Conditions: Solid Tumors
Allocation: NON_RANDOMIZED | Intervention model: PARALLEL
Enrollment: 58
Healthy volunteers: no

Brief summary:
The purpose of this study is to determine whether nivolumab is safe and effective in the treatment of advanced or recurrent solid tumors in Chinese subjects.

Detailed description:

Arms:
arm 1: Nivolumab specified dose on specified days arm 2: Nivolumab specified dose on specified days

Interventions: intervention 1: Nivolumab
Intervention descriptions: intervention 1: None

Protocol document:
Prot_SAP_000.pdf: 
Official Title of Study: 
A Phase 1/2, Open-Label Study of Nivolumab (BMS-936558) in Chinese Subjects With Previously 
Treated Advanced or Recurrent Solid Tumors (CheckMate 077: CHECKpoint Pathway and nivoluMAb 
Clinical Trial Evaluation 077) 
 
NCT Number: NCT02593786 
Document Date (Date in which document was last revised): August 15, 2018 


  
Page:
1
Protocol Number:
CA209077
IND Number:
Non-IND
EUDRACT Number
N/A
Date:
04-Mar-2013
Revised Date
15-Aug-2018
CLINICAL PROTOCOL CA209077
A Phase 1/2, Open-Label Study of Nivolumab (BMS-936558) in Chinese Subjects with 
Previously Treated Advanced or Recurrent Solid Tumors
CheckMate 077: CHECKpoint pathway and nivoluMAb clinical Trial Evaluation 077
Revised Protocol Number: 06
Study Director/Medical Monitor
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Shanghai 200040, P.R. China
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Company and its global affiliates (BMS). By reviewing this document, you agree to keep it 
confidential and to use and disclose it solely for the purpose of assessing whether your 
organization will participate in and/or the performance of the proposed BMS-sponsored 
study. Any permitted disclosures will be made only on a confidential "need to know" basis 
within your organization or to your independent ethics committee(s). Any other use, 
copying, disclosure or dissemination of this information is strictly prohibited unless 
expressly authorized in writing by BMS. Any supplemental information (eg, amendments) 
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Revised Protocol No.: 06
Date: 15-Aug-2018
2
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.
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Revised Protocol No.: 06
Date: 15-Aug-2018
3
DOCUMENT HISTORY
Document
Date of Issue
Summary of Change
Revised 
Protocol 06
15-Aug-2018
•
Cohort D target population changed from nasopharyngeal carcinoma 
to solid tumors. 
•
 
•
Updates to Management of Safety Algorithms in Appendix 1
•
Sample size change in cohorts C and D from 12 subjects to “up to” 
12 subjects.
Revised 
Protocol 05
07-Sep-2016
Incorporates Amendments 01, 02, 03, 04, & 05, Administrative Letter 01
Amendment 05
07-Sep-2016
•
Incorporates updates on duration of contraception
•
Removal of less effective method of contraception and addition of 
progestogen only hormonal contraception
•
Updates to Adverse event management algorithm in Appendix 1
•
To make any typographical edits, format updates and clarifications 
identified within and throughout the protocol
Revised 
Protocol 04
11-Apr-2016
Incorporates Amendment 01, 02, 03, & 04, Administrative Letter 01
Amendment 04
11-Apr-2016
Addition of 240 mg, 360 mg, and 480 mg flat dosing regimens in cohort 
expansion phase. Tumor type requirement changed to include all solid 
tumors at 3 mg/kg, 240 mg and 360 mg, and nasopharyngeal carcinoma 
at 480 mg in expansion. Infusion time changed from 60 minutes to 30 
minutes in cohort expansion phase.
Administrative 
Letter 01
04-Dec-2015
 
Revised 
Protocol 03
16-Sep-2015
Incorporates Amendment 01, 02, & 03
Amendment 03
16-Sep-2015
Include tumor types in addition to non-small cell lung cancer, gastric, 
nasopharyngeal, esophageal cancer. Provide recent clinical/safety 
information following the availability of additional study results for 
Nivolumab. Implement the latest changes from the program protocol 
template as well as latest updates from the standard protocol model 
document. 
Revised 
Protocol 02
01-May-2014
Incorporates Amendment 01 & 02
Amendment 02
01-May-2014
The purposes of this amendment are following:
•
To provide a detail breakdown for study duration, including 
approximately 1.5 years for recruitment.
•
To revise the exclusion criteria from HCV-RNA to HCV-Ab. 
The rationales are as below:
i) Among the patients with positive HCV antibody, 
about 60% patients will be HCV-RNA. It is 
appropriate to use HCV antibody as a stricter exclusion 
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Document
Date of Issue
Summary of Change
criteria, because most HCV-Ab positive patients are 
previously HCV infected or during chronic HCV 
infection. 
ii) Among the Chinese population, about 1% is HCV-
Ab positive. Compared with HCV-RNA positive 
exclusion, HCV-Ab exclusion will not exclude much 
more patients. 
iii) HCV-RNA testing takes a comparably longer 
duration and has a high false negative rate.
•
To make any typographical edits, format updates and 
clarifications identified within and throughout the protocol.
Revised 
Protocol 01
03-Jan-2014
Incorporates Amendment 01
Amendment 01
03-Jan-2014
The purposes of this amendment are the following: 
•
i) to include a multi-tumor Phase 1/2 study that serves as a 
Phase 1 study for both NSCLC and other indications with high 
priority in China; (ii) Detecting preliminary efficacy signal of 
nivolumab in specific tumor types to guide and accelerate the 
development in other tumor types in China. 
•
Nivolumab has demonstrated clinical activity across a variety of 
solid tumors from completed Phase 1 studies at multiple tumor 
types, and ongoing studies in NSCLC, Melanoma and renal 
cancer. Also the pharmacokinetic and safety profile are similar 
across various solid tumor types. Patients with metastatic and 
refractory solid tumors represent a large population who have 
unmet medical needs in China. Despite advances in multimodal 
therapy, improvement in overall survival has been limited.  The 
solid tumor types given priority consideration by China FDA 
for development include gastric cancer, esophageal cancer, and 
nasopharyngeal cancer. Thus this China phase 1/2 amendment 
will add 36 subjects with these 3 tumor types.
•
In the Section 1.1.1 study rationale, there is a comprehensive 
summary of nivolumab efficacy in a variety of tumors. The 
Section 1.4.4.3 anti-tumor activity summary is repeated and 
therefore is deleted.
•
The Section 1.5 risk/benefit assessment is revised for two 
considerations: i), instead of focusing only on NSCLC, there is 
general description of nivolumab efficacy in advanced solid 
tumors. ii), briefly explaining the mechanism of adverse events 
associated with nivolumab and management guideline.
•
To make any typographical edits, format updates and 
clarifications identified within and throughout the protocol.
Original 
Protocol
04-Mar-2013
Not applicable
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OVERALL RATIONALE FOR REVISED PROTOCOL 06:
Nivolumab monotherapy 480mg Q4W flat dose is approved in melanoma, non-small cell lung 
cancer, renal cell carcinoma, classical Hodgkin lymphoma, squamous cell carcinoma of head and 
neck cancer, urothelial carcinoma and hepatocellular carcinoma by the FDA, and approved in 
melanoma and renal cell carcinoma by the EMA. To provide intensive PK data in multiple tumor 
types in Chinese subjects, the target study population in cohort D will change from 
“nasopharyngeal carcinoma” to “solid tumors”. 
 
 
Sample size will change from 12 subjects to up to 12 subjects in cohorts C and D to allow flexibility
in study design.
This amendment applies to all enrolled subjects in cohort D.
SUMMARY OF KEY CHANGES FOR REVISED PROTOCOL 06
Section 
Number & 
Title
Description of Change
Brief Rationale
Synopsis
Section 3.1.2 
Cohort 
Expansion 
Phase
Target study population in cohort 
D changed from “nasopharyngeal 
carcinoma” to “solid tumors”.
To provide intense PK data in multiple 
tumor types.
Synopsis
Section 3.1.2 
Cohort 
Expansion 
Phase
Sample size changed from 12 
subjects to up to 12 subjects in 
cohorts C and D.
To allow flexibility in study design.
Section 3.3.2 
Exclusion 
Criteria
Section 3.4.1 
Prohibited 
and/or 
Restricted 
Treatments
2. Medical History and 
Concurrent Diseases has been 
updated. Live / attenuated vaccine 
within 30 days of first treatment is 
excluded, and minor updates in 
other exclusion criteria.
Investigator Brochure version 17 
updates.
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SUMMARY OF KEY CHANGES FOR REVISED PROTOCOL 06
Section 
Number & 
Title
Description of Change
Brief Rationale
All
Minor formatting and 
typographical corrections
Minor, therefore have not been 
summarized
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SYNOPSIS
Clinical Protocol CA209077
CheckMate 077: CHECKpoint pathway and nivoluMAb clinical Trial Evaluation 077
Protocol Title:  A Phase 1/2, Open-Label Study of Nivolumab (BMS-936558) in Chinese Subjects with Previously 
Treated Advanced or Recurrent Solid Tumors
Investigational Product(s), Dose and Mode of Administration, Duration of Treatment with Investigational 
Product(s):  
,Q the Dose Evaluation Phase, nivolumab (3mg/kg) will be administered as a single intravenous infusion (IV) over 
60 minutes every 14 days for a total of 4 infusions in each cycle. 
In the Cohort Expansion Phase,
•
Nivolumab administered IV over 30 minutes at 3 mg/kg every 14 days for a total of 4 infusions in each cycle.
or
•
Nivolumab administered IV over 30 minutes at 240 mg (flat dose) every 14 days for a total of 4 infusions in 
each cycle.
or
•
Nivolumab administered IV over 30 minutes at 360 mg (flat dose) every 3 weeks
or
•
Nivolumab administered IV over 30 minutes at 480 mg (flat dose) every 4 weeks
Subjects will receive nivolumab treatment until disease progression, intolerable toxicities, withdrawal of consent, or 
the study ends.
Study Phase:  1/2
Research Hypothesis:  There is no formal primary research hypothesis for this study to be statistically tested.  
Objectives:
Primary Objectives:  To characterize the safety, tolerability, and dose limiting-toxicities (DLTs) of nivolumab in 
Chinese subjects with previously treated advanced or recurrent solid tumors.  
Secondary Objectives: 
•
To characterize the pharmacokinetics (PK) of nivolumab in Chinese subjects;
•
To assess the immunogenicity of nivolumab in Chinese subjects;
•
To assess preliminary anti-tumor activity of nivolumab in Chinese subjects.
Study Design:  This is a Phase 1/2 open-label study of nivolumab monotherapy in Chinese subjects with previously 
treated advanced or recurrent solid tumors. Nivolumab is a fully human monoclonal IgG4 antibody, targeting the 
programmed death-1 (PD-1) membrane receptor on T-lymphocytes and other cells of the immune system. 
The study will consist of 3 periods:  screening period (up to 28 days); treatment period (until disease progression or 
intolerable toxicities); and a follow-up period (up to 100 days). In the dose evaluation phase, each treatment cycle is 
comprised of 4 doses of assigned study drug (see table below) administered at Days 1, 15, 29 and 43 with a response 
assessment between Days 49 to 56. The response assessment must be completed before the first dose in the next
cycle. In cohort expansion phase, the 3 mg/kg and 240 mg Q2W cohorts (cohort A and B) will be administered 4 
doses in each 8-week treatment cycle, the same as the dose evaluation treatment cycle. The response assessment 
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must be completed before the first dose in the next cycle. The 360 mg Q3W cohort (cohort C) will be administered 
one dose of study drug in each 3-week treatment cycle. Tumor assessment must be completed every 6 weeks. The 
480 mg Q4W cohort (cohort D) will be administered one doses of study drug in each 4-week treatment cycle. Tumor 
assessment must be completed every 8 weeks.
Every effort should be made to schedule visits within the timeframe stated in the protocol. In the case that the visits 
cannot be within the timeframe stated in protocol then the treatment period study procedures can be performed ± 2 
days of the scheduled visit. 
Nivolumab Dose Levels
Nivolumab Dose Level in Dose Evaluation Phase
Dose
1
3 mg/kg 
-1a
1 mg/kg
Nivolumab Dose Level in Cohort Expansion Phase
Dose
3 mg/kg Q2W
3 mg/kg
240 mg Q2W
240 mg
360 mg Q3W
360 mg
480 mg Q4W
480 mg
a Dose level -1 will only be considered if the safety and tolerability profile for 3 mg/kg is evaluated as not 
acceptable.
In 3mg/kg cohort and 240mg Q2W cohort, for the purpose of PK sample collection, subjects will be admitted to the 
clinical facility prior to dosing (Day -1) only for Cycle 1/Day 1 and Cycle 3/Day 1 and will remain in the clinical 
facility until 24 hours after study drug administration. In 360mg Q3W Cohort, for the purpose of PK sample 
collection, subjects will be admitted to the clinical facility prior to dosing (Day -1) only for Cycle 1/Day 1 and Cycle 
6/Day 1 and will remain in the clinical facility until 24 hours after study drug administration. In 480mg Q4W 
Cohort, for the purpose of PK sample collection, subjects will be admitted to the clinical facility prior to dosing 
(Day -1) only for Cycle 1/Day 1 and Cycle 5/Day 1 and will remain in the clinical facility until 24 hours after study 
drug administration.
Collection of tumor tissue [archival or recent acquisition, formalin-fixed, paraffin-embedded (FFPE) tumor tissue 
block or unstained slides] for determination of PD-L1 expression status is highly encouraged. Recent biopsy tissue is 
preferred when available. Submission of archival tissue is also encouraged for all subjects, irrespective of whether 
recent biopsy tissue is available. This is not applicable to cohort D
Physical examinations, vital sign measurements, 12-lead electrocardiograms (ECG), and clinical laboratory 
evaluations will be performed at selected times (see Time and Events Schedule Table 5.1-1, Table 5.1-2, Table 5.1-3 
and Table 5.1-4) throughout the dosing interval. Subjects will be closely monitored for AEs throughout the study.
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Study Design Schematic
Dose Evaluation Phase
Cohort Expansion Phase
PD= progressive disease; AE= adverse event
Dose Evaluation Phase
Based on clinical experience with over 300 subjects on up to 2 years of treatment (study CA209003/MDX1106-03), 
the recommended dose of nivolumab during the dose evaluation phase of the study is 3 mg/kg. Dose limiting 
toxicity (DLT) observation period for each subject is defined as the 1st cycle of treatment (56 days of dosing). 
Initially 6 eligible NSCLC subjects will be treated at the dose level of 3 mg/kg.  An additional 3 NSCLC subjects 
may be added to the same dose level, and hence a total number of 6 or 9 subjects will be treated during the dose 
evaluation phase for a given dose level. A decision to enter cohort expansion phase, or to consider the next lower 
dose level (1 mg/kg) in dose evaluation phase, will be guided by the number of subjects with DLTs observed during 
the dose evaluation phase (see table below). 
Subjects who do not complete the DLT observation period for reasons other than DLTs will be replaced. A dose 
level of 1 mg/kg may be considered if the safety and tolerability profile for 3 mg/kg is evaluated as not acceptable, 
after consultation and agreement between the Investigator(s) and the sponsor as well as review of the existing 
clinical safety database from earlier studies. Following a similar procedure, if the dose level of 1 mg/kg is evaluated 
as not acceptable as well, the findings will be discussed between the Investigator(s) and the sponsor and an 
agreement will be reached as to whether a lower dose of nivolumab should be examined.
Safety monitoring during the dose evaluation phase will be based on the probability of the toxicity given the 
observed DLTs, with target toxicity of 0.25 (± 0.05). (Ji et al. Clinical Trials 2010; 7: 653–663, A modified toxicity 
probability interval method for dose-finding trials). Guidance for safety monitoring after the toxicity outcomes 
observed is presented in the following table:  
Guidance for Safety Monitoring Based on Observed Toxicity Outcomes during the Dose Evaluation Phase
Number of Subjects Treated
6
9
Number of Subjects 
with DLTs
0 
E 
E 
1 
S 
E 
2 
S 
E 
3 
D 
E 
4 
NA
D 
PD, AE leading to discontinuation
Screening 28 days
Treatment: 8 wks/cycle
Toxicity Follow-up 
100 days
Screening 28 days
Treatment: 8 wks/cycle, 
or 3 wks/cycle,
or 4 wks/cycle
Toxicity Follow-up 
100 days
PD, AE leading to discontinuation
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E: Expand to 56 - 64 subjects; S: Stay at the same dose level by treating additional 3 subjects; D: Discuss of 
proceeding with the next lower dose level.
Cohort Expansion Phase
If the safety and tolerability profile is established at the dose level of 3 mg/kg in the dose evaluation phase, then 
cohort expansion phase will be initiated, including:
•
Cohort A: Continue to accrue up to at least 12 - 20 subjects with solid tumors (including but not limited to 
NSCLC) at the dose level of 3 mg/kg;
•
Cohort B: Accrue 20 subjects with solid tumors (including but not limited to HCC, SCLC) at the dose level 
of 240 mg (flat dose) Q2W;
•
Cohort C: Accrue up to 12 subjects with solid tumors (including but not limited to GC, NSCLC) at 360 mg 
(flat dose) Q3W;
•
Cohort D: Accrue up to 12 subjects with solid tumors at 480 mg (flat dose) Q4W
Clinical safety monitoring of subjects during the cohort expansion phase will be performed. If in a given dose level, 
the combined incidence exceeds 33% for study drug related toxicity requiring treatment discontinuation, then further 
enrollment to that dose level will be interrupted and a decision whether or not to continue dosing will be based on 
discussions of the observed aggregate (acute and chronic) toxicities between the Investigator(s) and the sponsor, if 
needed. An agreement will be reached as to whether a lower dose should be examined, or whether any additional 
treatment guidelines should be implemented prior to enrollment of additional subjects to that arm. Depending on 
preliminary efficacy data, certain tumor types may be expanded to collect additional efficacy data.
Administration of Additional Cycles:
Tumor response will be evaluated using Response Evaluation Criteria in Solid Tumor (RECIST v1.1). In 3 mg/kg 
cohort and 240mg Q2W cohort, end of cycle tumor response assessment for all subjects will occur between Days 49 
to 56 (results of the assessments must be reviewed and documented before the first dose of next cycle). In 360 mg 
Q3W cohort, tumor assessment must be completed every 6 weeks. In 480 mg Q4W cohort, tumor assessment must 
be completed every 8 weeks.
Subjects will continue to receive nivolumab treatment until disease progression (or until discontinuation of study 
therapy in subjects receiving nivolumab beyond progression, defined in Section 4.3.2.5), discontinuation due to 
toxicity, or withdrawal of consent. The maximum duration of study therapy to be administered to an individual 
subject in this study is 2 years.
Follow-up Period:
•
Begins when the decision to discontinue a subject from study therapy is made (no further treatment with 
nivolumab);
•
The first two follow-up visits (follow up #1 and follow up #2) include PK and immunogenicity samples. Follow 
up #1 = 30 days from last dose ± 5 days; Follow up #2 = 70 days from follow up #1 ± 5 days;
•
Subjects will be followed for drug-related toxicities until these toxicities resolve, return to baseline, or are 
deemed irreversible.
Duration of Study:  The expected maximum duration of a subject’s participation in the study (on-treatment and 
follow-up periods) is approximately 2.5 years. The study is expected to accrue over a period of approximately 1.5 
years. 
•
maximum 28 days of screening,
•
Maximum of 2 years of therapy.
•
approximately 100 days follow-up office visits. 
Number of Subjects: approximately 56 - 64 PK evaluable subjects.
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Study Population:  Male and female subjects, 18 years of age or older, who have histological confirmation of solid 
tumor that is clinically advanced or recurrent, and have progressed after previous therapies, and for whom no 
alternative standard therapy is available will be eligible to enroll in the study: 
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 first dose.
Study Assessments:  
•
Safety Assessment:  Safety assessments will be based on the following: clinical laboratory tests, pregnancy 
testing, Eastern Cooperative Oncology Group (ECOG) status, physical examination including vital signs and 
electrocardiogram (ECG), and adverse events (AEs). Toxicity will be evaluated by the National Cancer Institute 
Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.03;
•
Dose-Limiting Toxicity:  DLTs are defined in protocol Section 4.3.1 and will be determined based on the 
incidence, intensity, and duration of adverse event (AE) that are related to study drug, and that occur within 56 
days (8 weeks, through completion of cycle 1) of initiation of study drug;
•
Immunogenicity Assessment:  Blood samples to evaluate development of positive anti-drug antibody (ADA) 
response will be collected at specified time points for all subjects;
•
Pharmacokinetics Assessment:  Serial blood samples for PK assessments will be collected from all subjects at 
specified time points. PK samples will also be collected to evaluate serum concentrations of nivolumab at 
follow-up visits. PK parameters such as Cmax, Tmax, AUC(TAU), Ctrough, and Accumulation Index (AI) will 
be derived from serum concentration versus time data in all subjects. 
•
Efficacy Assessment:  Computed tomography/magnetic resonance imaging (CT/MRI) for chest, abdomen, 
pelvis, and brain will be performed at screening and at specified time points in Table 5.1-2, Table 5.1-3 and 
Table 5.1-4.. Measurement of tumor burden must be reviewed and documented before initiating further
treatment with nivolumab. Tumor response status will be assessed with RECIST v1.1;
•
 
 
 
 
Statistical Considerations:
Sample Size:  This is a Phase 1/2 safety trial and the sample size during the dose evaluation phase depends on the 
observed toxicity.  Six or 9 NSCLC subjects per dose level will be treated according to the Guidance for Safety 
Monitoring Based on Observed Toxicity Outcomes during the Dose Evaluation Phase. Utilizing the information on 
the observed toxicity of related AEs with Grades 3 and 4 (16%) among 304 subjects in a multidose, dose-ascending 
study with nivolumab monotherapy in subjects with selected advanced or recurrent malignancies 
(CA209003/MDX1106-03), there is a less than 20% posterior probability with this guidance that the toxicity rate 
could be 40% or higher, for different total number of subjects (6 or 9) in the dose evaluation phase.  The posterior 
probability calculations assume a Beta(1, 4) prior distribution, which implies a toxicity rate around 20% as estimated 
from CA209003/MDX1106-03 study.  Similarly, there is a less than 10% posterior probabilities that the toxicity rate 
could be 45% or higher for the dose evaluation phase.  
One of the objectives of expansion cohorts is to characterize the pharmacokinetics (PK) of nivolumab in Chinese 
subjects in different dosing regimens.  The sample size of 12-20 in the expansion cohorts is adequate to characterize
PK within a dosing group. 
Approximately 6-9 subjects are expected to be enrolled in dose evaluation and to be expanded to approximately 56-
64 in total.
Endpoints:  
Primary endpoints
The primary objective is to characterize the safety and tolerability of nivolumab in Chinese subjects.  The primary 
objective will be measured by:
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•
Number and percent of subjects that experience drug-related grade 3-4 AEs occurring up to 100 days after 
the last dose of study drug. [Time Frame - On a continuous basis up to 100 days after the last dose of study 
drug];
•
Number and percent of subjects that experience drug-related grade 3-4 SAEs occurring up to 100 days after 
the last dose of study drug. [Time Frame - On a continuous basis up to 100 days after the last dose of study 
drug];
•
Number and percent of subjects with clinical laboratory abnormalities by worst toxicity grade by NCI 
CTCAE version 4.03 (as assessed at the planned times listed in Table 5.1-1, Table 5.1-2, Table 5.1-3, and 
Table 5.1-4). [Time Frame - On a continuous basis up to 100 days after the last dose of study drug].
Secondary endpoints
The secondary objective of characterizing the PK of nivolumab in Chinese subjects will be measured by:
•
Nivolumab PK parameters, including Cmax, Tmax, AUC(TAU), Ctrough, CLT, T-HALFeff and AI.
The secondary objective of assessing the immunogenicity of nivolumab will be measured by: 
•
Frequency of ADA positive status and ADA negative status, relative to baseline.
The secondary objective of assessing the anti-tumor response of nivolumab will be measured by the following 
efficacy endpoints at subject level: 
•
BOR by investigator using Response Evaluation Criteria in Solid Tumor (RECIST v1.1);
•
Duration of response is computed for subjects with a best overall response (BOR) of CR or PR, and defined 
as the time between the date of first response and the subsequent date of objectively documented disease 
progression or death, whichever occurs first. For those subjects who remain alive and have not progressed 
or received subsequent therapy, duration of response will be censored on the date of last tumor assessment;
The following efficacy endpoints for each tumor type may be assessed by dose and/or across dose depending on data 
availability.
•
Objective response rate (ORR) is defined as the proportion of all treated subjects whose best overall 
response (BOR) is either a complete response (CR) or partial response (PR) by investigator using Response 
Evaluation Criteria in Solid Tumor (RECIST v1.1); 
•
Median duration of response 
•
Response rate at 24 weeks: is defined as the proportion of all treated subjects who has CR or PR by 24 
weeks.
•
Disease control rate (DCR) at 24 weeks is defined as the proportion of all treated subjects who has CR, PR 
or SD by 24 weeks
Analyses:
Safety analysis
All recorded AEs will be coded according to the most current version of MedDRA and listed by dose level and 
tumor type and overall. AEs will be summarized for each dose level and tumor type and overall by system organ 
class and preferred term using the worst grade within each category within a subject. Toxicity changes from baseline 
in clinical laboratory test results will be summarized by dose level and tumor type and overall using the worst on-
treatment CTC grade values. Vital signs, ECGs and clinical laboratory test results will be listed and summarized by 
dose level and tumor type and overall.
Efficacy analysis
Individual subject’s BOR will be listed by dose and/or across dose if appropriate for each tumor type based on 
RECIST v1.1. BOR outcomes will be tabulated, by dose and/or across dose if appropriate, for each tumor type 
depending on data availability. 
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Individual subject’s DOR will be listed by dose and/or across dose if appropriate for each tumor type.
The following analysis for each tumor type may be summarized by dose and/or across dose depending on data 
availability.
ORR will be calculated and corresponding two-sided 95% exact confidence intervals using Clopper and Pearson 
method will be provided by dose and/or across dose for each tumor type depending on data availability. 
Response rate and disease control rate at 24 weeks will be estimated by Kaplan-Meier analysis of time to response 
and the corresponding two-sided 95% confidence interval by Greenwood formula will be provided by dose and /or 
across dose for each tumor type as appropriate.  
Median duration of response will be estimated by Kaplan-Meier analysis and corresponding two-sided 95% 
confidence intervals by Greenwood formula will be provided by dose and/or across dose for each tumor type as 
appropriate.
Pharmacokinetic analysis
Summary statistics will be tabulated for PK parameters of nivolumab as specified in Section 5.5. by dose and study 
cycle as appropriate.
The nivolumab concentration data obtained in this study may be combined with data from other studies in the 
clinical development programs to develop or refine a population PK model in a separate report. 
Immunogenicity analysis
Data from the assessment of immunogenicity markers will be listed by subjects. Number and frequency of ADA 
response classifications will be summarized by dose level. The details of the ADA response classifications will be 
provided in the study statistical analyses plan (SAP) document. Effect of immunogenicity on safety/efficacy 
 
 and PK may be explored.
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TABLE OF CONTENTS 
TITLE PAGE ................................................................................................................ 
DOCUMENT HISTORY .............................................................................................. 
OVERALL RATIONALE FOR REVISED PROTOCOL 06: ..................................... 
SUMMARY OF KEY CHANGES FOR REVISED PROTOCOL 06 ......................... 
SYNOPSIS .................................................................................................................... 
TABLE OF CONTENTS .............................................................................................. 
1 INTRODUCTION AND STUDY RATIONALE ..................................................... 
1.1 Study Rationale ................................................................................................. 
1.1.1 Rationale for Nivolumab as Monotherapy in Advanced Solid Tumors ... 
1.1.2 Rationale for schedule and dose selection in dose evaluation phase ...... 
1.1.3 Rational for flat dose in cohort expansion phase .................................... 
1.1.4 Rationale for Shorter Infusion Times ....................................................... 
1.1.5 Rationale for Nivolumab Treatment Beyond Progression ....................... 
1.2 Research Hypothesis ......................................................................................... 
1.3 Objectives ......................................................................................................... 
1.3.1 Primary Objective .................................................................................... 
1.3.2 Secondary Objectives ............................................................................... 
1.4 Product Development Background ................................................................... 
1.4.1 Pharmacology .......................................................................................... 
1.4.2 Toxicity ..................................................................................................... 
1.4.3 Preclinical Metabolism and Pharmacokinetics ....................................... 
1.4.4 Clinical Pharmacology and Safety .......................................................... 
1.4.4.1 Pharmacokinetics of Nivolumab ..................................................... 
1.4.4.2 Safety Summary ............................................................................... 
1.4.5 Clinical efficacy in Selected Tumor Types ............................................... 
1.5 Overall Risk/Benefit Assessment ..................................................................... 
2 ETHICAL CONSIDERATIONS ............................................................................... 
2.1 Good Clinical Practice ...................................................................................... 
2.2 Institutional Review Board/Independent Ethics Committee ............................. 
2.3 Informed Consent.............................................................................................. 
3 INVESTIGATIONAL PLAN .................................................................................... 
3.1 Study Design and Duration ............................................................................... 
3.1.1 Dose Evaluation Phase ............................................................................ 
3.1.2 Cohort Expansion Phase.......................................................................... 
3.1.3 Administration of Additional Cycles ........................................................ 
3.1.4 Follow-up Period ..................................................................................... 
3.2 Post Study Access to Therapy ........................................................................... 
3.3 Study Population ............................................................................................... 
3.3.1 Inclusion Criteria ..................................................................................... 
3.3.2 Exclusion Criteria .................................................................................... 
3.3.3 Women of Childbearing Potential ........................................................... 
3.4 Concomitant Treatments ................................................................................... 
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3.4.1 Prohibited and/or Restricted Treatments................................................. 
3.4.2 Other Restrictions and Precautions ......................................................... 
3.4.2.1 Permitted Corticosteroid Therapy .................................................. 
3.4.3 Antiviral therapy (HCC specific) ............................................................. 
3.5 Discontinuation of Subjects from Treatment .................................................... 
3.6 Post Study Treatment Follow up ....................................................................... 
3.6.1 Withdrawal of Consent ............................................................................ 
3.6.2 Lost to Follow-Up .................................................................................... 
4 STUDY DRUG .......................................................................................................... 
4.1 Study Treatments .............................................................................................. 
4.1.1 Investigational Product ............................................................................ 
4.1.2 Non-investigational Product .................................................................... 
4.1.3 Storage and Dispensing ........................................................................... 
4.2 Method of Assigning Subject Identification ..................................................... 
4.2.1 Management Algorithms for Immuno-Oncology Agents ......................... 
4.2.1.1 Protocol-specific Recommendations for Management of Hepatic 
Events in HCC Subjects ........................................................................ 
4.3 Selection and Timing of Dose for Each Subject ............................................... 
4.3.1 Dose-limiting Toxicities ........................................................................... 
4.3.1.1 Hepatic DLT.................................................................................... 
4.3.1.2 Non-hematologic DLT .................................................................... 
4.3.1.3 Hematologic DLT............................................................................ 
4.3.2 Dose Modification .................................................................................... 
4.3.2.1 Dose Adjustments ............................................................................ 
4.3.2.2 Dose Delay Criteria ........................................................................ 
4.3.2.3 Criteria to Resume Dosing.............................................................. 
4.3.2.4 Nivolumab Dose Discontinuation ................................................... 
4.3.2.5 Treatment Beyond Disease Progression ......................................... 
4.3.2.6 Treatment of Nivolumab Related Infusion Reactions ..................... 
4.4 Blinding/Unblinding ......................................................................................... 
4.5 Treatment Compliance ...................................................................................... 
4.6 Destruction and Return of Study Drug ............................................................. 
4.6.1 Destruction of Study Drug ....................................................................... 
4.6.2 Return of Study Drug ............................................................................... 
5 STUDY ASSESSMENTS AND PROCEDURES ..................................................... 
5.1 Flow Chart/Time and Events Schedule ............................................................. 
5.2 Study Materials ................................................................................................. 
5.3 Safety Assessments ........................................................................................... 
5.3.1 Imaging Assessment for the Study............................................................ 
5.3.2 Laboratory Test Assessments ................................................................... 
5.4 Efficacy Assessments ........................................................................................ 
5.4.1 Primary Efficacy Assessment ................................................................... 
5.4.2 Secondary Efficacy Assessments .............................................................. 
5.5 Pharmacokinetic Assessments .......................................................................... 
5.5.1 Pharmacokinetics and Immunogenicity Collection and Processing ....... 
5.5.2 Pharmacokinetics and Immunogenicity Sample Analyses ....................... 
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5.5.3 Labeling and Shipping of Biological Samples ......................................... 
5.8 Outcomes Research Assessments ..................................................................... 
5.9 Other Assessments ............................................................................................ 
5.10 Results of Central Assessments ...................................................................... 
6 ADVERSE EVENTS ................................................................................................. 
6.1 Serious Adverse Events .................................................................................... 
6.1.1 Serious Adverse Event Collection and Reporting .................................... 
6.2 Nonserious Adverse Events .............................................................................. 
6.2.1 Nonserious Adverse Event Collection and Reporting .............................. 
6.3 Laboratory Test Result Abnormalities .............................................................. 
6.4 Pregnancy .......................................................................................................... 
6.5 Overdose ........................................................................................................... 
6.6 Potential Drug Induced Liver Injury (DILI) ..................................................... 
6.7 Other Safety Considerations ............................................................................. 
7 DATA MONITORING COMMITTEE AND OTHER EXTERNAL COMMITTEES
................................................................................................................................. 
8 STATISTICAL CONSIDERATIONS....................................................................... 
8.1 Sample Size Determination ............................................................................... 
8.2 Populations for Analyses .................................................................................. 
8.3 Endpoints .......................................................................................................... 
8.3.1 Primary Endpoint(s) ................................................................................ 
8.3.2 Secondary Endpoint(s) ............................................................................. 
8.3.2.1 Pharmacokinetics ............................................................................ 
8.3.2.2 Immunogenicity ............................................................................... 
8.3.2.3 Anti-tumor response ........................................................................ 
8.4 Analyses ............................................................................................................ 
8.4.1 Demographics and Baseline Characteristics........................................... 
8.4.2 Efficacy Analyses ..................................................................................... 
8.4.3 Safety Analyses......................................................................................... 
8.4.4 Pharmacokinetic Analyses ....................................................................... 
8.4.7 Outcomes Research Analyses .................................................................. 
8.4.8 Other Analyses ......................................................................................... 
8.4.8.1 Immunogenicity analyses ................................................................ 
8.5 Interim Analyses ............................................................................................... 
9 STUDY MANAGEMENT ........................................................................................ 
9.1 Compliance ....................................................................................................... 
9.1.1 Compliance with the Protocol and Protocol Revisions ........................... 
9.1.2 Monitoring ............................................................................................... 
9.1.2.1 Source Documentation .................................................................... 
9.1.3 Investigational Site Training.................................................................... 
9.2 Records ............................................................................................................. 
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9.2.1 Records Retention .................................................................................... 
9.2.2 Study Drug Records ................................................................................. 
9.2.3 Case Report Forms .................................................................................. 
9.3 Clinical Study Report and Publications ............................................................ 
10 GLOSSARY OF TERMS ........................................................................................ 
11 LIST OF ABBREVIATIONS .................................................................................. 
12 REFERENCES ........................................................................................................ 
APPENDIX 1 MANAGEMENT OF SAFETY ALGORITHMS FOR IMMUNO-
ONCOLOGY AGENTS ......................................................................................... 
APPENDIX 2 SIMULATION TO EXAMINE PROBABILITY-BASED DESIGN VS. 
ALGORITHM BASED A+B DESIGNS ................................................................ 
APPENDIX 3 RECIST 1.1 GUIDELINES .................................................................. 
APPENDIX 4 ECOG PERFORMANCE STATUS ..................................................... 
APPENDIX 5 CHILD-PUGH SCORE ........................................................................ 
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1
INTRODUCTION AND STUDY RATIONALE
Cancer immunotherapy rests on the premise that tumors can be recognized as foreign rather than 
as self, and can be effectively attacked by an activated immune system. Many tumors express 
tumor-specific antigens and ongoing immune surveillance may abort the emergency of many 
tumors as they arise. Meanwhile, tumor progression may depend upon acquisition of 
mechanisms that allow cancer cells to evade immune surveillance and an effective immune 
response.1
Current immunotherapy efforts attempt to break the apparent tolerance of the immune system to 
tumor cells and antigens by either introducing cancer antigens by therapeutic vaccination or by 
modulating regulatory checkpoints of the immune system - either indirectly by cytokine
manipulation or directly by stimulation of immune cells by antibodies directed to receptors on 
T and B cells.
Unmet medical needs
Patients with metastatic or refractory solid tumors have very poor prognosis. Despite advances in 
multimodal therapy, improvement in overall survival has been limited. Thus, these patients 
represent a large population who have unmet medical needs and it is necessary to test 
compounds that have novel mechanisms of action in clinical studies.
In China, cancer is becoming the leading cause of death in urban area and the second one in rural 
area.2, 3 There are certain tumor types given high priority consideration in China due to the high 
incidence rate, etiology, clinical characteristic and outcomes. These tumor types include lung, 
stomach, esophageal and nasopharyngeal cancer.
Lung cancer is the most common type of cancer in China and leading cause of cancer-related 
death globally and in China. The reported number of lung cancer cases in China in 2008 was 
522,050 with an incidence of 33.5 per 100,000 age standardized rate (ASR).4 The reported 
number of deaths in China from lung cancer for 2008 was 452,813. Approximately 80-85% of 
lung cancer patients have Non-Small-Cell Lung Cancer (NSCLC). The majority of patients 
present with locally advanced or distant metastatic disease that is not amenable to cure by 
surgery and/or radiotherapy, and therefore eligible for systemic treatment. Despite the 
availability of new agents, the prognosis for advanced NSCLC patients remains poor. Almost all 
patients eventually develop progressive disease.
Gastric cancer is the second highest malignancy in terms of incidence in China, and yearly new 
cases in China accounts for more than 40% of all the new gastric cancer cases in the world.4 The 
prognosis of advanced gastric cancer patients is very poor with an overall survival of about 6 to 
8 months.5
Esophageal cancer ranks as the fifth tumor for incidence rate in China, and new cases in China 
each year account for 50% of all new cases in the world.4,6 The primary treatment regimens for 
esophageal cancer in China are surgery and radiotherapy. For the advanced esophageal cancer 
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patients, the treatment options are very limited and there is high unmet medical needs for this 
population.
Nasopharyngeal cancer (NPC) is a type of tumor distributed in specific regions and ethnic groups 
such as the Asians. About 80% of nasopharyngeal cancer patients come from Asia with China 
accounting for about 40% for all new cases worldwide yearly.6,7 Nasopharyngeal cancer can be 
cured by radiotherapy if diagnosed at early stage. In China, 75% of newly diagnosed NPC are 
stage III or IV.8 For recurrent, unresectable or metastatic nasopharyngeal cancer, the treatment 
options are very limited and the prognosis remains poor with TTP of 5 to 10 months and OS of 
12 to 18 months. 9,10,11
Nivolumab Mechanism of Action
T cell stimulation is a complex process involving the integration of numerous positive as well as 
negative co-stimulatory signals in addition to antigen recognition by the T cell receptor (TCR) 
Figure 1-1.12  Collectively, these signals govern the balance between T cell activation and 
tolerance to antigens.
Figure 1-1:
T cell Stimulation
Programmed death-1 (PD-1 or CD279), primarily expressed on activated T cells, B cells and 
myeloid cells, is a 55 kD type I transmembrane protein that is a member of the CD28 family of 
T cell co-stimulatory receptors that also includes CD28, CTLA-4, ICOS, and BTLA.13 Two
ligands specific for PD-1 have been identified: PD-L1 (also known as B7-H1 or CD274) and 
PDL2 (also known as B7-DC or CD273), each of which are primarily expressed on antigen 
presenting cells. PD-L1 and PD-L2 have been shown to downregulate T cell activation upon 
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binding to PD-1 in both murine and human systems.14,15,16 The interaction of PD-1 with its 
ligands, PD-L1 and PD-L2 transmits a negative regulatory stimulus to down-modulate the 
activated T cell immune response.
The absence or inhibition of PD-1 in murine models has resulted in development of various 
autoimmune phenotypes or autoimmune diseases,17 which suggests inhibition of PD-1 binding to 
its ligands has the potential to activate anti-self T cell. 
Preclinical animal models of tumors have shown that blockade of PD-1 by monoclonal 
antibodies (mAbs) can enhance the anti-tumor immune response and result in tumor rejection. 
The effects of anti-PD-1 blockade in combination with a variety of chemotherapeutic agents 
were tested in several murine tumor models (MC38, SA1/N, and PAN02).
In humans, PD-L1 expression has been found in a number of tumors.18,19 PD-L1 expression by 
tumor cells has been shown to enhance apoptosis of activated tumor-specific T cells in vitro.20
Moreover, the expression of PD-L1 may protect tumor cells from the induction of apoptosis by 
activated tumor-specific T cells.21 PD-1 expression has also been associated with poor prognosis 
in renal, esophageal, gastric, ovarian, pancreatic, and lung cancer.22,23,24 PD-1 engagement on 
T cells by PD-L1+ APC or PD-L1 + tumor cells may prematurely limit the effective immune 
response. 
Thus, blocking PD-1 in PD-L1+ tumors may reverse the inactivation of tumor-specific effector 
T cells as well as activate antitumor immune responses that are limited by expression of PD-L1 
on adenomatous polyposis coli (APC) or tumor cells.
Nivolumab (also known as BMS-936558, MDX-1106, Ono-4538, anti-PD-1) is a fully human, 
IgG4 (kappa) isotype mAb, PD-1 receptor blocker. Blockade of the PD-1 pathway by nivolumab 
was studied using the mixed lymphocyte reaction (MLR). PD-1 blockade resulted in a 
reproducible enhancement of both proliferation and interferon (IFN)-γ release in the MLR. The 
effect of nivolumab on antigen-specific recall response was investigated using a 
CMV-restimulation assay with human peripheral blood mononuclear cell (PBMC), and was 
evaluated by enzyme-linked immunosorbent assay (ELISA). These data indicated that nivolumab, 
versus an isotype-matched control antibody, augmented IFN-γ secretion from CMV-specific 
memory T cells in a dose-dependent manner. PD-1 blockade by nivolumab has, therefore, been 
pursued as a promising avenue for immunotherapy of tumors.
1.1
Study Rationale
Nivolumab has demonstrated clinical activity in a variety of solid tumor malignancies from 
completed and ongoing studies. Patients with metastatic and refractory solid tumors represent a 
large population who have unmet medical needs in China and throughout the world.  Nivolumab 
has demonstrated durable responses exceeding 6 months as monotherapy and in combination 
with ipilimumab in several tumor types, including NSCLC, melanoma, RCC, and some 
lymphomas. In confirmatory trials, nivolumab as monotherapy demonstrated a statistically 
significant improvement in OS as compared with the current standard of care in subjects with 
advanced or metastatic NSCLC and in subjects with unresectable or metastatic melanoma. The 
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overall safety experience with nivolumab, as a monotherapy or in combination with other 
therapeutics, is based on experience in approximately 8,600 subjects treated to date. The most 
common adverse events were inflammatory, consistent with its mechanism of action, and were 
generally manageable.  These safety data were established in a population predominantly by 
Caucasian subjects; therefore, the safety, tolerability and pharmacokinetics of nivolumab will be 
assessed in Chinese subjects with advanced solid tumors, to provide a more comprehensive 
understanding of nivolumab’s properties in Chinese.
1.1.1
Rationale for Nivolumab as Monotherapy in Advanced Solid Tumors
CA209003/MDX1106-03 is a completed Ph1 study of Nivolumab monotherapy in selected 
advanced malignancies. A total 306 subjects were treated with Nivolumab monotherapy, 
including 129 NSCLC, 107 melanoma, 34 RCC, 17 CRPC and 19 CRC patients.  The objective, 
durable responses were observed in subjects with NSCLC, melanoma, and RCC (see Table 
1.1.1-1 from CA209003/MDX1106-03 CSR25). Responses were even observed in subjects who 
were heavily pretreated (nearly half had received ≥3 prior therapies).  The observed responses
were durable with a median duration of response (DOR) ranging from 56 -104 weeks across 
tumor types. An analysis of PFSR in all treated NSCLC, melanoma and RCC subjects showed a 
24-week rate of 33%, 45% and 58% respectively. An analysis of OS in all treated NSCLC, 
melanoma and RCC subjects showed 1-year rate of 42%, 62% and 70%.
Table 1.1.1-1:
Summary of Efficacy - All Treated Subjects with Non-small Cell Lung 
Cancer (NSCLC), Melanoma, or Renal Cell Carcinoma (RCC)
Efficacy parameter
SQ NSCLC
n = 54
NSQ 
NSCLC
n = 74
TOTAL 
NSCLC
N = 129
Melanoma
N = 107
RCC
N = 34
Best Overall Response (BOR) a, 
N (%)
Complete Response
0
0
0
1(0.9)
1(2.9)
Partial Response
9 (16.7)
13 (17.6)
22 (17.1)
32 (29.9)
9 (26.5)
Stable Disease
15 (27.8)
16 (21.6)
32 (24.8)
24 (22.4)
14 (41.2)
Disease Progression
20 (37)
38 (51.4)
58 (45.0)
41 (38.3)
8 (23.5)
Unable to Determined
10 (18.5)
7 (9.5)
17 (13.2)
9 (8.4)
2 (5.9)
Objective response rate (ORR)b, 
N (%)
9 (16.7)
13 (17.6)
22 (17.1)
33 (30.8)
10 (29.4)
      95% CI
7.9, 29.3
9.7, 28.2
11.0, 24.7
22.3, 40.5
15.1, 47.5
Time to response (range, weeks)
7.4 - 15.4
7.6 - 31.4
7.4 - 31.4
7.1 - 40.0
7.7 - 47.7
Median DOR (weeks)
NR
63.9
74.0
104
56.1
      95% CI from K-M
42.1, -
29, -
42.1, -
73.9, -
49.4, -
PFSR (95% CI)
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Table 1.1.1-1:
Summary of Efficacy - All Treated Subjects with Non-small Cell Lung 
Cancer (NSCLC), Melanoma, or Renal Cell Carcinoma (RCC)
Efficacy parameter
SQ NSCLC
n = 54
NSQ 
NSCLC
n = 74
TOTAL 
NSCLC
N = 129
Melanoma
N = 107
RCC
N = 34
      At 8 weeks
94 (87, 100)
90 (83, 97)
92 (87, 97)
90 (85, 96)
100 (NC)
     At 24 weeks
42 (27, 57)
29 (18, 39)
33 (25, 42)
45 (35, 55)
73 (58, 88)
a BOR was derived centrally by the sponsor using RECIST 1.0 criteria on investigator assessed tumor 
measurements.
b Includes all subjects with a response of CR or PR.
Source: Supplemental Tables S.5.1.1A, S.5.1.2, S.5.1.3, S.5.2.2A.
Abbreviations: CI: confidence interval, CR: complete response, DOR: duration of response, NR: not reached, ORR: 
objective response rate, OS: overall survival, PFS: progression-free survival, PR: partial response, SD: stable disease
Nivolumab monotherapy has demonstrated to have significant survival benefit with a more 
favorable safety profile compared to docetaxel in 2 recently completed Phase III NSCLC second-
line studies (CA209017 for squamous NSCLC and CA209057 for non squamous NSCLC).26
These data suggested that nivolumab monotherapy induced substantial durable disease control in
(heavily) pretreated subjects with advanced solid tumors.
Thus, the study design and target 
population in this Phase 1 trial is to determine the safety, tolerability and pharmacokinetics of 
nivolumab monotherapy in Chinese subjects with advanced or recurrent solid tumors.
1.1.2
Rationale for schedule and dose selection in dose evaluation phase
In CA209003/MDX1106-03 study, nivolumab was administered every 2 weeks at doses of 0.1,
0.3, 1, 3 and 10 mg/kg. For melanoma and RCC, there was no apparent dose-response effect, 
whereas in NSCLC, nivolumab at ≥3mg/kg yielded greater responses than at 1mg/kg. The data 
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indicates that anti-tumor activity observed in NSCLC appeared to approach a plateau (see Table 
1.1.2-1). Consistent with these observations, the results of exposure-response analyses showed 
that the probability of a tumor response tended to approach a plateau for trough concentrations 
produced by 3 and 10 mg/kg administered every 2 weeks.
Table 1.1.2-1:
Objective Response Rate per RECIST 1.0 and Progression Free 
Survival 24 Weeks Rate by Histology in Non-small Cell Lung Cancer 
Subjects - MDX1106-03
Dose
(mg/kg)
N
Histology
ORR
No. of 
Subjects (%)
95% CI of 
ORR
PFSR at 24 
weeks (%)
95% CI of 
PFSR
All NSCLC
129
NA
22(17)
11 - 25
34
25 - 42
1.0
15
SQ
0
0
36
11-61
18
NSQ
1(6)
0.1 - 27
19
0-39
3.0
18
SQ
4(22)
6-48
45
21-70
19
NSQ
5(26)
9-51
42
20-64
10.0
21
SQ
5(24)
8-47
45
23-67
37
NSQ
7(19)
8-35
25
11-39
Abbreviations: CI: confidence interval, NA: not applicable, NOS: not otherwise specified; NSCLC: non-small cell 
lung cancer; NSQ: non-squamous, ORR: objective response rate; PFSR: progression free survival rate, SQ: 
squamous
Source: Preliminary data, MDX1106-03. Clinical cut-off date 18-Mar-2013.
Also, the safety profile of nivolumab as a single agent is consistent across completed and 
ongoing clinical trials with no maximum tolerated dose (MTD) reached at any dose tested up to 
10mg/kg. There is no apparent dose-related toxicity pattern in terms of incidence, severity and 
drug-related AEs and drug-related SAEs. Please refer to the most current version of the 
BMS-936558 Investigators Brochure (IB).
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Based on the safety and anti-tumor activity in western and Japanese subjects, nivolumab will be 
administered every 2 weeks with a starting dose of 3 mg/kg in Study CA209077.
1.1.3
Rational for flat dose in cohort expansion phase
The safety and efficacy of 240 mg Q2W flat dose of nivolumab is expected to be similar to 3 
mg/kg Q2W dosing regimen. Across the various tumor types in the clinical program, nivolumab 
has been shown to be safe and well tolerated up to a dose level of 10 mg/kg, and the relationship 
between nivolumab exposure produced by 3 mg/kg and efficacy and safety has been found to be 
relatively flat. Given the similarity of nivolumab PK across tumor types and the similar 
exposures predicted following administration of 240 mg flat dose compared to 3 mg/kg, it is 
expected that the safety and efficacy profile of 240 mg nivolumab will be similar to that of 3 
mg/kg nivolumab. Hence, a flat dose of 240 mg nivolumab is under investigation in nivolumab 
global program.
The nivolumab dose of 240 mg every 2 weeks (Q2W) was selected based on clinical data and 
modeling and simulation approaches using population PK (PPK) and exposure-response analyses
of data from studies in multiple tumor types (melanoma, non-small-cell lung cancer [NSCLC],
and renal cell carcinoma [RCC]) where body weight normalized dosing (mg/kg) has been used.
PPK analyses have shown that the PK of nivolumab is linear with proportional exposure over a
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dose range of 0.1 to 10 mg/kg, and no differences in PK across ethnicities and tumor types were
observed. Nivolumab clearance and volume of distribution were found to increase as the body
weight increases, but less than the proportional with increasing weight, indicating that mg/kg
dosing represents an over-adjustment for the effect of body weight on nivolumab PK. The PPK
model previously developed using data from NSCLC subjects has recently been updated, using
data from 1544 subjects from 7 studies investigating nivolumab in the treatment of melanoma,
NSCLC, and RCC. In this dataset, the median (minimum - maximum) weight was 77 kg (35 kg -
160 kg) and thus, an approximately equivalent dose of 3 mg/kg for an 80 kg subject, nivolumab 
240 mg Q2W was selected for future studies. To predict relevant summary exposures of 
nivolumab 240 mg Q2W, the PPK model was used to simulate 100 virtual trials, each consisting 
of two arms, nivolumab 3 mg/kg Q2W and 240 mg Q2W. In the simulations, the simulated 
patient populations consisted of 1000 subjects per treatment arm randomly sampled from 
aforementioned pooled database of cancer patients. Because no differences in PK were noted 
across ethnicities and tumor types, these simulated melanoma and NSCLC data will be
applicable to patients with other tumor types. The simulated measure of exposure of interest,
time-averaged concentrations (Cavgss) for 240 mg Q2W are predicted to be similar for all
subjects in reference to 80 kg subjects receiving 3 mg/kg Q2W. In the range of 50 to 70 kg, the
exposures following 240 mg Q2W are predicted to be approximately 16.8% greater for those
subjects in comparison to the 3 mg/kg, 80 kg reference group. Two more flat dosing regimens, 
nivolumab 360 mg Q3W and 480 mg Q4W, will be investigated in this protocol to further 
explore a convenient dosing regimen for nivolumab monotherapy and in combination with other 
therapies. As the PK of nivolumab is linear, 360 mg Q3W and 480 mg Q4W dosing regimens are 
predicted to provide Cavgss similar to 3 mg/kg or 240 mg Q2W. However, these two regimens 
are expected to result in higher Cmax (up to approximately 20%), and lower Cminss (up to 
approximately 10%) compared to 3 mg/kg Q2W. Given that nivolumab was adequately tolerated 
up to 10 mg/kg, and the exposure-response relationship for safety is flat, a slight increase in 
Cmaxss is not expected to increase the safety risk of nivolumab. A marginal decrease in Cminss
is also not expected to reduce the efficacy as high trough concentrations and > 90% PD-1
receptor occupancy are still maintained. Thus, Nivolumab 360 mg Q3W and 480 mg Q4W are
expected to have similar efficacy and safety profile to nivolumab 3 mg/kg Q2W, and these two 
regimens are currently under investigation in nivolumab program as well.
1.1.4
Rationale for Shorter Infusion Times
Long infusion times place a burden on patients and treatment centers. Establishing that 
nivolumab can be safely administered using shorter infusion times of 30 minutes duration in 
subjects will diminish the burden provided no change in safety profile.
Previous clinical studies show that nivolumab has been administered safely over 60 minutes at 
doses ranging up to 10 mg/kg over long treatment duration. In Study CA209010, (a Phase 2, 
randomized, 
double 
blinded, 
dose-ranging 
study 
of 
nivolumab 
in 
subjects 
with 
advanced/metastatic clear cell RCC) a dose association was observed for infusion site reactions 
and hypersensitivity reactions (1.7% at 0.3 mg/kg, 3.7% at 2 mg/kg and 18.5% at 10 mg/kg). All 
the events were grade 1-2 and were manageable. Assuming ~60kg body weight on average in 
Revised Protocol No.: 06
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Clinical Protocol
CA209077
BMS-936558
nivolumab
Chinese subjects, therefore, 240mg (~4mg/kg), 360(~6mg/kg), 480(~8mg/kg) would be all 
within the exposure range of 10mg/kg (safe up to 20mg/kg in Japan ph1), thus additional safety 
concern is not expected. Preliminary analysis from CA209153 demonstrated that nivolumab 3
mg/kg can be safely infused over 30 min. The safety profile of 30 min infusion (N=322) is 
comparable to that of 60 min infusion (N=355), with a similar incidence of infusion-related 
reactions (3% vs. 2%, respectively).  Grade 3/4 reactions were rare (less 1% for both) in both 
cases. Therefore, an infusion duration of 30 minutes for 3 mg/kg, 240 mg, 360 mg, and 480 mg 
is not expected to present any safety concerns compared to the prior experience at 10 mg/kg 
nivolumab dose infused over a 60 minute duration.
Overall, infusion reactions including high-grade hypersensitivity reactions have been uncommon 
across nivolumab clinical studies. A change in safety profile is not anticipated with 30-minute 
infusion of nivolumab.
1.1.5
Rationale for Nivolumab Treatment Beyond Progression
Accumulating evidence indicates a minority of subjects treated with immunotherapy may derive 
clinical benefit despite initial evidence of progression of disease (by conventional response 
criteria) before demonstrating clinical objective responses and/or stable disease. 27 This 
phenomenon was observed in approximately 10% of subjects in the Phase I study of nivolumab.  
Two hypotheses have been put forth to explain this phenomenon. First, enhanced inflammation 
within tumors could lead to an increase in tumor size which would appear as enlarged index 
lesions and as new lesions. Over time, both the malignant and inflammatory portions of the mass 
may then decrease leading to overt signs of radiographic improvement. Alternatively, in some 
individuals, the kinetics of tumor growth may initially outpace anti-tumor immune activity. With 
sufficient time, the anti-tumor activity will dominate and become radiographic apparent. 
Therefore subjects will be allowed to continue study therapy after initial investigator-assessed 
RECIST 1.1 defined progression if they are assessed to be deriving clinical benefit and tolerating 
study drug (Section 4.3.2.5). Such subjects must discontinue study therapy upon evidence of 
further progression in subsequent radiographic evaluation.
1.2
Research Hypothesis 
There is no formal primary research hypothesis for this study to be statistically tested. 
1.3
Objectives
1.3.1
Primary Objective
To characterize the safety, tolerability, and dose limiting-toxicities (DLTs) of nivolumab in 
Chinese subjects with previously treated advanced or recurrent solid tumors.  
1.3.2
Secondary Objectives
•
To characterize the pharmacokinetics (PK) of nivolumab in Chinese subjects;
•
To assess the immunogenicity of nivolumab in Chinese subjects;
•
To assess preliminary anti-tumor activity of nivolumab in Chinese subjects. 
Revised Protocol No.: 06
Date: 15-Aug-2018
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CA209077
BMS-936558
nivolumab
1.4
Product Development Background
1.4.1
Pharmacology
The ability of nivolumab to bind to PD-1 was determined using Biacore and ELISA as well as 
FACS and Scatchard analysis to PD-1+ transfectants and activated T cells. Nivolumab binds to 
PD-1 with high affinity (EC50 0.39-2.62 nM), and inhibit the binding of PD-1 to its ligands 
PD-L1 and PD-L2. Nivolumab binds specifically to PD-1 and not to related members of the 
CD28 family such as CD28, ICOS, CTLA-4 and BTLA. 
Nivolumab was shown to promote the proliferation of human T cells in a variety of assays.
Detailed information can be found in the current version of the BMS-936558 IB.
1.4.2
Toxicity
Detailed information can be found in the current version of the BMS-936558 IB.
1.4.3
Preclinical Metabolism and Pharmacokinetics
In accordance with regulatory guidelines for biotechnology-derived pharmaceuticals, no 
metabolism studies with nivolumab have been conducted in animals. The expected in vivo 
degradation of mAbs is to small peptides and amino acids via biochemical pathways that are 
independent of cytochrome P450 enzymes.
The apparent elimination half-life (T-HALF) of nivolumab at 1 mg/kg in Cynomolgus monkey
estimates was 124 to 139 hours. The T-HALF estimate at 10 mg/kg for was 261 hours, but the 
data were variable (SD=200 hours). Consistent with the long T-HALF, total serum clearance was 
low.  Systemic exposure to nivolumab increased in an approximately dose-proportional manner.
Detailed information can be found in the current version of the BMS-936558 IB.
1.4.4
Clinical Pharmacology and Safety
1.4.4.1
Pharmacokinetics of Nivolumab
Single dose PK of nivolumab was evaluated in subjects with multiple tumor types in CA209001, 
whereas multiple doses PK were being evaluated in subjects in CA209003/MDX1106-03. In 
addition, a preliminary population pharmacokinetic (PPK) model has been developed with data 
from about 350 subjects from MDX1106-01, MDX1106-02, and CA209003/MDX1106-03. 
Single dose PK of nivolumab was evaluated in 39 subjects with multiple tumor types in study 
CA209001 in the dose range of 0.3 to 10 mg/kg.  The median Tmax across single doses ranged 
from 1.6 to 3 hours with individual values ranging from 0.9 to 7 hours.  The PK of nivolumab is 
linear in the range of 0.3 to 10 mg/kg with dose-proportional increase in Cmax and AUC(INF) 
with low to moderate inter-subject variability observed at each dose level (i.e., CV ranging from 
7 to 45%).  Geometric mean clearance (CL) after a single intravenous (IV) dose ranged from 
0.13 to 0.19 mL/h/kg, while mean volume of distribution (Vz) varied between 83 to 113 mL/kg 
Revised Protocol No.: 06
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CA209077
BMS-936558
nivolumab
across doses.  The mean terminal T-HALF of nivolumab is 17 to 25 days, which is consistent 
with half-life of endogenous IgG4, indicating that the elimination mechanism of nivolumab may 
be similar to IgG4.  Both elimination and distribution of nivolumab appear to be independent of 
dose in the dose range studied. Additional details are provided in the current version of the IB. 
A preliminary PPK model was developed by nonlinear mixed effect modeling using data from 
350 subjects from MDX1106-01, MDX1106-02 and CA209003/MDX1106-03. The body weight 
normalized dosing produces approximately constant trough concentrations over a wide range of 
body weights, and hence is appropriate for future clinical trials of nivolumab.
1.4.4.2
Safety Summary
CA209003/MDX1106-03 was a Phase 1 multi-dose escalation study in subjects with previously 
treated advanced or metastatic melanoma, RCC, NSCLC, colorectal cancer, or hormone-
refractory prostate cancer. In CA209003/MDX1106-03, subjects were administered nivolumab 
intravenously every 2 weeks with doses of 0.1, 0.3, 1, 3, or 10 mg/kg.
No MTD was identified in CA209003/MDX1106-03. The maximum dose level evaluated was 
10 mg/kg. The incidence, severity and relationship of AEs were generally similar across dose 
levels and tumor types.
As of the clinical cut-off date (3-July-2012), 296 (97.4%) out of 304 subjects treated by 
nivolumab had at least 1 reported AE regardless of causality. There was no pattern in the 
incidence, severity or relationship of AEs to the nivolumab dose level. Treatment-related AEs of 
any grade occurred in 220 (72.4%) of subjects. The most frequent drug-related AEs occurring in 
≥ 5% of subjects included: fatigue (25.7%), rash (13.5%), diarrhea (11.8%), pruritus (10.2%), 
nausea (7.9%), decreased appetite (7.9%), hemoglobin decreased (5.9%) and pyrexia (5.3%). 
Most treatment related AEs were low grade (Grade 1-2). Treatment related high-grade 
(Grade 3-4) AEs were reported in 45 (14.8%) of subjects, with the most common being fatigue 
(1.6%), decreased appetite (1.0%) and diarrhea (1.0%). At least one SAE was reported for 
150 (49.3%) of the 304 subjects at all dose levels. Grade 3-4 SAEs were reported for 23 subjects 
(7.6%). Drug-related serious adverse events (SAEs) occurred in 11.5% of subjects.  Grade 3-4 
drug-related SAEs reported in at least 2 subjects included diarrhea:  3 subjects (1.0%), 
pneumonitis: 3 subjects (1.0%), pneumonia: 2 subjects (0.7%) and lipase increased: 2 subjects 
(0.7%). Similar to the overall AE profile, there was no apparent relationship in the incidence or 
severity of drug-related AEs to nivolumab dose level. There were no apparent differences in the 
frequency of AEs based on subjects’ tumor type. 
Additional select treatment-related AEs have occurred with low frequency (< 5%) but are 
considered clinically meaningful, as they require greater vigilance for early recognition and 
prompt intervention. These AEs include:  alanine aminotransferase (ALT) increased (4.3%), 
aspartate aminotransferase (AST) increased (3.6%), pneumonitis (3.3%), hypothyroidism (3.0%), 
hyperthyroidism (1.3%), adrenal insufficiency (0.7%) and colitis (0.7%).  Grade 3-4 events of 
pneumonitis were reported in 3 subjects (1.0%) as described above (1 event was Grade 4).  
Grade 3 events of colitis, ALT increased and AST increased were reported in 2 subjects (0.7%) 
each. Grade 3 events of adrenal insufficiency, hyperthyroidism and hypothyroidism were 
Revised Protocol No.: 06
Date: 15-Aug-2018
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Cli nical Pr ot oc ol
C A 2 0 9 0 7 7
B M S- 9 3 6 5 5 8
ni v ol u ma b
re p orte d  i n  o ne  s u bject  ( 0. 3 %)  eac h.  Beca use  of  t he  p ote ntial  for  cli nicall y mea ni n gf ul 
ni v ol u ma b  relate d  A Es  re q uiri n g  earl y  rec o g niti o n  a n d  pr o m pt  i n t er ve nti o n,  ma na ge me nt 
al g orit h ms ha ve bee n de vel o pe d f or s us p ecte d p ul m o nar y t o xicit y, diarr hea or s us pecte d c olitis, 
he pat ot o xicit y,  e n d ocri n o pat h y  a n d  ne p hr ot o xicit y  ( A p pe n di x  1 ).  T hese  al g orit h ms  are  u p date d 
re g ularl y a n d are, t heref ore, c o ntai ne d wit hi n t he m ost rece nt versi o n of t he B M S- 9 3 6 5 5 8 I B.
Treat me nt-relate d A Es lea di n g t o dis c o nti n uati o n were re p orte d i n 1 8 ( 5. 9 %) of t he 3 0 4 treate d 
s u bjects  o n  C A 2 0 9 0 0 3/ M D X 1 1 0 6- 0 3.  T he  o nl y  e ve nts  re p orte d  i n  m o re  t ha n  o ne  s u bject  were 
p ne u m o nitis:  4  s u bjects  ( 1. 3 %)  a n d  he patitis:  2  s u bjects  ( 0. 7 %) .  T here  were  3  ( 1. 0 %) 
dr u g-relate d deat hs; eac h occ urre d after t he de vel o p me nt of p ne u m o nitis.
I n  C A 2 0 9 0 6 3  ( P hase II  si n gle  ar m  st u d y  wit h  1 1 7  s q ua m o us  N S C L C patie nts  faile d  at  le ast  2 
pri or re gi me ns), se ve nt y-f o ur perce nta ges of patie nts re p orte d a treat me nt-relate d  a d verse e ve nt 
of  a n y  gra de;  m ost  c o m m o nl y,  fati g ue  ( 3 3 %),  decrease d  a p petit e ( 1 9 %),  a n d  na usea  ( 1 5 %). 
Gra de  3  ~  4  treat me nt-r elate d  a d verse  e ve nts  o cc urre d  i n  2 0  of 1 1 7  ( 1 7 %)  of  patie nts,  m ost 
c o m m o nl y fati g ue ( 4 %), p ne u m o nitis ( 3 %), a n d diarr h oea ( 3 %). M o st treat me nt-relate d i m m u ne 
me diate d a d verse e ve nts were of l o w gra de, wit h s ki n dis or ders ( 1 5 %) a n d gastr oi ntesti nal e ve nts 
( 1 0 %)  m ost pre vale nt.  Ni v ol u ma b  has  a  ma na gea ble  safet y  pr ofile i n  pre vi o usl y  treate d 
a d va nce d s q ua m o us N S C L C. 2 8
I n C A 2 0 9 0 1 7 ( P hase III ra n d o mize d st u d y wit h 2 7 2 s q ua m o us N S C L C patie nts faile d fr o m o ne 
plati n u m  d o u blet  c he m ot hera p y),  treat me nt-r elate d  a d verse  e ve nt s,  i ncl u di n g  b ot h  he mat ol o gic 
a n d n o n he mat ol o gic t o xic e ve nts, occ urre d less  fr e q ue ntl y wit h ni v ol u ma b t ha n wit h d oceta xel. 
I n t he ni v ol u ma b gr o u p, 5 8 % of t he patie nts ha d e ve nts of a n y gra de, 7 % ha d e ve nts of Gra de 3 
or 4, a n d n o ne ha d Gra de 5 e ve nts; i n t he d oceta xel gr o u p, 8 6 % of t he patie nts ha d e ve nts of a n y 
gra de,  5 5 %  ha d  e ve nts  of  Gra de  3 or  4,  a n d  2 %  ha d  e ve nts  of  Gra de  5.  T he  m ost  fre q ue ntl y 
re p orte d treat me nt-r elate d a d verse e ve nts wit h ni v ol u ma b were fati g ue ( 1 6 %), decrease d a p petite 
( 1 1 %),  a n d  ast he nia  ( 1 0 %);  d oceta xel-treate d   patie nts  m ost  fre que ntl y  ha d  ne utr o pe nia  ( 3 3 %), 
fati g ue  ( 3 3 %),  al opecia ( 2 2 %),  a n d  na usea  ( 2 3 %).  T he  m ost  fre q ue ntl y  re p orte d  (i n  
3 % of
patie nts)  treat me nt-r elate d  select  a d verse  e v e nts  of  a n y  gra de were  h y p ot h yr oi dis m  ( 4 %  wit h 
ni v ol u ma b vs. 0 % wit h d oceta xel), diarr hea ( 8 % vs. 2 0 %), p ne u m o nitis ( 5 % vs. 0 %), i ncrease d 
bl o o d creati ni ne le vel ( 3 % vs. 2 %), a n d ras h ( 4 % vs. 6 %). 2 9
I n C A 2 0 9 0 5 7 ( P hase III ra n d omize d st u d y wit h  5 8 2 n o n-s q ua m o us N S C L C patie nts faile d fr o m 
o ne plati n u m d o u blet c he m ot hera p y ), t he safet y pr ofile of ni v olu ma b was fa v ora ble vs. d oceta xel 
a n d  c o nsiste nt  wit h  pri or  st u dies.  Gra de  3 ~ 5  dr u g-relate d  A Es  o cc urre d  i n  1 0. 5 %  ( 3 0/ 2 8 7)  of 
ni v ol u ma b a n d 5 3. 7 % ( 1 4 4/ 2 6 8) of d oceta xel patie nts. N o deat hs were relate d t o ni v ol u ma b vs 1 
d oceta xel-relate d  deat h  ( d ue  t o  gra de   4  fe brile  ne utr o pe nia).  The  m ost  fre q ue ntl y  re p orte d 
treat me nt-relate d a d verse e ve nts of a n y gra de wit h ni v ol u ma b were fati g ue ( 1 6 %), na usea ( 1 2 %), 
decrease d  a p petit e  ( 1 1 %),  a n d  ast he nia  ( 1 0 %).  D o ceta xel-r elate d  patie nts  m ost   fre q ue ntl y  ha d 
ne utr o pe nia ( 3 1 %), fati g ue  ( 2 9 %), na usea ( 2 6 %), al o pecia ( 2 5 %), a n d diarr hea ( 2 3 %). T he m ost 
fre q ue ntl y re p orte d treat me nt-r elate d select a d verse e ve nts of a n y gra de were h y p ot h yr oi dis m ( 7 % 
wit h  ni v ol u ma b  vs.  0 %  wit h  d oceta xel),  diarr h ea  ( 8 %  vs.  2 3 %),  A L T  i ncrease d   ( 3 %  vs.  1 %), 
A S T i ncrease d ( 3 % vs. 1 %), p ne u m o nitis ( 3 % vs. < 1 %), a n d ras h ( 9 % vs. 3 %).3 0
Re vise d Pr ot oc ol N o.: 0 6
Date: 1 5- A u g- 2 0 1 8
2 9
A p p r o v e d 
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Clinical Protocol
CA209077
BMS-936558
nivolumab
Preliminary new non-clinical safety findings of adverse pregnancy outcomes and infant losses in 
the absence of overt maternal toxicity have been reported.31 The findings of increased late stage 
pregnancy loss and early infant deaths/euthanasia in nivolumab exposed pregnant monkeys 
suggest a potential risk to human pregnancy if there is continued treatment with nivolumab 
during pregnancy.
Additional details on the safety profile of nivolumab, including results from other clinical studies, 
are available in the most recent version of the BMS-936558 IB.
Revised Protocol No.: 06
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CA209077
BMS-936558
nivolumab
1.4.5
Clinical efficacy in Selected Tumor Types
Six clinical studies contributed to the clinical experience with nivolumab in subjects with 
NSCLC: 
•
CA209001 is a Phase I single-dose escalation study in subjects (N = 39) with previously 
treated advanced or metastatic cancer. Subjects received a single dose of nivolumab at 0.3, 1, 
3, or 10 mg/kg with an option for re-treatment at 3 months. 
•
CA209003 is a Phase I/II open-label, multiple doses escalation study in subjects with select 
previously treated advanced solid tumors, including melanoma, RCC, NSCLC (squamous 
and non-squamous), colorectal cancer, and hormone-refractory prostate cancer. Subjects 
received nivolumab at doses of 0.1, 0.3, 1, 3 or 10 mg/kg intravenously every 2 weeks, up to 
a maximum of 2 years of total therapy. As of data cutoff date (04-Feb-2013), 306 subjects 
were treated in CA209003, including 129 NSCLC subjects.
•
CA209012 is a multi-arm Phase I safety study of nivolumab in combination with 
gemcitabine/cisplatin, 
pemetrexed/cisplatin, 
carboplatin/paclitaxel, 
bevacizumab 
maintenance, erlotinib, ipilimumab or as monotherapy in subjects with Stage IIIB/IV 
NSCLC.
•
CA209063 is a Phase II single arm study in squamous NSCLC subjects (N = 117) who had 
failed from two or more previous treatments received nivolumab 3 mg/kg every 2 weeks.  
•
CA209017 is an open-label randomized Phase III study of nivolumab monotherapy (3 mg/kg) 
versus docetaxel for advanced squamous NSCLC patients with disease progression during or 
after one prior platinum doublet chemotherapy, 272 subjects were randomized.
•
CA209057 is an open-label randomized Phase III study of nivolumab monotherapy (3 mg/kg) 
versus docetaxel for advanced non-squamous NSCLC patients with disease progression 
during or after one prior platinum doublet chemotherapy, 582 subjects were randomized.   
In summary, Nivolumab has demonstrated durable responses as monotherapy in NSCLC. 
Nivolumab as monotherapy demonstrated a statistically significant improvement in OS as 
compared with the current standard of care in previously treated subjects with advanced or 
metastatic NSCLC.
Detailed information in other selected tumor types can be found in the current version of the 
BMS-936558 IB.
1.5
Overall Risk/Benefit Assessment
Patients with advanced or refractory solid tumors have great unmet medical need. Nivolumab
monotherapy has encouraging anti-tumor activity (CR and PR) in Phase 1 studies in heavily 
pretreated advanced solid tumors (NSCLC, melanoma, RCC). The clinical activity of nivolumab
observed to date suggests the potential for improved outcome as monotherapy.
Nivolumab appears to have a manageable safety profile, which is consistent across completed 
and ongoing trials. The most common adverse events associated with nivolumab include 
development of adverse events, the most common of which are inflammatory in nature, 
Revised Protocol No.: 06
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CA209077
BMS-936558
nivolumab
consistent with nivolumab’s mechanism of action.  Most adverse events were low-grade 
(Grade 1 to Grade 2) with few high-grade adverse events. Most high-grade adverse events were 
manageable with the use of corticosteroid and hormone-replacement therapy. Nevertheless, these
safety data were established in a population mainly of Caucasians. Therefore, it is possible that 
Chinese subjects may experience unanticipated adverse events. This protocol has been designed 
to minimize overall risk to participating subjects. Adverse events will be reviewed expeditiously 
by the medical monitor and discussed with the study investigators. Also, there are detailed 
management guidelines for adverse events listed in the protocol.
The potential direct benefit to subjects who participate in this study is that therapy with 
nivolumab may result in stable disease, partial response or complete response, thus suggesting an 
acceptable risk to benefit ratio.
2
ETHICAL CONSIDERATIONS
2.1
Good Clinical Practice
This study will be conducted in accordance with Good Clinical Practice (GCP), as defined by the 
International Conference on Harmonisation (ICH) and in accordance with the ethical principles 
underlying European Union Directive 2001/20/EC and the United States Code of Federal 
Regulations, Title 21, Part 50 (21CFR50).
The study will be conducted in compliance with the protocol. The protocol and any amendments 
and the subject informed consent will receive Institutional Review Board/Independent Ethics 
Committee (IRB/IEC) approval/favorable opinion prior to initiation of the study.
All potential serious breaches must be reported to Bristol-Myers Squibb (BMS) 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). 
2.2
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, subject 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 or BMS 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.: 06
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Clinical Protocol
CA209077
BMS-936558
nivolumab
2.3
Informed Consent
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 subject volunteers to participate. 
BMS 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:
1) Provide a copy of the consent form and written information about the study in the language 
in which the subject is most proficient prior to clinical study participation. The language 
must be non-technical and easily understood. 
2) Allow time necessary for subject or subject's legally acceptable representative to inquire 
about the details of the study.
3) Obtain an informed consent signed and personally dated by the subject or the subject's 
legally acceptable representative and by the person who conducted the informed consent 
discussion. 
4) 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.
5) If informed consent is initially given by a subject’s legally acceptable representative or legal 
guardian, and the subject subsequently becomes capable of making and communicating his 
or her informed consent during the study, consent must additionally be obtained from the 
subject.
6) Revise the informed consent whenever important new information becomes available that is 
relevant to the subject's consent. The investigator, or a person designated by the investigator,
should fully inform the subject or the subject's legally acceptable representative or legal 
guardian, of all pertinent aspects of the study and of any new information relevant to the 
subject'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.
The consent form must also include a statement that BMS and regulatory authorities have direct 
access to subject records. 
The rights, safety, and well-being of the study subjects are the most important considerations and 
should prevail over interests of science and society.
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3
INVESTIGATIONAL PLAN
3.1
Study Design and Duration
This is a Phase 1/2 open-label study of nivolumab monotherapy in Chinese subjects with
previously treated advanced or recurrent solid tumor. Nivolumab is a fully human monoclonal 
IgG4 antibody, targeting the programmed death-1 (PD-1) membrane receptor on T-lymphocytes 
and other cells of the immune system.
The study will consist of 3 periods: screening period (up to 28 days); treatment period (until 
disease progression or intolerable toxicities); follow-up period (up to 100 days). In dose 
evaluation phase, each treatment cycle is comprised of 4 doses of assigned study drug (see Table 
3.1-1) administered at Days 1, 15, 29 and 43 with a response assessment between Days 49 to 56.
The response assessment must be completed before the first dose in the next cycle. In cohort 
expansion phase, the 3 mg/kg and 240 mg Q2W cohorts will be administered 4 doses in each 8-
week treatment cycle, the same as the dose evaluation treatment cycle. The response assessment 
must be completed before the first dose in the next cycle. The 360 mg Q3W cohort will be 
administered one dose of study drug in each 3-week treatment cycle. Tumor assessment must be 
completed every 6 weeks. The 480 mg Q4W cohort will be administered one doses of study drug 
in each 4-week treatment cycle. Tumor assessment must be completed every 8 weeks.
For subjects enrolled in dose evaluation phase, nivolumab is to be administered over 60 minutes. 
For subjects enrolled in cohort expansion phase, nivolumab is to be administered over 30 
minutes.
Every effort should be made to schedule visits within the timeframe stated in the protocol. In the 
case that the visits cannot be within the timeframe stated in protocol then the treatment period 
study procedures can be performed ± 2 days of the scheduled visit
Table 3.1-1:
Nivolumab Dose Levels 
Nivolumab Dose Level in Dose Evaluation Phase
Dose
1
3 mg/kg 
-1a
1 mg/kg 
Nivolumab Dose Level in Cohort Expansion Phase
Dose
3 mg/kg Q2W
3 mg/kg
240 mg Q2W
240 mg
360 mg Q3W
360 mg
480 mg Q4W
480 mg
a Dose level -1 will only be considered if the safety and tolerability profile for 3 mg/kg is evaluated as not 
acceptable.
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In 3 mg/kg cohort and 240 mg Q2W cohort, for the purpose of PK sample collection, subjects 
will be admitted to the clinical facility prior to dosing (Day -1) only for Cycle 1/Day 1 and Cycle 
3/Day 1 and will remain in the clinical facility until 24 hours after study drug administration. In 
360mg Q3W Cohort, for the purpose of PK sample collection, subjects will be admitted to the 
clinical facility prior to dosing (Day -1) only for Cycle 1/Day 1 and Cycle 6/Day 1 and will 
remain in the clinical facility until 24 hours after study drug administration. In 480mg Q4W 
Cohort, for the purpose of PK sample collection, subjects will be admitted to the clinical facility 
prior to dosing (Day -1) only for Cycle 1/Day 1 and Cycle 5/Day 1 and will remain in the clinical 
facility until 24 hours after study drug administration.
Collection of tumor tissue [archival or recent acquisition, formalin-fixed, paraffin-embedded 
(FFPE) tumor tissue block or unstained slides] for determination of PD-L1 expression status is 
highly encouraged. Recent biopsy tissue is preferred when available. Submission of archival 
tissue is also encouraged for all subjects, irrespective of whether recent biopsy tissue is available.  
This is not applicable to cohort D.
Physical examinations, vital sign measurements, 12-lead electrocardiograms (ECG), and clinical 
laboratory evaluations will be performed at selected times (see Time and Events Schedule Table 
5.1-1, Table 5.1-2, Table 5.1-3, and Table 5.1-4) throughout the dosing interval. Subjects will be 
closely monitored for AEs throughout the study. 
Approximately 350 mL of blood will be drawn from each subject during the study.
The expected maximum duration of a subject’s participation in the study (on-treatment and 
follow-up periods) is approximately 2.5 years.
•
maximum 28 days of screening,
•
maximum of 2 years of therapy,
•
approximately 100 days follow-up office visits.
The end of the trial will occur on the day of the last visit of the last subject.
The study design schematic is presented in Figure 3.1-1
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Figure 3.1-1:
Study Design Schematic
Dose Evaluation Phase
Cohort Expansion Phase
PD= progressive disease; AE= adverse event; 
3.1.1
Dose Evaluation Phase
Based on clinical experience with over 300 subjects on up to 2 years of treatment 
(CA209003/MDX1106-03), the recommended dose of nivolumab during the dose evaluation 
phase of the study is 3 mg/kg.  Dose limiting toxicity (DLT) observation period for each subject 
is defined as the 1st cycle of treatment (56 days following the first dose). Initially 6 eligible 
NSCLC subjects will be treated at the dose level of 3 mg/kg. An additional 3 NSCLC subjects 
may be added to the same dose level, and hence a total number of 6 or 9 subjects will be treated 
during the dose evaluation phase for a given dose level. A decision to enter cohort expansion 
phaseˈor to consider the next lower dose level (1 mg/kg) in dose evaluation phase will be 
guided by the number of subjects with DLTs observed during the dose evaluation phase (see 
Table 3.1.1-1).  Subjects who do not complete the DLT observation period for reasons other than 
DLTs will be replaced.  A dose level of 1 mg/kg may be considered if the safety and tolerability 
profile for 3 mg/kg is evaluated as not acceptable, after consultation and agreement between the 
Investigator(s) and the sponsor as well as review of the existing clinical safety database from 
earlier studies. Following a similar procedure, if the dose level of 1 mg/kg is evaluated as not 
acceptable as well, the findings will be discussed between the study investigators and the sponsor 
and an agreement will be reached as to whether a lower dose of nivolumab should be examined.
Safety monitoring during the dose evaluation phase will be based on the probability of the 
toxicity given the observed DLTs, with target toxicity of 0.25 (± 0.05).32 Guidance for safety 
monitoring after the toxicity outcomes observed is presented in Table 3.1.1-1, and the 
performance of the design is reported in Appendix 2.
PD, AE leading to discontinuation
Screening
28 days
Treatment: 8 wks/cycle 
Toxicity Follow-up 
100 days
PD, AE leading to discontinuation
Toxicity Follow-up 
100 days
Treatment: 8 wks/cycle 
or 3 wks/cycle
or 4 wks/cycle
Screening
28 days
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Table 3.1.1-1:
Guidance for Safety Monitoring Based on Observed 
Toxicity Outcomes during the Dose Evaluation 
Phase
Number of Subjects Treated
6
9
Number of Subjects 
with DLTs
0 
E 
E 
1 
S 
E 
2 
S 
E 
3 
D 
E 
4 
NA
D 
E: Expand to 56-64 subjects; S: Stay at the same dose level by treating additional 3 subjects; D: Discuss of 
proceeding with the next lower dose level.
3.1.2
Cohort Expansion Phase
If the safety and tolerability profile is established at the dose level of 3 mg/kg in the dose 
evaluation phase, then cohort expansion phase will be initiated, including:
•
Cohort A: Continue to accrue up to at least 12 - 20 subjects with solid tumors including but 
not limited to NSCLC at the dose level of 3 mg/kg;
•
Cohort B: Accrue 20 subjects with solid tumors (including but not limited to hepatocellular 
carcinoma, small cell lung cancer ) at the dose level of 240 mg (flat dose) Q2W;
•
Cohort C: Accrue up to 12 subjects with solid tumor (including but not limited to gastric 
cancer, NSCLC) at 360 mg (flat dose) Q3W;
•
Cohort D: Accrue up to 12 subjects with solid tumors at 480 mg (flat dose) Q4W.
Clinical safety monitoring of subjects during the cohort expansion phase will be performed. If in
a given dose level, the combined incidence exceeds 33% for study drug related toxicity requiring 
treatment discontinuation, then further enrollment to that dose level will be interrupted and a 
decision whether or not to continue dosing will be based on discussions of the observed 
aggregate (acute and chronic) toxicities between the Investigator(s) and the sponsor, if needed. 
An agreement will be reached as to whether a lower dose should be examined, or whether any 
additional treatment guidelines should be implemented prior to enrollment of additional subjects 
to that arm. Depending on preliminary efficacy data, certain tumor types may be expanded to 
collect additional efficacy data.
3.1.3
Administration of Additional Cycles
Tumor response will be evaluated using RECIST v1.1. In 3 mg/kg cohort and 240mg Q2W 
cohort, end of cycle tumor response assessment for all subjects will occur between Days 49 to 56 
(results of the assessments must be reviewed and documented before the first dose of next cycle).
In 360 mg Q3W cohort, tumor assessment must be completed every 6 weeks. In 480 mg Q4W 
cohort, tumor assessment must be completed every 8 weeks.
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Subjects will continue to receive nivolumab treatment until disease progression (or until 
discontinuation of study therapy in subjects receiving nivolumab beyond progression), 
discontinuation due to toxicity, withdrawal of consent. The maximum duration of study therapy 
to be administered to an individual subject in this study is 2 years.
3.1.4
Follow-up Period
•
Follow-up begins when decision to discontinue a subject from study therapy is made (no 
further treatment with nivolumab);
•
The first two follow-up visits (follow up #1 and follow up #2) include PK and 
immunogenicity samples. Follow up #1 = 30 days from last dose ±5 days; Follow up #2 = 
70 days from follow up #1 ± 5 days;
•
Subjects will be followed for study drug-related toxicities until resolve, return to baseline, 
or are deemed irreversible.
3.2
Post Study Access to Therapy
At the end of the treatment phase of the study, BMS will not continue to supply study drug to 
subjects/investigators unless BMS chooses to extend the study. The investigator should ensure 
that the subject receives appropriate standard of care to treat the condition under study.
3.3
Study Population
For entry into the study, the following criteria MUST be met prior to dosing on Day 1. No 
exceptions will be granted.
3.3.1
Inclusion Criteria
1. Signed Written Informed Consent
a) Subjects must have signed and dated an IRB/IEC approved written informed consent 
form in accordance with regulatory and institutional guidelines. This must be obtained 
before the performance of any protocol related procedures that are not part of normal 
subject care.
b) Subjects must be willing and able to comply with scheduled visits (including overnight 
stays), treatment schedule, laboratory tests and other requirements of the study.
c) Subject re-enrollment: This study permits the re-enrollment of a subject that has 
discontinued the study as a pre-treatment failure (i.e., subject has not been treated). If re-
enrolled, the subject must be re-consented. Obtain agreement from the Medical Monitor 
prior to re-enrolling a subject. 
2. Target Population
a) Chinese subjects with advanced or recurrent solid tumors:
i). histologically or cytologically confirmed
ii). must have failed at least one prior systemic therapy, OR well documented refusal of 
subjects to receive chemo or biological therapy.
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iii). must have at least 1 measurable lesion per Response Evaluation Criteria in Solid 
Tumors (RECIST v1.1) (Appendix 3)
b) Life expectancy ≥3 months.
c) Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1 
(Appendix 4).
d) Prior systemic cancer therapy must have been completed at least 4 weeks before the study 
drug administration, and all adverse events have been returned to baseline or stabilized.
e) Prior radiotherapy must have been completed at least 2 weeks before the study drug 
administration.
f)
Immunosuppressive doses of systemic medications, such as steroids (dose >10 mg/day 
prednisone or equivalent) must be discontinued at least 2 weeks before study drug 
administration.
g) Prior major surgery requiring general anesthesia must be completed at least 2 weeks 
before study drug administration. Surgery requiring regional/epidural anesthesia must be 
completed at least 72 hours before study drug administration and subjects must be 
recovered. Cutaneous biopsies with only local anesthesia should be completed at least 1 
hour prior to study drug administration.
h) Screening laboratory values must meet the following criteria:
i)
WBC ı2000/uL
ii) Neutrophils  ı1500/uL
iii) Platelets  ı 100 x 103/uL
iv) Hemoglobin ı9.0 g/dL
v) Creatinine ≤ 1.5 mg/dL or Creatinine Clearance > 40mL/min
vi) AST ≤ 3.0x ULN (AST ≤ 5.0x ULN in HCC patients)
vii)ALT ≤ 3.0x ULN (ALT ≤ 5.0x ULN in HCC patients)
viii)
Bilirubin ≤1.5 x ULN (except subjects with HCC or Gilbert Syndrome who must 
have total bilirubin < 3.0 mg/dL)
i)
Hepatocellular carcinoma (HCC) Subjects with the following specific inclusion criteria in 
addition: 
i)
Cirrhotic status of Child-Pugh Class A (Appendix 5)
ii) Subjects are eligible to enroll if they have non-viral-HCC, or if they have HBV-HCC, 
or HCV-HCC defined as follows:
•
HBV-HCC: Resolved HBV infection (as evidenced by detectable HBV surface 
antibody, detectable HBV core antibody, undetectable HBV DNA, and 
undetectable HBV surface antigen) or Chronic HBV infection (as evidenced by 
detectable HBV surface antigen or HBV DNA). Subjects with chronic HBV 
infection must have HBV DNA < 100 IU/mL and must be on antiviral therapy.
•
HCV-HCC: Active or resolved HCV infection as evidenced by detectable HCV 
RNA or antibody
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3. Age and Reproductive Status
a) Males and females ≥18 years of age.
b) 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 the study drug.
c) Women must not be breastfeeding.
d) WOCBP must agree to follow instructions for method(s) of contraception for the duration 
of treatment plus 5 half-lives of Nivolumab plus 30 days (duration of ovulatory cycle) for 
a total of 5 months post-treatment completion.
e) Males who are sexually active with WOCBP must agree to follow instructions for 
method(s) of contraception 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.
f)
Azoospermic males and WOCBP who are continuously not heterosexually active are 
exempt from contraceptive requirements. However they must still undergo pregnancy 
testing as described in this section.
Investigators shall counsel WOCBP and male subjects who are sexually active with WOCBP 
on the importance of pregnancy prevention and the implications of an unexpected pregnancy. 
Investigators shall advise WOCBP and male subjects who are sexually active with WOCBP 
on the use of highly effective methods of contraception. Highly effective methods of 
contraception have a failure rate of < 1% when used consistently and correctly.
At a minimum, subjects must agree to the use of one highly effective method listed below:
HIGHLY EFFECTIVE METHODS OF CONTRACEPTION
•
Hormonal methods of contraception including combined oral contraceptive pills, 
vaginal ring, injectables, implants and intrauterine devices (IUDs) such as 
Mirena® by WOCBP subject and male subject’s WOCBP partner. Female partners of 
male subjects participating in the study may use hormone based contraceptives as one 
of the acceptable methods of contraception since they will not be receiving study drug. 
•
Progestogen-only hormonal contraception associated with inhibition of ovulation
including oral and injectable
•
Nonhormonal IUDs, such as ParaGard®
•
Tubal ligation
•
Vasectomy
•
Complete Abstinence*
*Complete abstinence is defined as complete avoidance of heterosexual intercourse and 
is an acceptable form of contraception for all study drugs. Female subjects must continue 
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to have pregnancy tests. Acceptable alternate methods of highly effective contraception 
must be discussed in the event that the subject chooses to forego complete abstinence.
3.3.2
Exclusion Criteria
Subjects who fulfill any of the following criteria will not be eligible for admission to the study:
1. Target Disease Exceptions
a) Subjects with active central nervous system (CNS) metastases are excluded. Subjects are 
eligible if CNS metastases are adequately treated and subjects are neurologically returned 
to baseline (except for residual signs or symptoms related to the CNS treatment) for at 
least 2 weeks prior to enrollment. In addition, subjects must be either off corticosteroids, 
or on a stable or decreasing dose of ≤10 mg daily prednisone (or equivalent).
b) Subjects with carcinomatous meningitis.
2. Medical History and Concurrent Diseases
a) Prior malignancy active within the previous 3 years except for locally curable cancers 
that have been apparently cured, such as basal or squamous cell skin cancer, superficial 
bladder cancer, or carcinoma in situ of the prostate, cervix, or breast.
b) Subjects with active, known or suspected autoimmune disease. Subjects with vitiligo, 
type I diabetes mellitus, residual hypothyroidism due to autoimmune thyroiditis only
requiring hormone replacement, or conditions not expected to recur in the absence of an 
external trigger are permitted to enroll.
c) Prior treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2, , or anti-CTLA-4 antibody, or 
any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint 
pathways
d) Active Tuberculosis (TB) infection based on chest X-ray, sputum tests, and clinical 
examination. Subjects with a history of active TB infection within last 1 year are 
excluded, even if it was treated. Subjects with a history of active TB infection greater 
than 1 year ago are excluded unless there is documentation of adequate prior anti-TB 
treatment.
e) Known history of testing positive for human immunodeficiency virus (HIV) or known 
acquired immunodeficiency syndrome (AIDS).
f)
Concurrent medical condition requiring the use of immunosuppressive medications, or 
immunosuppressive doses of systemic or topical corticosteroids.
g) Use of other investigational drugs within 28 days or 5 half-lives (whichever is longer) 
before administration of study drug.
h) Participants who have received a live / attenuated vaccine within 30 days of first 
treatment.
i)
Pregnant or nursing.
j)
Inability to be venipunctured and/or tolerate venous access.
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k) Any other sound medical, psychiatric and/or social reason as determined by the 
investigator.
l)
Subjects with interstitial lung disease that is symptomatic or may interfere with the 
detection or management of suspected drug-related pulmonary toxicity.
m) Any use of systemic or topical corticosteroids at doses > 10 mg/day of prednisone or
equivalent within 2 weeks of study drug administration.
n) Any use of traditional medicinal herbal preparations within 2 weeks of study drug
administration.
o) HCC subjects with the following specific exclusion criteria in addition
i)
Any history of hepatic encephalopathy
ii) Any prior (within 1 year) or current clinically significant ascites as measured by 
physical examination and that requires active paracentesis for control
iii) Active coinfection with both hepatitis B and C
iv) Hepatitis D infection in subjects with hepatitis B
v) Prothrombin time (PT)-international normalized ratio (INR) ≤2.3 or Prothrombin 
time (PT) ≤6 seconds above control
3. Physical and Laboratory Test Findings
a) Underlying medical conditions that, in the Investigator’s opinion, will make the 
administration of study drug hazardous or obscure the interpretation of toxicity 
determination of adverse events.
b)
Any positive test result for hepatitis B virus or hepatitis C virus indicating presence of 
virus, e.g. Hepatitis B surface antigen (HBsAg) positive, or Hepatitis C antibody (anti-
HCV) positive (except if HCV-RNA negative).
c) Subjects with ≥Grade 2 peripheral neuropathy.
4. Allergies and Adverse Drug Reaction
a) History of severe hypersensitivity reactions to other monoclonal antibodies or related 
compounds.
b) History of any significant drug allergy (such as anaphylaxis) or hepatotoxicity.
5. Other Exclusion Criteria
a) Prisoners or subjects who are involuntarily incarcerated.
b) Subjects who are compulsorily detained for treatment of either a psychiatric or physical 
(e.g., infectious disease) illness.
c) Inability to comply with restrictions and prohibited activities/treatments as listed in 
Section 3.4.
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Eligibility criteria for this study have been carefully considered to ensure the safety of the study 
subjects and that the results of the study can be used. It is imperative that subjects fully meet all 
eligibility criteria.
3.3.3
Women of Childbearing Potential
WOCBP is defined as any female who has experienced menarche and who has not undergone 
surgical sterilization (hysterectomy or bilateral oophorectomy) or is not postmenopausal. 
Menopause is defined clinically as 12 months of amenorrhea in a woman over age 45 in the 
absence of other biological or physiological causes. In addition, women under the age of 55 must 
have a documented serum follicle stimulating hormone (FSH) level > 40mIU/mL to confirm 
menopause.
Women 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 
judgment in checking serum FSH levels. If the serum FSH level is >40 mIU/ml at any time 
during the washout period, the woman can be considered postmenopausal: 
•
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.
3.4
Concomitant Treatments
All medication administered during the 2 weeks preceding first study drug administration must 
be recorded in the case report form (CRF) including the name, start and if applicable stop date. 
Concomitant medication administered during the study must be recorded in the CRF including 
the generic name and start and end date of therapy. Any change in documented, concomitant 
medication must also be recorded.
3.4.1
Prohibited and/or Restricted Treatments
The following medications are prohibited during the study:
1) Any concurrent anti-cancer therapy ( chemotherapy, immunotherapy, biologics, extensive
radiotherapy, hormone therapy, target therapy, surgery), investigational or approved;
2) Immunosuppressive agents, unless they are utilized to treat an adverse event, and with the 
exception of those listed in Section 3.4.2.
3) Immunosuppressive doses of systemic corticosteroids (except as stated in the Section 3.4.2.1). 
4) Administration of concomitant medication (prescription, over-the-counter or traditional
herbal medicine) is prohibited, unless it is prescribed by the investigator for treatment of
specific clinical events.
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5) Any live / attenuated vaccine (eg varicella, zoster, yellow fever, rotavirus, oral polio and 
measles, mumps, rubella (MMR)) during treatment and until 100 days post last dose.
Bisphosphonates and RANK-L inhibitors are allowed for bone metastases if initiated prior to
signing informed consent form.
Palliative and supportive care for disease related symptoms may be offered to all subjects on 
study after dose evaluation period. Palliative (limit-field) radiation therapy is permitted for 
subjects who have investigator assessed clinical benefit following consultation with BMS 
medical monitor. Subjects should not receive study treatment during radiation and must meet 
eligibility criteria prior to resume treatment.
3.4.2
Other Restrictions and Precautions
3.4.2.1
Permitted Corticosteroid Therapy
Subjects are permitted the use of topical, ocular, intra-articular, intranasal and inhalational 
corticosteroids (with minimal systemic absorption). Physiologic replacement doses of systemic 
corticosteroids (i.e., prednisone ≤10 mg/day) are permitted. A brief course of corticosteroids for 
prophylaxis (e.g., contrast dye allergy) or for treatment of non-autoimmune conditions (e.g., 
delayed-type hypersensitivity reaction caused by a contact allergen) or for management of study 
drug-induced adverse events are permitted.
3.4.3
Antiviral therapy (HCC specific)
Subjects on antiviral therapy for hepatitis B or C should continue the treatment during the study.
Changing of dosage and regimens of antiviral therapy will be at the discretion of the investigator.
If a subject has a > 1 log IU/mL increase in HBV DNA, then virologic breakthrough should be
considered and HBV DNA confirmed. Adherence to current antiviral therapy should be assessed,
and resistance testing performed according to local practices. If a subject has documented
virologic breakthrough due to antiviral resistance, then this should be managed based on
standardized regional guidelines and treatment with nivolumab temporarily held. The subject
may resume treatment with nivolumab once virologic control is reestablished (HBV DNA < 100 
IU/mL).
For any subject who continues to be HCV RNA positive after receiving nivolumab, current
guidelines for management of chronic HCV infection, including those from AASLD, EASL, or
APASL may be consulted. Initiation of direct acting antivirals (DAAs) for HCV is allowed at the
discretion of the investigator after discussion with the BMS medical monitor.
3.5
Discontinuation of Subjects from Treatment
Subjects MUST discontinue investigational product (and non-investigational product at the 
discretion of the investigator) for any of the following reasons:
•
Subject’s request to stop study treatment;
•
Any clinical AE, laboratory abnormality or intercurrent illness which, in the opinion of 
the investigator, indicates that continued participation in the study is not in the best 
interest of the subject;
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•
Pregnancy;
•
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 (e.g., infectious disease) 
illness;
•
Inability to comply with protocol;
•
Disease progression or clinical deterioration (except treatment beyond progression; see 
Section 4.3.2.5);
•
Dose delay greater than the maximum allowed dosing delay (see Section 4.3.2.3);
•
Discretion of the investigator;
•
Any adverse event meeting discontinuation criteria (see Section 4.3.2.4).
*In the case of pregnancy, the investigator must immediately notify the BMS Medical 
Monitor/designee of this event. In most cases, the study drug will be permanently 
discontinued in an appropriate manner. If the investigator determines a possible favorable 
benefit/risk ratio that warrants continuation of study drug, a discussion between the 
investigator and the BMS Medical Monitor/designee must occur
All subjects who discontinue investigational product should comply with protocol specified 
follow-up procedures as outlined in Section 5. The only exception to this requirement is when a 
subject 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 drug is discontinued prior to the subject’s completion of the study, the reason for the 
discontinuation must be documented in the subject’s medical records and entered on the CRF 
page.
3.6
Post Study Treatment Follow up
Subjects who discontinue study treatment may continue to be followed.
3.6.1
Withdrawal of Consent
Subjects who request to discontinue study drug 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 
subject specifically withdraws consent for any further contact with him/her or persons previously 
authorized by subject to provide this information. Subjects 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 drug 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 subject 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.
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3.6.2
Lost to Follow-Up
All reasonable efforts must be made to locate subjects to determine and report their ongoing 
status. This includes follow-up with persons authorized by the subject as noted above. Lost to 
follow-up is defined by the inability to reach the subject after a minimum of three documented 
phone calls, faxes, or emails as well as lack of response by subject to one registered mail letter. 
All attempts should be documented in the subject’s medical records. If it is determined that the 
subject has died, the site will use permissible local methods to obtain the date and cause of death.
If investigator’s use of third-party representative to assist in the follow-up portion of the study 
has been included in the subject’s informed consent, then the investigator may use a Sponsor-
retained third-party representative to assist site staff with obtaining subject’s contact information 
or other public vital status data necessary to complete the follow-up portion of the study. If after 
all attempts, the subject remains lost to follow-up, then the last known alive date as determined 
by the investigator should be reported and documented in the subject’s medical records.
4
STUDY DRUG
Study drugs include both non-investigational (NIMP) and Investigational Medicinal Products 
(IMP) and can consist of the following:
•
All products, active or placebo, being tested or used as a comparator in a clinical trial; 
•
Study required premedication; 
•
Other drugs administered as part of the study that are critical to claims of efficacy (e.g., 
background therapy, rescue medications);
•
Diagnostic agents: (such as glucose for glucose challenge) given as part of the protocol 
requirements must also be included in the dosing data collection.
4.1
Study Treatments
BMS-936558 100 mg (10 mg/mL) will be packaged in an open-label fashion. Five (5) 
BMS-936558 10 mL vials will be packaged within a carton. The vials are not subject or 
treatment group specific although there will be specific vial assignments by subject distributed 
by the IVRS in order to track drug usage and re-supply.
Product description and storage information is described in Table 4.1-1.
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Table 4.1-1:
Product Description- Treatment Period
Product Description 
and Dosage Form
Potency
Primary Packaging
(Volume)/ Label Type
Secondary Packaging
(Qty) /Label Type
Appearance
Storage Conditions
(per label)
BMS-936558-01 
Solution for Injection
100 mg (10 mg/mL)
10 mL vial/ Open-label
5 vials per carton/ 
Open-label
Clear to opalescent 
colorless to pale yellow 
liquid. May contain 
particles
Store at 2 to 8°C. 
Protect from light and 
freezing
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nivolumab
4.1.1
Investigational Product
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.
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 subjects. The investigational product must be dispensed only from official study sites by 
authorized personnel according to local regulations. 
In this protocol, investigational product(s) is/are:  BMS-936558.
4.1.2
Non-investigational Product
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. 
In this protocol, non-investigational product(s) is/are:  Any medications used to treat infusion-
related reactions (Section 4.3.2.6).
4.1.3
Storage and Dispensing
The product storage manager should ensure that the study drug 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 drug arise, the study drug should not be 
dispensed and contact BMS immediately.
Investigational product documentation must be maintained that includes all processes required to 
ensure drug is accurately administered. This includes documentation of drug storage, 
administration and, as applicable, storage temperatures, reconstitution, and use of required 
processes (e.g., required diluents, administration sets).
For non-investigational product, if marketed product is utilized, it should be stored in accordance 
with the package insert, summary of product characteristics (SmPC), or similar.
Refer to the BMS-936558 IB and/or pharmacy instruction sheets for details related to handling 
and dose preparation.
The sites are responsible for procuring their own diluent, IV bags, filters, administration sets, etc.
4.2
Method of Assigning Subject Identification
CA209077 is an open-label study. After it has been determined that the subject meets all 
eligibility criteria of the study, the subject will be enrolled and a subject number will be assigned 
through an interactive voice response system (IVRS). Specific instructions and procedures for 
using IVRS will be provided to the investigational site in a separate document/ manual. The 
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investigator (or designee) will register the subject by following the enrollment procedures 
established by BMS. The following information is required for enrollment:
•
Date of informed consent
•
Date of birth
•
Gender at birth
Subjects will not be replaced if they are discontinued from the study secondary to an adverse 
event unless the adverse event can be determined to be unrelated to treatment. 
4.2.1
Management Algorithms for Immuno-Oncology Agents
Immuno-oncology (I-O) agents are associated with adverse events that can differ in severity and 
duration than adverse events caused by other therapeutic classes. Nivolumab is considered 
immuno-oncology agents in this protocol. Early recognition and management of adverse events 
associated with immuno-oncology agents may mitigate severe toxicity. Management algorithms 
have been developed to assist investigators in assessing and managing the following groups of 
adverse events: gastrointestinal, renal, pulmonary, pancreatitis, hepatic, endocrinopathies, skin 
and neurological. The management algorithms can be found in the Nivolumab investigator 
brochure and Appendix 1 of this protocol.
4.2.1.1
Protocol-specific Recommendations for Management of Hepatic Events 
in HCC Subjects
The nivolumab program has developed a standardized approach for the management of hepatic 
events based on cumulative data across the program in subjects with normal hepatic function. 
Across most nivolumab studies, the eligibility criteria for inclusion are based on a maximum 
AST or ALT < 3x ULN; therefore, only subjects with normal to grade 1 LFTs have been 
enrolled.
Subjects with advanced HCC generally have underlying cirrhosis with decreased hepatic 
function. They may also have a concomitant chronic viral infection. For HCC subjects to be 
potentially enrolled in this study, the upper limits for inclusion were therefore adjusted to 
account for baseline liver dysfunction. Subjects with AST or ALT elevations within the CTCAE 
Grade 2 range are eligible for inclusion. In contrast, the majority of subjects included in prior 
nivolumab studies have had no higher than a CTCAE grade 1 AST or ALT elevation. Therefore, 
this requires a protocol-specific approach for the management of hepatic events in HCC subjects,
outlined as follows:
•
Dose delay criteria for hepatic events are outlined in Appendix 1. If AST or ALT levels 
do not improve with a dose delay of 3-5 days or if the levels worsen, initiate steroid 
therapy at 0.5-2 mg/kg/day methylprednisolone or oral equivalent;
•
For ALT or AST levels > 8x ULN, initiate steroid therapy promptly at 1-2 mg/kg/day 
methylprednisolone or oral equivalent;
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•
For all subjects initiating steroids, consult the BMS Medical Monitor within 24 hours 
after initiation of steroids. Gastroenterology consult is recommended;
•
If AST or ALT levels do not improve within 3-5 days or the levels worsen after the start 
of steroid therapy, discuss with the BMS Medical Monitor the possibility of adding 
mycophenolate mofetil at 1 g BID;
•
Tapering of steroids can start once AST or ALT levels have declined by 1 CTCAE grade. 
Taper steroids slowly over no less than 1 month
As outlined in Section 4.3.2.3, nivolumab therapy may resume when AST or ALT have returned 
to near baseline unless the criteria for permanent discontinuation are reached (Section 4.3.2.4).
4.3
Selection and Timing of Dose for Each Subject
4.3.1
Dose-limiting Toxicities
Any event listed below, if occurring during Cycle 1 and related to nivolumab, is defined as a 
DLT. 
4.3.1.1
Hepatic DLT
•
ALT or AST > 5 and ≤10 ULN for > 2 weeks;
•
ALT or AST >10 ULN regardless of duration;
•
Total bilirubin > 5 ULN;
•
Concurrent ALT or AST > 3 ULN and total bilirubin > 2 ULN.
4.3.1.2
Non-hematologic DLT
z
Grade 2 drug-related uveitis or eye pain that does not respond to topical therapy and does 
not improve to Grade 1severity within the re-treatment period (14 days) or requires systemic 
treatment;
z
Grade 3 non-skin, drug-related adverse event with the following exceptions:
¾
Grade 3 endocrinopathy is not considered as DLT if well controlled with hormone 
replacement therapy;
¾
Grade 3 drug-related laboratory abnormalities without clinical sequelae are not 
considered as DLTs;
•
Grade 4 drug-related AEs, including laboratory abnormalities.
Note that isolated Grade 4 electrolyte imbalances/abnormalities that are not associated with 
clinical sequelae and are corrected with supplementation/appropriate management within 72 
hours of their onset will not be considered DLTs.
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BMS-936558
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4.3.1.3
Hematologic DLT
•
Grade 3 drug -related thrombocytopenia associated with bleeding;
•
Grade 3 drug-related febrile neutropenia;
•
Grade 4  drug-related neutropenia;
•
Grade 4 drug-related thrombocytopenia.
4.3.2
Dose Modification
4.3.2.1
Dose Adjustments
There will be no dose adjustment allowed for nivolumab except for weight change (10% or 
greater increase or decrease) at beginning of each cycle. 
4.3.2.2
Dose Delay Criteria
Nivolumab administration should be delayed for the following AEs:
•
Grade 2 non-skin, drug-related AE with the exception of fatigue.
•
Grade 2 drug-related creatinine, AST, ALT and/or Total Bilirubin abnormalities
•
Grade 3 skin, drug-related adverse event;
•
Grade 3 drug-related laboratory abnormalities, with the following exceptions:
−
Grade 3 lymphopenia does not require a dose delay
−
Grade ≥3 drug-related amylase or lipase abnormality that is not associated with 
symptoms or clinical manifestations of pancreatitis does not require dose delay. The 
BMS Medical Monitor should be consulted for such Grade ≥3 amylase or lipase 
abnormalities.
−
Grade ≥3 AST, ALT, Total Bilirubin will require dose discontinuation
−
If a subject has a baseline AST, ALT, or total bilirubin that is within normal limits, delay
dosing for drug-related Grade ≥2 toxicity
−
If a subject has baseline AST, ALT, or total bilirubin within the Grade 1 toxicity range,
delay dosing for drug-related Grade ≥3 toxicity
−
If a subject has baseline AST or ALT within the Grade 2 toxicity range, delay dosing for 
a two-fold drug-related increase in AST or ALT or for AST or ALT values 8x ULN 
(whichever is lower). (HCC patients specific)
•
Any adverse event, laboratory abnormality, or intercurrent illness which, in the judgment of 
the investigator, warrants delaying the dose of study medication.
Subjects who require delay of nivolumab should be re-evaluated weekly or more frequently if 
clinically indicated and resume nivolumab dosing when re-treatment criteria are met (section 
4.3.2.3).
4.3.2.3
Criteria to Resume Dosing
Subjects may resume treatment with nivolumab when the drug-related AE(s) resolve(s) to 
Grade ≤1 or baseline, with the following exceptions:
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•
Subjects may resume treatment in the presence of Grade 2 fatigue 
•
Subjects who have not experienced a Grade 3 drug-related skin AE may resume treatment in 
the presence of Grade 2 skin toxicity 
•
Subjects with baseline AST/ALT or total bilirubin in the Grade 1 toxicity range who require 
dose delays for reasons other than a 2-grade shift in AST/ALT or total bilirubin may resume 
treatment in the presence of Grade 2 AST/ALT OR total bilirubin
•
Subjects with combined Grade 2 AST/ALT AND total bilirubin values meeting 
discontinuation parameters (Section 4.3.2.4) should have treatment permanently 
discontinued
•
Subjects who require dose delays for drug-related elevations in AST, ALT, or total bilirubin 
may resume treatment when these values have returned to their baseline CTCAE Grade or 
normal, provided the criteria for permanent discontinuation are not met. (HCC patients 
specific)
•
Drug-related pulmonary toxicity, diarrhea, or colitis must have resolved to baseline before 
treatment is resumed. Subjects with persistent Grade 1 pneumonitis after completion of a 
steroid taper over at least 1 month may be eligible for retreatment if discussed with and 
approved by the BMS medical Monitor
•
Drug-related endocrinopathies adequately controlled with only physiologic hormone 
replacement may resume treatment after consultation with the BMS Medical Monitor
•
If treatment is delayed > 6 weeks, the subject must be permanently discontinued from study 
therapy, except as specified in Section 4.3.2.4.
4.3.2.4
Nivolumab Dose Discontinuation
Nivolumab treatment should be permanently discontinued for the following:
•
Any Grade ≥2 drug-related uveitis, eye pain or blurred vision that does not respond to 
topical therapy and does not improve to Grade 1 severity within the re-treatment period OR 
requires systemic treatment; 
•
Any ≥ Grade 3 non-skin, drug-related adverse event lasting > 7 days, with the following 
exceptions:
−
Grade 3 drug-related uveitis, pneumonitis, diarrhea, colitis, neurologic toxicity, 
bronchospasm, hypersensitivity reaction, or infusion reaction of any duration requires 
discontinuation.
−
Grade 3 drug-related laboratory abnormalities do not require treatment discontinuation 
except:
♦Grade 3 drug-related thrombocytopenia lasting > 7 days or associated with bleeding
requires discontinuation;
♦Any drug-related liver function test (LFT) abnormality that meets the following 
criteria require discontinuation (also see Hepatic Adverse Event Management 
algorithm): 
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BMS-936558
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•
AST or ALT > 5 -10x ULN for > 2 weeks
•
AST or ALT > 10x ULN
•
Total bilirubin > 5x ULN
•
Concurrent AST or ALT > 3x ULN and total bilirubin > 2x ULN
•
Exception: for HCC patients, hepatotoxicity as evidenced by the following:
−
AST or ALT > 10 x ULN for > 2 weeks,
−
AST or ALT > 15 x ULN irrespective of duration,
−
Total bilirubin > 8 x ULN irrespective of duration for subjects with elevated 
bilirubin at study entry or > 5 x ULN for those with normal T bilirubin at 
entry,
−
Concurrent AST or ALT > 3 x ULN and Total bilirubin > 5 x ULN for 
subjects entering treatment with a normal bilirubin and up to 8 x ULN for 
subjects with elevated bilirubin.
•
Creatinine > 6x ULN
•
Any severe or Grade 3 immune-mediated adverse reaction that recurs on reintroduction of 
Nivolumab, or an inability to reduce corticosteroid dose to 10 mg or less of prednisone or 
equivalent per day within 12 weeks
•
Persistent Grade 2 or 3 immune-mediated adverse reaction that do not recover to Grade 1 or 
resolve within 12 weeks after the last dose of Nivolumab
•
Any Grade 4 drug-related adverse event or laboratory abnormality, except for the following 
events which do not require discontinuation:
−
Grade 4 neutropenia ≤7 days
−
Grade 4 lymphopenia or leukopenia
−
Isolated Grade 4 electrolyte imbalances/abnormalities that are not associated with clinical 
sequelae and are corrected with supplementation/appropriate management within 
72 hours of their onset;
−
Isolated Grade 4 amylase or lipase abnormalities that are not associated with symptoms 
or clinical manifestations of pancreatitis and decrease to < grade 4 within 1 week of onset. 
The BMS Medical Monitor should be consulted for Grade 4 amylase or lipase 
abnormalities
−
Grade 4 drug-related endocrinopathy adverse events such as adrenal insufficiency, ACTH 
deficiency, hyper- or hypothyroidism, or glucose intolerance, which resolve or are 
adequately controlled with physiologic hormone replacement (corticosteroids, thyroid 
hormones) or glucose controlling agents, respectively, may not require discontinuation 
after discussion with and approval from the BMS Medical Monitor
•
Any dosing delays lasting > 6 weeks with the following exceptions:
−
Dosing delay to allow for prolonged steroid tapers to manage drug-related adverse events 
are allowed. Prior to re-initiating treatment in a subject with a dosing delay lasting > 6 
weeks, the BMS medical monitor must be consulted. Tumor assessments should continue 
as per protocol even if dosing is delayed.
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BMS-936558
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−
Dosing delays > 6 weeks that occur for non-drug-related reasons may be allowed if 
approved by the BMS medical monitor. Prior to re-initiating treatment in a subject with a 
dosing delay lasting > 6 weeks, the BMS medical monitor must be consulted. Tumor 
assessments should continue as per protocol even if dosing is delayed
•
Any adverse event, laboratory abnormality, or intercurrent illness which, in the judgment of 
the Investigator, presents a substantial clinical risk to the subject with continued nivolumab 
dosing.
4.3.2.5
Treatment Beyond Disease Progression
Accumulating evidence indicates a subset of subjects treated with immunotherapy may derive 
clinical benefit despite initial evidence of PD.
Subjects will be permitted to continue treatment beyond initial RECIST v1.1 defined PD as long 
as they meet the following criteria:
1. Investigator-assessed clinical benefit, and do not have rapid disease progression;
2. Subject provides written informed consent prior to receiving additional nivolumab treatment, 
using an ICF describing any reasonably foreseeable risks or discomforts, or other alternative 
treatment options.
3. Tolerance of study drug;
4. Stable performance status;
5. Treatment beyond progression will not delay an imminent intervention to prevent serious 
complications of disease progression (e.g., CNS metastases).
A follow-up scan should be performed at the next scheduled imaging evaluation 8 weeks later 
(but no sooner than 4 weeks) to determine whether there has been a decrease in the tumor size, or 
continued PD. The assessment of clinical benefit should be balanced by clinical judgment as to 
whether the subject is clinically deteriorating and unlikely to receive any benefit from continued 
treatment with nivolumab. If the investigator feels that the subject continues to achieve clinical 
benefit by continuing treatment, the subject should remain on the trial and continue to receive 
monitoring according to the Time and Events Schedule (Table 5.1-2, Table 5.1-3, Table 5.1-4). 
The decision to continue treatment should be discussed with the BMS Medical Monitor and 
documented in the study records.
For the subjects who continue study therapy beyond progression, further progression is defined
as an additional 10% increase in tumor burden volume from time of initial PD. This includes an
increase in all target lesions and/ or the development of new measurable lesions. Study therapy
should be discontinued if further progression is documented.
New lesions are considered measureable at the time of initial progression if the longest diameter 
is at least 10 mm (except for pathological lymph nodes which must have a short axis of at least 
15 mm). Any new lesion considered non-measureable at the time of initial progression may 
become measureable and therefore included in the tumor burden volume if the longest diameter 
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increases to at least 10 mm (except for pathological lymph nodes which must have a short axis of 
at least 15 mm).
4.3.2.6
Treatment of Nivolumab Related Infusion Reactions
Since nivolumab contains only human immunoglobulin protein sequences, it is unlikely to be 
immunogenic and induce infusion or hypersensitivity reactions. However, if such a reaction were 
to occur, it might manifest with fever, chills, rigors, headache, rash, pruritus, arthralgia, 
hypotension, hypertension, bronchospasm, or other allergic-like reactions. All Grade 3 or 
4 infusion reactions should be reported within 24 hours to the BMS medical monitor and 
reported as an SAE if it meets the criteria. Infusion reactions should be graded according to 
National Cancer Institute Common Terminology Criteria for Adverse Events (Version 4.03) 
(NCI CTCAE) 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 subject until recovery from symptoms.  The following
prophylactic premedications are recommended for future infusions: diphenhydramine
50 mg (or equivalent) and/or acetaminophen/paracetamol 325 to 1000 mg at least
30 minutes before additional nivolumab administrations.
For Grade 2 symptoms: (Moderate reaction requires therapy or infusion interruption but 
responds promptly to symptomatic treatment [e.g., antihistamines, non-steroidal anti-
inflammatory drugs, narcotics, corticosteroids, bronchodilators, IV fluids]; prophylactic 
medications indicated for ≤24 hours).
•
Stop the nivolumab infusion, begin an IV infusion of normal saline, and treat the subject 
with diphenhydramine 50 mg IV (or equivalent) and/or acetaminophen/paracetamol 
325 to 1000 mg; remain at bedside and monitor subject until resolution of symptoms. 
Corticosteroid 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 subject closely. If symptoms 
recur, then no further nivolumab will be administered at that visit.
For future infusions, the following prophylactic premedications are recommended: 
Diphenhydramine 50 mg (or equivalent) and/or acetaminophen/paracetamol 325 to 1000 mg 
should be administered at least 30 minutes before nivolumab infusions. If necessary, 
corticosteroids (up to 25 mg of SoluCortef or equivalent) may be used.
For Grade 3 or 4 symptoms: (Severe reaction, Grade 3: prolonged [i.e., not rapidly
responsive to symptomatic medication and/or brief interruption of infusion]; recurrence of 
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BMS-936558
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symptoms following initial improvement; hospitalization indicated for other clinical 
sequelae [e.g., renal impairment, pulmonary infiltrates]. Grade 4: Life-threatening; pressor 
or ventilatory support indicated).
•
Immediately discontinue infusion of nivolumab. Begin an IV infusion of normal saline 
and treat the subject as follows: Recommend bronchodilators, epinephrine 0.2 to 1 mg of 
a 1:1000 solution for subcutaneous administration or 0.1 to 0.25 mg of a 1:10,000 
solution injected slowly for IV administration, and/or diphenhydramine 50 mg IV with 
methylprednisolone 100 mg IV (or equivalent), as needed. Subject should be monitored 
until the Investigator is comfortable that the symptoms will not recur. nivolumab will be 
permanently discontinued. Investigators should follow their institutional guidelines for 
the treatment of anaphylaxis. Remain at bedside and monitor subject until recovery of the 
symptoms.
In case of late-occurring hypersensitivity symptoms (e.g., appearance of a localized or 
generalized pruritus within 1 week after treatment), symptomatic treatment may be given 
(e.g., oral antihistamine or corticosteroids).
4.4
Blinding/Unblinding
Not applicable.
4.5
Treatment Compliance
Study drug will be administered in the clinical facility. Treatment compliance will be monitored
by drug accountability as well as the subject’s medical record and eCRF.
4.6
Destruction and Return of Study Drug
4.6.1
Destruction of Study Drug
For this study, study drugs (those supplied by BMS or sourced by the investigator) such as 
partially used study drug containers, vials and syringes may be destroyed on site. 
Any unused study drugs can only be destroyed after being inspected and reconciled by the 
responsible BMS Study Monitor unless study drug containers must be immediately destroyed as 
required for safety, or to meet local regulations (e.g., cytotoxics or biologics). 
On-site destruction is allowed provided the following minimal standards are met:
•
On-site disposal practices must not expose humans to risks from the drug;
•
On-site disposal practices and procedures are in agreement with applicable laws and 
regulations, including any special requirements for controlled or hazardous substances;
•
Written procedures for on-site disposal are available and followed. The procedures must be 
filed with the site’s SOPs and a copy provided to BMS upon request;
•
Records are maintained that allow for traceability of each container, including the date 
disposed of, quantity disposed, and identification of the person disposing the containers. The 
method of disposal, i.e., incinerator, licensed sanitary landfill, or licensed waste disposal 
vendor must be documented;
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nivolumab
•
Accountability and disposal records are complete, up-to-date, and available for the Monitor 
to review throughout the clinical trial period.
If conditions for destruction cannot be met the responsible BMS Study Monitor will make 
arrangements for return of study drug.
It is the investigator’s responsibility to arrange for disposal of all empty containers, 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.
4.6.2
Return of Study Drug
If study drug will not be destroyed upon completion or termination of the study, all unused 
and/or partially used study drug that was supplied by BMS must be returned to BMS. The return 
of study drug will be arranged by the responsible BMS Study Monitor. 
It is the investigator’s responsibility to arrange for disposal of all empty containers, 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.
5
STUDY ASSESSMENTS AND PROCEDURES
5.1
Flow Chart/Time and Events Schedule 
Study assessments and procedures are presented in Table 5.1-1, Table 5.1-2, Table 5.1-3, and 
Table 5.1-4.
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Table 5.1-1:
Screening Procedural Outline (CA209077) - All Cohorts
Procedure
Screening 
Visita
Day -1
Notes
Eligibility Assessments
Admit to Clinical Facility
x
For the purpose of PK sample collection, subjects will be admitted to the clinical facility 
the evening prior to dosing (Day -1) for Cycle 1/Day 1 and will remain in the clinical 
facility until 24 hrs after study drug administration.
Informed Consent
x
A subject is considered enrolled only when a protocol specific informed consent is 
signed.
Inclusion/Exclusion Criteria
x
Medical History
x
Baseline signs and symptoms are those that are assessed within 2 weeks prior to dosing. 
Include any toxicities or allergy related to previous treatments.
Concomitant Medication
x
x
All medications taken within 2 weeks of dosing will be recorded.
Diagnosis confirmation and stage
x
Tumor-specific therapy information 
x
Serology (HCV, HBV & HIV)
x
HBsAg, HCVAb, and HIV Ab.  Serology tests must be available and reviewed prior to 
dosing on Day 1.
*For HCC subjects to be potentially enrolled, test following serology for Hep B, Hep C, 
Hep D: Hep B surface antigen, Hep B surface antibody, Hep B Core antibody, Hep B 
DNA Viral load (PCR), Hep C viral load (PCR) and Hep C Antibody, Hep D antibody.
Child-Pugh Score (For HCC 
subjects only)
x
See Appendix 5.
Coagulation profile (For HCC 
subjects only)
x
Include International Normalized Ratio (INR). If INR cannot be done by the local 
laboratory, then Prothrombin Time (PT) may be provided instead.
Safety Assessments
Complete Physical Examination 
(PE)
x
Physical Measurements
x
Includes height and weight.
Vital Signs and Oxygen Saturation
x
Includes body temperature, seated or supine blood pressure and heart rate, respiratory 
Revised Protocol No.: 06
Date: 15-Aug-2018
58
Approved
9.0
v
Approved
1.0
v


Clinical Protocol
CA209077
BMS-936558
nivolumab
Table 5.1-1:
Screening Procedural Outline (CA209077) - All Cohorts
Procedure
Screening 
Visita
Day -1
Notes
rate, O2 saturation by pulse oximetry at rest. Blood pressure and heart rate should be 
measured after the subject has been resting quietly for at least 5 minutes.
ECOG Performance
x
See Appendix 4.
Laboratory Tests
x
CBC w/differential and platelets; Full Chemistry Panel: LDH, AST, ALT, ALP, T.Bili, 
(Direct Bili if T.Bili > ULN) BUN, creatinine, Ca+, Mg+, Na+, K+, HCO3- (CO2), Cl-, 
glucose, albumin, T. Protein, TSH, (free T3, Free T4 if TSH not within normal limits); 
lipase and amylase; Urinalysis including glucose, ketones, pH, blood, leukocyte esterase 
(leucocyte) and protein.  (Note: Microscopic exam of the sediment if blood, protein or 
leukocyte esterase are positive)
Pregnancy Test
x
x
All WOCBP must have a negative urine or serum β-HCG pregnancy test minimum 
sensitivity 25 IU/L or equivalent units of HCG within 24 hours before the first infusion; 
urine pregnancy test at all other timepoints for WOCBP.
Electrocardiogram (ECGs)
x
ECGs should be recorded after the subject has been supine for at least 5 minutes. 
Baseline ECG done as part of the subject’s previous routine care before signing the 
informed consent form and completed within 28 days prior to study drug administration 
need not be repeated.  
CT/MRI (brain)
x
Baseline imaging done as part of the subject’s previous routine care before signing the 
informed consent form and completed within 28 days prior to study drug administration 
need not be repeated.  The same technique (CT/MRI) used at baseline should be utilized 
throughout the study. 
CT/MRI (chest, abdomen, pelvis
and any clinically indicated sites)
x
Baseline imaging done as part of the subject’s previous routine care before signing the 
informed consent form and completed within 28 days prior to study drug administration 
need not be repeated.  The same technique (CT/MRI) used at baseline should be utilized 
throughout the study.
Archived Tumor Tissue or Recent 
Tumor Biopsy (optional)
x
May be archival or recent sample. 1 FFPE tissue block, or minimum of 10 FFPE 
unstained slides are recommended. Submit a copy of the original pathology report along 
with the sample.  Submission of less than 10 unstained slides may be acceptable after 
approval by BMS Medical Monitor). Tumor tissue collection is not applicable to cohort 
D per protocol amendment 06.
Adverse Event Reporting
Revised Protocol No.: 06
Date: 15-Aug-2018
59
Approved
9.0
v
Approved
1.0
v


Clinical Protocol
CA209077
BMS-936558
nivolumab
Table 5.1-1:
Screening Procedural Outline (CA209077) - All Cohorts
Procedure
Screening 
Visita
Day -1
Notes
Monitor for Serious Adverse Events
x
x
All SAEs must be collected from the date of subject’s written consent until 100 days post 
discontinuation of dosing or subject’s participation in the study if the last scheduled visit 
occurs at a later time.
a Within 28 days of dosing on Day 1
Revised Protocol No.: 06
Date: 15-Aug-2018
60
Approved
9.0
v
Approved
1.0
v


Clinical Protocol
CA209077
BMS-936558
nivolumab
Table 5.1-2:
On Treatment Procedural Outline (CA209077)- 3 mg/kg and 240 mg Q2W Cohorts
Procedure
Treatment
Follow-upa
Notes
Cycle 1
Cycles 2+
C1:D1
C1:D15
C1:D29
C1:D43
C1:D56b
Cn:D1
Cn:D15
Cn:D29
Cn:D43
Cn:D56b
Follow-up 
1
Follow-up 
2
Timepoint Per 
Cycle (Day)
1c
15c
29c
43c
56c
1c
15c
29c
43c
56c
Last Visit + 
30 days (+/-
5 days)
Previous 
Follow-up 
Visit + 70 
Days (+/- 5 
days)
Admit to Clinical 
Facility
x
x
For the purpose of PK sample 
collection, subjects will be 
admitted to the clinical facility 
prior to dosing (Day -1) only on
Cycle 1/Day 1 and Cycle 3/Day 1 
and will remain in the clinical 
facility until 24 hrs after study 
drug administration.
Safety Assessments
Complete Physical 
Examination (PE)
x
Targeted PE
x
x
x
x
x
x
x
x
x
Physical 
Measurements 
x
x
Weight only. For 3 mg/kg cohort 
only, dose adjustments are 
required to be made if there has 
been a > 10% percent weight 
change (increase or decrease) 
since the previous cycle.  
Vital Signs and 
Oxygen Saturation
x
x
x
x
x
x
x
x
x
x
Vital signs should be taken as per 
institutional standard of care at 
Revised Protocol No.: 06
Date: 15-Aug-2018
61
Approved
9.0
v
Approved
1.0
v


Clinical Protocol
CA209077
BMS-936558
nivolumab
Table 5.1-2:
On Treatment Procedural Outline (CA209077)- 3 mg/kg and 240 mg Q2W Cohorts
Procedure
Treatment
Follow-upa
Notes
Cycle 1
Cycles 2+
C1:D1
C1:D15
C1:D29
C1:D43
C1:D56b
Cn:D1
Cn:D15
Cn:D29
Cn:D43
Cn:D56b
Follow-up 
1
Follow-up 
2
Timepoint Per 
Cycle (Day)
1c
15c
29c
43c
56c
1c
15c
29c
43c
56c
Last Visit + 
30 days (+/-
5 days)
Previous 
Follow-up 
Visit + 70 
Days (+/- 5 
days)
visits and prior to, during, and 
after the infusion with nivolumab.
See note in screening procedures. 
Electrocardiogram 
(ECGs)
x
See note in screening procedures.
ECOG Performance
x
x
x
x
x
x
x
x
x
x
See Appendix 4.
Laboratory Tests
x
x
x
x
x
x
x
x
x
x
Within 72 hours prior to dosing. 
Include CBC w/differential and 
platelets; Full Chemistry Panel: 
LDH, AST, ALT, ALP, T.Bili, 
(Direct Bili if T.Bili > ULN) 
BUN, creatinine, Ca+, Mg+, Na+, 
K+, HCO3- (CO2), Cl-, amylase, 
lipase, glucose, albumin, 
T.Protein, TSH, (free T3, Free T4 
if TSH not within normal limits);  
Urinalysis including glucose, 
ketones, pH, blood, leukocyte 
esterase (leucocyte) and protein.  
(Note: Microscopic exam of the 
sediment if blood, protein or 
leukocyte esterase are positive).  
Revised Protocol No.: 06
Date: 15-Aug-2018
62
Approved
9.0
v
Approved
1.0
v


Clinical Protocol
CA209077
BMS-936558
nivolumab
Table 5.1-2:
On Treatment Procedural Outline (CA209077)- 3 mg/kg and 240 mg Q2W Cohorts
Procedure
Treatment
Follow-upa
Notes
Cycle 1
Cycles 2+
C1:D1
C1:D15
C1:D29
C1:D43
C1:D56b
Cn:D1
Cn:D15
Cn:D29
Cn:D43
Cn:D56b
Follow-up 
1
Follow-up 
2
Timepoint Per 
Cycle (Day)
1c
15c
29c
43c
56c
1c
15c
29c
43c
56c
Last Visit + 
30 days (+/-
5 days)
Previous 
Follow-up 
Visit + 70 
Days (+/- 5 
days)
Lab results must be reviewed 
prior to dosing.  
Child-Pugh Score 
(for HCC subjects 
only)
x
x
x
x
x
x
x
x
Prior to dosing. See Appendix 5.
Coagulation profile 
(For HCC subjects 
only)
x
x
x
x
x
x
x
x
x
Prior to dosing.
Viral biomarkers 
(for HCV and HBV 
infected HCC 
subjects)
x
x
For HBV infected--HBV DNA 
every 4 weeks on treatment.
For HCV infected--HCV RNA 
every 4 weeks on treatment 
through week 20, then every 12 
weeks thereafter.
Review of 
Concomitant 
Medications
x
x
x
Should occur at every visit 
throughout the study.
Monitor for Non-
Serious Adverse 
Events
x
x
x
Should occur at every visit 
throughout the study.
Revised Protocol No.: 06
Date: 15-Aug-2018
63
Approved
9.0
v
Approved
1.0
v


Clinical Protocol
CA209077
BMS-936558
nivolumab
Table 5.1-2:
On Treatment Procedural Outline (CA209077)- 3 mg/kg and 240 mg Q2W Cohorts
Procedure
Treatment
Follow-upa
Notes
Cycle 1
Cycles 2+
C1:D1
C1:D15
C1:D29
C1:D43
C1:D56b
Cn:D1
Cn:D15
Cn:D29
Cn:D43
Cn:D56b
Follow-up 
1
Follow-up 
2
Timepoint Per 
Cycle (Day)
1c
15c
29c
43c
56c
1c
15c
29c
43c
56c
Last Visit + 
30 days (+/-
5 days)
Previous 
Follow-up 
Visit + 70 
Days (+/- 5 
days)
Monitor for Serious 
Adverse Events
x
x
x
See note in screening procedure.
Pregnancy Test
x
x
x
x
x
x
x
x
See note in screening procedure.
CT/MRI (brain)
x
x
Brain scans during treatment and 
follow up. periods are required 
only if there is a prior history of 
lesions present at Screening, or as 
clinically indicated for new signs 
and symptoms that suggest central 
nervous system (CNS) 
involvement.
CT/MRI (chest, 
abdomen, pelvis and 
any clinically 
indicated sites)
x
x
Response 
Assessment
x
x
x
x
Tumor response status will be 
assessed by the Investigators using 
RECIST v1.1. See Appendix 3.
Pharmacokinetic 
(PK) Assessments
Revised Protocol No.: 06
Date: 15-Aug-2018
64
Approved
9.0
v
Approved
1.0
v


Clinical Protocol
CA209077
BMS-936558
nivolumab
Table 5.1-2:
On Treatment Procedural Outline (CA209077)- 3 mg/kg and 240 mg Q2W Cohorts
Procedure
Treatment
Follow-upa
Notes
Cycle 1
Cycles 2+
C1:D1
C1:D15
C1:D29
C1:D43
C1:D56b
Cn:D1
Cn:D15
Cn:D29
Cn:D43
Cn:D56b
Follow-up 
1
Follow-up 
2
Timepoint Per 
Cycle (Day)
1c
15c
29c
43c
56c
1c
15c
29c
43c
56c
Last Visit + 
30 days (+/-
5 days)
Previous 
Follow-up 
Visit + 70 
Days (+/- 5 
days)
Blood PK Sampling
x
x
x
PK sampling timepoints 
throughout the study. Refer to 
Table 5.5.1-1 for specific 
timepoints. See Section 5.5. 
Immunogenicity 
(ADA) Assessments
Blood ADA Sample
x
x
x
Refer to Table 5.5.1-1 and Table 
5.5.1-2 for specific timepoints.
Revised Protocol No.: 06
Date: 15-Aug-2018
65
Approved
9.0
v
Approved
1.0
v


Clinical Protocol
CA209077
BMS-936558
nivolumab
Table 5.1-2:
On Treatment Procedural Outline (CA209077)- 3 mg/kg and 240 mg Q2W Cohorts
Procedure
Treatment
Follow-upa
Notes
Cycle 1
Cycles 2+
C1:D1
C1:D15
C1:D29
C1:D43
C1:D56b
Cn:D1
Cn:D15
Cn:D29
Cn:D43
Cn:D56b
Follow-up 
1
Follow-up 
2
Timepoint Per 
Cycle (Day)
1c
15c
29c
43c
56c
1c
15c
29c
43c
56c
Last Visit + 
30 days (+/-
5 days)
Previous 
Follow-up 
Visit + 70 
Days (+/- 5 
days)
Clinical Drug 
Supplies
Study Drug 
Administration
x
x
x
x
x
x
x
x
Supplied by BMS 
a When a subject discontinues study drug treatment, all remaining visits of that treatment cycle should be completed (without infusion and with only a single 
pharmacokinetic samples taken at applicable visits), and the subject should enter the Follow-up Period.  When a subject is withdrawn from the study (during 
the Treatment or Follow-up Period), all evaluations associated with that study visit should be performed and the date and reason for study discontinuation 
should be documented on the CRF.
b This visit is not a clinic visit. The purpose of this visit is for radiologic assessment and subsequent evaluation of results by the Investigator (response 
assessment). Radiologic procedures and response assessments should occur between Days 49 and 56 before administering the first dose of study drug in the 
next cycle.
Revised Protocol No.: 06
Date: 15-Aug-2018
66
Approved
9.0
v
Approved
1.0
v


Clinical Protocol
CA209077
BMS-936558
nivolumab
c To be done ± 2 days of scheduled visit. Every effort should be made to schedule visits within the timeframe stated in the protocol. In the case that the visits 
cannot be within the timeframe stated in protocol then the treatment period study procedures can be performed ± 2 days of the scheduled visit
Abbreviations: D = Day, C=Cycles (eg.,C1:D1= Cycle 1, Day 1); n=Cycle 2+ as appropriate
Revised Protocol No.: 06
Date: 15-Aug-2018
67
Approved
9.0
v
Approved
1.0
v


Clinical Protocol
CA209077
BMS-936558
nivolumab
Table 5.1-3:
On Treatment Procedural Outline (CA209077)- 360 mg Q3W Cohort
Procedure
Treatment (Cycle=21 days)
Follow-upa
Notes
Cycle 1
Cycles 2+
C1:D1
Cn:D1
Cn:D21
Follow-up 1
Follow-up 2
Timepoint Per 
Cycle (Day)
1c
1c
21c
Last Visit + 30 
days (+/- 5 days)
Previous Follow-
up Visit + 70 Days 
(+/- 5 days)
Admit to Clinical 
Facility
x
For the purpose of PK sample collection, subjects will 
be admitted to the clinical facility the evening prior to 
dosing (Day -1) only for Cycle 1/Day 1 and Cycle 
6/Day 1 and will remain in the clinical facility until 24 
hrs after study drug administration.
Safety Assessments
Complete Physical 
Examination (PE)
x
Targeted PE
x
x
x
On Day 1 of each cycle.
Physical 
Measurements 
x
x
Weight only.  
Vital Signs and 
Oxygen Saturation
x
x
x
x
Vital signs should be taken as per institutional 
standard of care at visits and prior to, during, and after 
the infusion with nivolumab. See note in screening 
procedures 
Electrocardiogram 
(ECGs)
x
Every other cycle starting Cycle 3. See note in 
screening procedures.
ECOG Performance
x
x
x
x
See Appendix 4.
Revised Protocol No.: 06
Date: 15-Aug-2018
68
Approved
9.0
v
Approved
1.0
v


Clinical Protocol
CA209077
BMS-936558
nivolumab
Table 5.1-3:
On Treatment Procedural Outline (CA209077)- 360 mg Q3W Cohort
Procedure
Treatment (Cycle=21 days)
Follow-upa
Notes
Cycle 1
Cycles 2+
C1:D1
Cn:D1
Cn:D21
Follow-up 1
Follow-up 2
Timepoint Per 
Cycle (Day)
1c
1c
21c
Last Visit + 30 
days (+/- 5 days)
Previous Follow-
up Visit + 70 Days 
(+/- 5 days)
Laboratory Tests
x
x
x
x
Within 72 hours prior to dosing. Include CBC 
w/differential and platelets; Full Chemistry Panel: 
LDH, AST, ALT, ALP, T.Bili, (Direct Bili if T.Bili > 
ULN) BUN, creatinine, Ca+, Mg+, Na+, K+, HCO3-
(CO2), Cl-, amylase, lipase, glucose, albumin, 
T.Protein, TSH, (free T3, Free T4 if TSH not within 
normal limits);  Urinalysis including glucose, ketones, 
pH, blood, leukocyte esterase (leucocyte) and protein.  
(Note: Microscopic exam of the sediment if blood, 
protein or leukocyte esterase are positive).  Lab 
results must be reviewed prior to dosing.  
Child-Pugh Score 
(for HCC subjects 
only)
x
x
Prior to dosing. See Appendix 5. 
Coagulation profile 
(For HCC subjects 
only)
x
x
x
Prior to dosing.
Viral biomarkers (for 
HCV and HBV 
infected HCC 
x
x
For HBV infected--HBV DNA every 3 weeks on 
treatment.
For HCV infected--HCV RNA every 3 weeks on 
Revised Protocol No.: 06
Date: 15-Aug-2018
69
Approved
9.0
v
Approved
1.0
v


Clinical Protocol
CA209077
BMS-936558
nivolumab
Table 5.1-3:
On Treatment Procedural Outline (CA209077)- 360 mg Q3W Cohort
Procedure
Treatment (Cycle=21 days)
Follow-upa
Notes
Cycle 1
Cycles 2+
C1:D1
Cn:D1
Cn:D21
Follow-up 1
Follow-up 2
Timepoint Per 
Cycle (Day)
1c
1c
21c
Last Visit + 30 
days (+/- 5 days)
Previous Follow-
up Visit + 70 Days 
(+/- 5 days)
subjects)
treatment through week 18, then every 12 weeks 
thereafter.
Review of 
Concomitant 
Medications
x
x
x
Should occur at every visit throughout the study.
Monitor for Non-
Serious Adverse 
Events
x
x
x
Should occur at every visit throughout the study.
Monitor for Serious 
Adverse Events
x
x
x
See note in screening procedure.
Pregnancy Test
x
x
See note in screening procedure.
CT/MRI (brain)
xb
Brain scans during treatment and follow up. periods 
are required only if there is a prior history of lesions 
present at Screening, or as clinically indicated for new 
signs and symptoms that suggest central nervous 
system (CNS) involvement.
CT/MRI (chest, 
abdomen, pelvis and 
any clinically 
xb
Revised Protocol No.: 06
Date: 15-Aug-2018
70
Approved
9.0
v
Approved
1.0
v


Clinical Protocol
CA209077
BMS-936558
nivolumab
Table 5.1-3:
On Treatment Procedural Outline (CA209077)- 360 mg Q3W Cohort
Procedure
Treatment (Cycle=21 days)
Follow-upa
Notes
Cycle 1
Cycles 2+
C1:D1
Cn:D1
Cn:D21
Follow-up 1
Follow-up 2
Timepoint Per 
Cycle (Day)
1c
1c
21c
Last Visit + 30 
days (+/- 5 days)
Previous Follow-
up Visit + 70 Days 
(+/- 5 days)
indicated sites)
Response Assessment
xb
x
x
Every 6 weeks. Tumor response status will be 
assessed by the Investigators using RECIST v1.1. See 
Appendix 3.
Pharmacokinetic 
(PK) Assessments
Blood PK Sampling
x
x
x
PK sampling timepoints throughout the study. Refer 
to Table 5.5.1-2 for specific timepoints. See Section
5.5.
Immunogenicity 
(ADA) Assessments
Blood ADA Sample
x
x
x
Refer to Table 5.5.1-2 for specific timepoints.
Revised Protocol No.: 06
Date: 15-Aug-2018
71
Approved
9.0
v
Approved
1.0
v


Clinical Protocol
CA209077
BMS-936558
nivolumab
Table 5.1-3:
On Treatment Procedural Outline (CA209077)- 360 mg Q3W Cohort
Procedure
Treatment (Cycle=21 days)
Follow-upa
Notes
Cycle 1
Cycles 2+
C1:D1
Cn:D1
Cn:D21
Follow-up 1
Follow-up 2
Timepoint Per 
Cycle (Day)
1c
1c
21c
Last Visit + 30 
days (+/- 5 days)
Previous Follow-
up Visit + 70 Days 
(+/- 5 days)
Clinical Drug 
Supplies
Study Drug 
Administration
x
x
Supplied by BMS 
a When a subject discontinues study drug treatment, all remaining visits of that treatment cycle should be completed (without infusion and with only a single 
pharmacokinetic samples taken at applicable visits), and the subject should enter the Follow-up Period.  When a subject is withdrawn from the study (during 
the Treatment or Follow-up Period), all evaluations associated with that study visit should be performed and the date and reason for study discontinuation 
should be documented on the CRF.
b This visit is not a clinic visit. The purpose of this visit is for radiologic assessment and subsequent evaluation of results by the Investigator (response 
assessment). Radiologic procedures and response assessments will begin at week 6 post first dose date (± 7 days) and be performed every 6 weeks (± 7 days) 
subsequently.
c To be done ± 2 days of scheduled visit. Every effort should be made to schedule visits within the timeframe stated in the protocol. In the case that the visits 
cannot be within the timeframe stated in protocol then the treatment period study procedures can be performed ± 2 days of the scheduled visit
Abbreviations: D = Day, C=Cycles (eg.,C1:D1= Cycle 1, Day 1); n=Cycle 2+ as appropriate
Revised Protocol No.: 06
Date: 15-Aug-2018
72
Approved
9.0
v
Approved
1.0
v


Clinical Protocol
CA209077
BMS-936558
nivolumab
Table 5.1-4:
On Treatment Procedural Outline (CA209077)- 480 mg Q4W Cohort
Procedure
Treatment (Cycle=28 days)
Follow-upa
Notes
Cycle 1
Cycles 2+
C1:D1
C1:D15
Cn:D1
Cn:D15
Cn:D28
Follow-up 1
Follow-up 2
Timepoint Per 
Cycle (Day)
1c
15c
1c
15c
28c
Last Visit + 30 
days (+/- 5 days)
Previous 
Follow-up Visit 
+ 70 Days (+/- 5 
days)
Admit to Clinical 
Facility
x
x
For the purpose of PK sample collection, subjects will 
be admitted to the clinical facility the evening prior to 
dosing (Day -1) only for Cycle 1/Day 1 and Cycle 
5/Day 1 and will remain in the clinical facility until 24 
hrs after study drug administration.
Safety 
Assessments
Complete Physical 
Examination (PE)
x
Targeted PE
x
x
x
On Day 1 of each cycle.
Physical 
Measurements 
x
x
Weight only. 
Vital Signs and 
Oxygen Saturation
x
x
x
x
Vital signs should be taken as per institutional standard 
of care at visits and prior to, during, and after the 
infusion with nivolumab. See note in screening 
procedures 
Electrocardiogram 
(ECGs)
x
Every other cycle starting Cycle 3. See note in 
screening procedures.
Revised Protocol No.: 06
Date: 15-Aug-2018
73
Approved
9.0
v
Approved
1.0
v


Clinical Protocol
CA209077
BMS-936558
nivolumab
Table 5.1-4:
On Treatment Procedural Outline (CA209077)- 480 mg Q4W Cohort
Procedure
Treatment (Cycle=28 days)
Follow-upa
Notes
Cycle 1
Cycles 2+
C1:D1
C1:D15
Cn:D1
Cn:D15
Cn:D28
Follow-up 1
Follow-up 2
Timepoint Per 
Cycle (Day)
1c
15c
1c
15c
28c
Last Visit + 30 
days (+/- 5 days)
Previous 
Follow-up Visit 
+ 70 Days (+/- 5 
days)
ECOG 
Performance
x
x
x
x
Please see Appendix 4.
Laboratory Tests
x
x
x
x
x
x
On D1 and D15 in Cycles 1 to 5. On D1 only in Cycles 
6+. Within 72 hours prior to dosing. Include CBC 
w/differential and platelets; Full Chemistry Panel: 
LDH, AST, ALT, ALP, T.Bili, (Direct Bili if T.Bili > 
ULN) BUN, creatinine, Ca+, Mg+, Na+, K+, HCO3-
(CO2), Cl-, amylase, lipase, glucose, albumin, 
T.Protein, TSH, (free T3, Free T4 if TSH not within 
normal limits);  Urinalysis including glucose, ketones, 
pH, blood, leukocyte esterase (leucocyte) and protein.  
(Note: Microscopic exam of the sediment if blood, 
protein or leukocyte esterase are positive).  Lab results 
must be reviewed prior to dosing.  
Review of 
Concomitant 
Medications
x
x
x
Should occur at every visit throughout the study.
Monitor for Non-
Serious Adverse 
Events
x
x
x
Should occur at every visit throughout the study.
Revised Protocol No.: 06
Date: 15-Aug-2018
74
Approved
9.0
v
Approved
1.0
v


Clinical Protocol
CA209077
BMS-936558
nivolumab
Table 5.1-4:
On Treatment Procedural Outline (CA209077)- 480 mg Q4W Cohort
Procedure
Treatment (Cycle=28 days)
Follow-upa
Notes
Cycle 1
Cycles 2+
C1:D1
C1:D15
Cn:D1
Cn:D15
Cn:D28
Follow-up 1
Follow-up 2
Timepoint Per 
Cycle (Day)
1c
15c
1c
15c
28c
Last Visit + 30 
days (+/- 5 days)
Previous 
Follow-up Visit 
+ 70 Days (+/- 5 
days)
Monitor for 
Serious Adverse 
Events
x
x
x
See note in screening procedure.
Pregnancy Test
x
x
See note in screening procedure.
CT/MRI (brain)
xb
Brain scans during treatment and follow up. periods are 
required only if there is a prior history of lesions 
present at Screening, or as clinically indicated for new 
signs and symptoms that suggest central nervous 
system (CNS) involvement.
CT/MRI (chest, 
abdomen, pelvis
and any clinically 
indicated sites)
xb
Response 
Assessment
xb
x
x
Every 8 weeks. Tumor response status will be assessed 
by the Investigators using RECIST v1.1. See Appendix 
3.
Pharmacokinetic 
(PK) Assessments
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Table 5.1-4:
On Treatment Procedural Outline (CA209077)- 480 mg Q4W Cohort
Procedure
Treatment (Cycle=28 days)
Follow-upa
Notes
Cycle 1
Cycles 2+
C1:D1
C1:D15
Cn:D1
Cn:D15
Cn:D28
Follow-up 1
Follow-up 2
Timepoint Per 
Cycle (Day)
1c
15c
1c
15c
28c
Last Visit + 30 
days (+/- 5 days)
Previous 
Follow-up Visit 
+ 70 Days (+/- 5 
days)
Blood PK 
Sampling
x
x
x
PK sampling timepoints throughout the study. Refer to
Table 5.5.1-3 for specific timepoints. See Section 5.5.
Immunogenicity
(ADA) 
Assessments
Blood ADA 
Sample
x
x
x
Refer to Table 5.5.1-3 for specific timepoints.
Clinical Drug 
Supplies
Study Drug 
Administration
x
x
Supplied by BMS 
a When a subject discontinues study drug treatment, all remaining visits of that treatment cycle should be completed (without infusion and with only a single 
pharmacokinetic samples taken at applicable visits), and the subject should enter the Follow-up Period.  When a subject is withdrawn from the study (during 
the Treatment or Follow-up Period), all evaluations associated with that study visit should be performed and the date and reason for study discontinuation 
should be documented on the CRF.
b This visit is not a clinic visit. The purpose of this visit is for radiologic assessment and subsequent evaluation of results by the Investigator (response 
assessment). Radiologic procedures and response assessments will begin at week 8 post first dose date (± 7 days) and be performed every 8 weeks (± 7 days) 
subsequently.
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c To be done ± 2 days of scheduled visit. Every effort should be made to schedule visits within the timeframe stated in the protocol. In the case that the visits 
cannot be within the timeframe stated in protocol then the treatment period study procedures can be performed ± 2 days of the scheduled visit
Abbreviations: D = Day, C=Cycles (eg.,C1:D1= Cycle 1, Day 1); n=Cycle 2+ as appropriate
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5.2
Study Materials
The following materials will be provided at study start:
•
NCI CTCAE version 4.03;
•
Nivolumab Investigator Brochure;
•
Pharmacy binder;
•
Laboratory manuals for collection and handling of blood (including PKs
 and 
immunogenicity) and tissue specimens;
•
Site manual for operation of interactive voice response system;
•
Enrollment worksheets;
•
Serious Adverse Event (or eSAE) case report form pages;
•
Pregnancy Surveillance Forms. 
5.3
Safety Assessments
At baseline, a medical history will be obtained to capture relevant underlying conditions. 
Baseline signs and symptoms are those that are assessed within 2 weeks prior to dosing. The 
baseline physical examination should include weight, height, BP, HR, and temperature. These 
should be performed within 28 days of treatment. Concomitant medications will be collected 
from within 2 weeks prior to treatment assignment through the study treatment period.
Toxicity assessments will be continuous during the treatment phase until 100 days (equal to 
approximately 5 half lives of nivolumab) after the last dose of nivolumab. 
Adverse events and laboratory values will be graded according to the NCI CTCAE version 4.03.
Vital signs should be taken as per institutional standard of care at visits and prior to, during, and 
after the infusion with nivolumab. The start and stop time of the study drug infusion should be
documented. If there are any new or worsening clinically significant changes since the last exam,
report these changes on the appropriate AE or SAE page.
Additional measures including non-study required laboratory tests should be performed as 
clinically indicated.
5.3.1
Imaging Assessment for the Study
CT with contrast of the chest, abdomen, pelvis and any clinically indicated sites are to be 
performed for tumor assessments at the timepoints outlined in Table 5.1-1, Table 5.1-2, Table 
5.1-3, and Table 5.1-4. 
CT scans should be acquired with ≤5mm slices with no intervening gap (contiguous). Should a 
subject have a contraindication for CT IV contrast, a non contrast CT of the chest and a contrast 
enhanced MRI of the abdomen and pelvis may be obtained. MRI’s should be acquired with slice 
thickness of ≤5 mm and <2mm gap (preferably no gap / contiguous). Every attempt should be 
made to image each subject using an identical acquisition protocol on the same scanner for all 
imaging timepoints.
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MRI brain scans during on-study treatment and follow up periods are required only if there is a 
prior history of lesions present at Screening, or as clinically indicated for new signs and 
symptoms that suggest CNS involvement.
Any incidental findings of potential clinical relevance that are not directly associated with the 
objectives of the protocol should be evaluated and handled by the Study Investigator as per 
standard medical/clinical judgment.
5.3.2
Laboratory Test Assessments
Results of clinical laboratory tests performed on Day -1 visit must be available prior to dosing.
A central/local laboratory will perform the analyses and will provide reference ranges for these 
tests.
Results of all laboratory tests required by this protocol must be provided to BMS, either recorded 
on the laboratory pages of the CRF or by another mechanism as agreed upon between the 
investigator and BMS (e.g., provided electronically). If the units of a test result differ from those 
printed on the CRF, the recorded laboratory values must specify the correct units. Any abnormal 
laboratory test result considered clinically significant by the investigator must be recorded on the 
appropriate AE page of the CRF (see Section 6.3 Laboratory Test Result Abnormalities).
Please refer to Table 5.1-1, Table 5.1-2, Table 5.1-3, and Table 5.1-4 for required laboratory tests 
and schedule.
5.4
Efficacy Assessments
Study evaluations will take place in accordance with Table 5.1-1, Table 5.1-2, Table 5.1-3, and 
Table 5.1-4. Baseline assessments should be performed within 28 days of study treatment. Chest, 
abdomen, pelvis and any clinically indicated sites as determined by the investigator should be 
assessed at baseline. Subsequent assessments should utilize the same imaging modality. Subjects 
will be evaluated for tumor response every 8 weeks from the first dose of study drug until tumor 
progression is documented. 
Change in tumor measurements and tumor response will be assessed by the investigator using the 
RECIST v1.1 criteria (Appendix 3).
5.4.1
Primary Efficacy Assessment
Not applicable.
5.4.2
Secondary Efficacy Assessments
Not applicable.
5.5
Pharmacokinetic Assessments
5.5.1
Pharmacokinetics and Immunogenicity Collection and Processing
Table 5.5.1-1, Table 5.5.1-2, and Table 5.5.1-3 list the sampling schedule to be followed for the 
assessment of nivolumab pharmacokinetics and immunogenicity for all cohorts. Blood samples
should be drawn from a site other than the infusion site (ie, contralateral arm) on days of infusion. 
All samples collected predose should be taken just prior to the administration, and end-of-
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infusion (EOI) samples should be taken as close to EOI as possible (preferably 2 minutes prior to 
EOI) on the contralateral arm (ie, the arm not for the infusion). If the infusion was interrupted, 
the reason for interruption should also be documented on the CRF. Blood samples will be 
processed to collect serum. The serum samples will be analyzed for nivolumab by validated 
methods. Further details of blood collection, labeling, processing, storage and shipping will be 
provided to the site in the procedure manual.
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Table 5.5.1-1:
Pharmacokinetics and Immunogenicity Sampling Schedule 
for 3 mg/kg Q2W (Dose Evaluation and Cohort Expansion) 
and 240 mg Q2W
CYCLE
(1 CYCLE = 8 
WEEKS)
Study Day 
of Sample 
Collectiona
Event
Time 
(Relative To Start of 
Infusion of 
Nivolumab)
Hour: Min
PK Blood 
Sample
ADA Blood 
Sample
1
1
Predoseb
00:00
X
X
EOIc
00:30
X
04:00
X
08:00
X
2
24:00
X
3
48:00
X
5
96:00
X
8
168:00
X
15
predoseb
336:00
X
X
29
predoseb
00:00
X
X
2
1
predoseb
00:00
X
X
3
1
predoseb
00:00
X
X
EOIc
00:30
X
04:00
X
08:00
X
2
24:00
X
3
48:00
X
5
96:00
X
8
168:00
X
15
predoseb
336:00
X
5
1
predoseb
00:00
X
X
7
1
predoseb
00:00
X
X
Day 1 of every 
2 cycles after 
C7 until 
discontinuation 
of Study 
Treatment  
1
predoseb
00:00
X
X
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Table 5.5.1-1:
Pharmacokinetics and Immunogenicity Sampling Schedule 
for 3 mg/kg Q2W (Dose Evaluation and Cohort Expansion) 
and 240 mg Q2W
CYCLE
(1 CYCLE = 8 
WEEKS)
Study Day 
of Sample 
Collectiona
Event
Time 
(Relative To Start of 
Infusion of 
Nivolumab)
Hour: Min
PK Blood 
Sample
ADA Blood 
Sample
First 2 Follow-up Visits 
(EXCEPT for subjects that 
WITHDRAW CONSENT)d
X
X
a If a subject permanently discontinues study drug treatment, or is not receiving an infusion at a given visit, a single 
pharmacokinetic sample will be taken at that visit.
b Predose samples should be collected on the day of dosing just prior to the start of the infusion
c EOI: End of Infusion. This sample should be taken immediately prior to stopping the infusion. In the event of a 
delay beyond 30 min, the sample should be taken immediately prior to the actual END of the infusion. For 
subjects in the evaluation phase receiving nivolumab over 60 min infusion, EOI sample will be collected 
immediately prior to the infusion stopping time at 60 min. 
d Pharmacokinetic and immunogenicity samples will be taken at Follow-up Visits.
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Table 5.5.1-2:
Pharmacokinetics and Immunogenicity Sampling Schedule for, 
360 mg Q3W 
CYCLE
(1 CYCLE =   
3 WEEKS)
Study Day of 
Sample 
Collectiona
Event
Time 
(Relative To Start of 
Infusion of 
Nivolumab)
Hour: Min
PK Blood 
Sample
ADA Blood 
Sample
1
1
Predoseb
00:00
X
X
EOIc
00:30
X
04:00
X
08:00
X
2
24:00
X
3
48:00
X
5
96:00
X
8
168:00
X
15
336:00
X
2
1
predoseb
00:00
X
X
4
1
predoseb
00:00
X
X
6
1
predoseb
00:00
X
X
EOIc
00:30
X
04:00
X
08:00
X
2
24:00
X
3
48:00
X
5
96:00
X
8
168:00
X
15
336:00
X
7
1
predoseb
00:00
X
11
1
predoseb
00:00
X
X
Day 1 of every 
6 cycles after 
C11 until 
discontinuation 
of Study 
Treatment  
1
predoseb
00:00
X
X
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Table 5.5.1-2:
Pharmacokinetics and Immunogenicity Sampling Schedule for, 
360 mg Q3W 
CYCLE
(1 CYCLE =   
3 WEEKS)
Study Day of 
Sample 
Collectiona
Event
Time 
(Relative To Start of 
Infusion of 
Nivolumab)
Hour: Min
PK Blood 
Sample
ADA Blood 
Sample
First 2 Follow-up Visits 
(EXCEPT for subjects that 
WITHDRAW CONSENT)d
X
X
a If a subject permanently discontinues study drug treatment, or is not receiving an infusion at a given visit, a single 
pharmacokinetic sample will be taken at that visit.
b Predose samples should be collected on the day of dosing just prior to the start of the infusion.
c EOI: End of Infusion. This sample should be taken immediately prior to stopping the infusion. In the event of a 
delay beyond 30 min, the sample should be taken immediately prior to the actual END of the infusion. 
d Pharmacokinetic and immunogenicity samples will be taken at Follow-up Visits.
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Table 5.5.1-3:
Pharmacokinetics and Immunogenicity Sampling Schedule for 
480 mg Q4W 
CYCLE
(1 CYCLE = 
4 WEEKS)
Study Day of 
Sample 
Collectiona
Event
Time 
(Relative To Start 
of Infusion of 
Nivolumab)
Hour: Min
PK Blood 
Sample
ADA Blood 
Sample
1
1
Predoseb
00:00
X
X
EOIc
00:30
X
04:00
X
08:00
X
2
24:00
X
3
48:00
X
5
96:00
X
8
168:00
X
15
336:00
X
X
2
1
predoseb
00:00
X
X
3
1
predoseb
00:00
X
X
5
1
predoseb
00:00
X
X
EOIc
00:30
X
04:00
X
08:00
X
2
24:00
X
3
48:00
X
5
96:00
X
8
168:00
X
15
336:00
X
6
1
predoseb
00:00
X
X
Day 1 of every 
4 cycles after 
C6 until 
discontinuatio
n of Study 
Treatment  
1
predoseb
00:00
X
X
First 2 Follow-up Visits 
(EXCEPT for subjects that 
WITHDRAW CONSENT)d
X
X
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a If a subject permanently discontinues study drug treatment, or is not receiving an infusion at a given visit, a single 
pharmacokinetic sample will be taken at that visit.
b Predose samples should be collected on the day of dosing just prior to the start of the infusion (preferably within 
30 minutes). If it is known that a dose is going to be delayed, then the predose sample should be collected just 
prior to the delayed dose. However, if a predose sample is collected but the dose is subsequently delayed, an 
additional predose sample should not be collected.
c 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). In the event of a delay beyond 30 min, the sample should be taken 
immediately prior to the actual END of the infusion. 
d Pharmacokinetic and immunogenicity samples will be taken at Follow-up Visits.
5.5.2
Pharmacokinetics and Immunogenicity Sample Analyses
A detailed schedule of PK and immunogenicity evaluations is provided in Table 5.5.1-1, Table 
5.5.1-2, and Table 5.5.1-3. PK and immunogenicity samples will be analyzed for nivolumab and 
nivolumab anti-drug antibodies, respectively, by validated immunoassays. 
 
 
 Serum samples designated for PK 
 
 assessments may also be used for immunogenicity analysis if required (eg, 
insufficient volume for complete immunogenicity assessment or to follow up on suspected 
immunogenicity related AE).
5.5.3
Labeling and Shipping of Biological Samples
Detailed instructions for the pharmacokinetic blood collection, labeling, processing, storage, and 
shipping will be provided to the site in the procedure manual.
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5.8
Outcomes Research Assessments
Not applicable.
5.9
Other Assessments 
Not applicable
5.10
Results of Central Assessments
Not applicable.
6
ADVERSE EVENTS
An Adverse Event (AE) is defined as any new untoward medical occurrence or worsening of a 
preexisting medical condition in a clinical investigation subject 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.
The causal relationship to study drug is determined by a physician and should be used to assess 
all adverse events (AE). The casual relationship can be one of the following:
Related: There is a reasonable causal relationship between study drug administration and 
the AE.
Not related: There is not a reasonable causal relationship between study drug 
administration and the AE. 
The term "reasonable causal relationship" means there is evidence to suggest a causal 
relationship. 
Adverse events can be spontaneously reported or elicited during open-ended questioning, 
examination, or evaluation of a subject. (In order to prevent reporting bias, subjects should not be 
questioned regarding the specific occurrence of one or more AEs.)
BMS 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.
6.1
Serious Adverse Events
A Serious Adverse Event (SAE) is any untoward medical occurrence that at any dose: 
•
results in death;
•
is life-threatening (defined as an event in which the subject 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);
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•
requires inpatient hospitalization or causes prolongation of existing hospitalization (see 
NOTE below);
•
results in persistent or significant disability/incapacity;
•
is a congenital anomaly/birth defect; 
•
is an important medical event (defined as a medical event(s) that may not be immediately 
life-threatening or result in death or hospitalization but, based upon appropriate medical and 
scientific judgment, may jeopardize the subject or may require intervention [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 6.6 for the definition of potential DILI.).
Suspected transmission of an infectious agent (e.g., pathogenic or nonpathogenic) via the study 
drug 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 6.4
for reporting pregnancies).
NOTE: 
The following hospitalizations are not considered SAEs in BMS clinical studies: 
−
a visit to the emergency room or other hospital department < 24 hours, that does not 
result in admission (unless considered an important medical or life-threatening event).
−
elective surgery, planned prior to signing consent.
−
admissions as per protocol for a planned medical/surgical procedure.
−
routine health assessment requiring admission for baseline/trending of health status (e.g., 
routine colonoscopy).
−
medical/surgical admission other than to remedy ill health and planned prior to entry into 
the study. Appropriate documentation is required in these cases.
−
admission encountered for another life circumstance that carries no bearing on health 
status and requires no medical/surgical intervention (e.g., lack of housing, economic 
inadequacy, caregiver respite, family circumstances, administrative reason).
−
Admission for administration of anticancer therapy in the absence of any other SAEs 
(applies to oncology protocols)
6.1.1
Serious Adverse Event Collection and Reporting
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 subject’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. All SAEs must be collected that occur during the screening period 
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and within 100 days of discontinuation of dosing. If applicable, SAEs must be collected that 
relate to any later protocol-specified procedure (e.g., a follow-up skin biopsy).
The investigator must report any SAE that occurs after these time periods and that is believed to 
be related to study drug or protocol-specified procedure. 
An SAE report must be completed for any event where doubt exists regarding its seriousness. 
If the investigator believes that an SAE is not related to study drug, but is potentially related to 
the conditions of the study (such as withdrawal of previous therapy or a complication of a study 
procedure), the relationship must be specified in the narrative section of the SAE Report Form.
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). When using 
paper forms, the reports 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. The paper forms should be used and submitted immediately, only 
in the event the electronic system is unavailable for transmission. 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.
If only limited information is initially available, follow-up reports are required. (Note: Follow-up 
SAE reports should include the same investigator term(s) initially reported.) 
If an ongoing SAE changes in its intensity or relationship to study drug or if new information 
becomes available, a follow-up SAE report should be sent within 24 hours to the BMS (or 
designee) using the same procedure used for transmitting the initial SAE report.
All SAEs should be followed to resolution or stabilization.
6.2
Nonserious Adverse Events
A nonserious adverse event is an AE not classified as serious.
6.2.1
Nonserious Adverse Event Collection and Reporting
The collection of nonserious AE information should begin at initiation of study drug. 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 subjects. 
Nonserious AEs should be followed to resolution or stabilization, or reported as SAEs if they 
become serious (see Section 6.1.1). Follow-up is also required for nonserious AEs that cause 
interruption or discontinuation of study drug and for those present at the end of study treatment 
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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.
6.3
Laboratory Test Result Abnormalities
The following laboratory test result abnormalities should be captured on the nonserious AE CRF 
page or SAE Report Form (paper or electronic) as appropriate:
•
Any laboratory test result that is clinically significant or meets the definition of an SAE 
•
Any laboratory test result abnormality that required the subject to have study drug 
discontinued or interrupted
•
Any laboratory test result abnormality that required the subject to receive specific corrective 
therapy.
It is expected that wherever possible, the clinical rather than laboratory term would be used by 
the reporting investigator (e.g., anemia versus low hemoglobin value).
6.4
Pregnancy
If, following initiation of the investigational product, it is subsequently discovered that a study 
subject is pregnant or may have been pregnant at the time of study drug 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 Section 6.1.1.
In most cases, the study drug will be permanently discontinued in an appropriate manner (eg,
dose tapering if necessary for subject 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 
subject.
The investigator must immediately notify the BMS (or designee) Medical Monitor of this event 
and complete and forward a Pregnancy Surveillance Form to BMS (or designee) within 24 hours 
and in accordance with SAE reporting procedures described in Section 6.1.1.
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 
BMS. Information on this pregnancy will be collected on the Pregnancy Surveillance Form.
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6.5
Overdose
An overdose is defined as the accidental or intentional administration of any dose of a product 
that is considered both excessive and medically important. All occurrences of overdose must be 
reported as an SAE (see Section 6.1.1 for reporting details.).
6.6
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 6.1.1 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. 
The following definition takes into account anticipated baseline compromise of liver function in
patients with HCC.
Potential drug induced liver injury is defined as:
•
Concurrent ALT ≥10 x ULN, AND
•
Total bilirubin ≥2 times ULN or baseline value (if elevated bilirubin at study entry), AND
•
No other immediately apparent possible causes of ALT elevation and hyperbilirubinemia,
including, but not limited to, tumor progression, acute viral hepatitis, cholestasis, pre-
existing hepatic disease or the administration of other drug(s), herbal medications and 
substances known to be hepatotoxic.
6.7
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. 
7
DATA MONITORING COMMITTEE AND OTHER EXTERNAL 
COMMITTEES
Not applicable.
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8
STATISTICAL CONSIDERATIONS
8.1
Sample Size Determination
This is a Phase 1/2 safety trial and the sample size during the dose evaluation phase depends on 
the observed toxicity.  Six or 9 NSCLC subjects per dose level will be treated according to the
Guidance for Safety Monitoring as shown in Table 3.1.1-1.  Utilizing the information on the 
observed toxicity of related AEs with Grades 3 and 4 (16%) among 304 subjects in a multidose, 
dose-ascending study with nivolumab monotherapy in subjects with selected advanced or 
recurrent malignancies (CA209003/MDX1106-03), there is a less than 20% posterior probability 
with this guidance that the toxicity rate could be 40% or higher, for different total number of 
subjects (6 or 9) in the dose evaluation phase, as shown in Table 8.1-1 (all numbers in the third 
column are less than 20%).  The posterior probability calculations assume a Beta(1, 4) prior 
distribution, which implies a toxicity rate around 20% as estimated from CA209003/MDX1106-
03 study.  Similarly, there is a less than 10% posterior probability that the toxicity rate could be 
45% or higher for the dose evaluation phase (all numbers in the last column of Table 8.1-1 are 
less than 10%).  
Table 8.1-1:
Posterior Probability of Toxicity Rate based on an Observed Number 
of Subjects with DLTs
Number of Subjects 
Treated
Observed Number of 
Subjects with DLTs*
P(toxicity rate ≥ 40%|Data)
P(toxicity rate ≥ 45%|Data)
6
0
0.006
0.003
1
0.046
0.023
2
0.167
0.0996
9
0
0.001
<0.001
1
0.013
0.005
2
0.058
0.027
3
0.169
0.093
* The number of subjects with DLTs allowed by the Guidance for Safety Monitoring Based on Observed Toxicity 
Outcomes during the Dose Evaluation Phase as described in Table 3.1.1-1.
If the safety and tolerability profile is established at a dose level in the dose evaluation phase, 
then that dose level will be expanded to a total of 20 PK evaluable subjects.  A subject will be 
considered PK evaluable when an adequate sampling has been completed during Cycle 1.  In the 
event of a higher than expected dropout rate prior to PK sampling in Cycle 3, additional subjects 
may be enrolled to reach an adequate number of subjects with PK profiles in Cycle 3.
One of the objectives of expansion cohorts is to characterize the pharmacokinetics (PK) of 
nivolumab in Chinese subjects in different dosing regimens. The sample size of 12-20 in the 
expansion cohorts is adequate to characterize PK within a dosing group.
Approximately 6-9 subjects are expected to be enrolled in dose evaluation and expanded to 
approximately 56-64 in total.
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8.2
Populations for Analyses
The following subject populations will be used in the study:
•
All enrolled subjects: All subjects who signed an informed consent form and were registered 
into the IVRS;
•
All treated subjects: All subjects who received at least one dose of study medication;
•
Pharmacokinetic Population: All subjects who received any nivolumab and have available 
concentration time data;
•
Immunogenicity Population: All subjects who received nivolumab and have at least pre-and
1 post treatment immunogenicity measurement; 
•
8.3
Endpoints
8.3.1
Primary Endpoint(s)
The primary objective is to characterize the safety, tolerability of nivolumab in Chinese subjects.  
The primary objective will be measured by:
•
Number and percent of subjects that experience drug-related grade 3-4 AEs occurring up to 
100 days after the last dose of study drug. [Time Frame - On a continuous basis up to 
100 days after the last dose of study drug];
•
Number and percent of subjects that experience drug-related grade 3-4 SAEs occurring up to 
100 days after the last dose of study drug. [Time Frame - On a continuous basis up to 
100 days after the last dose of study drug];
Number and percent of subjects with clinical laboratory abnormalities by worst toxicity grade by 
NCI CTCAE version 4.03 (as assessed at the planned times listed in Table 5.1-1, Table 5.1-2, 
Table 5.1-3, and Table 5.1-4). [Time Frame - On a continuous basis up to 100 days after the last 
dose of study drug].
8.3.2
Secondary Endpoint(s)
8.3.2.1
Pharmacokinetics
The secondary objective of characterizing the PK of nivolumab in Chinese subjects will be 
measured by nivolumab PK parameters derived from serum concentration versus time data, as 
described in Section 5.5. The pharmacokinetic parameters to be assessed, if data permits, in all 
cohorts include but are not limited to:
Cmax - Maximum observed serum concentration
Tmax - Time of maximum observed serum concentration
In addition, the following parameters will be determined for all subjects:
AUC(0-T) -Area under the plasma concentration-time curve from time zero to the last time of
the last quantifiable concentration.
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AUC(TAU) - Area under the concentration-time curve in one dosing interval
Ceoinf - Serum concentration achieved at the end of study drug infusion
Ctrough - Trough observed serum concentration at the end of dosing interval
Ctau - Concentration at the end of dosing interval
AI - Accumulation index; calculated based on ratio of an exposure measure at steady state to that 
after the first dose (exposure measure includes AUC(TAU), Cmax and Ctau)
T-HALFeff - Effective elimination half-life that explains the degree of observed AUC 
accumulation.
CLT - Total body clearance
8.3.2.2
Immunogenicity
The secondary objective relating to immunogenicity will be measured by the ADA status both at
the sample level and at the subject level. At the sample level a sample is characterized as
baseline ADA-positive, ADA-positive or ADA-negative to each study drug. At the subject level,
relevant ADA endpoints include proportion of subjects with a Baseline ADA-positive sample,
and proportion of ADA-positive subjects for each study drug. Time points for collection are
specified in Table 5.5.1-1, Table 5.5.1-2, and Table 5.5.1-3. Additional details will be presented 
in the SAP.
8.3.2.3
Anti-tumor response
The secondary objective of assessing the anti-tumor response of nivolumab will be measured by
the following endpoints at subject level:
•
Best overall response (BOR) by investigator using Response Evaluation Criteria in Solid 
Tumor (RECIST v1.1);  
•
Duration of response: is computed for subjects with a BOR of CR or PR, and defined as 
the time between the date of first response and the subsequent date of objectively 
documented disease progression or death, whichever occurs first.  For those subjects who
remain alive and have not progressed or received subsequent therapy, duration of 
response will be censored on the date of last tumor assessment; 
The following efficacy endpoints for each tumor type may be summarized by dose and/or across 
dose depending on data availability.
•
Objective response rate (ORR) is defined as the proportion of all treated subjects whose 
best overall response (BOR) is either a complete response (CR) or partial response (PR)
by investigator using Response Evaluation Criteria in Solid Tumor (RECIST v1.1); 
•
Median duration of response
•
Response rate at 24 weeks: is defined as the proportion of all treated subjects who has CR 
or PR by 24 weeks.
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•
Disease control rate (DCR) at 24 weeks is defined as the proportion of all treated subjects 
who has CR, PR or SD by 24 weeks
8.4
Analyses
8.4.1
Demographics and Baseline Characteristics
Demographics and disease baseline pertinent characteristics will be summarized by dose level 
and tumor type and overall using descriptive statistics (n, mean, standard deviation (SD), 
median, minimum, and maximum for continuous variables; n and percent for categorical 
variables). 
8.4.2
Efficacy Analyses
Individual subject’s BOR will be listed by dose and/or across dose if appropriate for each tumor 
type based on RECIST v1.1. BOR outcomes will be tabulated, by dose and/or across dose if 
appropriate, for each tumor type depending on data availability. 
Individual subject’s DOR will be listed by dose and/or across dose if appropriate for each tumor 
type.
The following analysis for each tumor type may be summarized by dose and/or across dose 
depending on data availability.
ORR will be calculated and corresponding two-sided 95% exact confidence intervals using 
Clopper and Pearson method will be provided by dose and/or across dose for each tumor type
depending on data availability. 
Response rate and disease control rate at 24 weeks will be estimated by Kaplan-Meier analysis of 
time to response and the corresponding two-sided 95% confidence interval by Greenwood 
formula will be provided by dose and /or across dose for each tumor type depending on data 
availability. 
Median duration of response will be estimated by Kaplan-Meier analysis and corresponding two-
sided 95% confidence intervals by Greenwood formula will be provided by dose and/or across 
dose for each tumor type as appropriate.
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8.4.3
Safety Analyses
All recorded AEs will be coded according to the most current version of MedDRA and listed by 
dose level and tumor type and overall. AEs will be summarized for each dose level and tumor 
type and overall by system organ class and preferred term using the worst grade within each 
category within a subject. Toxicity changes from baseline in clinical laboratory test results will 
be summarized by dose level and tumor type and overall using the worst on-treatment CTC 
grade values. Vital signs, ECGs and clinical laboratory test results will be listed and summarized 
by dose level and tumor type and overall.
8.4.4
Pharmacokinetic Analyses
Summary statistics will be tabulated for PK parameters of nivolumab as specified in Section 5.5. 
by dosing schedule and study cycle as appropriate. Ctrough will be summarized for all subjects. 
To assess attainment of steady state, plots of Ctrough versus time will be provided for all 
subjects. Pharmacokinetic concentrations of nivolumab from all subjects will be listed, and may 
be used in combination with other studies for exposure-response or population pharmacokinetic 
modeling, which will be part of a separate report.
8.4.7
Outcomes Research Analyses
Not applicable.
8.4.8
Other Analyses 
8.4.8.1
Immunogenicity analyses 
Data from the assessment of immunogenicity markers will be listed by subjects. Number and 
frequency of ADA response classifications will be summarized by dosing regimen. The details of
the ADA response classifications will be provided in the study statistical analyses plan (SAP) 
document. 
8.5
Interim Analyses
Administrative interim analyses may be performed at several times prior to completion of the 
study in order to facilitate program decisions and to support presentations or publications.
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STUDY MANAGEMENT
9.1
Compliance
9.1.1
Compliance with the Protocol and Protocol Revisions
The study shall be conducted as described in this approved protocol. All revisions to the protocol 
must be discussed with, and be prepared by, BMS. The investigator should not implement any 
deviation or change to the protocol without prior review and documented approval/favorable 
opinion from the IRB/IEC of an amendment, 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 IRB/IEC approval/favorable opinion, as soon as possible the deviation or change 
will be submitted to:
•
IRB/IEC for review and approval/favorable opinion;
•
BMS;
•
Regulatory Authority(ies), if required by local regulations.
Documentation of approval signed by the chairperson or designee of the IRB(s)/IEC(s) must be 
sent to BMS.
If an amendment substantially alters the study design or increases the potential risk to the subject: 
(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).
9.1.2
Monitoring
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 BMS internal auditors and government inspectors 
who must be allowed access to CRFs, source documents, other study files, and study facilities. 
BMS audit reports will be kept confidential.
The investigator must notify BMS promptly of any inspections scheduled by regulatory 
authorities, and promptly forward copies of inspection reports to BMS. 
9.1.2.1
Source Documentation
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 
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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.
9.1.3
Investigational Site Training
Bristol-Myers Squibb will provide quality investigational staff training prior to study initiation. 
Training topics will include but are not limited to: GCP, AE reporting, study details and 
procedure, electronic CRFs, study documentation, informed consent, and enrollment of WOCBP.
9.2
Records
9.2.1
Records Retention
The investigator 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, whichever is longer. The investigator must contact BMS prior to destroying 
any records associated with the study.
BMS will notify the investigator when the study records are no longer needed.
If the investigator withdraws from the study (eg, relocation, retirement), the records shall be 
transferred to a mutually agreed upon designee (eg, another investigator, IRB). Notice of such 
transfer will be given in writing to BMS.
9.2.2
Study Drug Records 
It is the responsibility of the investigator to ensure that a current disposition record of study drug 
(inventoried and dispensed) is maintained at the study site where study drug are inventoried and 
dispensed. 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 subject, including unique subject identifiers;
•
amount transferred to another area/site for dispensing or storage;
•
nonstudy disposition (eg, lost, wasted); 
•
amount destroyed at study site, if applicable;
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•
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.
BMS will provide forms to facilitate inventory control if the investigational site does not have an 
established system that meets these requirements.
9.2.3
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 BMS 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 paper or electronic SAE form and Pregnancy Surveillance form, respectively. Spaces may be 
left blank only in those circumstances permitted by study-specific CRF completion guidelines 
provided by BMS. 
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, including any paper or electronic 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. 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 BMS training requirements 
and must only access the BMS electronic data capture tool using the unique user account 
provided by BMS. User accounts are not to be shared or reassigned to other individuals.
9.3
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:
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• Subject recruitment (eg, among the top quartile of enrollers);
• Involvement in trial design;
• Other criteria (as determined by the study team).
The data collected during this study are confidential and proprietary to BMS. 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 BMS at 
the earliest practicable time prior to submission or presentation and otherwise within the time 
period set forth in the CTA.
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GLOSSARY OF TERMS
Term
Definition
Adverse Reaction
An adverse event that is considered by either the investigator 
or BMS as related to the investigational product
Unexpected Adverse Reaction
An adverse reaction, the nature or severity of which is not 
consistent with the applicable product information (eg, 
Investigator Brochure for an unapproved investigational 
product)
Serious Adverse Event
Serious adverse event defined as any untoward medical 
occurrence that at any dose: results in death; is life 
threatening (defined as an event in which the subject 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; results in 
persistent or significant disability/incapacity, is a congenital 
anomaly/birth defect; is an important medical event (defined 
as a medical event(s) that may not be immediately life 
threatening or result in death or hospitalization but, based 
upon appropriate medical and scientific judgment, may 
jeopardize the subject or may require intervention [eg, 
medical, surgical] to prevent one of the other serious 
outcomes listed in the definition above). Examples of such 
events include, but are not limited to, intensive treatment in 
an emergency room or at home for allergic bronchospasm; 
blood dyscrasias or convulsions that do not result in 
hospitalization.). For reporting purposes only, BMS also 
considers the occurrence of pregnancy, overdose (regardless 
of association with an AE), and cancer as important medical 
events.
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LIST OF ABBREVIATIONS
Term
Definition
ADA
anti-drug antibody
AE
adverse event
AI
accumulation index
AI_AUC
AUC Accumulation Index; ratio of AUC(TAU) at steady state to 
AUC(TAU) after the first dose
AI_Cmax
Cmax Accumulation Index; ratio of Cmax at steady state to Cmax after 
the first dose
AI_Ctau
Ctau Accumulation Index; ratio of Ctau at steady state to Ctau after the 
first dose
AIDS
acquired immunodeficiency syndrome
ALT
alanine aminotransferase
ANOVA
analysis of variance
APC
adenomatous polyposis coli
aPTT
activated partial thromboplastin time
ASR
age standardized rate
AST
aspartate aminotransferase
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
β-HCG
beta-human chorionic gonadotrophin
BA/BE
bioavailability/bioequivalence
%BE
percent biliary excretion
BMI
body mass index
BMS
Bristol-Myers Squibb
BOR
best overall response
BP
blood pressure
BUN
blood urea nitrogen
C
Celsius
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Term
Definition
Cavg
average concentration
Cexpected-tau
expected concentration in a dosing interval
CD28
Cluster of differentiation 28
CFR
Code of Federal Regulations 
CI
confidence interval
CLcr
creatinine clearance
CLT
total body clearance
Cmax, CMAX
maximum observed concentration
CNS
central nervous system
CRF
Case Report Form, paper or electronic
Ct
Expected concentration at a certain time, usually at the end of an 
expected future dosing interval (eg, concentration at 24 hours, 
concentration at 12 hours, etc.)
Ctau
Concentration in a dosing interval (eg, concentration at 24 hours, 
concentration at 12 hours, etc.)
CTC
common toxicity criteria
Ctrough
Trough observed plasma concentration
CV
coefficient of variation
DC
discontinue
dL
deciliter
DNA
deoxyribonucleic acid
DOR
duration of response
ECG
electrocardiogram
eCRF
Electronic Case Report Form
eg
exempli gratia (for example)
EGFR-TKI
epidermal growth factor receptor tyrosine kinase inhibitors
ECOG
Eastern Cooperation Oncology Group
ELISA
enzyme-linked immunosorbent assay 
EOI
end of infusion 
eSAE
electronic (submission) of SAE
FDA
Food and Drug Administration
FSH
follicle stimulating hormone
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Term
Definition
g
gram
GCP
Good Clinical Practice
G criteria
adjusted R2 value of terminal elimination phase
HBsAg
hepatitis B surface antigen
HBV
hepatitis B virus
HCG
human chorionic gonadotropin
HCV
hepatitis C virus
HIPAA
Health Insurance Portability and Accountability Act
HIV
Human Immunodeficiency Virus
HR
heart rate
HRT
hormone replacement therapy
ICH
International Conference on Harmonisation 
ie
id est (that is)
IEC
Independent Ethics Committee
IFN
interferon 
IMP
investigational medicinal products
IND
Investigational New Drug Exemption
IRB
Institutional Review Board
IU
International Unit
IV
intravenous
K
slope of the terminal phase of the log concentration-time curve
kg
kilogram
L
liter
LDH
lactate dehydrogenase
mAbs
monoclonal antibodies 
mg
milligram
MIC
minimum inhibitory concentration
min
minute
mL
milliliter
mPFS
median PFS
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Term
Definition
MTD
maximum tolerated dose
μg
microgram
N
number of subjects or observations
N/A
not applicable
NCCM
National Comprehensive Cancer Network
NCI CTCAE
National Cancer Institute Common Terminology Criteria for Adverse 
Events
ng
nanogram
NIMP
non-investigational medicinal products 
pAUCe
Extrapolated partial AUC from last quantifiable concentration to infinity
Pb
percent of bound drug
PBMC
peripheral blood mononuclear cell
PK
pharmacokinetics
PPK
population pharmacokinetic 
PR
partial response
PT
prothrombin time
PTT
partial thromboplastin time
Pu
percent of unbound drug
SAE
serious adverse event
SD
standard deviation
SLD
sum of the longest diameters
SmPC
summary of product characteristics 
SOP
Standard Operating Procedures
sp.
species
T
time
TCR
T-Cell Receptor
T-HALFeff
Effective elimination half life that explains the degree of AUC 
accumulation observed
Tmax, TMAX
time of maximum observed concentration
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Term
Definition
ULN
upper limit of normal
WOCBP
women of childbearing potential
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REFERENCES
1
Pardoll D. Does immune system see tumors as foreign or self?  Annu Rev Immunol 2003; 21: 
807-30.
2
Zhao P,  Dai M, Chen WQ, Li N. Cancer trends in China. JPN J Clin Oncol 2010; 40(4): 
281-285.
3
Wang YC, Wei LJ, Liu JT, Li SX, Wang QS. Comparison of cancer incidence between 
China and the USA.  Cancer Biol Med. 2012 June; 9(2): 128-132.
4
Globocan (Globocan 2008 data)
5
Tsunehiro T, Yoshiro S, Yuko K.  Gastric Cancer: current status of diagnosis and treatment.  
Cancers 2013, 5, 48-63.
6
China Cancer Registry Report (2009)
7
Lee A, et al. The battle against nasopharyngeal cancer. Radiotherapy and Oncology 2012, 
104: 272-278.
8
Qing X, Xie M, Jiang G.  Present situation and development of chemotherapy in 
nasopharyngeal cancinoma. J Clin Otorhinolaryngol Head Neck Surg(China) 2013; 27 (3).
9
Ma BB,Hui EP,Chan AT. Systemic approach to improving treatment outcome in 
nasopharyngeal carcinoma: Current and future directions. Cancer Sci 2008; 99(7) : 1311-
1318. 
10 Foo KF, et al. Systemic approach to improving treatment outcome in nasopharyngeal 
carcinoma: Current and future directions. Annals of Oncology 2002; 13: 150-156.
11 Chua D, et al. Capecitabine monotherapy for recurrent and metastatic nasopharyngeal cancer. 
JPN J Clin Oncol 2008; 38(4): 244-249.
12 Drew M. Pardoll. The blockade of immune checkpoints in cancer immunotherapy. Nature 
Review. 2012; Apr:252-264.
13 Nishimura H, Honjo T. PD-1: an inhbitory immunoreceptor involved in peripheral tolerance. 
Trends Immunol. 2001; 22: 265-8.
14 Freeman GJ, Long AJ, Iwai Y, et al. Engagement of the PD-1 immunoinhibitory receptor by 
a novel B7 family member leads to negative regulation of lymphocyte activation. J Exp Med. 
2000; 192: 1027-34.
15 Latchman Y, Wood CR, Chernova T, et al. PD-L2 is a second ligand for PD-1 and inhibits T 
cell activation. Nat Immunol. 2001; 2: 261-8.
16 Carter LL, Fouser LA, Jussif J, et al. PD-1:PD-l1 inhibitory pathway affects both CD4+ and 
CD8+ T cells and is overcome by IL-2. Eur J Immunol. 2002; 32: 634-43.
17 Sharpe AH, Wherry EJ, Ahmed R, Freeman GI. The function of programmed death 1 and its 
ligands in regulating autoimmunity and infections. Nat Immunol. 2007; 8(3): 239-45.
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18 Thompson RH, Gillett MD, Cheville JC, et al. Costumulatory B7-H1 in renal cell carcinoma 
patients: indicator of tumor aggressiveness and potential therapeutic target. Proc Natl Acad 
Sci. 2004; 101(49): 17174-9.
19 Konishi J, Yamazaki K, Azuma M, Kinoshita I, Dosaka-Akita H, Nishimura M. B7-H1 
expression on non-small cell lung cancer cells and its relationship with tumor-infiltrating 
lymphocytes and their PD-1 expression. Clin Cancer Res. 2004; 10 (15): 5094-100.
20 Strome SE, Dong H, Tamura H, Voss SG, Flies DB, Tamada K, et al. B7-H1 blockade 
augments adoptive T-cell immunotherapy for squamous cell carcinoma. Cancer Res 2003; 63: 
6501-5.
21 Azuma T, Yao S, Zhu G, Flies A, Flies S, Chen L. BY-H1 is a ubiquitous antiapoptotic 
receptor on cancer cells. Blood 2008; 111 (7): 3535-3643.
22 Thompson RH, Gillett MD, Cheville JC, et al. Costimulatory molecule B7-H1 in primary and 
metastatic clear cell renal cell carcinoma. Cancer. 2005; 104 (10): 2084-2091.
23 Wu C, Zhu Y, Jiang J, et al. Immunohistochemical localization of programmed death-1 
ligand (PD-L1) in gastric carcinoma and its clinical significance. Acta Histochem. 2006; 108 
(1): 19-24.
24 Nomi  T, Sho S, Akahori T, et al. Clinical significance and therapeutic potential of the 
programmed death-1 pathway in human pancreatic cancer. Clin. Cancer Res. 2007; 13 (7): 
2151-2157.
25 Clinical Study Report: MDX1106-03 (CA209003). A Phase 1, Open-Label, Multicenter, 
Multidose, Dose-escalation Study of BMS-936558 (MDX1106) in Subjects with Selected 
Advanced or Recurrent Malignancies. Bristol-Myers Squibb Company; 2013. Document 
Control No. 930044417.
26 Nivolumab Investigator Brochure version 14 (30-Jun-2015)
27 Wolchok JD, Hoos A, O'Day S, et al. Guidelines for the evaluation of immune therapy 
activity in solid tumors: immune-related response criteria. Clin. Cancer Res. 2009;15:7412-
20.
28 Rizvi NA, Mazières J, Planchard D, et al. Activity and safety of nivolumab, an anti-PD-1 
immune checkpoint inhibitor, for patients with advanced, refractory squamous non-small-cell 
lung cancer (ChckMate 063): a phase 2, single-arm trial. Lancet Oncol. 2015 Mar; 16(3): 
257-65.
29 Julie Brahmer, Karen L. Reckamp, Paul Bass, et al. Nivolumab versus Docetaxel in 
Advanced Squamous-Cell Non-Small-Cell Lung Cancer. N Engl J Med, 2015 May 31. [Epub 
ahead of print]
30 Luis Paz-Ares, Leora Horn, Hossein Borghaei, et al. Phase III, randomized trial (CheckMate 
057) of nivolumab (NIVO) versus docetaxel (DOC) in advanced non-squamous cell (non-SQ) 
non-small cell lung cancer (NSCLC). 2015 ASCO, LBA 109.
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31 Non-Clinical Expedited Safety Report for Nivolumab (Ad Hoc CARES #54344.1); BMS 
DCN 930067627 1.0
32 Ji et al. 2009, Clinical Trials 2010; 7: 653–663.
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APPENDIX 1
MANAGEMENT OF SAFETY ALGORITHMS FOR IMMUNO-
ONCOLOGY AGENTS
These general guidelines constitute guidance to the Investigator and may be supplemented by 
discussions with the Medical Monitor representing the Sponsor. The guidance applies to all 
immuno-oncology agents and regimens.
A general principle is that differential diagnoses should be diligently evaluated according to 
standard medical practice. Non inflammatory etiologies should be considered and appropriately 
treated.
Corticosteroids are a primary therapy for immuno-oncology drug-related adverse events. The 
oral equivalent of the recommended IV doses may be considered for ambulatory patients with 
low-grade toxicity. The lower bioavailability of oral corticosteroids should be taken into account 
when switching to the equivalent dose of oral corticosteroids.
Consultation with a medical or surgical specialist, especially prior to an invasive diagnostic or 
therapeutic procedure, is recommended. 
The frequency and severity of the related adverse events covered by these algorithms will depend 
on the immuno-oncology agent or regimen being used. 
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APPENDIX 2
SIMULATION TO EXAMINE PROBABILITY-BASED DESIGN VS. 
ALGORITHM BASED A+B DESIGNS
Guidance for safety monitoring during the dose evaluation phase listed in Table 1 is based on the 
probability of toxicity given observed DLTs, with a target toxicity of 0.25 (± 0.05). The target 
toxicity of 0.25 (± 0.05) gives 3 intervals in the toxicity probability scale: (0, 20%) that is 
considered lower than the target toxicity rate, [20%, 30%] that is considered within the toxicity 
target range, and (30%, 100%) that is considered toxic. For simplicity, we refer to this design as
the probability-based design. 
Using this probability-based design, during the dose evaluation phase, initially 6 eligible subjects 
will be treated at the dose level of 3 mg/kg. An additional 3 subjects may be added to the same 
dose level, i.e. a total number of 6 or 9 subjects will be treated during the dose evaluation phase 
for a given dose level.  A decision to stay at the same dose level (3 mg/kg) by treating an 
additional 3 subjects, to expand to 20 subjects, or to consider the next lower dose level (1 
mg/kg), will be guided by the number of subjects with dose-limiting toxicities (DLTs) observed 
during the dose evaluation phase (see Table 1). Subjects who do not complete the DLT 
observation period for reasons other than DLTs will be replaced, where the DLT observation 
period for each subject is defined as the 1st cycle of treatment (56 days of dosing).  A dose level 
of 1 mg/kg may be considered if the safety and tolerability profile for 3 mg/kg is evaluated as not 
acceptable, after consultation and agreement between the Investigator(s) and the sponsor as well 
as review of the existing clinical safety database from earlier studies.  Following a similar 
procedure, if the dose level of 1 mg/kg is evaluated as not acceptable as well, the findings will be 
discussed between the study investigators and the sponsor and an agreement will be reached as to 
whether a lower dose of nivolumab should be examined.
Table 1:
Guidance for Safety Monitoring Based on Observed 
Toxicity Outcomes during the Dose Evaluation 
Phase
Number of Subjects Treated
6
9
Number of Subjects 
with DLTs
0 
E 
E 
1 
S 
E 
2 
S 
E 
3 
D 
E 
4 
NA
D 
E: Expand to 20 subjects; 
S: Stay at the same dose level by treating additional 3 subjects; 
D: Discuss of proceeding with the next lower dose level
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Simulations were conducted to examine the performances of the probability-based design and the 
algorithm-based A+B designs (including a 3+3 design and a 6+3 design) for this study.  The 3+3
design starts from the higher dose level (3 mg/kg); adapts every cohort of 3 patients; considers 
the next dose level if unacceptable toxicity rate observed.  The 6+3 design is a variation of the 
3+3 design, which starts with 6 subjects instead of 3 subjects and then adapts a cohort of 3 
subjects afterwards.  The “1/3” Rule has been used in these two designs, in the way that:
•
If the observed toxicity rate is <1/3 in the first cohort of subjects (3 subjects for the 3+3 
design and 6 subjects for the 6+3 design), then this dose level will be considered safe to 
continue to the dose expansion phase;
•
If the observed toxicity rate is 1/3 in the first cohort of subjects, then another 3 subjects will 
be enrolled to evaluate this dose level further; 
•
If the observed toxicity rate is >1/3 in the first cohort of subjects, then this dose level will be 
considered too toxic and proceeding with the next lower dose level will be discussed;
•
If the observed toxicity rate is <1/3 in the two cohorts of subjects together (6 subjects in total 
for the 3+3 design and 9 subjects in total for the 6+3 design), then this dose level will be 
considered safe to continue to the dose expansion phase;
•
If the observed toxicity rate is ≥1/3 in the two cohorts of subjects together, then this dose 
level will be considered as too toxic and proceeding with the next lower dose level will be 
discussed.
The probability-based design is knowledge-driven, which assumes a target toxicity rate. On the 
contrary, the algorithm-based A+B design is algorithm-driven, which uses the “1/3” rule.  
Simulation implementation:
•
1000 simulated trials
•
Probability-based design as described above 
•
Algorithm-based 6+3 design as described above
•
Algorithm-based 3+3 design as described above
Toxicity scenarios for each dose level:
Dose
1mg
3mg
C1:
0.20,
0.30 
C2:
0.15,
0.30
C3:
0.20,
0.25
C4:
0.15,
0.25
C5:
0.15,
0.20
C6:
0.10,
0.20
C7:
0.10,
0.15
Assumption:  Monotonicity
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Simulation results: 
Table -2:
Simulation Results Summary
% Selected
Avg. tox rate (%)
1 mg/kg
3 mg/kg
Scenario 1
Tox level
0.20
0.30
Probability-based
% MTD
32.8
67.2
27.4
Algorithm-based 3+3 
% MTD
50.0
50.0
28.9
Algorithm-based 6+3 
% MTD
47.8
52.2
29.6
Note: Probability-based design selects the correct dose (3 mg/kg) more frequently than the algorithm-
based A+B designs (67.2% vs 50.0% or 52.2%); the algorithm-based A+B designs select sub-optimal 
dose level (1 mg/kg) more frequently (50.0% or 47.8% vs 32.8%); the average toxicity rates for the 
probability-based design is lower than the algorithm-based A+B designs, closer to the target toxicity rate 
of 25% and within the interval of [0.2, 0.3].
% Selected
Avg. tox rate (%)
1 mg/kg
3 mg/kg
Scenario 2
Tox level
0.15
0.30
Probability-based
% MTD
36.2
63.8
26.7
Algorithm-based 3+3 
% MTD
50.0
50.0
28.9
Algorithm-based 6+3 
% MTD
47.8
52.2
29.6
Note: Probability-based design selects the correct dose (3 mg/kg) more frequently than the algorithm-
based A+B designs (63.8% vs 50.0% or 52.2%); the algorithm-based A+B designs select sub-optimal 
dose level (1 mg/kg) more frequently (50.0% or 47.8% vs 36.2%); the average toxicity rates for the 
probability-based design is lower than the algorithm-based A+B designs, closer to the target toxicity rate 
of 25% and within the interval of [0.2, 0.3]. 
% Selected
Avg. tox rate (%)
1 mg/kg
3 mg/kg
Scenario 3
Tox level
0.20
0.25
Probability-based
% MTD
22.4
77.6
24.2
Algorithm-based 3+3 
% MTD
40.0
60.0
22.8
Algorithm-based 6+3 
% MTD
34.1
65.9
23.6
Note: Probability-based design selects the correct dose (3 mg/kg) more frequently than the algorithm-
based A+B designs (77.6% vs 60.0% or 65.9%); the algorithm-based A+B designs select sub-optimal 
dose level (1 mg/kg) more frequently (40.0% or 34.1% vs 22.4%); the average toxicity rates for the 
probability-based design is higher than the algorithm-based A+B designs, closer to the target toxicity rate 
of 25% and within the interval of [0.2, 0.3]. 
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Table -2:
Simulation Results Summary
% Selected
Avg. tox rate (%)
1 mg/kg
3 mg/kg
Scenario 4
Tox level
0.15
0.25
Probability-based
% MTD
22.8
77.2
22.9
Algorithm-based 3+3 
% MTD
40.0
60.0
22.8
Algorithm-based 6+3 
% MTD
34.1
65.9
23.6
Note: Probability-based design selects the correct dose (3 mg/kg) more frequently than the algorithm-
based A+B designs (77.2% vs 60.0% or 65.9%); the algorithm-based A+B designs select sub-optimal 
dose level (1 mg/kg) more frequently (40.0% or 34.1% vs 22.8%); the average toxicity rates for 
probability-based design is between that of the algorithm-based A+B designs and within the interval of 
[0.2, 0.3].
% Selected
Avg. tox rate (%)
1 mg/kg
3 mg/kg
Scenario 5
Tox level
0.15
0.20
Probability-based
% MTD
13.9
86.1
19.5
Algorithm-based 3+3 
% MTD
30.2
69.8
17.7
Algorithm-based 6+3 
% MTD
22.0
78.0
18.7
Note: Probability-based design selects the correct dose (3 mg/kg) more frequently than the algorithm-
based A+B designs (86.1% vs 69.8% or 78.0%); the algorithm-based A+B designs select sub-optimal 
dose level (1 mg/kg) more frequently (30.2% or 22.0% vs 13.9%); the average toxicity rates for 
probability-based design is higher than the algorithm-based A+B designs, closer to the target toxicity rate 
of 25% and within the interval of [0.2, 0.3]. 
% Selected
Avg. tox rate (%)
1 mg/kg
3 mg/kg
Scenario 6
Tox level
0.10
0.20
Probability-based
% MTD
13.7
86.3
19.1
Algorithm-based 3+3 
% MTD
30.2
69.8
17.7
Algorithm-based 6+3 
% MTD
22.0
78.0
18.7
Note: Probability-based design selects the correct dose (3 mg/kg) more frequently than the algorithm-
based A+B designs (86.3% vs 69.8% or 78.0%); the algorithm-based A+B designs select sub-optimal 
dose level (1 mg/kg) more frequently (30.2% or 22.0% vs 13.7%); the average toxicity rates for 
probability-based design is higher than the algorithm-based A+B designs, closer to the target toxicity rate 
of 25% and within the interval of [0.2, 0.3].
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Table -2:
Simulation Results Summary
% Selected
Avg. tox rate (%)
1 mg/kg
3 mg/kg
Scenario 7
Tox level
0.10
0.15
Probability-based
% MTD
7.1
92.9
15.3
Algorithm-based 3+3 
% MTD
18.6
81.4
11.9
Algorithm-based 6+3 
% MTD
11.2
88.8
13.8
Note: Probability-based design selects the correct dose (3 mg/kg) more frequently than the algorithm-
based A+B designs (92.9% vs 81.4% or 88.8%); the algorithm-based A+B designs select sub-optimal 
dose level (1 mg/kg) more frequently (18.6% or 11.2% vs 7.1%); the average toxicity rates for 
probability-based design is higher than the algorithm-based A+B designs, closer to the target toxicity rate 
of 25% and within the interval of [0.2, 0.3].
In summary, the probability-based design selects the correct dose (3 mg/kg) more frequently than 
the algorithm-based A+B designs for all the scenarios evaluated.  The average toxicity rates for 
probability-based design are closer to the target toxicity rate of 25% in most cases, except for
scenario 4, where three average toxicity rates are close to each other.  The algorithm-based A+B
designs are more conservative than the probability-based design, and tend to select sub-optimal 
dose (1 mg/kg) more frequently.
In summary, the probability-based design selects the correct dose (3 mg/kg) more frequently than 
the algorithm-based A+B designs for all the scenarios evaluated.  The average toxicity rates for 
probability-based design are closer to the target toxicity rate of 25% in most cases, except for
scenario 4, where three average toxicity rates are close to each other.  The algorithm-based A+B
designs are more conservative than the probability-based design, and tend to select sub-optimal 
dose (1 mg/kg) more frequently.
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APPENDIX 3
RECIST 1.1 GUIDELINES
1
EVALUATION OF LESIONS
At baseline, tumor lesions/lymph nodes will be categorized measurable or non-measurable as 
follows:
1.1
Measurable
Tumor lesions: Must be accurately measured in at least one dimension (longest diameter in the 
plane of measurement is to be recorded) with a minimum size of:
1. 10 mm by CT scan (CT scan slice thickness no greater than 5 mm)
2. 10 mm caliper measurement by clinical exam (lesions which cannot be accurately measured 
with calipers should be recorded as non-measurable)
3. 20 mm by chest x-ray
Malignant lymph nodes: To be considered pathologically enlarged and measurable, a lymph 
node must be ≥15 mm in short axis when assessed by CT scan (CT scan slice thickness 
recommended to be no greater than 5 mm).
Lymph nodes merit special mention since they are normal anatomical structures which may be 
visible by imaging even if not involved by tumor. Pathological nodes which are defined as 
measurable and may be identified as target lesions must meet the criterion of a short axis of 
≥15 mm by CT scan. Only the short axis of these nodes will contribute to the baseline sum. The 
short axis of the node is the diameter normally used by radiologists to judge if a node is involved 
by solid tumor. Nodal size is normally reported as two dimensions in the plane in which the 
image is obtained (for CT scan this is almost always the axial plane; for MRI the plane of 
acquisition may be axial, saggital or coronal). The smaller of these measures is the short axis. 
For example, an abdominal node which is reported as being 20 mm x 30 mm has a short axis of 
20 mm and qualifies as a malignant, measurable node. In this example, 20 mm should be 
recorded as the node measurement. All other pathological nodes (those with short axis ≥10 mm 
but < 15 mm) should be considered non-target lesions. Nodes that have a short axis < 10 mm are 
considered non-pathological and should not be recorded or followed.
1.2
Non-Measurable
All other lesions are considered non-measurable, including small lesions (longest diameter 
< 10mm or pathological lymph nodes with ≥10 to < 15 mm short axis) as well as truly 
non-measurable lesions. Lesions considered truly non-measurable include: leptomeningeal 
disease, ascites, pleural or pericardial effusion, inflammatory breast disease, lymphangitic 
involvement of skin or lung, abdominal masses/abdominal organomegaly identified by physical 
exam that is not measurable by reproducible imaging techniques.
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2
BASELINE DOCUMENTATION OF ‘TARGET’ AND ‘NON-TARGET’
LESIONS
When more than one measurable lesion is present at baseline all lesions up to a maximum of five 
lesions total (and a maximum of two lesions per organ) representative of all involved organs 
should be identified as target lesions and will be recorded and measured at baseline (this means 
in instances where patients have only one or two organ sites involved a maximum of two and 
four lesions respectively will be recorded).
Target lesions should be selected on the basis of their size (lesions with the longest diameter), be 
representative of all involved organs, but in addition should be those that lend themselves to 
reproducible repeated measurements. It may be the case that, on occasion, the largest lesion does 
not lend itself to reproducible measurement in which circumstance the next largest lesion which 
can be measured reproducibly should be selected.
A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target 
lesions will be calculated and reported as the baseline sum diameters. If lymph nodes are to be 
included in the sum, then as noted above, only the short axis is added into the sum. The baseline 
sum diameters will be used as reference to further characterize any objective tumor regression in 
the measurable dimension of the disease.
All other lesions (or sites of disease) including pathological lymph nodes should be identified as 
non-target lesions and should also be recorded at baseline. Measurements are not required and 
these lesions should be followed as ‘present’, ‘absent’, or in rare cases ‘unequivocal progression’ 
(more details to follow). In addition, it is possible to record multiple nontarget lesions involving 
the same organ as a single item on the case record form (eg, ‘multiple enlarged pelvic lymph 
nodes’ or ‘multiple liver metastases’).
3
RESPONSE CRITERIA
3.1
Evaluation of Target Lesions
Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes 
(whether target or non-target) must have reduction in short axis to < 10 mm.
Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, taking 
as reference the baseline sum diameters.
Progressive Disease (PD): At least a 20% increase in the sum of diameters of target lesions, 
taking as reference the smallest sum on study (this includes the baseline sum if that 
is the smallest on study). In addition to the relative increase of 20%, the sum must 
also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of 
one or more new lesions is also considered progression).
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest sum diameters while on study.
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3.1.1
Special Notes on the Assessment of Target Lesions
3.1.1.1
Lymph nodes
Lymph nodes identified as target lesions should always have the actual short axis measurement 
recorded (measured in the same anatomical plane as the baseline examination), even if the nodes 
regress to below 10 mm on study. This means that when lymph nodes are included as target 
lesions, the ‘sum’ of lesions may not be zero even if complete response criteria are met, since a 
normal lymph node is defined as having a short axis of < 10 mm. Case report forms or other data 
collection methods may therefore be designed to have target nodal lesions recorded in a separate 
section where, in order to qualify for CR, each node must achieve a short axis < 10 mm. For PR, 
SD and PD, the actual short axis measurement of the nodes is to be included in the sum of target 
lesions.
3.1.1.2
Target lesions that become ‘too small to measure’
While on study, all lesions (nodal and non-nodal) recorded at baseline should have their actual 
measurements recorded at each subsequent evaluation, even when very small (eg, 2 mm). 
However, sometimes lesions or lymph nodes which are recorded as target lesions at baseline 
become so faint on CT scan that the radiologist may not feel comfortable assigning an exact 
measure and may report them as being ‘too small to measure’. When this occurs it is important 
that a value be recorded on the case report form. If it is the opinion of the radiologist that the 
lesion has likely disappeared, the measurement should be recorded as 0 mm. If the lesion is 
believed to be present and is faintly seen but too small to measure, a default value of 5 mm 
should be assigned (Note: It is less likely that this rule will be used for lymph nodes since they 
usually have a definable size when normal and are frequently surrounded by fat such as in the 
retroperitoneum; however, if a lymph node is believed to be present and is faintly seen but too 
small to measure, a default value of 5 mm should be assigned in this circumstance as well). This 
default value is derived from the 5 mm CT slice thickness (but should not be changed with
varying CT slice thickness). The measurement of these lesions is potentially non-reproducible, 
therefore providing this default value will prevent false responses or progressions based upon 
measurement error. To reiterate, however, if the radiologist is able to provide an actual measure, 
that should be recorded, even if it is below 5 mm.
3.1.1.3
Lesions that split or coalesce on treatment
When non-nodal lesions ‘fragment’, the longest diameters of the fragmented portions should be 
added together to calculate the target lesion sum. Similarly, as lesions coalesce, a plane between 
them may be maintained that would aid in obtaining maximal diameter measurements of each 
individual lesion. If the lesions have truly coalesced such that they are no longer separable, the 
vector of the longest diameter in this instance should be the maximal longest diameter for the 
‘coalesced lesion’.
3.2
Evaluation of Non-Target Lesions
This section provides the definitions of the criteria used to determine the tumor response for the 
group of non-target lesions. While some non-target lesions may actually be measurable, they 
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need not be measured and instead should be assessed only qualitatively at the time points 
specified in the protocol.
Complete Response (CR): Disappearance of all non-target lesions and normalization of tumor 
marker level. All lymph nodes must be non-pathological in size (< 10mm short 
axis). 
Non-CR/Non-PD: Persistence of one or more non-target lesion(s) and/or maintenance of tumor 
marker level above the normal limits.
Progressive Disease (PD): Unequivocal progression (see comments below) of existing non-
target lesions. (Note: the appearance of one or more new lesions is also considered 
progression).
3.2.1
Special Notes on Assessment of Progression of Non-Target Disease
The concept of progression of non-target disease requires additional explanation as follows:
3.2.1.1
When the patient also has measurable disease
In this setting, to achieve ‘unequivocal progression’ on the basis of the non-target disease, there 
must be an overall level of substantial worsening in non-target disease such that, even in 
presence of SD or PR in target disease, the overall tumor burden has increased sufficiently to 
merit discontinuation of therapy (see examples in Appendix 2 and further details below). A 
modest ‘increase’ in the size of one or more non-target lesions is usually not sufficient to qualify 
for unequivocal progression status. The designation of overall progression solely on the basis of 
change in non-target disease in the face of SD or PR of target disease will therefore be extremely 
rare.
3.2.1.2
When the patient has only non-measurable disease
This circumstance arises in some trials when it is not a criterion of study entry to have 
measurable disease. The same general concepts apply here as noted above, however, in this 
instance there is no measurable disease assessment to factor into the interpretation of an increase 
in non-measurable disease burden. Because worsening in non-target disease cannot be easily 
quantified (by definition: if all lesions are truly non-measurable) a useful test that can be applied 
when assessing patients for unequivocal progression is to consider if the increase in overall 
disease burden based on the change in non-measurable disease is comparable in magnitude to the 
increase that would be required to declare PD for measurable disease: ie, an increase in tumor 
burden representing an additional 73% increase in ‘volume’ (which is equivalent to a 20% 
increase diameter in a measurable lesion). Examples include an increase in a pleural effusion
from ‘trace’ to ‘large’, an increase in lymphangitic disease from localized to widespread, or may 
be described in protocols as ‘sufficient to require a change in therapy’. If ‘unequivocal 
progression’ is seen, the patient should be considered to have had overall PD at that point. While 
it would be ideal to have objective criteria to apply to non-measurable disease, the very nature of 
that disease makes it impossible to do so; therefore the increase must be substantial.
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3.2.2
New Lesions
The appearance of new malignant lesions denotes disease progression; therefore, some 
comments on detection of new lesions are important. There are no specific criteria for the 
identification of new radiographic lesions; however, the finding of a new lesion should be 
unequivocal: ie, not attributable to differences in scanning technique, change in imaging 
modality or findings thought to represent something other than tumor (for example, some ‘new’ 
bone lesions may be simply healing or flare of pre-existing lesions). This is particularly 
important when the patient’s baseline lesions show partial or complete response. For example, 
necrosis of a liver lesion may be reported on a CT scan report as a ‘new’ cystic lesion, which it is 
not.
A lesion identified on a follow-up study in an anatomical location that was not scanned at 
baseline is considered a new lesion and will indicate disease progression. An example of this is 
the patient who has visceral disease at baseline and while on study has a CT or MRI brain 
ordered which reveals metastases. The patient’s brain metastases are considered to be evidence 
of PD even if he/she did not have brain imaging at baseline.
If a new lesion is equivocal, for example because of its small size, continued therapy and 
follow-up evaluation will clarify if it represents truly new disease. If repeat scans confirm there 
is definitely a new lesion, then progression should be declared using the date of the initial scan. 
While FDG-PET response assessments need additional study, it is sometimes reasonable to 
incorporate the use of FDG-PET scanning to complement CT scanning in assessment of 
progression (particularly possible ‘new’ disease). New lesions on the basis of FDG-PET imaging 
can be identified according to the following algorithm:
1. Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of PD based 
on a new lesion.
2. No FDG-PET at baseline and a positive FDG-PET at follow-up: If the positive FDG-PET at 
follow-up corresponds to a new site of disease confirmed by CT, this is PD. If the positive 
FDG-PET at follow-up is not confirmed as a new site of disease on CT, additional follow-up 
CT scans are needed to determine if there is truly progression occurring at that site (if so, the 
date of PD will be the date of the initial abnormal FDG-PET scan). If the positive FDG-PET 
at follow-up corresponds to a pre-existing site of disease on CT that is not progressing on the 
basis of the anatomic images, this is not PD.
3.3
Response Assessment
3.3.1
Evaluation of Best Overall Response
The best overall response is the best response recorded from the start of the study treatment until 
the end of treatment taking into account any requirement for confirmation. The patient’s best 
overall response assignment will depend on the findings of both target and non-target disease and 
will also take into consideration the appearance of new lesions. Furthermore, depending on the 
nature of the study and the protocol requirements, it may also require confirmatory measurement.
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3.3.2
Time Point Response
It is assumed that at each protocol specified time point, a response assessment occurs. Table 
3.3.2A provides a summary of the overall response status calculation at each time point for 
patients who have measurable disease at baseline. When patients have non-measurable (therefore 
non-target) disease only, Table 3.3.2B is to be used. 
Table 3.3.2A:
Time Point Response: Patients With Target (± Non-Target) 
Disease
Target Lesions
Non-Target Lesions
New Lesions
Overall 
Response
CR
CR
No
CR
CR
Non-CR/non-PD
No
PR
CR
Not evaluated
No
PR
PR
Non-PD or not all 
evaluated
No
PR
SD
Non-PD or not all 
evaluated
No
SD
Not all evaluated
Non-PD
No
NE
PD
Any
Yes or No
PD
Any
PD
Yes or No
PD
Any
Any
Yes
PD
CR = complete response, PR = partial response, SD = stable disease, PD = progressive disease and 
NE = inevaluable
Table 3.3.2B:
Time Point Response: Patients with Non-target Disease Only
Non-Target Lesions
New Lesions
Overall Response
CR
No
CR
Non-CR/non-PD
No
Non-CR/non-PDa
Not all evaluated
No
NE
Unequivocal PD
Yes or No
PD
Any
Yes
PD
CR = complete response, PD = progressive disease and NE = inevaluable
a Non-CR/non-PD is preferred over SD for non-target disease since SD is increasingly used as endpoint for 
assessment of efficacy in some trials so to assign this category when no lesions can be measured is not advised.
3.3.3
Best Overall Response 
Best response determination of complete or partial response requires confirmation: Complete or 
partial responses may be claimed only if the criteria for each are met at a subsequent time point 
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of ≥4 weeks later. In this circumstance, the best overall response can be interpreted as in 
Table 3.3.3.
Special note on response assessment: When nodal disease is included in the sum of target 
lesions and the nodes decrease to ‘normal’ size (< 10 mm), they may still have a measurement 
reported on scans. This measurement should be recorded even though the nodes are normal in 
order not to overstate progression should it be based on increase in size of the nodes. As noted 
earlier, this means that patients with CR may not have a total sum of ‘zero’ on the case report 
form (CRF).
Table 3.3.3:
Best Overall Response (Confirmation of CR&PR Required)
Overall Response 
First Time Point
Overall Response 
Subsequent Time Point
BEST Overall Response
CR
CR
CR
CR
PR
SD, PD OR PRa
CR
SD
SD provided minimum criteria for SD durationb met, 
otherwise, PD
CR
PD
SD provided minimum criteria for SD durationb met, 
otherwise, PD
CR
NE
SD provided minimum criteria for SD durationb met, 
otherwise, NE
PR
CR
PR
PR
PR
PR
PR
SD
SD
PR
PD
SD provided minimum criteria for SD durationb met, 
otherwise, PD
PR
NE
SD provided minimum criteria for SD duration bmet, 
otherwise, NE
NE
NE
NE
CR = complete response, PR = partial response, SD = stable disease, PD = progressive disease, and 
NE = inevaluable
a If a CR is truly met at first time point, then any disease seen at a subsequent time point, even disease meeting PR 
criteria relative to baseline, makes the disease PD at that point (since disease must have reappeared after CR). 
Best response would depend on whether minimum duration for SD was met. However, sometimes ‘CR’ may be 
claimed when subsequent scans suggest small lesions were likely still present and in fact the patient had PR, not 
CR at the first time point. Under these circumstances, the original CR should be changed to PR and the best 
response is PR.
b Minimum criteria for SD duration is 6 weeks.
3.3.4
Confirmation Scans
Verification of Response: To be assigned a status of CR or PR, changes in tumor measurements 
must be confirmed by consecutive repeat assessments that should be performed no less than 
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28 days after the criteria for response are first met. For this study, the next scheduled tumor 
assessment can meet this requirement.
Verification of Progression: Progression of disease should be verified in cases where progression 
is equivocal. If repeat scans confirm PD, then progression should be declared using the date of 
the initial scan. If repeat scans do not confirm PD, then the subject is considered to not have 
progressive disease.
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APPENDIX 4
ECOG PERFORMANCE STATUS
ECOG PERFORMANCE STATUS
Grade
ECOG
0
Fully active, able to carry on all pre-disease performance without restriction.
1
Restricted in physically strenuous activity but ambulatory and able to carry out work of a 
light or sedentary nature, e.g., light house work, office work.
2
Ambulatory and capable of all self-care but unable to carry out any work activities. Up 
and about more than 50% of waking hours.
3
Capable of only limited selfcare, confined to bed or chair more than 50% of waking 
hours.
4
Completely disabled. Cannot carry on any selfcare. Totally confined to bed or chair.
5
Dead
Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, T.E., McFadden, E.T., Carbone, P.P.: Toxicity 
And Response Criteria Of The Eastern Cooperative Oncology Group. Am J Clin Oncol 5: 649 - 655, 1982
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APPENDIX 5
CHILD-PUGH SCORE
Score
Points
Child-Pugh A
5 - 6
Child-Pugh B
7 - 9
Child-Pugh C
> 9
Scoring
Score
Measure
1 Point
2 Points
3 Points
Ascites
Absent
Slight
Moderate
Serum bilirubin (mg/dl)
< 2.0
2.0 - 3.0
> 3.0
Serum albumin (g/dl)
> 3.5
2.8 - 3.5
< 2.8
PT prolongation
or INR
< 4 sec
< 1.7
4 - 6 sec
1.7 - 2.3
> 6 sec
> 2.3
Encephalopathy grade
None
1 - 2
3 - 4
Encephalopathy Grading
Encephalopathy
Grade
Clinical Definition
Grade 0
Normal consciousness, personality, and neurological examination
Grade 1
Restless, sleep disturbed, irritable/agitated, tremor, and impaired 
handwriting
Grade 2
Lethargic, time-disoriented, inappropriate, asterixis, and ataxia
Grade 3
Somnolent, stuporous, place-disoriented, hyperactive reflexes, and 
rigidity
Grade 4
Unrousable coma, no personality/behavior, decerebrate
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