procedures 
and in Section 9.4.4
Pregnancy Test
X
X
X
WOCBP only. See 
note in Section 9.4.4.
Thyroid function 
testing
X
X
X
See note in Section 
9.4.4
Adverse Event 
Reporting
Monitor for Non-
Serious Adverse 
Events 
Collection of nonserious adverse events begins at initiation of study treatment.  Adverse events must be collected up to Day 90.
Monitor for Serious 
Adverse Events
See note in Screening procedures.  SAEs must be collected up to Day 90. 
Other Assessments
Revised Protocol No.: 01
Date: 03-Mar-2017
12
2.0
Approved
930105656
2.0
v

Clinical Protocol
CA209923
BMS-936558
nivolumab
Table 2.-2:
On Treatment Procedural Outline (CA209923)
Procedure
WK 1
D1-7
WK2 
D10    
WK2
D14
WK3
D21
WK4
D28
WK6 
D42
WK8
D56
WK10
D70
Indexa
Hospitaliza
tion 
Discharge
Studyb
Discharge
D90
Notes
Ventilator Usage
In days counting from the day of study treatment administration during participant’s index hospitalization. 
Vasopressor Usage
In days counting from the day of study treatment administration during participant’s index hospitalization.
Dialysis Usage
In days counting from the day of study treatment administration during participant’s index hospitalization.
Mortality
Date and primary cause of death. 
SOFA Score
Daily during the first week after study treatment administration, and weekly thereafter while participant is in ICU during participant’s
index hospitalization.
Length of ICU stay 
During Index 
Hospitalization
ICU discharge date during index hospitalization.
Length of Index 
Hospitalization
Hospital discharge date during index hospitalization.
Pharmacokinetic 
(PK) and 
Immunogenicity 
Assessments
See Section 9.5 for details and collection schedule.
Biomarker 
Assessments
See Section 9.8 for details and collection schedule.
Exploratory 
Biomarker 
Assessments
See Section 9.8 for details and collection schedule.
Additional 
Research Sampling 
See Section 9.8.1
a Index hospitalization discharge can occur at any time after dosing. Index hospitalization discharge assessments may be performed within 96 hours prior to 
hospital discharge. Study labs performed within 96 hours prior to hospital discharge can be counted for both the study day and hospital discharge visits.
b Study Discharge assessments should also performed for participants who are prematurely discontinued. 
Abbreviations: D=Day
Revised Protocol No.: 01
Date: 03-Mar-2017
13
2.0
Approved
930105656
2.0
v

Clinical Protocol
CA209923
BMS-936558
nivolumab
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
3.2
Background
PD-1 is a member of the CD28 family of T-cell signaling receptors that also includes CD28, 
CTLA 4, ICOS, and BTLA.67 PD-1 signaling has been shown to inhibit CD-28-mediated 
upregulation of IL-2, IL-10, IL-13, interferon-γ (IFN-γ) and Bcl-xL. PD-1 expression has also 
been noted to inhibit T cell activation, and expansion of previously activated cells. Evidence for 
a negative regulatory role of PD-1 comes from studies of PD-1 deficient mice, which develop a 
variety of autoimmune phenotypes.68 These results suggest that PD-1 blockade has the potential 
to activate anti-self T-cell responses, but these responses are variable and dependent upon 
various host genetic factors. 
In vitro, nivolumab binds to PD-1 with high affinity (EC50 0.39-2.62 nM), and inhibits the 
binding of PD-1 to its ligands PD-L1 and PD-L2 (IC50 ±1 nM). Nivolumab binds specifically to 
PD-1 and not to related members of the CD28 family such as CD28, ICOS, CTLA-4 and BTLA. 
Blockade of the PD-1 pathway by nivolumab results in a reproducible enhancement of both 
Revised Protocol No.: 01
Date: 03-Mar-2017
15
2.0
Approved
930105656
2.0
v

Clinical Protocol
CA209923
BMS-936558
nivolumab
proliferation and IFN-γ release in the mixed lymphocyte reaction (MLR). Using a CMV 
stimulation assay with human PBMC, the effect of nivolumab on antigen specific recall response 
indicates that nivolumab augmented IFN-γ secretion from CMV specific memory T cells in a 
dose-dependent manner versus isotype-matched control. In vivo blockade of PD-1 by a murine 
analog of nivolumab enhances the anti-tumor immune response and result in tumor rejection in 
several immunocompetent mouse tumor models (MC38, SA1/N, and PAN02).69
Nivolumab is approved in multiple oncology indications. The overall safety experience with 
nivolumab, as a monotherapy or in combination with other therapeutics, is based on experience, 
as of May-2015, in approximately 12,300 oncology clinical trial subjects.70 Details on the safety 
profile of nivolumab in oncology subjects are available in the Investigator Brochure and will not 
be repeated here.70 Study CA209923 is the first clinical trial of nivolumab in sepsis.
The single-dose
and
multiple dose
pharmacokinetics of nivolumab
were
previously 
well-characterized in oncology subjects and are known to be linear and dose-proportional in the 
range of 0.1 to 10 mg/kg. The geometric mean (% CV) clearance (CL) was 9.5 mL/h (49.7%), 
geometric mean volume of distribution at steady state (Vss) was 8.0 L (30.4%), and geometric 
mean elimination half-life (t1/2) was 26.7 days (101%). Nivolumab accumulation following 
every 2 weeks administration in oncology subjects was in the range of 2.9 to 3.3 based on 
AUC(TAU), 2.0 to 2.4 based on Cmax, and 3.1 to 4.8 based on Cmin. There was no dose-related 
trend in the accumulation index of AUC(TAU), Cmax, or Cmin. There was no meaningful change 
in cytokines known to have indirect effects on CYP enzymes across all studied dose levels of 
nivolumab (0.3, 2 and 10 mg/kg) during the course of treatment.70 This lack of cytokine 
modulation suggests that nivolumab has no or low potential for modulating CYP enzymes, 
thereby indicating a low risk of therapeutic protein-drug interaction. Nivolumab is an IgG4 
monoclonal antibody, which is likely eliminated by mechanisms similar to that of other 
antibodies, namely by non-specific catabolism (mainly by enzymes in the reticuloendothelial 
system). These enzymes are not known to be inhibited or induced by drugs, and therefore it is 
unlikely that other drugs will have an impact on the PK of nivolumab. The immunogenic 
potential of nivolumab was minimal with low titers, low persistent positive rates, low incidences 
of neutralizing antibodies and no impact of immunogenicity on safety or PK.70
A detailed description of the chemistry, pharmacology, efficacy, and safety of nivolumab is 
provided in the Investigator Brochure.70
3.3
Benefit/Risk Assessment
As described below, the risk profile for evaluation of a single dose of nivolumab in participants 
with severe sepsis or septic shock is acceptable.
Potential risks of nivolumab
Overall, the safety profile of nivolumab monotherapy is manageable and generally consistent 
across completed and ongoing clinical trials in oncology with no MTD reached at any dose 
Revised Protocol No.: 01
Date: 03-Mar-2017
16
2.0
Approved
930105656
2.0
v

Clinical Protocol
CA209923
BMS-936558
nivolumab
tested up to 10 mg/kg Q2W. Most AEs were low-grade (Grade 1 to 2) with relatively few related 
high-grade (Grade 3 to 4) AEs. There was no pattern in the incidence, severity, or causality of 
AEs with respect to nivolumab dose level. Based on dosing simulations, the proposed 480 mg 
and 960 mg single-dose regimens in CA209923 provide comparable or higher exposures as 
steady-state levels of the approved 3 mg/kg Q2W regimen and the projected exposures are within 
the safety margins of the previously studied 10 mg/kg Q2W regimen. 
In clinical trials of nivolumab monotherapy in oncology, select AEs thought to be due to the 
effects of inflammatory cells on specific tissues have been identified which include, but are not 
limited to, pneumonitis, diarrhea/colitis, hepatitis, endocrinopathies, rash, and nephritis. Potential 
safety concerns and recommended management guidelines regarding pulmonary toxicities, GI 
toxicities, hepatotoxicities, endocrinopathies, dermatologic toxicities, and other toxicities of 
concern are summarized in the Investigator Brochure.70 In clinical trials of nivolumab 
monotherapy, most high-grade immune-mediated AEs were manageable with the use of 
corticosteroids or hormone replacement therapy (for endocrinopathies). Use of corticosteroids or 
hormone replacement therapy to manage immune-mediated AEs is not expected to present an 
undue risk to a patient with severe sepsis or septic shock.
Potential benefit of nivolumab in severe sepsis
As described earlier, the data from a mouse model of sepsis and from patients with sepsis 
suggests a role for the PD-1/PD-L1 pathway in sepsis. Taking these data together with evidence 
of an immunosuppressive phase in severe sepsis associated with poor clinical outcomes, 
interventions with the potential to improve host immune function, such as nivolumab, may 
benefit patients with severe sepsis.
Risk mitigation approaches in CA209923
Eligibility criteria. In CA209923, the target population is patients with severe sepsis/septic shock 
and sepsis-associated immunosuppression. As such, the eligibility criteria are written in order to 
avoid enrolling participants in the early, predominantly pro-inflammatory phase of sepsis and 
rather to enroll participants in the immunosuppressive phase. To achieve this, in CA209923 
participants with severe sepsis or septic shock must have the onset of organ dysfunction at least 
24 hours prior to study treatment administration and immunosuppression as assessed by a 
depressed absolute lymphocyte count. The rationale for this approach is that pro-inflammatory 
cytokines are typically high in the early stages of severe sepsis and septic shock, generally 
peaking between 3 and 36 hours and diminishing over subsequent hours.71
Single-dose administration and dose levels to be studied. In the current study only single-dose 
administration will be studied and in any potential future clinical development program for 
nivolumab in severe sepsis only short-term administration is anticipated.  Using a population 
pharmacokinetic (PPK) model, nivolumab concentration-time profiles were predicted for the 
proposed 480 mg and 960 mg single-dose regimens in CA209923 and the profiles were 
compared to the steady state levels of the approved 3 mg/kg Q2W regimen and the 10 mg/kg 
Q2W regimen, previously studied in oncology. Based on dosing simulations, it is anticipated that 
Revised Protocol No.: 01
Date: 03-Mar-2017
17
2.0
Approved
930105656
2.0
v

Clinical Protocol
CA209923
BMS-936558
nivolumab
5.1.1
Data Monitoring Committee and Other External Committees
Not applicable.
5.2
Number of Participants
Up to approximately 30 participants will be randomized in a 1:1 ratio into one of two treatment 
groups, in order to obtain a PK profile from at least 6 subjects per dose level.
Refer to Section 10.1 for sample size rationale.
5.3
End of Study Definition
The start of the trial is defined as the first visit for first participant screened.
The last visit is defined as the last scheduled visit in the Table of Procedures, Section 2.
The end of study is defined as the date of the last visit.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Revised Protocol No.: 01
Date: 03-Mar-2017
20
2.0
Approved
930105656
2.0
v

Clinical Protocol
CA209923
BMS-936558
nivolumab
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
5.5
Justification for Dose
As stated above, the goal of the current study is to determine whether the PK exposures attained 
after a single dose of nivolumab in participants with severe sepsis or septic shock are comparable 
to the PK exposures observed at steady state dosing of nivolumab in participants with cancer. In 
the current study, single dose administration of either 480 mg or 960 mg nivolumab will be 
evaluated in participants with severe sepsis or septic shock. The pharmacokinetics and safety of 
nivolumab monotherapy up to dose levels of 10 mg/kg Q2W and 10 mg/kg Q3W were 
previously well-characterized across multiple tumor types. Nivolumab 3 mg/kg Q2W is currently 
approved and indicated for the treatment of several cancers, including melanoma, squamous and 
non-squamous non-small cell lung carcinoma, renal cell carcinoma, and classical Hodgkin 
lymphoma.
Nivolumab concentration-time profiles were predicted for the proposed 480 mg and 960 mg 
single-dose regimens and compared to the steady state levels of the approved 3 mg/kg Q2W 
regimen using a population pharmacokinetic model (PPK). In the PPK model, the disposition of 
nivolumab was well-described by a linear 2-compartment model, which incorporates time-
varying clearance. The model was developed with data from 1895 participants with solid tumors 
who received 0.3 to 10.0 mg/kg nivolumab in 11 clinical trials during the course of nivolumab 
development across multiple tumor types.70  A full covariate model was developed to assess 
Revised Protocol No.: 01
Date: 03-Mar-2017
21
2.0
Approved
930105656
2.0
v

Clinical Protocol
CA209923
BMS-936558
nivolumab
covariate effects on pharmacokinetic parameters. The only potentially clinically relevant (>20%) 
covariate was baseline body weight; such that participants with higher baseline body weight have 
higher baseline clearance and central volume of distribution. 
Simulations performed using the PPK model showed that Cmax values produced by the proposed 
480 mg and 960 mg dosing regimens are either equivalent to, or higher than those of the steady 
state levels of approved 3 mg/kg Q2W regimen but lower than the steady state levels of 10 
mg/kg Q2W regimen (see Figure 5.5-1). Cavg values produced by the proposed 480 mg and 960 
mg dosing regimens are either equivalent to (at 960 mg), or lower (at 480 mg) than those of the 
steady state levels of approved 3 mg/kg Q2W regimen and lower than the steady state levels of 
10 mg/kg Q2W regimen. Whereas Cmin values produced by the proposed regimens were 
comparable or lower than that of the 3 mg/kg Q2W approved regimen and significantly lower 
than the 10 mg/kg Q2W regimen (Table 5.5-1). Based on previous studies, steady-state Cmax
(Cmaxss) and Cmin at Day-28 (Cmind28) were identified as the exposure measures most likely to 
impact safety and efficacy of nivolumab, respectively. The Cmax of the proposed 960 mg dose 
was higher than that of the approved 3 mg/kg Q2W dose but lower than the 10 mg/kg Q2W dose 
(see Figure 5.5-2). The safety data accumulated for nivolumab up to steady state dose levels of 
10 mg/kg Q2W in multiple tumor types provide a wide safety margin. Cmax values produced by a 
single dose of up to 960 mg will be lower than the 10 mg/kg Q2W dose (see Figure 5.5-2). Thus 
based on dosing simulations, 480 mg and 960 mg dosing regimens will provide comparable or 
higher overall exposures as the steady state levels of 3 mg/kg Q2W regimen, and will be within
the safety margins of 10 mg/kg Q2W regimen at steady-state.
Figure 5.5-1:
Predicted nivolumab geometric mean concentration vs time profile for 
a single dose of 480 mg and 960 mg compared with steady state 
multiple dose of 3 mg/kg and 10 mg/kg 
Analysis directory source: /global/pkms/data/CA/209/923/prd/ppk/final
PPK model: Analysis directory/nm/a-2202-3p1.ctl
Revised Protocol No.: 01
Date: 03-Mar-2017
22
2.0
Approved
930105656
2.0
v

Clinical Protocol
CA209923
BMS-936558
nivolumab
Figure 5.5-2:
Simulated nivolumab exposure for a single dose of 480 mg and 960 mg 
The solid lines and shaded band represent the simulation-based median and 
90% prediction intervals. The dotted lines and values represent median and 
95th percentile.
Analysis directory source: /global/pkms/data/CA/209/923/prd/ppk/final
PPK model: Analysis directory/nm/a-2202-3p1.ctl
Revised Protocol No.: 01
Date: 03-Mar-2017
23
2.0
Approved
930105656
2.0
v

Clinical Protocol
CA209923
BMS-936558
nivolumab
Table 5.5-1:
Comparisons of Cmin, Cmax, and Cavg for geometric mean and median of 3mg/kg Q2W steady state 
and 480 mg and 960 mg single dosing regimens
Summary Exposure
3 mg/kg Q2W
Steady State
GM [g/mL] (%CV)
480 mg Single Dose
GM [g/mL] (%CV)
% Difference 
in GMs
3 mg/kg Q2W
Steady State
Median [g/mL]
(5th, 95th percentile)
480 mg Single Dose
Median [g/mL] 
(5th, 95th percentile)
Cmin
63.9 ( 62.5 )
21.6 ( 39 )
-66.2
66.4 ( 27.9 , 120 )
22.3 ( 10.6 , 39.3 )
Cmax
126 ( 51.2 )
123 ( 85.4 )
-2.38
126 ( 74.9 , 202 )
121 ( 74.7 , 204 )
Cavg
83.5 ( 51.3 )
42.7 ( 28.5 )
-48.9
85.1 ( 42.7 , 143 )
42.8 ( 27 , 67.7 )
Summary Exposure
3 mg/kg Q2W
Steady State
GM [g/mL] (%CV)
960 mg Single Dose
GM [g/mL] (%CV)
% Difference 
in GMs
3 mg/kg Q2W
Steady State
Median [g/mL]
(5th, 95th percentile)
960 mg Single Dose
Median [g/mL] 
(5th, 95th percentile)
Cmin
63.9 ( 62.5 )
43.2 ( 39 )
-32.4
66.4 ( 27.9 , 120 )
44.6 ( 21.2 , 78.6)
Cmax
126 ( 51.2 )
246 ( 85.4 )
95.2
126 ( 74.9 , 202 )
242 ( 149 , 408)
Cavg
83.5 ( 51.3 )
85.4 ( 28.5 )
2.28
85.1 ( 42.7 , 143 )
85.6 (54 , 135)
Cmin: Trough nivolumab serum concentration, Cmax: Peak nivolumab serum concentration, Cavg: Average nivolumab serum concentration, GM: Geometric 
mean, CV: Coefficient of variation
Analysis directory source: /global/pkms/data/CA/209/923/prd/ppk/final
PPK model: Analysis directory/nm/a-2202-3p1.ctl
Revised Protocol No.: 01
Date: 03-Mar-2017
24
2.0
Approved
930105656
2.0
v

Clinical Protocol
CA209923
BMS-936558
nivolumab
6.
STUDY POPULATION
For entry into the study, the following criteria MUST be met.
6.1
Inclusion Criteria
1) Signed Written Informed Consent
a) The informed consent form signed by the participant or the participant’s legally 
acceptable representative
2) Type of Participant and Target Disease Characteristics
a) Men and women ages ≥ 18 years old
b) Participant has documented OR suspected infection
i)
Documented infection is infection confirmed with a microbiologic diagnosis
ii) Suspected infection is infection being treated with ongoing antimicrobial therapy at 
the time of study treatment administration
c) Participant has the onset of severe sepsis or septic shock at least 24 hours prior to study 
treatment administration based on having at least 1 of the 3 organ dysfunction criteria 
below. Organ dysfunction must be new and thought to be due to sepsis.
i)
Hypotension defined as the need for treatment with any vasopressor(s) for at least 6 
hours to maintain a systolic pressure ≥ 90 mmHg or a mean arterial pressure ≥70
mmHg
OR
ii) Acute respiratory failure defined as the need for invasive mechanical ventilation for at 
least 24 hours to support pulmonary function
OR
iii) Acute kidney injury defined as creatinine > 2.0 mg/dL (from a creatinine that was 
within the normal reference range prior to onset of sepsis) OR urine output < 0.5 
mL/kg/hr for > 2 hours despite adequate fluid resuscitation. In the presence of pre-
existing impairment of renal function (defined as a serum creatinine concentration >2 
times the upper limit of the normal reference range prior to the onset of sepsis), the 
participant should meet 1 of the other 2 organ dysfunction criteria above.
d) Participant has sepsis- associated immunosuppression based on an absolute lymphocyte 
count ≤ 1100 cells/μL on at least one assessment within the 96 hours prior to study 
treatment administration
e) Participant is in an intensive care unit at the time of study treatment administration and, 
based on their medical condition, there are no plans to discharge from the ICU in the next 
24 hours
f)
Participant Re-enrollment: This study permits the re-enrollment of a participant who has 
discontinued the study as a pre-treatment failure (ie, participant has not been randomized 
/has not been treated). If re-enrolled, the participant must be re-consented.
Revised Protocol No.: 01
Date: 03-Mar-2017
25
2.0
Approved
930105656
2.0
v

Clinical Protocol
CA209923
BMS-936558
nivolumab
3) Age and Reproductive Status
a) Women of childbearing potential (WOCBP) must have a negative serum or urine 
pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 24 
hours prior to the start of study treatment
b) Women must not be breastfeeding
c) Women of childbearing potential (WOCBP) must agree to follow instructions for 
method(s) of contraception for the duration of treatment with nivolumab plus 5 half-lives
of nivolumab (the terminal half-life of nivolumab is up to 25 days) plus 30 days (duration 
of ovulatory cycle) for a total of 5 months post-treatment completion (See Appendix 4).
d) Males who are sexually active with WOCBP must agree to follow instructions for 
method(s) of contraception (Appendix 4) for the duration of treatment with nivolumab 
plus 5 half-lives of nivolumab plus 90 days (duration of sperm turnover) for a total of 7 
months post-treatment completion. In addition, male participants must be willing to 
refrain from sperm donation during this time (See Appendix 4).
e) Azoospermic males are exempt from contraceptive requirements. 
f)
WOCBP who are continuously not heterosexually active are also exempt from 
contraceptive requirements but still must undergo pregnancy testing as described in this 
section.
Investigators shall counsel WOCBP, and male participants who are sexually active with 
WOCBP, on the importance of pregnancy prevention and the implications of an unexpected 
pregnancy. Investigators shall advise on the use of highly effective methods of contraception
(Appendix 4) which have a failure rate of < 1% when used consistently and correctly.
6.2
Exclusion Criteria
1) Medical Conditions
a) Previous episode of severe sepsis or septic shock with ICU admission during the current 
hospitalization 
b) Active, known, or suspected autoimmune disease NOTE: Participants with type I 
diabetes mellitus, hypothyroidism only requiring hormone replacement, skin disorders 
(such as vitiligo, psoriasis, or alopecia) not requiring systemic treatment, or conditions 
not expected to recur in the absence of an external trigger are permitted to enroll.
c) History of solid organ or bone marrow transplant.
d) Known history of malignancy and has undergone treatment for such within 6 weeks prior 
to study treatment administration.
e) Known history of infection with HIV and not on antiretroviral therapy prior to the current 
hospitalization or CD4 ≤ 200 cells/mm3 or AIDS-defining illness in the past year.
f)
Known history of chronic HBV infection and not on treatment with an HBV 
nucleos(t)ide analogue prior to the current hospitalization or HBV DNA > 100 IU/mL.
g) Known history of infection with HCV and currently undergoing treatment for HCV 
infection or has detectable HCV RNA.
Revised Protocol No.: 01
Date: 03-Mar-2017
26
2.0
Approved
930105656
2.0
v

Clinical Protocol
CA209923
BMS-936558
nivolumab
h) Known active illicit drug use disorder (defined as illicit drug use on 5 or more days in the 
past 30 days) OR known active alcohol use disorder (defined as drinking 5 or more 
alcoholic drinks on the same occasion on 5 or more days in the past 30 days)
i)
Any other sound medical, psychiatric and/or social reason as determined by the 
investigator
2) Prior/Concomitant Therapy
a) Prior exposure to nivolumab or to an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, 
anti-CTLA-4 antibody, or any other antibody or drug specifically targeting T-cell co-
stimulation or checkpoint pathways 
b) Prior exposure to any other investigational agent within 4 weeks or 5 half-lives 
(whichever is longer) of study treatment administration 
c) Prior exposure to GM-CSF (Granulocyte-macrophage colony-stimulating factor; 
Sargramostim; Leukine) within 4 weeks or 5 half-lives (whichever is longer) of study 
treatment administration
3) Physical and Laboratory Test Findings
a) Body weight ≤50 kg or ≥ 180 kg
4) Allergies and Adverse Drug Reaction
a) History of severe hypersensitivity reaction to monoclonal antibodies or related 
compounds.
5) Other Exclusion Criteria
a) Prisoners or participants who are involuntarily incarcerated. (Note: under certain specific 
circumstances a person who has been imprisoned may be included or permitted to 
continue as a participant. Strict conditions apply and Bristol-Myers Squibb approval is 
required.)
b) Participants who are compulsorily detained for treatment of either a psychiatric or 
physical illness
c) Concurrent participation in another interventional clinical trial of an investigational drug
d) Presence of an advanced directive to withhold or withdraw life-sustaining treatment, a do 
not resuscitate (DNR) order, a no CPR order, or a comfort measures only (CMO) order
e) Participant’s family, treating physician, or both are not in favor of aggressive support of 
the participant
Eligibility criteria for this study have been carefully considered to ensure the safety of the study 
participants and that the results of the study can be used. It is imperative that participants fully 
meet all eligibility criteria.
6.3
Lifestyle Restrictions
6.3.1
Meals and Dietary Restrictions
Not applicable.
6.3.2
Caffeine, Alcohol and Tobacco
Not applicable.
Revised Protocol No.: 01
Date: 03-Mar-2017
27
2.0
Approved
930105656
2.0
v

Clinical Protocol
CA209923
BMS-936558
nivolumab
6.3.3
Activity
Not applicable.
6.4
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study but are 
not subsequently randomized. A minimal set of screen failure information is required to ensure 
transparent reporting of screen failure participants, to meet the Consolidated Standards of 
Reporting Trials (CONSORT) publishing requirements, and to respond to queries from 
regulatory authorities. Minimal information includes date of consent, demography, screen failure 
details, eligibility criteria, and any serious AEs.
6.4.1
Retesting During Screening or Lead-In Period
Participant Re-enrollment: This study permits the re-enrollment of a participant that has 
discontinued the study as a pre-treatment failure (i.e., participant has not been randomized / has 
not been treated). If re-enrolled, the participant must be re-consented.
Retesting of laboratory parameters and/or other assessments within any single Screening or 
Lead-in period will be permitted (in addition to any parameters that require a confirmatory 
value).
The most current result prior to Randomization is the value by which study inclusion will be 
assessed, as it represents the participant’s most current, clinical state.
Laboratory parameters and/or assessments that are included in Table 2.-1 Screening Procedural 
Outline may be repeated in an effort to find all possible well-qualified participants. Consultation 
with the Medical Monitor may be needed to identify whether repeat testing of any particular 
parameter is clinically relevant.
7.
TREATMENT
Study treatment is defined as any investigational treatment(s), marketed product(s), placebo or 
medical device intended to be administered to a study participant according to the study 
randomization or treatment allocation
Study 
treatment
includes 
both 
Investigational 
[Medicinal] 
Product 
(IP/IMP) 
and 
Non-investigational [Medicinal] Product (Non-IP/Non-IMP) and can consist of the following:

Nivolumab
An investigational product, also known as investigational medicinal product in some regions, is 
defined a pharmaceutical form of an active substance or placebo being tested or used as a 
reference in a clinical study, including products already with a marketing authorization but used 
or assembled (formulated or packaged) differently than the authorized form, or used for an 
unauthorized indication, or when used to gain further information about the authorized form.
Revised Protocol No.: 01
Date: 03-Mar-2017
28
2.0
Approved
930105656
2.0
v

Clinical Protocol
CA209923
BMS-936558
nivolumab
Other medications used as support or escape medication for preventative, diagnostic, or 
therapeutic reasons, as components of the standard of care for a given diagnosis, may be 
considered as non-investigational products.
Revised Protocol No.: 01
Date: 03-Mar-2017
29
2.0
Approved
930105656
2.0
v

Clinical Protocol
CA209923
BMS-936558
nivolumab
Table 7.-1:
Study treatments for CA209923
Product Description / 
Class and Dosage 
Form
Potency
IP/
Non-IMP
Blinded or 
Open Label
Packaging / Appearance
Storage 
Conditions
(per label)
Nivolumab Solution 
for Injection
100 mg (10 mg/mL)
and 40 mg (10 mg/mL)
IP
Open label a
Clear to opalescent colorless to pale yellow liquid. 
May contain particles.
240 mg kit contains: 2 x 100 mg vials (10 mL/vial) 
and 1 x 40 mg vial (4 mL/vial) or carton containing 
5 vials of  100 mg (10 mL/vial)
2 to 8C. Protect 
from light and 
freezing
May be labelled as either ‘BMS-936558-01’ or ‘Nivolumab’.
a The term ‘Open label’ refers to the medication as it is upon receipt at the pharmacy (unblinded pharmacist).  Trial design and conduct are double-blind.
Revised Protocol No.: 01
Date: 03-Mar-2017
30
2.0
Approved
930105656
2.0
v

Clinical Protocol
CA209923
BMS-936558
nivolumab
7.1
Treatments Administered
The selection and timing of dose for each participant is as follows:
Table 7.1-1:
Selection and Timing of Dose
Study Treatment
Unit dose strength(s)
Dosage formulation
Frequency of 
Administration
Route of Administration
BMS-936558-01 
(nivolumab) 
480 mg or 960 mg
100 mg (10 mg/mL) 
and 40 mg (10 mg/mL)
sterile solution
Single dose infusion
Intravenous
Participants are randomized to receive double-blind nivolumab at a dose of 480 mg or 960 mg as 
a 90 minute infusion on Day 1. 
Infusions will be prepared by an unblinded pharmacist according to a pharmacy manual, 
provided separately.
The infusion volume for the two treatment groups will be the same, to 
preserve the blind.
Participants should be carefully monitored for infusion reactions during nivolumab 
administration. Nivolumab contains only human immunoglobulin protein sequences, therefore it 
is unlikely to be immunogenic and induce infusion or hypersensitivity reactions. However, if 
such a reaction were to occur, it might manifest with fever, chills, rigors, headache, rash, 
pruritus, arthralgias, hypotension, hypertension, bronchospasm, or other allergic-like reactions. 
All Grade 3 or 4 infusion reactions should be reported within 24 hours to the study medical 
monitor and reported as an SAE if it meets the criteria. Infusion reactions should be graded 
according to CTCAE (Version 4) guidelines.
Treatment recommendations are provided below and may be modified based on local 
treatment standards and guidelines, as appropriate:
For Grade 1 symptoms: (mild reaction; infusion interruption not indicated; intervention not 
indicated):

Remain at bedside and monitor participant until recovery from symptoms. 
For Grade 2 symptoms: (moderate reaction requiring infusion interruption but responds promptly 
to symptomatic treatment [eg, antihistamines, non-steroidal anti-inflammatory drugs, narcotics, 
corticosteroids, bronchodilators, IV fluids]):

Stop the nivolumab infusion, begin an IV infusion of normal saline, and treat the participant
with diphenhydramine 50 mg IV (or equivalent) and/or acetaminophen/paracetamol 325 to 
1000 mg; remain at bedside and monitor participant until resolution of symptoms. 
Corticosteroid and/or bronchodilator therapy may also be administered as appropriate. If the 
infusion is interrupted, then restart the infusion at 50% of the original infusion rate when 
symptoms resolve; if no further complications ensue after 30 minutes, the rate may be 
increased to 100% of the original infusion rate. Monitor participant closely. If symptoms 
recur, then no further nivolumab will be administered.
Revised Protocol No.: 01
Date: 03-Mar-2017
31
2.0
Approved
930105656
2.0
v

Clinical Protocol
CA209923
BMS-936558
nivolumab
For Grade 3 or 4 symptoms: (Grade 3: severe reaction: prolonged symptoms [e.g., not rapidly 
responsive to symptomatic medication and/or brief interruption of infusion] or recurrence of 
symptoms following initial improvement; Grade 4: Life-threatening; pressor or ventilatory 
support indicated):

Immediately discontinue infusion of nivolumab. Begin an IV infusion of normal saline and 
treat the participant as follows: Recommend bronchodilators, epinephrine 0.2 to 1 mg of a 
1:1000 solution for subcutaneous administration or 0.1 to 0.25 mg of a 1:10,000 solution 
injected slowly for IV administration, and/or diphenhydramine 50 mg IV with 
methylprednisolone 100 mg IV (or equivalent), as needed. Participant should be monitored 
until the Investigator is comfortable that the symptoms will not recur. Nivolumab will be 
permanently discontinued. Investigators should follow their institutional guidelines for the 
treatment of anaphylaxis. Remain at bedside and monitor participant until recovery from the 
symptoms.
For late-occurring hypersensitivity symptoms: (eg, appearance of a localized or generalized 
pruritus within 1 week after treatment) symptomatic treatment may be given (e.g., oral 
antihistamine or corticosteroids).
7.2
Method of Treatment Assignment
Study using Interactive Response Technology (IRT): All participants will be centrally 
randomized using an Interactive Response Technology (IRT). Before the study is initiated, each 
user will receive log in information and directions on how to access the IRT.
Study treatment will be dispensed at the study visits as listed in Schedule of Activities (Section 
2). 
Enrolled participants, including those not dosed, will be assigned sequential participant numbers 
comprised of the site number and a unique participant identifier. Those enrolled participants 
meeting inclusion and exclusion criteria will be eligible to be randomized. Randomization 
numbers will be assigned prior to dosing. 
During the screening visit, the investigative site will contact the Interactive Response 
Technology (IRT) system to assign the participant identification number. Once it is determined 
that the participant meets the eligibility criteria following the screening visit, the investigative 
site will call the IRT to randomize the participant into the open dose panel. 
7.3
Blinding
Blinding of treatment assignment is critical to the integrity of this clinical study. However, in the 
event of a medical emergency or pregnancy in an individual participant in which knowledge of 
the investigational product is critical to the participant's management, the blind for that 
participant may be broken by the investigator. The participant’s safety takes priority over any 
other considerations in determining if a treatment assignment should be unblinded.
Before breaking the blind of an individual participant's treatment, the investigator should 
determine that the unblinded information is necessary, i.e., that it will alter the participant's 
Revised Protocol No.: 01
Date: 03-Mar-2017
32
2.0
Approved
930105656
2.0
v

Clinical Protocol
CA209923
BMS-936558
nivolumab
immediate management. In many cases, particularly when the emergency is clearly not related to 
the investigational product, the problem may be properly managed by assuming that the 
participant is receiving active product. It is highly desirable that the decision to unblind treatment 
assignment be discussed with the Medical Monitor, but the investigator always has ultimate 
authority for the decision to unblind. The Principal Investigator should only call in for 
emergency unblinding AFTER the decision to discontinue the participant has been made.
For this study, the method of unblinding for emergency purposes is IRT.  
In cases of accidental unblinding, contact the Medical Monitor and ensure every attempt is made 
to preserve the blind.
Any request to unblind a participant for non-emergency purposes should be discussed with the 
Medical Monitor.
In case of an emergency, the investigator(s) has unrestricted access to randomization information 
via the Interactive Response Technology (IRT) and is capable of breaking the blind through the 
IRT system without prior approval from sponsor. Following the unblinding the Investigator shall 
notify the medical monitor and/or study director. For information on how to unblind in an 
emergency, consult the IRT manual.
Study participants and all clinical research site personnel, except the pharmacist, will be blinded.
The pharmacist at the site and/or designee will be unblinded to the randomized treatment 
assignments in order to dispense treatment from bulk supplies, as needed. 
Members of BMS Research and Development and their designees will be unblinded to study 
treatments to facilitate real-time analyses of PK, RO, and safety data in support of dose selection 
for future studies. No unblinded data will be communicated to Investigators. This unblinding is 
not expected to affect the integrity of the trial. PK endpoints are objective assessments that 
should not be affected by unblinding.
7.4
Dosage Modification
Not applicable.
7.5
Preparation/Handling/Storage/Accountability
The investigational product should be stored in a secure area according to local regulations. It is 
the responsibility of the investigator to ensure that investigational product is only dispensed to 
study Participants. The investigational product must be dispensed only from official study sites 
by authorized personnel according to local regulations.
The product storage manager should ensure that the study treatment is stored in accordance with 
the environmental conditions (temperature, light, and humidity) as determined by BMS. If 
concerns regarding the quality or appearance of the study treatment arise, the study treatment
should not be dispensed and contact BMS immediately.
Study treatment not supplied by BMS will be stored in accordance with the package insert.
Revised Protocol No.: 01
Date: 03-Mar-2017
33
2.0
Approved
930105656
2.0
v

Clinical Protocol
CA209923
BMS-936558
nivolumab
Investigational product documentation (whether supplied by BMS or not) must be maintained 
that includes all processes required to ensure drug is accurately administered. This includes 
documentation of drug storage, administration and, as applicable, storage temperatures, 
reconstitution, and use of required processes (e.g., required diluents, administration sets).
Participants should be carefully monitored for infusion
reactions during nivolumab 
administration. Infusion of nivolumab may be interrupted or discontinued depending on how 
well the participant tolerates the treatment. If an acute infusion reaction is noted, participants 
should be managed according to Section 7.1.
Nivolumab Injection, 100 mg/10 mL (10 mg/mL) and 40 mg/mL (10 mg/mL) Nivolumab 
injection is to be administered as an IV infusion through a 0.2-micron to 1.2-micron pore size, 
low-protein binding in-line filter at the protocol-specified doses. It is not to be administered as an 
IV push or bolus injection. Nivolumab injection can be infused undiluted (10 mg/mL) or diluted 
with 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP to protein 
concentrations as low as 0.35 mg/mL. Instructions for dilution and infusion of nivolumab 
injection may be provided in the clinical protocol, pharmacy binder, or pharmacy reference 
sheet. Care must be taken to assure sterility of the prepared solution as the product does not 
contain any antimicrobial preservative or bacteriostatic agent. Infusion-related supplies (eg. IV 
bags, in-line filters, 0.9% NaCl solution) will not be provided by the Sponsor and should be 
purchased locally if permitted by local regulations.
No incompatibilities have been observed between nivolumab injection and polyvinyl chloride 
(PVC), non-PVC/non-DEHP (di(2-ethylhexyl)phthalate) IV components, or glass bottles have 
been observed.
Further guidance and information for final disposition of unused study treatment are provided in 
Appendix 2.
7.6
Retained Samples for Bioavailability / Bioequivalence
Not applicable.
7.7
Treatment Compliance
Study drug will be administered in the clinical facility. Treatment compliance will be monitored 
by drug accountability and eCRF.
7.8
Concomitant Therapy
7.8.1
Prohibited and/or Restricted Treatments
Prohibited and/or restricted medications taken prior to study treatment administration or during 
the study are described below. Medications administered during the index hospitalization within 
Revised Protocol No.: 01
Date: 03-Mar-2017
34
2.0
Approved
930105656
2.0
v

Clinical Protocol
CA209923
BMS-936558
nivolumab
1 week prior to study treatment administration must be recorded on the CRF. Any concomitant 
therapies must be recorded on the CRF.
1) During the study, immunosuppressive agents are prohibited unless utilized to treat a drug 
related adverse event. NOTE: Adrenal replacement steroid doses up to the equivalent of 
hydrocortisone 300 mg/day for the treatment of septic shock are permitted. 
7.8.2
Other Restrictions and Precautions
Not applicable.
7.9
Treatment After the End of the Study
At the end of the study, BMS will not continue to provide BMS supplied study treatment to 
participants/investigators unless BMS chooses to extend the study. The investigator should 
ensure that the participant receives appropriate standard of care to treat the condition under 
study.
8.
DISCONTINUATION CRITERIA
8.1
Discontinuation from Study Treatment
Participants MUST discontinue investigational product (and non-investigational product at the 
discretion of the investigator) for any of the following reasons:

Participant’s request to stop study treatment. Participants who request to discontinue study 
treatment will remain in the study and must continue to be followed for protocol-specified 
follow-up procedures. The only exception to this is when a participant specifically withdraws 
consent for any further contact with him/her or persons previously authorized by participant 
to provide this information.

Any clinical adverse event (AE), laboratory abnormality or intercurrent illness which, in the 
opinion of the investigator, indicates that continued participation in the study is not in the 
best interest of the participant

Termination of the study by Bristol-Myers Squibb (BMS)

Loss of ability to freely provide consent through imprisonment or involuntarily incarceration 
for treatment of either a psychiatric or physical illness
Discontinuation of the study treatment for abnormal liver tests should be considered by the 
investigator when a participant meets one of the conditions outlined Section 9.2.8 or if the 
investigator believes that it is in best interest of the participant.
Refer to the Schedule of Activities for data to be collected at the time of treatment 
discontinuation and follow-up and for any further evaluations that can be completed
Revised Protocol No.: 01
Date: 03-Mar-2017
35
2.0
Approved
930105656
2.0
v

Clinical Protocol
CA209923
BMS-936558
nivolumab
In the case of pregnancy, the investigator must immediately notify the BMS Medical 
Monitor/designee of this event.  Please call the BMS Medical Monitor/designee within 24 hours 
of awareness of the pregnancy. See Section 9.2.6 for additional details.
All participants who discontinue study treatment should comply with protocol specified follow-
up procedures as outlined in Section 2. The only exception to this requirement is when a 
participant withdraws consent for all study procedures including post-treatment study follow-up 
or loses the ability to consent freely (i.e., is imprisoned or involuntarily incarcerated for the 
treatment of either a psychiatric or physical illness).
If study treatment is discontinued prior to the participant’s completion of the study, the reason 
for the discontinuation must be documented in the participant’s medical records and entered on 
the appropriate case report form (CRF) page.
8.1.1
Post Study Treatment Study Follow-up
Participants who discontinue study treatment may continue to be followed.
8.2
Discontinuation from the Study
Participants who request to discontinue study treatment will remain in the study and must 
continue to be followed for protocol-specified follow-up procedures. The only exception to this 
is when a participant specifically withdraws consent for any further contact with him/her or 
persons previously authorized by participant to provide this information. 

Participants should notify the investigator of the decision to withdraw consent from future 
follow-up in writing, whenever possible.

The withdrawal of consent should be explained in detail in the medical records by the 
investigator, as to whether the withdrawal is from further treatment with study treatment only 
or also from study procedures and/or post treatment study follow-up, and entered on the 
appropriate CRF page.

In the event that vital status (whether the participant is alive or dead) is being measured, 
publicly available information should be used to determine vital status only as appropriately 
directed in accordance with local law.

If the participant withdraws consent for disclosure of future information, the sponsor may 
retain and continue to use any data collected before such a withdrawal of consent.
8.3
Lost to Follow-Up

All reasonable efforts must be made to locate participants to determine and report their 
ongoing status. This includes follow-up with persons authorized by the participant.

Lost to follow-up is defined by the inability to reach the participant after a minimum of three
documented phone calls, faxes, or emails as well as lack of response by participant to one 
registered mail letter. All attempts should be documented in the participant’s medical 
records.

If it is determined that the participant has died, the site will use permissible local methods to 
obtain date and cause of death.
Revised Protocol No.: 01
Date: 03-Mar-2017
36
2.0
Approved
930105656
2.0
v

Clinical Protocol
CA209923
BMS-936558
nivolumab

If investigator’s use of third-party representative to assist in the follow-up portion of the 
study has been included in the participant’s informed consent, then the investigator may use a 
Sponsor retained third-party representative to assist site staff with obtaining participant’s 
contact information or other public vital status data necessary to complete the follow-up 
portion of the study. 

The site staff and representative will consult publicly available sources, such as public health 
registries and databases, in order to obtain updated contact information.

If after all attempts, the participant remains lost to follow-up, then the last known alive date 
as determined by the investigator should be reported and documented in the participant’s 
medical records.
8.4
Study Stopping Rules
If, at any time during the study, the perceived risk/benefit changes, the BMS Medical Monitor 
and BMS Medical Surveillance Team Lead have the authority to determine whether or not the 
study should stop or be modified. Enrollment will be paused in the event of the following 
observations, confirmed by review of unblinded safety data:

Mortality that is unusual for the study population as determined by the BMS team and 
Investigators

2 or more participants experience the same SAE and the event is not expected for the 
study population, is not expected for nivolumab, and is considered related to study 
treatment administration 

1 participant has potential drug-induced liver injury (pDILI) as defined in Section 9.2.8
9.
STUDY ASSESSMENTS AND PROCEDURES

Study procedures and timing are summarized in the Schedule of Activities (See Section 2). 

Protocol waivers or exemptions are not allowed.

All immediate safety concerns must be discussed with the Sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or discontinue 
treatment.

Adherence to the study design requirements, including those specified in the Schedule of 
Activities, is essential and required for study conduct.

All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria before randomization. The investigator will maintain a 
screening log to record details of all participants screened and to confirm eligibility or record 
reasons for screening failure, as applicable.

Procedures conducted as part of the participant’s routine clinical management (e.g., blood 
count) and obtained before signing of informed consent may be utilized for screening or 
baseline purposes provided the procedure meets the protocol-defined criteria and has been 
performed within the timeframe defined in the Schedule of Activities.
9.1
Efficacy Assessments
Exploratory efficacy assessments include the following:

Organ failure will be assessed by collection of SOFA score during index hospitalization
Revised Protocol No.: 01
Date: 03-Mar-2017
37
2.0
Approved
930105656
2.0
v

Clinical Protocol
CA209923
BMS-936558
nivolumab

Organ support will be assessed by duration of mechanical ventilation, vasopressor use, or 
dialysis use separately during the index hospitalization

Length of stay in the ICU and in the hospital during the index hospitalization will be 
assessed
9.1.1
Imaging Assessment for the Study
Not applicable.
9.2
Adverse Events
The definitions of an AE or serious adverse event (SAE) can be found in Appendix 3.
AEs will be reported by the participant (or, when appropriate, by a caregiver, surrogate, or the 
participant's legally authorized representative). 
The investigator and any designees are responsible for detecting, documenting, and reporting 
events that meet the definition of an AE or SAE and remain responsible for following up AEs 
that are serious, considered related to the study treatment or the study, or that caused the 
participant to discontinue before completing the study. 
Contacts for SAE reporting are specified in Appendix 3.
9.2.1
Immune-mediated Adverse Events
Immune-mediated AEs are AEs consistent with an immune-mediated mechanism or immune-
mediated component for which non-inflammatory etiologies (e.g. infection or tumor progression) 
have been ruled out. Immune-mediated AEs can include events with an alternate etiology which 
were exacerbated by the induction of autoimmunity. Information supporting the assessment will 
be collected on the subject’s case report form.
9.2.2
Time Period and Frequency for Collecting AE and SAE Information
The collection of nonserious AE information should begin at initiation of study treatment at the 
time points specified in the Schedule of Activities (Section 2) and for a minimum of 90 days 
following discontinuation of study treatment. Every adverse event must be assessed by the 
investigator with regard to whether it is considered immune-mediated. For events which are 
potentially immune-mediated, additional information will be collected on the participant’s case 
report form.  Nonserious 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 
participants.
Sections 5.6.1 and 5.6.2 in the Investigator Brochure (IB) represent the Reference Safety 
Information to determine expectedness of serious adverse events for expedited reporting. 
Following the participant’s written consent to participate in the study, all SAEs, whether related 
or not related to study drug, must be collected, including those thought to be associated with 
protocol-specified procedures.
Revised Protocol No.: 01
Date: 03-Mar-2017
38
2.0
Approved
930105656
2.0
v

Clinical Protocol
CA209923
BMS-936558
nivolumab
All SAEs must be collected that occur during the screening period and within 90 days of 
discontinuation of dosing.

Medical occurrences that begin before the start of study treatment but after obtaining 
informed consent will be recorded on the appropriate section of the eCRF section.

All SAEs will be recorded and reported to Sponsor or designee within 24 hours, as indicated 
in Appendix 3. 

The investigator will submit any updated SAE data to the sponsor within 24 hours of this 
being available.
Investigators are not obligated to actively seek AEs or SAEs in former study participants. 
However, if the investigator learns of any SAE, including a death, at any time after a participant 
has been discharged from the study, and he/she considers the event reasonably related to the 
study treatment or study participation, the investigator must promptly notify the sponsor.
The method of evaluating, and assessing causality of AEs and SAEs and the procedures for 
completing and reporting/transmitting SAE reports are provided in Appendix 3.
9.2.3
Method of Detecting AEs and SAEs
Adverse events can be spontaneously reported or elicited during open-ended questioning, 
examination, or evaluation of a participant. (In order to prevent reporting bias, participants 
should not be questioned regarding the specific occurrence of one or more AEs.)
9.2.4
Follow-up of AEs and SAEs

Nonserious AEs should be followed to resolution or stabilization, or reported as SAEs if they 
become serious (see Appendix 3).

Follow-up is also required for nonserious AEs that cause interruption or discontinuation of 
study treatment and for those present at the end of study treatment as appropriate.

All identified nonserious AEs must be recorded and described on the nonserious AE page of 
the CRF (paper or electronic). Completion of supplemental CRFs may be requested for AEs 
and/or laboratory abnormalities that are reported/identified during the course of the study.
After the initial AE/SAE report, the investigator is required to proactively follow each participant 
at subsequent visits/contacts. All SAEs, and non-serious immune-mediated AEs (as defined in 
Section 9.2 will be followed until resolution, until the condition stabilizes, until the event is 
otherwise explained, or until the participant is lost to follow-up (as defined in Section 8.3).
Further information on follow-up procedures is given in Appendix 3.
9.2.5
Regulatory Reporting Requirements for SAEs

Prompt notification by the investigator to the Sponsor of SAEs is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of a 
product under clinical investigation are met.

An investigator who receives an investigator safety report describing SAEs or other specific 
safety information (e.g., summary or listing of SAEs) from the Sponsor will file it along with 
the Investigator Brochure and will notify the IRB/IEC, if appropriate according to local 
requirements.
Revised Protocol No.: 01
Date: 03-Mar-2017
39
2.0
Approved
930105656
2.0
v

Clinical Protocol
CA209923
BMS-936558
nivolumab
Sponsor or designee will be reporting adverse events to regulatory authorities and ethics 
committees according to local applicable laws including European Directive 2001/20/EC and 
FDA Code of Federal Regulations 21 CFR Parts 312 and 320. A SUSAR (Suspected, 
Unexpected Serious Adverse Reaction) is a subset of SAEs and will be reported to the 
appropriate regulatory authorities and investigators following local and global guidelines and 
requirements.
9.2.6
Pregnancy
If, following initiation of the study treatment, it is subsequently discovered that a participant is 
pregnant or may have been pregnant at the time of study exposure, including during at least 
5 half-lives after product administration, the investigator must immediately notify the BMS 
Medical Monitor/designee of this event and complete and forward a Pregnancy Surveillance 
Form to BMS Designee within 24 hours of awareness of the event and in accordance with SAE 
reporting procedures described in Appendix 3.
In most cases, the study treatment will be permanently discontinued in an appropriate manner 
(e.g., dose tapering if necessary for participant safety). Please call the BMS Medical Monitor 
within 24 hours of awareness of the pregnancy.
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 Pregnancy 
Surveillance Form.
Any pregnancy that occurs in a female partner of a male study participant should be reported to 
Sponsor or designee. In order for Sponsor or designee to collect any pregnancy surveillance 
information from the female partner, the female partner must sign an informed consent form for 
disclosure of this information. Information on this pregnancy will be collected on the Pregnancy 
Surveillance Form.
9.2.7
Laboratory Test Result Abnormalities
The following laboratory test result abnormalities should be captured on the nonserious AE CRF 
page or SAE Report Form electronic, as appropriate. Paper forms are only intended as a back-up 
option when the electronic system is not functioning.

Any laboratory test result that is clinically significant or meets the definition of an SAE 

Any laboratory test result abnormality that required the participant to have study treatment
discontinued or interrupted

Any laboratory test result abnormality that required the participant to receive specific 
corrective therapy
It is expected that wherever possible, the clinical rather than laboratory term would be used by 
the reporting investigator (e.g., anemia versus low hemoglobin value).
Revised Protocol No.: 01
Date: 03-Mar-2017
40
2.0
Approved
930105656
2.0
v

Clinical Protocol
CA209923
BMS-936558
nivolumab
9.2.8
Potential Drug Induced Liver Injury (DILI)
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 (see Section 9.2 and Appendix 3 for 
reporting details).
Potential drug induced liver injury is defined as: 
1) AT (ALT or AST) elevation > 3 times upper limit of normal (ULN)
AND
2) Total bilirubin > 2 times ULN, without initial findings of cholestasis (elevated serum alkaline 
phosphatase),
AND
3) No other immediately apparent possible causes of AT elevation and hyperbilirubinemia, 
including, but not limited to, viral hepatitis, pre-existing chronic or acute liver disease, or the 
administration of other drug(s) known to be hepatotoxic.
Hepatotoxicity, such as transaminase elevations and hepatitis, has been identified as an important 
risk for nivolumab. Hepatic AE management recommendations for managing drug-induced liver 
injury (DILI) cases are provided in the nivolumab (OPDIVO®) label. The experience to date 
shows that hepatic AEs, including potential DILI cases, were manageable using the established 
management recommendations and thus do not meaningfully alter the benefit/risk of nivolumab.
9.2.9
Other Safety Considerations
Any 
significant 
worsening 
noted 
during 
interim 
or 
final 
physical 
examinations, 
electrocardiogram, x-ray filming, any other potential safety assessment required or not required 
by protocol should also be recorded as a nonserious or serious AE, as appropriate, and reported 
accordingly.
9.3
Overdose
All occurrences of overdose must be reported as SAEs (see Section 9.2).
For this study, any dose of nivolumab greater than 960 mg within a 24-hour time period will be 
considered an overdose.
9.4
Safety
Planned time points for all safety assessments are listed in the Schedule of Activities.  
Safety assessments will be based on medical review of physical examination findings, vital sign 
measurements, ECG, adverse event reports and clinical laboratory tests. Toxicity will be 
evaluated according to National Cancer Institute Common Terminology Criteria for Adverse 
Events (CTCAE) Version 4.03.
Revised Protocol No.: 01
Date: 03-Mar-2017
41
2.0
Approved
930105656
2.0
v

Clinical Protocol
CA209923
BMS-936558
nivolumab
Mortality will be assessed as all-cause mortality rates at 28 and 90 days as well as time to death.
Only data for the procedures and assessments specified in the protocol should be submitted to 
BMS on a case report form (CRF). Additional procedures and assessments may be performed as 
part of the standard of care; however data from these assessments should remain in the 
participant’s medical record and should not be provided to BMS, unless specifically requested by 
BMS.
9.4.1
Physical Examinations
Refer to Schedule of Activities.
9.4.2
Vital signs
Refer to Schedule of Activities.
9.4.3
Electrocardiograms
Refer to Schedule of Activities.
9.4.4
Clinical Safety Laboratory Assessments
Local laboratories will perform the analyses below and will provide reference ranges for these 
tests. Investigators must document their review of each laboratory safety report.  Results of 
clinical laboratory tests performed at Screening/Baseline must be available prior to dosing.
Hematology
Hemoglobin
Hematocrit
WBC count with differential to calculate absolute lymphocyte count
Platelet count
CD4+, CD8+ T-cell count and CD4+/CD8+ ratio
Serum Chemistry
Sodium
Potassium
Chloride
Bicarbonate
Blood Urea Nitrogen (BUN)
Creatinine
Glucose
Aspartate aminotransferase (AST)
Alanine aminotransferase (ALT)
Total bilirubin [reflex to direct Bilirubin if 
total bilirubin is > ULN]
Alkaline phosphatase
Lactate dehydrogenase (LDH)
Total Protein
Albumin
Calcium
Phosphorus
Magnesium
Amylase
Lipase
Urinalysis
Protein
Glucose
Revised Protocol No.: 01
Date: 03-Mar-2017
42
2.0
Approved
930105656
2.0
v

Clinical Protocol
CA209923
BMS-936558
nivolumab
Blood
Leukocyte esterase
Specific gravity
pH
Microscopic examination of the sediment if blood, protein or leukocytes esterase are positive 
on the dipstick
Other Analyses
Pregnancy test for WOCBP only: at screening; within 24 hours prior to the start of study drug 
(an extension up to 72 hours prior to start of study drug is permissible in situations where 
results cannot be obtained within the standard 24 hour window); monthly until Study 
Discharge; whenever pregnancy is suspected.
Follicle stimulating hormone (FSH) for women only: at screening, refer to Appendix 4 for 
applicability.
Thyroid function testing (TSH with reflex to free T3 and free T4): at baseline; at Day 56, at 
index hospitalization discharge and at study discharge.
9.4.5
Suicidal Risk Monitoring
Not applicable.
9.4.6
Imaging Safety Assessment
Not applicable.
9.5
Pharmacokinetic
Pharmacokinetics of nivolumab will be derived from serum concentration versus time data. The 
pharmacokinetic parameters to be assessed from Day 1 to Study Discharge include, but are not 
limited to:
Cmax
Peak nivolumab serum concentration
Cmin
Trough nivolumab serum concentration
Cavg
Average nivolumab serum concentration
Tmax
Time of maximum observed concentration
CLT
Total clearance
Vd
Volume of distribution 
T1/2.
Half-life
AUC(0-T)
Area under the serum concentration-time curve from time zero to time of 
last quantifiable concentration
Revised Protocol No.: 01
Date: 03-Mar-2017
43
2.0
Approved
930105656
2.0
v

Clinical Protocol
CA209923
BMS-936558
nivolumab
Table 9.5-1 lists the sampling schedule to be followed for the assessment of pharmacokinetics 
after single doses. 
Table 9.5-1:
Pharmacokinetic and Immunogenicity Sampling Schedule
Study Day of 
Sample Collection
Event
Time (Relative To 
Start of Infusion of
nivolumab)
Hour: Min
Blood Sample for 
nivolumab
Immunogenicity
Sample
1
predosea
00:00
X
X
1
EOIb
01:30
X
2c
24:00
X
3
48:00
X
4
72:00
X
5
96:00
X
6
120:00
X
7
144:00
X
10
216:00
X
14
312:00
X
X
21
480:00
X
28
648:00
X
X
42
984:00
X
56
1320:00
X
X
70
1656:00
X
Date of Index 
Hospitalization 
Discharge
Index 
Hospitalization 
Discharge
N/A
X
X
90
Study Discharge
2136:00
X
X
a Predose samples should be collected just before the administration of the first drug (preferably within 
30 minutes).
b EOI=End of Infusion, This sample should be taken immediately prior to stopping the infusion (preferably within 
2 minutes prior to the end of infusion). If the end of infusion is delayed to beyond the nominal infusion duration, 
the collection of this sample should also be delayed accordingly.
c Sample collection beginning on Day 2 and beyond to be performed on specified days 6 hours from nominal time 
point.  Please ensure accurate collection of time/date of sample collection.
PK samples will be analyzed for nivolumab by a validated assay. 
Detailed instructions for the pharmacokinetic blood collection, labeling, processing, storage, and 
shipping will be provided to the site in the procedure manual.
Revised Protocol No.: 01
Date: 03-Mar-2017
44
2.0
Approved
930105656
2.0
v

Clinical Protocol
CA209923
BMS-936558
nivolumab
9.6
Pharmacodynamics
Refer to Section 9.8 Biomarkers.
9.7
Pharmacogenomics
Not applicable.
9.7.1
ADME Sampling
Not applicable.
9.8
Biomarkers
Blood will be drawn at the times indicated in Table 9.8-1. Further details of blood collection and 
processing will be provided to the site in the procedure manual. 
Table 9.8-1:
Biomarker Sampling Schedule
Study Day
Time
(Event)
Hour
Time
(Relative 
To 
Dosing)
Hour: 
Min
Receptor 
Occupancy,
PD-1 levels
mHLA-
DR, 
caspase-3
Whole 
blood 
for 
DNAb
Whole 
blood 
for 
RNAc
Exploratory 
serum/
plasmad
1
Predose
00:00
X
X
X
X
X
1
EOIa
01:30
X
2
24:00
X
X
3
48:00
X
X
X
X
7
144:00
X
X
X
X
X
14
312:00
X
X
X
X
X
28
648:00
X
X
X
X
X
56
1320:00
X
X
X
X
X
Date of Index 
Hospitalization 
Discharge
Index 
Hospitalization 
Discharge
N/A
X
X
X
X
X
90
Study 
Discharge
2136:00
X
X
X
X
X
a EOI=End of Infusion, This sample should be taken immediately prior to stopping the infusion (preferably within
2 minutes prior to the end of infusion). If the end of infusion is delayed to beyond the nominal infusion duration,
the collection of this sample should also be delayed accordingly
b DNA will be stored and may be used for genotyping and T-cell receptor diversity.
c RNA will be stored and may be used to profile gene expression by RNA sequencing analysis
Revised Protocol No.: 01
Date: 03-Mar-2017
45
2.0
Approved
930105656
2.0
v

Clinical Protocol
CA209923
BMS-936558
nivolumab
d Exploratory serum/plasma samples will be stored for potential biomarker analysis related to the disease and 
mechanism of nivolumab
9.8.1
Additional Research Collection
Additional research retention samples are mandatory for all participants, except where prohibited 
by local laws or regulations.
This protocol will include residual sample storage for additional research (AR).
This collection for additional research is intended to expand the translational R&D capability at 
Bristol-Myers Squibb, and will support as yet undefined research aims that will advance our 
understanding of disease and options for treatment. It may also be used to support health 
authority requests for analysis, and advancement of pharmacodiagnostic development to better 
target drugs to the right patients.  This may also include genetic/genomic exploration aimed at 
exploring disease pathways, progression and response to treatment etc. 
All requests for access to samples or data for additional research will be vetted through a diverse 
committee of the study sponsor’s senior leaders in Research and Development to ensure the 
research supports appropriate and well-defined scientific research activities.

Residual cells from RO analysis will be saved on ZellKraftWerk Chip for potential analysis 
on immune cells, including but not limited to immuno-phenotyping.

Residual samples for PK, immunogenicity, exploratory serum/plasma, whole blood DNA and 
RNA will be stored for potential exploratory biomarker analysis including proteins, 
metabolites, DNA and RNA using technologies including but not limited to Next-gen 
sequencing and RNA sequencing.
Samples will be securely stored by the BMS Biorepository in Hopewell, NJ or at a BMS 
approved third party storage management facility.
Samples will be stored in a coded fashion, and no researcher will have access to the key. The key 
is securely held by the Investigator at the clinical site, so there is no direct ability for a researcher 
to connect a sample to a specific individual
Additional research samples will be retained for 15 years or the maximum allowed by applicable 
law. No additional sampling is required for residual collections. 
Further details of sample collection and processing will be provided to the site in the procedure 
manual.
Revised Protocol No.: 01
Date: 03-Mar-2017
46
2.0
Approved
930105656
2.0
v

Clinical Protocol
CA209923
BMS-936558
nivolumab
Sample Type
Time points for which residual samples will be retained
PK
all
Immunogenicity
All
Exploratory serum and plasma
All
Whole blood DNA
All
Whole blood RNA
all
Whole blood cells
Residual cells from RO analysis will be saved on ZellKraftWerk chip
9.8.2
Immunogenicity Assessments
Serum samples collected at time points identified in Table 9.5-1 will be analyzed for anti-
nivolumab antibodies by a validated immunogenicity assay. Additional characterization (i.e. 
neutralizing antibodies) for any detected anti-drug antibodies (ADA) response to nivolumab may 
also be performed using a validated functional cell based assay.  Selected serum samples may be 
analyzed by an exploratory method that measures anti-nivolumab antibodies for technology 
exploration purposes; exploratory data will not be reported.
In addition, serum samples designated for PK assessments may also be used for immunogenicity 
analysis if required (e.g., insufficient volume for complete immunogenicity assessment or to 
follow up on suspected immunogenicity related AE).
Detailed instructions for the immunogenicity blood collection, labeling, processing, storage, and 
shipping will be provided to the site in the procedure manual.
9.8.3
RNA Transcriptome Research 
RNA Transcriptome Research may be conducted using residual samples.
9.8.4
RNA Expression Research of a Subset of RNA Species 
RNA Expression Research may be conducted using residual samples.
9.8.5
Proteome Research 
Proteome Research may be conducted using residual samples.
9.8.6
Metabolomic Research 
Metabolomic Research may be conducted using residual samples.
9.8.7
Other Assessments
Organ failure will be assessed by collection of SOFA score during index hospitalization. Organ 
support will be assessed by duration of mechanical ventilation, vasopressor use, or dialysis use 
separately during the index hospitalization.
Length of stay in the ICU and in the hospital during the index hospitalization will be assessed.
Revised Protocol No.: 01
Date: 03-Mar-2017
47
2.0
Approved
930105656
2.0
v

Clinical Protocol
CA209923
BMS-936558
nivolumab
9.8.8
Receptor Occupancy
Fresh whole blood will be used to determine PD-1 receptor occupancy on CD3+, CD4+, CD8+ T 
cells by nivolumab at pre-treatment and selected time points post/on treatment using a flow 
cytometry based assay.
9.8.9
mHLA-DR
Expression of HLA-DR on monocytes will be measured by flow cytometry before and after 
treatment to determine if recovery of mHLA-DR is observed following treatment. mHLA-DR 
expression values from study participants may be compared to expression values from normal 
healthy volunteers to determine threshold values to identify sepsis participants.
9.9
Health Economics OR Medical Resource Utilization and Health 
Economics
Health Economics/Medical Resource Utilization and Health Economics parameters will not be 
evaluated in this study.
10.
STATISTICAL CONSIDERATIONS
10.1
Sample Size Determination 
The number of participants is not based on statistical power consideration. Administration of 
nivolumab to up to approximately 15 participants in each arm provides an 80% probability of 
observing at least one occurrence of any adverse event that would occur with ≥10% incidence in 
the population from which the sample is drawn. 
The overall purpose of Study CA209923 is to evaluate the safety, tolerability, pharmacokinetics, 
and pharmacodynamics of single doses of nivolumab in participants with severe sepsis or septic 
shock in order to inform feasibility of further study of nivolumab in this population. Specifically, 
a key objective is to determine whether the exposures observed after a single dose of nivolumab 
in participants with severe sepsis or septic shock are comparable to the overall exposures 
observed at steady-state dosing with the nivolumab regimen approved in oncology. In order to 
achieve this goal, up to 15 subjects per dose level are estimated in order to obtain a PK profile
from at least 6 subjects per dose level. 
10.2
Populations for Analyses
For purposes of analysis, the following populations are defined:
Population
Description
All Enrolled Participants
All participants who signed an informed consent
All Randomized 
Participants
All participants who are randomized to a treatment
All Treated Participants
All participants who have received at least one dose of study 
treatment
Pharmacodynamic 
All participants that receive any study medication and have PD 
Revised Protocol No.: 01
Date: 03-Mar-2017
48
2.0
Approved
930105656
2.0
v

Clinical Protocol
CA209923
BMS-936558
nivolumab

Persistent Positive Participant: ADA positive relative to baseline sample at 2 or more 
sequential time points, where the first and last ADA positive relative to baseline samples 
are at least 8 weeks apart.

Only the Last Sample Positive Participant: Not persistent but ADA positive relative to 
baseline sample in the last sampling time point

Other Positive Participant: Not persistent but some ADA positive relative to baseline 
samples with the last sample being not ADA positive relative to baseline sample

ADA Negative Participant: A participant with no ADA positive sample at any time
The number and percentage of participants with positive ADA samples in each of the ADA 
Positive Participant subgroups will be summarized by treatment and by time. A by-participant
listing will be provided with corresponding antibody titer values.
A summary table for the incidence of different types of ADA positive participants will be 
provided by treatment.
10.3.7
Interim Analyses 
Not applicable.
Revised Protocol No.: 01
Date: 03-Mar-2017
51
2.0
Approved
930105656
2.0
v

Clinical Protocol
CA209923
BMS-936558
nivolumab
12.
APPENDICES
Revised Protocol No.: 01
Date: 03-Mar-2017
57
2.0
Approved
930105656
2.0
v

Clinical Protocol
CA209923
BMS-936558
nivolumab
APPENDIX 1
ABBREVIATIONS AND TRADEMARKS
Term
Definition
AE
adverse event
ACLS
advanced cardiac life support
ALT
alanine aminotransferase
ANC
absolute neutrophil count
AST
aspartate aminotransferase
AT
aminotransaminases
AUC
area under the concentration-time curve
AUC(0-T)
area under the concentration-time curve from time zero to the time of the 
last quantifiable concentration
AUC(TAU)
area under the concentration-time curve in one dosing interval
A-V
atrioventricular
-HCG
beta-human chorionic gonadotrophin
BID, bid
bis in die, twice daily
BLQ
below limit of quantification 
BMI
body mass index
BMS
Bristol-Myers Squibb
BP
blood pressure
BUN
blood urea nitrogen
C
Celsius
Ca++
calcium
Cavg
average concentration
CBC
complete blood count
CFR
Code of Federal Regulations 
CI
confidence interval
C1-
chloride
CLcr
creatinine clearance
CLT
total body clearance
cm
centimeter
Revised Protocol No.: 01
Date: 03-Mar-2017
58
2.0
Approved
930105656
2.0
v

Clinical Protocol
CA209923
BMS-936558
nivolumab
Term
Definition
Cavg
Average observed concentration
Cmax, CMAX
maximum observed concentration
Cmin, CMIN
minimum observed concentration
CNS
Central nervous system
CRC
Clinical Research Center
CRF
Case Report Form, paper or electronic
CV
coefficient of variation
CYP
cytochrome p-450
dL
deciliter
DMC
Data monitoring committee
DSM IV
Diagnostic and Statistical Manual of Mental Disorders (4th Edition)
ECG
electrocardiogram
eCRF
Electronic Case Report Form
EDC
Electronic Data Capture
eg
exempli gratia (for example)
ESR
Expedited Safety Report
F
bioavailability
FDA
Food and Drug Administration
FSH
follicle stimulating hormone
g
gram
GCP
Good Clinical Practice
GGT
gamma-glutamyl transferase
h
hour
HBsAg
hepatitis B surface antigen
HBV
hepatitis B virus
HCV
hepatitis C virus
HCO3-
bicarbonate
HIV
Human Immunodeficiency Virus
HR
heart rate
HRT
hormone replacement therapy
Revised Protocol No.: 01
Date: 03-Mar-2017
59
2.0
Approved
930105656
2.0
v

Clinical Protocol
CA209923
BMS-936558
nivolumab
Term
Definition
ICH
International Conference on Harmonisation 
ie
id est (that is)
IEC
Independent Ethics Committee
IMP
investigational medicinal products
IND
Investigational New Drug Exemption
IRB
Institutional Review Board
IRT
Interactive Response Technology
IU
International Unit
IV
intravenous
K
slope of the terminal phase of the log concentration-time curve
K3EDTA
potassium ethylenediaminetetraacetic acid
K+
potassium
kg
kilogram
L
liter
LC
liquid chromatography
LDH
lactate dehydrogenase
ln
natural logarithm
mg
milligram
Mg++
magnesium
min
minute
mL
milliliter
mmHg
millimeters of mercury
MR
medical research
MS
mass spectrometry
MTD
maximum tolerated dose
g
microgram
N
number of subjects or observations
Na+
sodium
N/A
not applicable
ng
nanogram
Revised Protocol No.: 01
Date: 03-Mar-2017
60
2.0
Approved
930105656
2.0
v

Clinical Protocol
CA209923
BMS-936558
nivolumab
Term
Definition
NIMP
non-investigational medicinal products 
NSAID
nonsteroidal anti-inflammatory drug
PD
pharmacodynamics
PK
pharmacokinetics
QC
quality control
QD, qd
quaque die, once daily
RBC
red blood cell
SAE
serious adverse event
SD
standard deviation
SOP
Standard Operating Procedures
sp.
species
t
temperature
T
time
TAO
Trial Access Online, the BMS implementation of an EDC capability
T-HALF, T1/2
Half life
TID, tid
ter in die, three times a day
Tmax, TMAX
time of maximum observed concentration
Vd
volume of distribution
WBC
white blood cell
WOCBP
women of childbearing potential
x g
times gravity
Revised Protocol No.: 01
Date: 03-Mar-2017
61
2.0
Approved
930105656
2.0
v

Clinical Protocol
CA209923
BMS-936558
nivolumab
APPENDIX 2
STUDY GOVERNANCE CONSIDERATIONS
The term ‘Participant’ is used in the protocol to refer to a person who has consented to participate 
in the clinical research study.  The term ‘Subject’ used in the eCRF is intended to refer to a person 
(Participant) who has consented to participate in the clinical research study.
REGULATORY AND ETHICAL CONSIDERATIONS
GOOD CLINICAL PRACTICE
This study will be conducted in accordance with:

Good Clinical Practice (GCP), 

as defined by the International Council on Harmonisation (ICH)

in accordance with the ethical principles underlying European Union Directive 2001/20/EC

United States Code of Federal Regulations, Title 21, Part 50 (21CFR50) 

applicable local requirements.
The study will be conducted in compliance with the protocol. The protocol and any amendments 
and the participant informed consent will receive approval/favorable opinion by Institutional 
Review Board/Independent Ethics Committee (IRB/IEC), and regulatory authorities according to 
applicable local regulations prior to initiation of the study.
All potential serious breaches must be reported to Sponsor or designee immediately. A serious
breach is a breach of the conditions and principles of GCP in connection with the study or the 
protocol, which is likely to affect, to a significant degree, the safety or physical or mental integrity 
of the subjects of the study or the scientific value of the study.
Personnel involved in conducting this study will be qualified by education, training, and 
experience to perform their respective tasks.
This study will not use the services of study personnel where sanctions have been invoked or where 
there has been scientific misconduct or fraud (e.g., loss of medical licensure, debarment). 
INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS COMMITTEE
Before study initiation, the investigator must have written and dated approval/favorable opinion 
from the IRB/IEC for the protocol, consent form, participant recruitment materials (e.g., 
advertisements), and any other written information to be provided to subjects. The investigator or 
BMS should also provide the IRB/IEC with a copy of the Investigator Brochure or product labeling 
information to be provided to subjects and any updates. 
The investigator, Sponsor or designee should provide the IRB/IEC with reports, updates and other 
information (e.g., expedited safety reports, amendments, and administrative letters) according to 
regulatory requirements or institution procedures.
Revised Protocol No.: 01
Date: 03-Mar-2017
62
2.0
Approved
930105656
2.0
v

Clinical Protocol
CA209923
BMS-936558
nivolumab
COMPLIANCE WITH THE PROTOCOL AND PROTOCOL REVISIONS
The investigator should not implement any deviation or change to the protocol without prior 
review and documented approval/favorable opinion of an amendment from the IRB/IEC (and if 
applicable, also by local health authority) except where necessary to eliminate an immediate 
hazard(s) to study subjects. 
If a deviation or change to a protocol is implemented to eliminate an immediate hazard(s) prior to 
obtaining relevant  approval/favorable opinion(s) the deviation or change will be submitted, as 
soon as possible to:

IRB/IEC for 

Regulatory Authority(ies), if applicable by local regulations (per national requirements)
Documentation of approval/favorable opinion signed by the chairperson or designee of the 
IRB(s)/IEC(s) and if applicable, also by local health authority must be sent to BMS.
If an amendment substantially alters the study design or increases the potential risk to the 
participant: (1) the consent form must be revised and submitted to the IRB(s)/IEC(s) for review 
and approval/favorable opinion; (2) the revised form must be used to obtain consent from subjects 
currently enrolled in the study if they are affected by the amendment; and (3) the new form must 
be used to obtain consent from new subjects prior to enrollment.
If the revision is done via an administrative letter, investigators must inform their IRB(s)/IEC(s).
FINANCIAL DISCLOSURE
Investigators and sub-Investigators will provide the Sponsor with sufficient, accurate financial
information in accordance with local regulations to allow the Sponsor to submit complete and 
accurate financial certification or disclosure statements to the appropriate health authorities. 
Investigators are responsible for providing information on financial interests during the course of 
the study and for 1 year after completion of the study.
INFORMED CONSENT PROCESS
Investigators must ensure that subjects are clearly and fully informed about the purpose, potential 
risks, and other critical issues regarding clinical studies in which they volunteer to participate. 
In situations where consent cannot be given to subjects, their legally acceptable representatives (as 
per country guidelines) are clearly and fully informed about the purpose, potential risks, and other 
critical issues regarding clinical studies in which the participant volunteers to participate. 
Sponsor or designee will provide the investigator with an appropriate (i.e., Global or Local) sample
informed consent form which will include all elements required by ICH, GCP and applicable
regulatory requirements. The sample informed consent form will adhere to the ethical principles 
that have their origin in the Declaration of Helsinki.
Investigators must:
Revised Protocol No.: 01
Date: 03-Mar-2017
63
2.0
Approved
930105656
2.0
v

Clinical Protocol
CA209923
BMS-936558
nivolumab

Provide a copy of the consent form and written information about the study in the language 
in which the participant is most proficient prior to clinical study participation. The language 
must be non-technical and easily understood. 

Allow time necessary for participant or participant's legally acceptable representative to 
inquire about the details of the study.

Obtain an informed consent signed and personally dated by the participant or the 
participant's legally acceptable representative and by the person who conducted the 
informed consent discussion. 

Obtain the IRB/IEC’s written approval/favorable opinion of the written informed consent 
form and any other information to be provided to the subjects, prior to the beginning of the 
study, and after any revisions are completed for new information.
If informed consent is initially given by a participant’s legally acceptable representative or legal 
guardian, and the participant subsequently becomes capable of making and communicating his or 
her informed consent during the study, consent must additionally be obtained from the participant.
Revise the informed consent whenever important new information becomes available that is 
relevant to the participant's consent. The investigator, or a person designated by the investigator, 
should fully inform the participant or the participant's legally acceptable representative or legal 
guardian, of all pertinent aspects of the study and of any new information relevant to the 
participant's willingness to continue participation in the study. This communication should be 
documented. 
The confidentiality of records that could identify subjects must be protected, respecting the privacy 
and confidentiality rules applicable to regulatory requirements, the subjects' signed ICF and, in the 
US, the subjects’ signed HIPAA Authorization.
The consent form must also include a statement that BMS and regulatory authorities have direct 
access to participant records. 
Subjects unable to give their written consent (e.g., stroke or subjects with or severe dementia) may 
only be enrolled in the study with the consent of a legally acceptable representative. The participant
must also be informed about the nature of the study to the extent compatible with his or her 
understanding, and should this participant become capable, he or she should personally sign and 
date the consent form as soon as possible. The explicit wish of a participant who is unable to give 
his or her written consent, but who is capable of forming an opinion and assessing information to 
refuse participation in, or to be withdrawn from, the clinical study at any time should be considered 
by the investigator.
The rights, safety, and well-being of the study subjects are the most important considerations and 
should prevail over interests of science and society.
Revised Protocol No.: 01
Date: 03-Mar-2017
64
2.0
Approved
930105656
2.0
v

Clinical Protocol
CA209923
BMS-936558
nivolumab
SOURCE DOCUMENTS
The Investigator is responsible for ensuring that the source data are accurate, legible, 
contemporaneous, original and attributable, whether the data are hand-written on paper or entered 
electronically. If source data are created (first entered), modified, maintained, archived, retrieved, 
or transmitted electronically via computerized systems (and/or any other kind of electronic 
devices) as part of regulated clinical trial activities, such systems must be compliant with all 
applicable laws and regulations governing use of electronic records and/or electronic signatures. 
Such systems may include, but are not limited to, electronic medical/health records (EMRs/EHRs), 
adverse event tracking/reporting, protocol required assessments, and/or drug accountability 
records).
When paper records from such systems are used in place of electronic format to perform regulated 
activities, such paper records should be certified copies. A certified copy consists of a copy of 
original information that has been verified, as indicated by a dated signature, as an exact copy 
having all of the same attributes and information as the original. 
STUDY TREATMENT RECORDS
Records for study treatments (whether supplied by BMS, its vendors, or the site) must substantiate 
study treatment integrity and traceability from receipt, preparation, administration, and through 
destruction or return. Records must be made available for review at the request of BMS/designee 
or a Health Authority.
Revised Protocol No.: 01
Date: 03-Mar-2017
65
2.0
Approved
930105656
2.0
v

Clinical Protocol
CA209923
BMS-936558
nivolumab
If
Then
Supplied by BMS (or its vendors):
Records or logs must comply with applicable 
regulations and guidelines and should include:

amount received and placed in storage 
area

amount currently in storage area

label identification number or batch 
number

amount dispensed to and returned by each 
participant, including unique participant
identifiers

amount transferred to another area/site for 
dispensing or storage

nonstudy disposition (e.g., lost, wasted) 

amount destroyed at study site, if 
applicable

amount returned to BMS

retain samples for 
bioavailability/bioequivalence, if 
applicable 

dates and initials of person responsible for 
Investigational Product 
dispensing/accountability, as per the 
Delegation of Authority Form.
Sourced by site, and not supplied by BMS or 
its vendors (examples include IP sourced from 
the sites stock or commercial supply, or a 
specialty pharmacy)
The 
investigator 
or 
designee 
accepts 
responsibility for documenting traceability and 
study drug integrity in accordance with 
requirements applicable under law and the 
SOPs/standards of the sourcing pharmacy.   
These records should include:

label identification number or batch 
number 

amount dispensed to and returned by each 
participant, including unique participant
identifiers

dates and initials of person responsible for 
Investigational Product 
dispensing/accountability, as per the 
Delegation of Authority Form.
BMS or designee will provide forms to facilitate inventory control if the investigational site does not have an 
established system that meets these requirements.
Revised Protocol No.: 01
Date: 03-Mar-2017
66
2.0
Approved
930105656
2.0
v

Clinical Protocol
CA209923
BMS-936558
nivolumab
CASE REPORT FORMS
An investigator is required to prepare and maintain adequate and accurate case histories designed 
to record all observations and other data pertinent to the investigation on each individual treated 
or entered as a control in the investigation. Data that are derived from source documents and 
reported on the CRF must be consistent with the source documents or the discrepancies must be 
explained. Additional clinical information may be collected and analyzed in an effort to enhance 
understanding of product safety. CRFs may be requested for AEs and/or laboratory abnormalities 
that are reported or identified during the course of the study.
For sites using the Sponsor or designee electronic data capture tool, electronic CRFs will be 
prepared for all data collection fields except for fields specific to SAEs and pregnancy, which will 
be reported on the electronic SAE form and Pregnancy Surveillance form, respectively.  If 
electronic SAE form is not available, a paper SAE form can be used. Spaces may be left blank 
only in those circumstances permitted by study-specific CRF completion guidelines provided by 
Sponsor or designee. 
The confidentiality of records that could identify subjects must be protected, respecting the privacy 
and confidentiality rules in accordance with the applicable regulatory requirement(s).
The investigator will maintain a signature sheet to document signatures and initials of all persons 
authorized to make entries and/or corrections on CRFs. 
The completed CRF, SAE/pregnancy CRFs, must be promptly reviewed, signed, and dated by the 
investigator or qualified physician who is a subinvestigator and who is delegated this task on the 
Delegation of Authority Form. Subinvestigators in Japan may not be delegated the CRF approval 
task for electronic CRFs, review and approval/signature is completed electronically through the 
BMS electronic data capture tool. The investigator must retain a copy of the CRFs including 
records of the changes and corrections.
Each individual electronically signing electronic CRFs must meet Sponsor or designee training 
requirements and must only access the BMS electronic data capture tool using the unique user 
account provided by Sponsor or designee. User accounts are not to be shared or reassigned to other 
individuals
MONITORING
Sponsor or designee representatives will review data centrally to identify potential issues to 
determine a schedule of on-site visits for targeted review of study records. 
Representatives of BMS must be allowed to visit all study site locations periodically to assess the 
data quality and study integrity. On site they will review study records and directly compare them 
with source documents, discuss the conduct of the study with the investigator, and verify that the 
facilities remain acceptable .Certain CRF pages and/or electronic files may serve as the source 
documents:
In addition, the study may be evaluated by Sponsor or designee internal auditors and government 
inspectors who must be allowed access to CRFs, source documents, other study files, and study 
facilities. BMS audit reports will be kept confidential.
Revised Protocol No.: 01
Date: 03-Mar-2017
67
2.0
Approved
930105656
2.0
v

Clinical Protocol
CA209923
BMS-936558
nivolumab
The investigator must notify BMS promptly of any inspections scheduled by regulatory authorities, 
and promptly forward copies of inspection reports to Sponsor or designee.
RECORDS RETENTION
The investigator (or head of the study site in Japan) must retain all study records and source 
documents for the maximum period required by applicable regulations and guidelines, or 
institution procedures, or for the period specified by BMS or designee, whichever is longer. The 
investigator (or head of the study site in Japan) must contact BMS prior to destroying any records 
associated with the study.
BMS or designee will notify the investigator (or head of the study site in Japan) when the study 
records are no longer needed.
If the investigator withdraws from the study (e.g., relocation, retirement), the records shall be 
transferred to a mutually agreed upon designee (e.g., another investigator, study site, IRB). Notice 
of such transfer will be given in writing to BMS or designee. 
RETURN OF STUDY TREATMENT
For this study, study treatments (those supplied by BMS, a vendor or sourced by the investigator) 
such as partially used study treatment containers, vials and syringes may be destroyed on site. 
If..
Then
Study treatments supplied by BMS (including 
its vendors
Any unused study treatments supplied by BMS 
can only be destroyed after being inspected 
and reconciled by the responsible Study 
Monitor unless study treatments containers 
must be immediately destroyed as required for 
safety, or to meet local regulations (e.g., 
cytotoxics or biologics).
If study treatments will be returned, the return 
will be arranged by the responsible Study 
Monitor.
Study treatments sourced by site, not supplied 
by BMS (or its vendors) (examples include 
study treatments sourced from the sites stock 
or 
commercial 
supply, 
or 
a 
specialty 
pharmacy)
It 
is 
the 
investigator’s 
or 
designee’s 
responsibility to dispose of all containers 
according to the institutional guidelines and 
procedures.
It is the investigator’s or designee’s responsibility to arrange for disposal, provided that procedures 
for proper disposal have been established according to applicable federal, state, local, and 
institutional guidelines and procedures, and provided that appropriate records of disposal are kept. 
The following minimal standards must be met:
Revised Protocol No.: 01
Date: 03-Mar-2017
68
2.0
Approved
930105656
2.0
v

Clinical Protocol
CA209923
BMS-936558
nivolumab

On-site disposal practices must not expose humans to risks from the drug.

On-site disposal practices and procedures are in agreement with applicable laws and 
regulations, including any special requirements for controlled or hazardous substances.

Written procedures for on-site disposal are available and followed. The procedures must 
be filed with the site’s SOPs and a copy provided to BMS upon request.

Records are maintained that allow for traceability of each container, including the date 
disposed of, quantity disposed, and identification of the person disposing the containers. 
The method of disposal, i.e., incinerator, licensed sanitary landfill, or licensed waste 
disposal vendor must be documented.

Accountability and disposal records are complete, up-to-date, and available for the Monitor 
to review throughout the clinical trial period.
It is the investigator’s or designee’s responsibility to arrange for disposal of all empty containers.
If conditions for destruction cannot be met the responsible Study Monitor will make arrangements 
for return of study treatments provided by BMS (or its vendors). Destruction of non- study 
treatments sourced by the site, not supplied by BMS, is solely the responsibility of the investigator 
or designee.
CLINICAL STUDY REPORT AND PUBLICATIONS
A Signatory Investigator must be selected to sign the clinical study report. 
For this protocol, the Signatory Investigator will be selected as appropriate based on the following 
criteria:

Participant recruitment (e.g., among the top quartile of enrollers)

Other criteria (as determined by the study team)
The data collected during this study are confidential and proprietary to Sponsor or designee. Any 
publications or abstracts arising from this study must adhere to the publication requirements set 
forth in the clinical trial agreement (CTA) governing [Study site or Investigator] participation in 
the study. These requirements include, but are not limited to, submitting proposed publications to 
Sponsor or designee at the earliest practicable time prior to submission or presentation and 
otherwise within the time period set forth in the CTA.
Revised Protocol No.: 01
Date: 03-Mar-2017
69
2.0
Approved
930105656
2.0
v

Clinical Protocol
CA209923
BMS-936558
nivolumab
APPENDIX 3
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS: 
DEFINITIONS AND PROCEDURES FOR RECORDING, 
EVALUATING, FOLLOW UP AND REPORTING
ADVERSE EVENTS
Adverse Event Definition:
An Adverse Event (AE) is defined as any new untoward medical occurrence or worsening of a 
preexisting medical condition in a clinical investigation participant administered study 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 study drug, whether or not 
considered related to the study drug.
Revised Protocol No.: 01
Date: 03-Mar-2017
70
2.0
Approved
930105656
2.0
v

Clinical Protocol
CA209923
BMS-936558
nivolumab
SERIOUS ADVERSE EVENTS
Serious Adverse Event (SAE) is defined as any untoward medical occurrence that, at any 
dose:
Results in death
Is life-threatening (defined as an event in which the participant was at risk of death at the time 
of the event; it does not refer to an event which hypothetically might have caused death if it 
were more severe)
Requires inpatient hospitalization or causes prolongation of existing hospitalization (see 
NOTE below)
NOTE: 
The following hospitalizations are not considered SAEs in BMS clinical studies: 
o
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)
o
elective surgery, planned prior to signing consent
o
admissions as per protocol for a planned medical/surgical procedure
o
routine health assessment requiring admission for baseline/trending of health 
status (e.g., routine colonoscopy)
o
medical/surgical admission other than to remedy ill health and planned prior to 
entry into the study. Appropriate documentation is required in these cases
o
admission encountered for another life circumstance that carries no bearing on 
health status and requires no medical/surgical intervention (e.g., lack of 
housing, economic inadequacy, caregiver respite, family circumstances, 
administrative reason)
o
admission for administration of anticancer therapy in the absence of any other 
SAEs (applies to oncology protocols)
Results in persistent or significant disability/incapacity
Is a congenital anomaly/birth defect
is an important medical event (defined as a medical event(s) that may not be immediately life-
threatening or result in death or hospitalization but, based upon appropriate medical and 
scientific judgment, may jeopardize the participant or may require intervention [e.g., medical, 
surgical] to prevent one of the other serious outcomes listed in the definition above.) Examples 
of such events include, but are not limited to, intensive treatment in an emergency room or at 
home for allergic bronchospasm; blood dyscrasias or convulsions that do not result in 
hospitalization.) Potential drug induced liver injury (DILI) is also considered an important 
medical event. (See Section 8.1.1 for the definition of potential DILI.) 
Revised Protocol No.: 01
Date: 03-Mar-2017
71
2.0
Approved
930105656
2.0
v

Clinical Protocol
CA209923
BMS-936558
nivolumab
Suspected transmission of an infectious agent (e.g., pathogenic or nonpathogenic) via the study 
treatment is an SAE. 
Although pregnancy, overdose, cancer, and potential drug induced liver injury (DILI) are not 
always serious by regulatory definition, these events must be handled as SAEs. (See Section 
9.2.5 for reporting pregnancies).
In this study, the following events are study endpoints, per 21CFR 312.32 (c)(5), they are 
excluded from being reported as an SAE UNLESS the events are related to study drug.

Death

Hospitalization prolongation

ICU admission

Ventilator use

Vasopressor use

Dialysis use
These events will be recorded on other CRF pages instead of the SAE pages.
Any component of a study endpoint that is considered related to study therapy should be reported 
as SAE (e.g., death is an endpoint, if death occurred due to anaphylaxis, anaphylaxis must be 
reported).
EVALUATING AES AND SAES
Assessment of Causality
The causal relationship to study drug is determined by a physician and should be used to 
assess all adverse events (AE). The causal relationship can be one of the following:
Related: There is a reasonable causal relationship between study drug 
administration and the AE.
Not related: There is not a reasonable causal relationship between study drug 
administration and the AE. 
The term "reasonable causal relationship" means there is evidence to suggest a causal 
relationship. 
Follow-up of AEs and SAEs
If only limited information is initially available, follow-up reports are required. (Note: 
Follow-up SAE reports must include the same investigator term(s) initially reported.) 
If an ongoing SAE changes in its intensity or relationship to study drug or if new 
information becomes available, the SAE report must be updated and submitted within 24 
hours to BMS (or designee) using the same procedure used for transmitting the initial 
Revised Protocol No.: 01
Date: 03-Mar-2017
72
2.0
Approved
930105656
2.0
v

Clinical Protocol
CA209923
BMS-936558
nivolumab
SAE report.
All SAEs must be followed to resolution or stabilization.
REPORTING OF SAES TO SPONSOR OR DESIGNEE

SAEs, whether related or not related to study drug, and pregnancies must be 
reported to BMS (or designee) within 24 hours of awareness of the event.

SAEs must be recorded on the SAE Report Form; pregnancies on a Pregnancy 
Surveillance Form (electronic or paper forms).

The preferred method for SAE data reporting collection is through the eCRF.

The paper SAE/pregnancy surveillance forms are only intended as a back-up 
option when the eCRF system is not functioning.
o
In this case, the paper forms are to be transmitted via email or confirmed 
facsimile (fax) transmission to:
SAE Email Address: Refer to Contact Information list.
SAE Facsimile Number: Refer to Contact Information list.
For studies capturing SAEs through electronic data capture (EDC), electronic submission 
is the required method for reporting. In the event the electronic system is unavailable for 
transmission, paper forms must be used and submitted immediately. When paper forms 
are used, the original paper forms are to remain on site.
SAE Telephone Contact (required for SAE and pregnancy reporting): Refer to Contact 
Information list
Revised Protocol No.: 01
Date: 03-Mar-2017
73
2.0
Approved
930105656
2.0
v

Clinical Protocol
CA209923
BMS-936558
nivolumab
APPENDIX 4
WOMEN OF CHILDBEARING POTENTIAL DEFINITIONS AND 
METHODS OF CONTRACEPTION
DEFINITIONS
Woman of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming post-menopausal unless 
permanently sterile. Permanent sterilization methods include hysterectomy, bilateral 
salpingectomy, and bilateral oophorectomy.
Women in the following categories are not considered WOCBP

Premenarchal

Premenopausal female with 1 of the following:

Documented hysterectomy

Documented bilateral salpingectomy

Documented bilateral oophorectomy
Note: Documentation can come from the site personnel’s review of the participant’s medical 
records, medical examination, or medical history interview.

Postmenopausal female

A postmenopausal state is defined as 12 months of amenorrhea in a woman over age 45 
years in the absence of other biological or physiological causes. In addition, females under 
the age of 55 years must have a serum follicle stimulating hormone, (FSH) level > 40 
mIU/mL to confirm menopause.
Note: Females treated with hormone replacement therapy, (HRT) are likely to have artificially 
suppressed FSH levels and may require a washout period in order to obtain a physiologic FSH 
level. The duration of the washout period is a function of the type of HRT used. The duration of 
the washout period below are suggested guidelines and the investigators should use their 
judgement in checking serum FSH levels. 

1 week minimum for vaginal hormonal products (rings, creams, gels)

4 week minimum for transdermal products

8 week minimum for oral products
Other parenteral products may require washout periods as long as 6 months. If the serum FSH 
level is > 40 mIU/ml at any time during the washout period, the woman can be considered 
postmenopausal.
CONTRACEPTION GUIDANCE FOR FEMALE PARTICIPANTS OF CHILD BEARING 
POTENTIAL
One of the highly effective methods of contraception listed below is required during study duration 
and until the end of relevant systemic exposure, defined as 4 months after the end of study 
treatment, plus 30 days (a total of 5 months).
Revised Protocol No.: 01
Date: 03-Mar-2017
74
2.0
Approved
930105656
2.0
v

Clinical Protocol
CA209923
BMS-936558
nivolumab
Local laws and regulations may require use of alternative and/or additional contraception methods.
Highly Effective Contraceptive Methods That Are User Dependent 
Failure rate of <1% per year when used consistently and correctly.a

Combined (estrogen- and progestogen-containing) hormonal contraception associated with 
inhibition of ovulationb 

oral 

intravaginal 

transdermal 

Progestogen-only hormonal contraception associated with inhibition of ovulationb 

oral 

injectable 
Highly Effective Methods That Are User Independent

Implantable progestogen-only hormonal contraception associated with inhibition of 
ovulation b

Intrauterine device (IUD)c

Intrauterine hormone-releasing system (IUS)c

Bilateral tubal occlusion

Vasectomized partner 
A vasectomized partner is a highly effective contraception method provided that the partner 
is the sole male sexual partner of the WOCBP and the absence of sperm has been confirmed. 
If not, an additional highly effective method of contraception should be used. 

Sexual abstinence
Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study drug. The 
reliability of sexual abstinence needs to be evaluated in relation to the duration of the study 
and the preferred and usual lifestyle of the participant.

It is not necessary to use any other method of contraception when complete abstinence is 
elected. 

WOCBP participants who choose complete abstinence must continue to have pregnancy 
tests, as specified in Section 2. 

Acceptable alternate methods of highly effective contraception must be discussed in the 
event that the WOCBP participants chooses to forego complete abstinence 
Revised Protocol No.: 01
Date: 03-Mar-2017
75
2.0
Approved
930105656
2.0
v

Clinical Protocol
CA209923
BMS-936558
nivolumab
NOTES: 
a Typical use failure rates may differ from those when used consistently and correctly. Use should be consistent 
with local regulations regarding the use of contraceptive methods for participants participating in clinical studies. 
b Hormonal contraception may be susceptible to interaction with the study drug, which may reduce the efficacy 
of the contraceptive method.  Hormonal contraception is permissible only when there is sufficient evidence that 
the IMP and other study medications will not alter hormonal exposures such that contraception would be 
ineffective or result in increased exposures that could be potentially hazardous.  In this case, alternative methods 
of contraception should be utilized. 
c Intrauterine devices and intrauterine hormone releasing systems are acceptable methods of contraception in the 
absence of definitive drug interaction studies when hormone exposures from intrauterine devices do not alter 
contraception effectiveness
Less Than Highly Effective Contraceptive Methods That Are User Dependent
Failure rate of >1% per year when used consistently and correctly.

Male or female condom with or without spermicide.  Male and female condoms cannot be 
used simultaneously

Diaphragm with spermicide

Cervical cap with spermicide

Vaginal Sponge with spermicide

Progestogen-only oral hormonal contraception, where inhibition of ovulation is not the 
primary mechanism of action
Unacceptable Methods of Contraception

Periodic abstinence (calendar, symptothermal, post-ovulation methods)

Withdrawal(coitus interruptus).

Spermicide only

Lactation amenorrhea method (LAM)
CONTRACEPTION GUIDANCE FOR MALE PARTICIPANTS WITH PARTNER(S) OF
CHILD BEARING POTENTIAL.
Male participants with female partners of childbearing potential are eligible to participate if they 
agree to the following during the treatment and until the end of relevant systemic exposure.

Inform any and all partner(s) of their participation in a clinical drug study and the need to 
comply with contraception instructions as directed by the investigator.

Male participants are required to use a condom for study duration and until the end of relevant 
systemic exposure defined as 7 months after the end of treatment in the male participant.

Female partners of males participating in the study should consider use of effective methods 
of contraception until the end of relevant systemic exposure, defined as 5 months after the end 
of treatment in the male participant.

Male participants with a pregnant or breastfeeding partner must agree to remain abstinent from 
penile vaginal intercourse or use a male condom during each episode of penile penetration 
during the treatment and until 5 months after the end of treatment.
Revised Protocol No.: 01
Date: 03-Mar-2017
76
2.0
Approved
930105656
2.0
v

Clinical Protocol
CA209923
BMS-936558
nivolumab

Refrain from donating sperm for the duration of the study treatment and for 7 months after the 
end of treatment.
COLLECTION OF PREGNANCY INFORMATION
Guidance for collection of Pregnancy Information and outcome of pregnancy on the Pregnancy 
Surveillance Form is provided in Section 9.2.5 and the Appendix for Adverse Events and Serious 
Adverse Events Definitions and procedures for Evaluating, Follow-up and Reporting
Revised Protocol No.: 01
Date: 03-Mar-2017
77
2.0
Approved
930105656
2.0
v