Conditions: Melanoma
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 1009
Healthy volunteers: no

Brief summary:
The purpose of this study is to determine the rate and frequency of high-grade (CTCAE v4.0 Grade 3 or higher), treatment-related, select adverse events in subjects with histologically confirmed stage III (unresectable) or stage IV melanoma and progression post prior treatment containing an anti-Cytotoxic T Lymphocyte Antigen (CTLA-4) monoclonal antibody, treated with Nivolumab (BMS-936558) at a dose of 3 mg/kg every two weeks.

Detailed description:

Arms:
arm 1: Nivolumab (BMS-936558) Intravenous solution every 2 weeks

Interventions: intervention 1: Nivolumab (BMS-936558)
Intervention descriptions: intervention 1: None

Protocol document:
Prot_001.pdf: 
Page:
1
Protocol Number:
CA209172
IND Number:
NA
EUDRACT Number
2014-001286-28
Date:
18-Apr-2014
Revised Date
17-Nov-2017
Clinical Protocol CA209172
A Single-Arm, Open-Label, Multicenter Clinical Trial with Nivolumab (BMS-936558) for 
Subjects with Histologically Confirmed Stage III (unresectable) or Stage IV Melanoma 
Progressing After Prior Treatment Containing an Anti-CTLA-4 Monoclonal Antibody 
CheckMate 172: CHECKpoint pathway and nivoluMAb clinical Trial Evaluation 172
Revised Protocol 06
Incorporates Amendment 08 and Administrative Letter 06
Study Director
Elena Grigoryeva, MD, PhD
This document is the confidential and proprietary information of Bristol-Myers Squibb 
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) that may 
be added to this document is also confidential and proprietary to BMS and must be kept in 
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confidence in the same manner as the contents of this document. Any person who receives 
this document without due authorization from BMS is requested to return it to BMS or 
promptly destroy it. All other rights reserved. References to BMS in this protocol may apply 
to partners to which BMS has transferred obligations, eg, a Contract Research Organization 
(CRO).
Replaces all version(s) of this 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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Date: 17-Nov-2017
DOCUMENT HISTORY
Document
Date of Issue
Summary of Change
Revised 
Protocol 06
17-Nov-2017
Incorporates Amendment 08 and Administrative Letter 06
Amendment 08
17-Nov-2017
Changed the duration of follow-up from 5 years to 2 years after the first 
dose of study drug treatment due to a decision to close the study in 2018.
This decision was based on adequate safety data obtained since the 
study’s opening in 2014, which are consistent with the known safety 
profiles of the study drugs.
Administrative 
Letter 06
25-Jan-2017
Changed MM Address
Revised 
Protocol 05
08-Dec-2015
Incorporates Amendment 06
Amendment 06
08-Dec-2015
Adds dosing windows to the Time and Events Schedule
Revised 
Protocol 04
28-Oct-2015
Incorporates Administrative Letter 05 and Amendment 05
Amendment 05
28-Oct-2015

To provide further clarity on the requirements for lipase testing

To provide clarity on dose calculations 

To allow the EQ-5D-3L to be completed without an office visit if 
one is not otherwise needed.
Administrative 
Letter 05
23-Jul-2015

The of expectations when lipase results are not available prior to 
dosing

Aligning the footnotes of Table 5.1-2 and Section 5.3, Safety 
Assessments with the requirements for lipase described in Table 5.1-
2. 

Assessments allowed to be done according to standard of care

At what cycle assessments should start and assessment windows

When RECIST 1.1 criteria must be used.
NOTE: Administrative Letter 04 was not finalized because it was 
considered to not be needed. However, Administrative Letter 05 was 
created and finalized with the mistaken understanding that 
Administrative Letter 04 was finalized.
Revised 
Protocol 03
02-Jun-2015
Incorporates Amendment 04
Amendment 04
02-Jun-2015
Decreases sample size
Revised 
Protocol 02
19-Mar-2015
Incorporates Amendment 03
Amendment 03
19-Mar-2015
This Amendment removes the inclusion of the treatment-naïve patients, 
also referred to as the first-line cohort.
Revised 
Protocol 01
16-Jan-2015
Incorporates Amendment 02 and Administrative Letter 03.
Amendment 02
16-Jan-2015

The inclusion criteria have been expanded and the exclusion 
criteria have been minimized. 

The study rationale also offers greater support for the expanded 
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Revised Protocol No.: 06
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Date: 17-Nov-2017
Document
Date of Issue
Summary of Change
subject population. 

Treatment-naïve patients have been added. 

The options for palliative local therapy have also been expanded 
to meet the needs of the current patient populations. 

The EORTC QLQ-C30 has been eliminated from the patients’ 
follow up. 

The time points and frequency of assessments have been 
updated. 

The subjects in Cohort 2 will now be analyzed at the same 
frequency to Cohort 1, so the separate Time and Events 
Schedule for Cohort 2 was removed. 

The statistical section has been reformatted to aid understanding 
of the analyses to support the respective primary, secondary, 
objectives. 

The timing and frequency of all assessments have been removed 
from sections of the protocol outside of the Time and Events 
tables. 

The endpoints are more representative of the data that will be 
collected in support of the objectives. 

The requirement for electrocardiograms has been removed.
Administrative 
Letter 03
02-Oct-2014
Correct the tables in Section 5.1, Flow Chart/Time and Events Schedule 
so that the information in these tables is consistent with the text in the 
protocol.
Revised 
Protocol 01a
04-Jun-2014
Incorporates Administrative Letter 01, Administrative Letter 02, and 
Amendment 01.
Amendment 01
04-Jun-2014
Revisions aim to comply with the Health Authority requirements in 
Germany
Administrative 
Letter 02
21-May-2014
A number was missing from Exclusion Criterion 4cviii. This letter is to 
provide you with the missing number. This is an administrative protocol 
change and does not significantly affect the safety of subjects, study 
scope, or scientific quality of a Phase IIb. Accordingly, it may be 
implemented immediately.
Administrative 
Letter 01
12-May-2014
The title of this protocol has been modified for consistency with the 
BMS conventions for protocols in the nivolumab program. This is an 
administrative protocol change and does not significantly affect the 
safety of subjects, study scope, or scientific quality of a Phase II or III 
protocol. Accordingly, it may be implemented immediately.
Original 
Protocol
18-Apr-2014
Not applicable
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SYNOPSIS
Clinical Protocol CA209172
Protocol Title:  A Single-Arm, Open-Label, Multicenter Clinical Trial with Nivolumab (BMS-936558) for Subjects 
with Histologically Confirmed Stage III (unresectable) or Stage IV Melanoma Progressing After Prior Treatment 
Containing an Anti-CTLA-4 Monoclonal Antibody CheckMate 172: CHECKpoint pathway and nivoluMAb clinical 
Trial Evaluation 172
Investigational Product(s), Dose and Mode of Administration, Duration of Treatment with Investigational 
Product(s):  Nivolumab solution for injection, 3 mg/kg intravenous (IV) infusion over 60 minutes every 2 weeks for 
a maximum of 24 months
Study Phase:  II
Research Hypothesis:  High-grade (CTCAE v4.0 Grade 3 or higher), treatment-related, select adverse events occur 
with a low frequency in patients with histologically-confirmed, stage III (unresectable) or stage IV melanoma treated 
and progression after prior treatment containing an anti-CTLA-4 monoclonal antibody with nivolumab monotherapy. 
Objectives:  
The primary objective of this trial is to determine the incidence of high-grade (CTCAE v4.0 Grade 3 or higher), 
treatment-related, select adverse events in patients with histologically confirmed stage III (unresectable) or stage IV 
melanoma and progression after prior treatment containing an anti-CTLA-4 monoclonal antibody.
The secondary objectives of this study are: 

To determine the incidence and to characterize the outcome of all high-grade (CTCAE v4.0 Grade 3 or higher), 
select adverse events in patients with histologically confirmed stage III (unresectable) or stage IV melanoma and 
progression after prior treatment containing an anti-CTLA-4 antibody, treated with nivolumab monotherapy. 

To estimate overall survival (OS) in all treated subjects

To estimate Investigator-assessed objective response rate (ORR)
 
 
 
 
 
 
 
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Study Design:  The study will include patients with histologically-confirmed stage III (unresecteable) or stage IV 
advanced melanoma who have documented progression after treatment containing an anti-CTLA-4 monoclonal 
antibody. Patients will be treated with 3 mg/kg of nivolumab IV every 2 weeks for a maximum of 24 months. Patients 
will undergo screening evaluations to determine eligibility within 6 weeks prior to first dose following the signing of 
an informed consent. Each 14-day dosing period will constitute a cycle.
The Scientific Steering Committee will evaluate the clinical risk/benefit ratio closely following a defined Safety 
Management Plan. 
Study Schematic:
Study Population:  
Key inclusion criteria:
Patients with progression after prior treatment containing an anti-CTLA-4 monoclonal antibody (Cohorts 1 and 2):
a)
Patients with histologically confirmed malignant melanoma 
b)
Eastern Cooperative Oncology Group (ECOG) Performance Status (PS):
Endpoints: Safety, ORR, 
OS, EORTC QLQ-C30, 
and EQ-5D-3L
Treat until 
progression* or 
unacceptable 
toxicities.  Safety is 
followed continuously. 
Subjects followed for 
ongoing drug-related 
AEs until resolution, 
symptoms return to 
baseline, AE deemed 
irreversible, lost to 
follow/death, disease 
progression,* or 
withdrawal of consent.
*Subjects may be 
treated beyond 
progression under 
protocol-defined 
circumstances. 
N = approximately 
920 subjects
Study Population:
Subjects with 
histologically-
confirmed stage III 
(unresectable) or 
stage IV melanoma 
who have 
documented 
progression after 
prior treatment 
containing an anti-
CTLA-4 monoclonal 
antibody
Intervention:
Assuming a 14.7% 
screening failure rate, N = 
~800 treated with nivolumab 
3 mg/kg as a 60-minute IV 
infusion every 2 weeks for a 
maximum of 24 months.
Study Cohorts 
Progression after anti-
CTLA-4 therapy and ECOG 
PS 0-1 (n = ~735)
Progression after anti-
CTLA-4 and ECOG PS 2 
(minimum of 50; maximum 
of 185)
Safety assessments every 2 
weeks. First mandatory 
tumor assessments are at 
Week 12.  
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.
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Clinical Protocol
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i)
PS 0 to 1 (Cohort 1)
ii)
PS 2 (Cohort 2; a minimum of 50 patients and maximum of 185; clinical risk benefit ratio of Cohort 2 
will be monitored by the Scientific Steering Committee) 
c)
Previously treated unresectable stage III or stage IV melanoma as per the American Joint Committee on 
Cancer 2010 Guidelines regardless of BRAF mutation status
d)
Patients must have experienced disease progression or recurrence after prior treatment containing an anti-
CTLA-4 monoclonal antibody
e)
Prior treatment with chemotherapy, interferon (adjuvant setting), IL-2, BRAF/MEK inhibitors for subjects 
with known BRAF mutations, MEK inhibitors for NRAS mutations, and cKIT inhibitor subjects with known 
cKIT mutations are allowed
f)
Patients with CNS metastases:
i)
Patients are eligible if CNS metastases are 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, patients must be either off corticosteroids or on a stable or decreasing dose 10 
mg daily prednisone (or equivalent)
OR
ii)
Patients are eligible if they have previously untreated CNS metastases and are neurologically 
asymptomatic. In addition, patients must be either off corticosteroids or on a stable or decreasing dose 
of 10 mg daily prednisone (or equivalent)
OR 
iii) Patients with additional leptomeningeal metastases are eligible if they are treated and neurologically 
returned to baseline (except for residual signs or symptoms related to the CNS treatment) for at least 2 
weeks prior to enrollment and have a life expectancy of at least 3 months. In addition, subjects must be 
either off corticosteroids or on a stable or decreasing dose of 10 mg daily prednisone (or equivalent) 
g)
Patients must have evaluable disease by CT or MRI per RECIST 1.1 criteria (radiographic tumor assessment 
performed within 6 weeks of first dose of study drug) or clinically apparent disease that the investigator can 
follow for response. 
Key exclusion criteria:
h)
Subjects with untreated, symptomatic CNS metastases are excluded.
Study Drug: includes both Investigational [Medicinal] Products (IP/IMP) and Non-investigational [Medicinal] 
Products (Non-IP/Non-IMP) as listed:
Study Drug for CA209172
Medication 
Potency 
IP/Non-IP 
Nivolumab Injection
BMS-936558-01a
10 mg/mL; 100 mg/Vial; 10 or 5 vials per carton
Open-label
IP
Study Assessments:  Only data for the procedures and assessments specified in this protocol should be submitted to 
BMS on a case report form. Additional procedures and assessments may be performed as part of standard of care; 
however, data for these assessments should remain in the patient’s medical record and should not be provided to BMS 
unless specifically requested. 
The following assessments should be monitored starting on Cycle 1 Day 1 and will continue as per the schedule in the 
Time and Events Table at the specified frequency until discontinuation from study therapy:

Adverse events continuously throughout the study

Physical examination and physical measurements including weight and ECOG PS 
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
Complete blood count with differential, including white blood cells, lymphocyte count, absolute neutrophil count, 
hemoglobin, hematocrit, and platelet count. Results to be obtained prior to dosing on infusion days.

Serum chemistry tests (blood urea nitrogen or serum urea level, serum creatinine, sodium, calcium, phosphate, 
chloride, glucose, lipase, and lactate dehydrogenase). Results to be obtained prior to dosing on infusion days.  
Amylase should be performed in addition to lipase in cases where lipase results are not available prior to dosing. 

Liver function tests including aspartate aminotransferase, alanine transaminase total bilirubin, alkaline 
phosphatase, and albumin. Results to be obtained prior to dosing on infusion days.

Thyroid function testing includes thyroid stimulating hormone (free T3 and free T4 if abnormal results for TSH)
During the 100 days after the last dose of the study treatment, patients will have 2 additional follow up visits to assess 
safety. 
Efficacy assessments include initial mandatory tumor assessments at Week 12 (5 days). Further tumor assessments 
should be completed as required by local standards of care or at the investigator’s discretion and are recommended 
every 8 weeks. 
Changes in tumor measurements and tumor responses to guide ongoing study treatment decisions should be assessed 
by the investigator using RECIST 1.1.
Per Amendment 08, the EQ-5D-3L and survival follow up will be collected for up to 2 years from the first dose of 
study therapy or until death, withdrawal of study consent, or lost-to-follow-up as indicated in the assessment table.  
Statistical Considerations: 
Sample Size:  With an approximate 15% screening failure rate, a cohort of 735 screened PS1 patients is 
projected to a yield 640 treated patients. With n = 640 patients, about 3  will experience a rare adverse event with 
0.5% true cumulative event rate with a rate estimated within 95% confidence interval (CI) (0.2%-1.1%). 
Approximately 2 patients with events and a 95% CI of (0%-1.1%) for assumed true event rate of 0.3% are projected.
Endpoints:  The primary endpoint is the incidence for high-grade (CTCAE v4.0 Grade 3 or higher), 
treatment-related, select adverse events.
The secondary endpoints include:

Incidence of all high-grade (Grades 3 and higher), select adverse events 

Median time to onset and median time to resolution (Grades 3-4) of select adverse events

OS 

Investigator-assessed ORR 
 
 
 
Analyses:  The evidence for the research hypothesis of this clinical trial that high-grade (CTCAE v4.0 Grade 
3 or higher), treatment-related select adverse events occur with a low frequency in patients with advanced 
(unresectable or metastatic) melanoma will be presented in terms of the number, percentage of subjects, and 95% 
confidence interval for the percentage with these select adverse events during treatment and off-treatment overall and 
by cohort. 
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Adverse events from date of enrollment up to last contact with patients will be presented for the full study duration 
and separately for events that occur on- or post-treatment. In particular, safety data will be summarized and listed for 
all treated patients using the NCI CTCAE version 4.0. All on-study AEs, drug-related AEs, SAEs, and drug-related 
SAEs will be tabulated using worst grade per NCI CTCAE v4.0 criteria by system organ class and MedDRA preferred 
term. On-study laboratory parameters including hematology, chemistry, liver function, thyroid function, and renal 
function will be summarized using worst grade per NCI CTCAE v4.0 criteria.
Overall survival is defined as the time between the start of treatment and the date of death due to any cause. A subject 
who has not died will be censored at last known date alive. 
OS will be summarized using Kaplan-Meier (KM) product-limit method and associated statistics. Median values of 
OS, if estimable, along with 2-sided 95% CI using the Brookmeyer and Crowley method will be calculated. Overall 
survival rates at selected time points, including survival rates at Years 1 and 2, together with their 95% CIs will also
be estimated using KM estimates on the OS curves. Associated 2-sided 95% CIs will be calculated using the 
Greenwood formula. OS summary statistics by cohorts and subgroups will also be reported. OS will be further 
presented by initial investigator-assessed objective response under treatment with an anti-CTLA-4 monoclonal 
antibody. 
ORR is defined as the number and percentage of patients with a best overall response (BOR) of confirmed CR or PR. 
ORR as assessed by the investigator will be reported.
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TABLE OF CONTENTS 
TITLE PAGE ................................................................................................................ 
DOCUMENT HISTORY .............................................................................................. 
SYNOPSIS .................................................................................................................... 
TABLE OF CONTENTS .............................................................................................. 
1 INTRODUCTION AND STUDY RATIONALE ..................................................... 
1.1 Study Rationale ................................................................................................. 
1.1.1 Rationale for Schedule and Nivolumab Dose .......................................... 
1.1.2 Rationale for Permitting Continued Treatment in Select Cases Despite 
Initial Progressive Disease ......................................................................... 
1.1.3 Rationales for Cohorts/Subgroups and Extension of Target Population  
1.1.4 Rationale for Quality of Life Evaluation ................................................. 
1.2 Research Hypothesis ......................................................................................... 
1.3 Objectives(s) ..................................................................................................... 
1.3.1 Primary Objectives .................................................................................. 
1.3.2 Secondary Objectives ............................................................................... 
 
1.4 Product Development Background ................................................................... 
1.4.1 Clinical Activity of Nivolumab ................................................................. 
1.4.1.1 Clinical Activity in Sequential Administration of Nivolumab After 
Ipilimumab (CA209-004) ...................................................................... 
1.4.2 Adverse Effects with Nivolumab Therapy ................................................ 
1.4.3 Safety Aspects in Sequential Administration of Nivolumab After 
Ipilimumab (CA209-004): ........................................................................... 
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 ............................................................................... 
3.2 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 ........................................................... 
 
 
 
 
 
 
3.5 Discontinuation of Subjects Following Any Treatment with Study Drug ........ 
3.6 Post Study Drug Study Follow up .................................................................... 
3.6.1 Withdrawal of Consent ............................................................................ 
3.6.2 Lost to Follow-Up .................................................................................... 
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4 STUDY DRUG .......................................................................................................... 
4.1 Study Treatments .............................................................................................. 
4.2 Investigational Product ..................................................................................... 
4.3 Non-investigational Product ............................................................................. 
4.4 Storage and Dispensing..................................................................................... 
4.5 Method of Assigning Subject Identification ..................................................... 
4.6 Selection and Timing of Dose for Each Subject ............................................... 
4.6.1 Nivolumab Dose Delay Criteria .............................................................. 
4.6.1.1 Management Algorithms for Immuno-Oncology Agents ................ 
4.6.2 Nivolumab Modifications ......................................................................... 
4.6.3 Criteria to Resume Treatment with Nivolumab ....................................... 
4.6.4 Discontinuation Criteria for Nivolumab .................................................. 
4.6.5 Treatment Beyond Disease Progression .................................................. 
4.6.6 Treatment of Nivolumab Related Infusion Reactions .............................. 
4.7 Blinding/Unblinding ......................................................................................... 
4.8 Treatment Compliance ...................................................................................... 
4.9 Destruction of Study Drug ................................................................................ 
4.10 Return of Study Drug ...................................................................................... 
5 STUDY ASSESSMENTS AND PROCEDURES ..................................................... 
5.1 Flow Chart/Time and Events Schedule ............................................................. 
5.1.1 Retesting During Screening or Lead-in Period ....................................... 
5.2 Study Materials ................................................................................................. 
5.3 Safety Assessments ........................................................................................... 
5.3.1 Imaging Assessment for the Study............................................................ 
5.3.2 Vital Signs and Physical Examinations ................................................... 
5.3.3 Pregnancy Testing ................................................................................... 
5.4 Efficacy Assessments ........................................................................................ 
5.5 Pharmacokinetic Assessments .......................................................................... 
5.6 Biomarker Assessments .................................................................................... 
5.7 Outcomes Research Assessments ..................................................................... 
5.8 Other Assessments ............................................................................................ 
5.9 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 ............................................................................... 
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8.2 Populations for Analyses .................................................................................. 
8.3 Endpoints .......................................................................................................... 
8.3.1 Primary Endpoint(s) ................................................................................ 
8.3.2 Secondary Endpoint(s) ............................................................................. 
.
 
8.4 Analyses ............................................................................................................ 
8.4.1 Demographics and Baseline Characteristics........................................... 
8.4.2 Safety Analyses......................................................................................... 
8.4.2.1 Primary Analyses ............................................................................ 
8.4.2.2 Secondary Analyses ........................................................................ 
 
 
8.4.3 Efficacy Analyses ..................................................................................... 
8.4.4 Pharmacokinetic Analyses ....................................................................... 
8.4.5 Biomarker Analyses ................................................................................. 
8.4.6 Outcomes Research Analyses .................................................................. 
8.4.7 Other 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 ............................................................................................................. 
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 ........................................................................................................ 
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nivolumab
 
  
 
 
 
 
 
 
 
 
1.4
Product Development Background
1.4.1
Clinical Activity of Nivolumab
Efficacy with Nivolumab
In CA209003, the clinical activity of nivolumab was demonstrated in a variety of tumor types and 
across a range of doses (0.1 mg/kg, 0.3 mg/kg, 1 mg/kg, 3 mg/kg, 10 mg/kg). As of the clinical 
cut-off date of 05-Mar-2013, a total of 306 subjects with melanoma, RCC, and NSCLC have been 
treated with nivolumab. All subjects initiated treatment at least one year prior to analysis. A 
response of either CR or PR, as determined by investigator-assessed tumor evaluations based on 
modified RECIST 1.0, has been reported at all dose levels.
Among 107 patients with advanced melanoma who received nivolumab, the preliminary objective 
response rate was 33/107 (31%). Responses occurred at each dose level, with 6/17 (35%), 5/18 
(28%), 11/35 (31%), 7/17 (41%), and 4/20 (20%) melanoma subjects responding at 0.1, 0.3, 1, 3, 
and 10 mg/kg, respectively. Duration of response ranges from 24.1 to 48.7+, 18.4 to 66.3+, 32.4 
to 108.1+, 40.1+ to 115.4+, and 73.9 to 117.0+ months in melanoma subjects treated at 0.1, 0.3, 1, 
3, and 10 mg/kg, respectively. An additional 7% of melanoma subjects had stable disease for 24 
weeks or longer. More importantly, across dose levels, melanoma subjects achieved a median 
overall survival of 16.8 months (95% CI: 12.5, 31.6), with a 1- and 2-year overall survival rate of 
62% and 43%, respectively, which are favorable as compared with those reported in the literature 
in similar patient populations. Furthermore, 47 patients are still alive with a median overall follow-
up of 22 months and a range of 14 to 51 months.
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There are 4 trials in the clinical development program looking at the activity of nivolumab in first-
line (1L), second-line (2L), and third-line (3L) advanced melanoma. 

CA209-037:  2-arm Phase 3 study of nivolumab vs investigator’s choice in ipilimumab 
previously-treated melanoma patients (N=390)

CA209-066 (ex-US pivotal study): 2-arm Phase 3 study of nivolumab vs DTIC in previously-
untreated, unresectable or metastatic BRAF wild-type melanoma (N=410)

CA209-067: 3-arm Phase 3 study of nivolumab or nivolumab + ipilimumab vs ipilimumab in 
previously-untreated, unresectable or metastatic melanoma (N=915) 

CA209-069: 2-arm Phase 2 study of nivolumab + ipilimumab vs ipilimumab in previously 
untreated, unresectable or metastatic melanoma (N= 120) 
The Investigator Brochure (IB) will be updated with the final results of these studies as data 
become available.
1.4.1.1
Clinical Activity in Sequential Administration of Nivolumab After 
Ipilimumab (CA209-004)
Additionally, a Phase Ib study CA209-004, A Phase 1b, Open-label, Multicenter, Multidose, Dose-
Escalation Study of Nivolumab (BMS936558; MDX-1106) in Combination with Ipilimumab in 
Subjects with Unresectable Stage III or Stage IV Malignant Melanoma, primarily investigated
safety and tolerability of the combination and sequential approach of ipilimumab and nivolumab.32
A total of 86 patients were treated. Fifty-three patients received the concurrent regimen, and 33 
received the sequenced regimen. Most patients (73%) enrolled in the sequenced-regimen cohorts 
had progression as assessed radiographically during prior treatment with ipilimumab. In the 
sequenced-regimen cohorts, 6 of 30 patients (20%; 95% CI, 8 to 39) had an objective response, 
including 1 with a complete response. A total of 4 patients (13%) had tumor reduction of 80% or 
more at 8 weeks. An additional 6 patients had either an immune-related response (in 3 patients) or 
an unconfirmed response. When clinical activity was defined by objective, immune-related, or 
unconfirmed responses or stable disease for at least 24 weeks, 43% of patients (95% CI, 26 to 63) 
in the sequenced-regimen group had clinical activity. Some patients who had not had a response 
to previous treatment with ipilimumab did have a response to subsequent treatment with 
nivolumab. These data indicate the potential benefit of sequential administration of nivolumab 
after progression during or after ipilimumab treatment. 
The most advanced and robust data coming from the Phase III randomized clinical study 
(CA209037) versus chemotherapy of investigator’s choice have been presented at the European 
Society of Medical Oncology 2014 annual meeting.33 In total, 272 patients have been treated with 
nivolumab who have progressed following ipilimumab. The co-primary endpoint of objective 
response rate was assessed in the first 120 nivolumab-treated subjects that had a minimum of 6 
months follow-up. The confirmed ORR by RECIST 1.1 criteria by central review was 32% vs 11% 
in the chemotherapy cohort. This included 3% complete responses vs 0% CRs in the nivolumab 
and investigator’s choice arm, respectively. The majority of responses (95%) were ongoing in 
patients who received nivolumab, and the medial duration of response was not reached while the 
median duration of response was 3.6 months in the investigator’s choice arm. The Responses were 
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observed regardless of pre-treatment, PD-L1 expression status, BRAF mutation status, and prior 
ipilimumab benefit. 
1.4.2
Adverse Effects with Nivolumab Therapy
Two studies have contributed to most of the monotherapy clinical experience with nivolumab in 
subjects with melanoma and other solid malignancies. CA209001 was a Phase 1 single-dose dose 
escalation study in 39 subjects 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 retreatment at 3 
months. CA209003 is an ongoing Phase 1 open-label, multiple dose escalation study in 304 
subjects with select previously treated advanced solid tumors, including melanoma, RCC, NSCLC, 
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 03-Jul-2012, a total of 107 melanoma subjects were treated with nivolumab in the 
dose range of 0.1-10 mg/kg.
Adverse Events
Treatment-related AEs were reported in 230 (75.2%) of the 306 patients in the CA209003 study. 
The most frequently reported treatment-related AEs were fatigue (28.1%), rash (14.7%), diarrhea 
(13.4%), and pruritus (10.5%) (Table 1.4.2-1). Of the AEs, most were low-grade (Grade 1 to Grade 
2) with relatively few related high-grade (Grade 3 to Grade 4) AEs reported in 52 (17.0%) patients. 
The most frequently reported treatment-related, high-grade AE was fatigue (6.5%). Most high-
grade events were manageable with the use of corticosteroids or hormone replacement therapy 
(endocrinopathies). 
The one exception is pulmonary inflammation AEs, which may be numerically greater in patients 
with NSCLC because, in some cases, it can be difficult to distinguish between nivolumab-related 
and unrelated causes of pulmonary symptoms and radiographic changes. 
Due to the immune mechanism of action of nivolumab, there are select AEs that require more 
frequent monitoring and/or unique intervention, such as immunosuppression. These adverse events 
of special interest (AEOSIs) include GI AEs, pulmonary AEs, renal AEs, hepatic AEs, skin AEs, 
endocrinopathies, and infusion reactions. Each category is composed of a discrete set of preferred 
terms, and AE management algorithms have been developed for suspected pulmonary toxicity, 
diarrhea or suspected colitis, hepatotoxicity, endocrinopathy, and nephrotoxicity. These may be 
found in the investigators brochure for nivolumab. 
Three patients in CA209003 (one with colorectal carcinoma and two with NSCLC) died after 
developing pneumonitis. There was no clear relationship between the occurrence of pneumonitis 
and tumor type, dose level, or the number of doses received. Early grade pneumonitis was 
generally reversible with treatment discontinuation and corticosteroid administration. Several 
patients in these categories successfully reinitiated treatment with nivolumab. There were seven 
patients with treatment-related SAEs; of these, 4 patients had Grade 3-4 SAEs in CA209003. 
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Table 1.4.2-1:
Summary of Adverse Events Reported in 15% of All Treated 
Subjects - CA209003
No. of Subjects (%)
Preferred Term
AEs regardless of causality
Treatment-related AEs
Any Grade 
N=306
Grade 3-4           
N=306
Any Grade
N=306
Grade 3-4
N=306
Any AE
303 (99)
127 (42)
230 (75)
52 (17)
Fatigue
168 (55)
20 (7)
86 (28)
7 (2)
Decreased appetite
107 (35)
3 (1)
28 (9)
1(0.3)
Diarrhea
105 (34)
3 (1)
41 (13)
3 (1)
Nausea
92 (30)
9 (3)
27 (9)
2 (1)
Cough
90 (29)
4 (1)
11 (4)
1 (0.3)
Dyspnea
80 (26)
27 (9)
11 (4)
0
Constipation
78 (26)
2 (1)
5 (2)
0
Rash 
74 (24)
0
45 (15)
0
Vomiting
70 (23)
7 (2)
10 (3)
1 (0.3)
Back pain
68 (22)
7 (2)
3 (1)
1 (0.3)
Arthralgia
63 (21)
4 (1)
15 (5)
0
Pyrexia
61 (20)
1 (0.3)
17 (6)
0
Headache
59 (19)
1 (0.3)
8 (3)
0
Oedema peripheral
59 (19)
1 (0.3)
3 (1)
0
Dizziness
56 (18)
1 (0.3)
10 (3)
0
Pruritus
56 (18)
1 (0.3)
32 (11)
1 (0.3)
Weight decreased 
48 (16)
1 (0.3)
11 (4)
0
Malignant neoplasm 
progression
48 (16)
4 (1)
1 (0.3)
1 (0.3)
Abbreviations: AE: adverse event. Source: Preliminary data, CA209003. Clinical data cut-off date: 18-Mar-2013.
Serious Adverse Events
Treatment-related Grade 3-4 SAEs reported in at least 2 patients included pneumonitis (4 patients, 
1.3%), diarrhea (3 patients, 1.0%), lipase increased (2 patients, 0.7%), pneumonia (2 patients, 
0.7%), and hypersensitivity (2 patients, 0.7%). Two patients treated with 1 and 10 mg/kg 
nivolumab died due to sepsis related to study treatment.
Adverse Events Leading to Discontinuation
At least 1 treatment-related AE leading to discontinuation was reported in 32 (10.5%) of the 306 
treated patients. The frequency of treatment-related AEs leading to discontinuation was not 
associated with the dose of nivolumab. 
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Pneumonitis was the most common treatment-related AE leading to discontinuation (8 patients, 
2.6%); pneumonitis, reported in 3 (1.0%) patients, was Grade 3-4. Treatment-related AEs reported 
in ≥2 patients included: pneumonitis (8 patients, 2.6%), colitis (3 patients, 1.0%) and myalgia, 
hepatitis, hypersensitivity, and infusion-related reactions (each reported in 2 patients, 0.7%). 
Deaths
As of 18-Mar-2013, 195 deaths have been reported in CA209003 during the course of the study or 
within 30 days of last dose of study drug. The majority of the deaths were considered secondary 
to disease progression and malignant disease.  
Three patients in CA209003 died after developing pneumonitis thought to be related to the study 
drug. A 62-year-old male with NSCLC (adenocarcinoma) in the 1 mg/kg treatment group and a 
59-year old-male with CRC in the 10 mg/kg treatment group both died due to Grade 5 sepsis after 
developing Grade 4 pneumonitis.
The sepsis and pneumonitis were considered related to study drug by the investigator in both of 
these cases. 
Additional deaths reported as due to “other” in CA209003 included:

Patient on dose (10 mg/kg): Ischemic cardiomyopathy

Patient on dose (10 mg/kg): Death caused by superior mesenteric vein thrombosis

Patient on dose (1 mg/kg): Progressive lung cancer
Laboratory Abnormalities 
Among all treated patients in CA209003 (N=306), laboratory test results with shifts greater than 2 
grades from baseline value were reported for absolute neutrophils, ALT, creatinine, hemoglobin, 
leukocytes, lymphocytes, platelet count, and total bilirubin (Table 1.4.2-2). There were no dose-
related patterns with regard to frequency or severity. Laboratory value changes were recorded 
regardless of causality and may not correlate with reported laboratory-based AEs.
Table 1.4.2-2:
Summary of Select Laboratory Test Results with Shifts Greater 
Than 2-Grades From Baseline Value - Patients (%)
Laboratory Test
Laboratory Shifts
Total Treated (N=306)
ALT
Grade 0 to 2
10 (3.3)
Grade 0 to 3
4 (1.3)
AST
Grade 0 to 2
9 (2.9)
Grade 0 to 3
6 (2.0)
Grade 2 to 4
1 (0.3)
Bilirubin, Total
Grade 0 to 2
3 (1.0)
Grade 0 to 3
2 (0.7)
Grade 0 to 4
1 (0.3)
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Table 1.4.2-2:
Summary of Select Laboratory Test Results with Shifts Greater 
Than 2-Grades From Baseline Value - Patients (%)
Laboratory Test
Laboratory Shifts
Total Treated (N=306)
Grade 1 to 3
1 (0.3)
Creatinine
Grade 0 to 2
4 (1.3)
Grade 1 to 3
1 (0.3)
Hemoglobin
Grade 0 to 2
11 (3.6)
Grade 0 to 3
2 (0.7)
Grade 1 to 3
5 (1.6)
Grade 2 to 4
1 (0.3)
Lymphocytes
Grade 0 to 2
17 (5.6)
Grade 0 to 3
1 (0.3)
Grade 0 to 4
1 (0.3)
Grade 1 to 3
14 (4.6)
Grade 2 to 4
3 (1.0)
Neutrophils
Grade 0 to 2
9 (2.9)
Grade 0 to 3
4 (1.3)
Grade 0 to 4
1 (0.2)
Platelet count
Grade 0 to 2
4 (1.3)
Leukocytes
Grade 0 to 2
15 (4.9)
Grade 0 to 3
4 (1.3)
Abbreviations: ALT: alanine aminotransferase, AST: aspartate aminotransferase
1.4.3
Safety Aspects in Sequential Administration of Nivolumab After 
Ipilimumab (CA209-004):
Among the 33 patients in the sequenced-regimen group of the Phase Ib study investigating the 
combination/sequence of nivolumab plus ipilimumab or nivolumab after ipilimumab, adverse 
events of any grade, regardless of attribution, were observed in 29 patients (88%). Treatment-
related adverse events were observed in 24 patients (73%), with the most common events including 
pruritus (in 18% of patients) and elevated lipase levels (in 12%). Grade 3 or 4 adverse events, 
regardless of whether they were attributed to the therapy, were observed in 11 patients (33%), and 
Grades 3 or 4 adverse events related to therapy were observed in 6 (18%) with an elevated lipase 
level as the most common event (in 6% of patients). Serious adverse events related to therapy were 
reported in 7 patients (21%). Grade 3 or 4 endocrine events were noted as treatment-related 
selected adverse events in 2 patients. One patient had Grade 2 pneumonitis. Three patients (9%) 
discontinued therapy owing to treatment-related adverse events.34
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The most advanced safety data coming from the Phase III randomized clinical study (CA209037) 
versus chemotherapy of investigator’s choice have been presented at the European Society of 
Medical Oncology 2014 annual meeting.35
In total 268 patients treated with Nivolumab and 102 patients treated with chemotherapy of 
investigator´s choice have been analyzed for safety. 9% (24) of the patients in the Nivolumab arm 
have experienced drug-related grade 3 and 4 AEs, while 31% (32) of the patients in the 
chemotherapy arm have experienced grade 3 and 4 AEs. This was leading to 2% (6) of the patients 
in the Nivolumab arm and 8% (8) in the chemotherapy arm to discontinue treatment due to drug-
related adverse events.
All grade 3-4 drug-related AEs in the Nivolumab arm, belonging to the select AE categories 
resolved and in total, less than 5% of patients treated with Nivolumab reported Grade 3–4 select 
AE.
1.5
Overall Risk/Benefit Assessment
Patients with advanced (unresectable) stage III or metastatic stage IV melanoma progressing after 
treatment containing an anti-CTLA-4 monoclonal antibody represent a clear unmet medical need. 
Vermurafenib, dabrafenib, and trametinib are approved agents for patients who harbor BRAF 
mutations and can confer RECIST 1.1 criteria clinical response rates > 50%. Nevertheless, the 
responses are almost all short lived; median duration for BRAF inhibitors in multiple clinical trials 
has been approximately 5 months, and the overwhelming majority of patients develop disease 
progression within 1 year. 
Beyond these agents, no other EMA-approved therapy has demonstrated a median overall survival 
benefit in advanced melanoma patients in a Phase 3 randomized study. The clinical activity of 
nivolumab observed to date in melanoma suggests the potential for improved clinical outcomes, 
including survival, as monotherapy. Nivolumab has the potential for clinically relevant adverse 
events including events with a potential inflammatory mechanism, which may necessitate 
immunosuppressant intervention and/or endocrine replacement therapy. The most common AEs 
included fatigue, rash, pruritus, diarrhea, and nausea. Other AEs associated with nivolumab may 
include those that are GI, pulmonary, renal, hepatic, skin, endocrinopathies, or infusion reactions. 
However, the activity and manageable AE profile observed with nivolumab supports a clinical 
trial in subjects with histologically confirmed stage III (unresectable) or stage IV melanoma
progressing after prior treatment containing an anti-CTLA-4 monoclonal antibody for a better 
understanding of the safety profile in a Pan-European Clinical Trial and in formerly excluded 
patient populations. 
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).
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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 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 (eg, 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 (eg, 
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 
(eg, expedited safety reports, amendments, and administrative letters) according to regulatory 
requirements or institution procedures.
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 (ie, 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. 
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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.
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 and, in the 
US, the subjects’ signed HIPAA Authorization.
The consent form must also include a statement that BMS and regulatory authorities have direct 
access to subject records. 
Subjects unable to give their written consent (eg, stroke or subjects with or severe dementia) may 
only be enrolled in the study with the consent of a legally acceptable representative. The subject 
must also be informed about the nature of the study to the extent compatible with his or her 
understanding, and should this subject become capable, he or she should personally sign and date 
the consent form as soon as possible. The explicit wish of a subject who is unable to give his or 
her written consent, but who is capable of forming an opinion and assessing information to refuse 
participation in, or to be withdrawn from, the clinical study at any time should be considered by 
the investigator.
The rights, safety, and well-being of the study subjects are the most important considerations and 
should prevail over interests of science and society.
3
INVESTIGATIONAL PLAN
3.1
Study Design and Duration
The study will include patients with histologically-confirmed stage III (unresecteable) or stage IV 
advanced melanoma who have documented progression after treatment containing an anti-CTLA-
4 monoclonal antibody. Patients will be treated with 3 mg/kg of nivolumab IV every 2 weeks for 
a maximum of 24 months. Patients will undergo screening evaluations to determine eligibility 
within 6 weeks prior to the first dose following the signing of an informed consent. Each 14-day 
dosing period will constitute a cycle. 
The Scientific Steering Committee will evaluate the clinical risk/benefit ratio closely following a 
defined Safety Management Plan.
Patients will undergo screening evaluations to determine eligibility as indicated in Table 5.1-1
prior to first dose following signed informed consent. Patient’s demographic data will be collected: 
date of birth, gender, disease stage, date of diagnosis, previous treatments, comorbidities, 
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performance status, lactate dehydrogenase (LDH) level, type of melanoma (mucosal, uveal), and 
mutation status if known (BRAF, NRAS, cKIT).
Safety, including adverse event monitoring and physical examination, should be monitored 
continually, and safety assessments are discussed in Table 5.1-2. 
Mandatory initial tumor assessments are to be done at Week 12 (5 days). Further tumor 
assessments should be performed according to institutional standard of care and are recommended 
every 8 weeks until: 

disease progression 

a concurrent malignancy requires treatment

the patient is lost to follow up

the patient withdraws study consent 

completed 24 months of treatment 
Patients will not be permitted to continue their treatment beyond initial Investigator-assessed 
progressive disease unless they meet the following criteria:

Investigator-assessed clinical benefit 

Patient is tolerating study drug
The investigator should use his or her clinical judgment to assess clinical benefit by considering 
whether the patient is clinical deteriorating and unlikely to receive any benefit from continued 
treatment with nivolumab.
Per Amendment 08, follow up begins when the decision to discontinue a patient from study therapy 
is made (no further treatment with nivolumab) and continues from first dose of study therapy up 
to 2 years or until death, withdrawal of study consent, or lost-to-follow-up.
The cohorts are described in Table 3.1-1.
Table 3.1-1:
Patient Cohorts
(Cohort Number) 
Disease Criteria
Cohort 1: Advanced Melanoma 
(unresectable stage III or stage 
IV) 
(N >735)

ECOG Performance Status 0 to 1

Progressing after prior therapy containing treatment with an anti-CTLA-4 
monoclonal antibody
Cohort 2: Advanced Melanoma 
(unresectable stage III or stage 
IV)
(N 50 but< 185)

ECOG Performance Status 2 

Progressing after prior therapy  containing treatment with an anti-CTLA-4 
monoclonal antibody
Enrollment of new subjects on the study will stop at the time of marketing authorization 
approval. In those countries where nivolumab may not be immediately available upon marketing 
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authorization, enrollment will remain open for a maximum of 1 year after marketing 
authorization is granted or nivolumab becomes commercially available within the country, 
whichever occurs sooner. 
For those patients enrolled on the study, BMS will continue to provide drug per the timelines 
defined in the protocol.
The study design schematic is presented in Figure 3.1-1.
Figure 3.1-1:
Study Design Schematic
3.2
Post Study Access to Therapy
At the conclusion of the study, subjects who continue to demonstrate clinical benefit will be 
eligible to receive BMS supplied study drug up to 12 months after the approval of investigational 
product by the responsible health authority or until the investigational product becomes 
Endpoints: Safety, ORR, 
OS, EORTC QLQ-C30, 
and EQ-5D-3L
Treat until 
progression* or 
unacceptable 
toxicities.  Safety is 
followed continuously. 
Subjects followed for 
ongoing drug-related 
AEs until resolution, 
symptoms return to 
baseline, AE deemed 
irreversible, lost to 
follow/death, disease 
progression,* or 
withdrawal of consent.
*Subjects may be 
treated beyond 
progression under 
protocol-defined 
circumstances. 
N = approximately 
920 subjects
Study Population:
Subjects with 
histologically-
confirmed stage III 
(unresectable) or 
stage IV melanoma 
who have 
documented 
progression after 
prior treatment 
containing an anti-
CTLA-4 monoclonal 
antibody
Intervention:
Assuming a 14.7% 
screening failure rate, N = 
~800 treated with nivolumab 
3 mg/kg as a 60-minute IV 
infusion every 2 weeks for a 
maximum of 24 months.
Study Cohorts 
Progression after anti-
CTLA-4 therapy and ECOG 
PS 0-1 (n = ~735)
Progression after anti-
CTLA-4 and ECOG PS 2 
(minimum of 50; maximum 
of 185)
Safety assessments every 2 
weeks. First mandatory 
tumor assessments are at 
Week 12.  
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.
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commercially available within the country, whichever occurs sooner. Study drug will be provided 
via an extension of the study, a rollover study requiring approval by responsible health authorities 
and ethics committee, or through another mechanism at the discretion of BMS. BMS reserves the 
right to terminate access to study drug if any of the following occur: a) the marketing application 
is rejected by the responsible health authority; b) the study is terminated due to safety concerns; c) 
the subject can obtain medication from a government sponsored or private health program; or d) 
therapeutic alternatives become available in the local market.
3.3
Study Population
For entry into the study, the following criteria MUST be met.
3.3.1
Inclusion Criteria
1. Signed Written Informed Consent
a) Patients 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 
patient care.
b) Patients must be willing and able to comply with scheduled visits, treatment schedule, 
laboratory tests, and other requirements of the study.
2. Target Population
a) Patients with progression after prior treatment containing an anti-CTLA-4 
monoclonal antibody (Cohorts 1 and 2):
i)
Patients with histologically confirmed malignant melanoma 
ii) Eastern Cooperative Oncology Group (ECOG) PS:
(1) PS 0 to 1 (Cohort 1)
(2) PS 2 (Cohort 2; a minimum of 50 patients and a maximum of 185; clinical risk 
benefit ratio of Cohort 2 will be monitored by the Scientific Steering 
Committee)
iii) Previously treated unresectable stage III or stage IV melanoma as per the American 
Joint Committee on Cancer 2010 Guidelines36 regardless of BRAF mutation status
iv) Patients must have experienced disease progression or recurrence after prior 
treatment containing an anti-CTLA-4 monoclonal antibody
v) Prior treatment with chemotherapy, interferon (adjuvant setting), IL-2, 
BRAF/MEK inhibitors for patients with known BRAF mutations, MEK inhibitors 
for NRAS mutations, and cKIT inhibitor patients with known cKIT mutations are 
allowed
vi) Patients with CNS metastases:
(1) Patients are eligible if CNS metastases are treated and patients 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, patients must be either off corticosteroids or on a stable or decreasing 
dose 10 mg daily prednisone (or equivalent)
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OR
(2) Patients are eligible if they have previously untreated CNS metastases and are 
neurologically asymptomatic. In addition, patients must be either off 
corticosteroids or on a stable or decreasing dose of 10 mg daily prednisone (or 
equivalent)
OR
(3) Patients with additional leptomeningeal metastases are eligible if they are 
treated and neurologically returned to baseline (except for residual signs or 
symptoms related to the CNS treatment) for at least 2 weeks prior to enrollment 
and have a life expectancy of at least 3 months. In addition, patients must be 
either off corticosteroids or on a stable or decrease dose 10 mg daily 
prednisone (or equivalent)
vii)Prior chemotherapy or immunotherapy (tumor vaccine, cytokine, or growth factor 
given to control the cancer) must have been completed at least 4 weeks before study 
drug administration, and all adverse events have either returned to baseline or have 
been stabilized
viii)
Prior palliative radiotherapy must have been completed at least 2 weeks 
prior to study drug administration
ix) Prior targeted therapy must have been completed at least 2 weeks prior to study 
drug administration
x) Prior anti-CTLA-4 therapy must have been completed at least 4 weeks before study 
drug administration
xi) Prior radiotherapy or radiosurgery must have be completed at least 2 weeks prior 
to the first dose of study drug
xii)Primary uveal (minimum of 30 patients) and mucosal melanoma are allowed 
xiii)
Screening laboratory values must meet the following criteria prior to 
commencement of treatment:
(1) WBCs ≥2000/µL
(2) Neutrophils ≥1500/µL
(3) Platelets ≥100 x 10³/µL
(4) Hemoglobin ≥9.0 g/dL
(5) Serum creatinine of ≤1.5 X ULN or creatinine clearance > 40 mL/minute 
(using Cockcroft/Gault formula) 
(a) Female CrCl= [(140- age in years) x weight in kg x 0.85) ÷(72 x serum 
creatinine in mg/ dL)]
(b) Male CrCl= [(140- age in years) x weight in kg x 1.00) ÷(72 x serum 
creatinine in mg/ dL)]
(6) AST ≤3 X ULN
(7) ALT ≤3 X ULN
(8) Total bilirubin ≤1.5x ULN (except patients with Gilbert Syndrome who must 
have total bilirubin < 3.0 mg/dL)
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xiv)
Patients with a known history of Grades 3-4 adverse reactions during anti-
CTLA-4 therapy will be allowed to participate if all toxicities have resolved to Grade 
1 (NCI CTCAE version 4) or baseline before administration of nivolumab (minimum 
of 40 patients)
xv) Patients must have evaluable disease by CT or MRI per RECIST 1.1 criteria 
(radiographic tumor assessment performed within 6 weeks of first dose of study drug) 
or clinically apparent disease that the investigator can follow for response.
xvi) Patient Re-enrollment: This study permits the re-enrollment of a subject that has 
discontinued the study as a pre-treatment failure (ie, subject has not been treated). If 
re-enrolled, the subject must be re-consented.
b) As of Amendment 03, this criterion is not applicable. 
i)
As of Amendment 03, this criterion is not applicable. 
ii)
As of Amendment 03, this criterion is not applicable. 
(1) As of Amendment 03, this criterion is not applicable. 
(2) As of Amendment 03, this criterion is not applicable. 
iii) As of Amendment 03, this criterion is not applicable.
(1) As of Amendment 03, this criterion is not applicable. 
(2) As of Amendment 03, this criterion is not applicable. 
(3) As of Amendment 03, this criterion is not applicable.
iv) As of Amendment 03, this criterion is not applicable.
v) As of Amendment 03, this criterion is not applicable.
vi) As of Amendment 03, this criterion is not applicable.
vii)As of Amendment 03, this criterion is not applicable.
viii)
As of Amendment 03, this criterion is not applicable.
(1) As of Amendment 03, this criterion is not applicable. 
(2) As of Amendment 03, this criterion is not applicable. 
(3) As of Amendment 03, this criterion is not applicable. 
(4) As of Amendment 03, this criterion is not applicable. 
(5) As of Amendment 03, this criterion is not applicable. 
(a) As of Amendment 03, this criterion is not applicable. 
(b) As of Amendment 03, this criterion is not applicable. 
(6) As of Amendment 03, this criterion is not applicable. 
(7) As of Amendment 03, this criterion is not applicable. 
(8) As of Amendment 03, this criterion is not applicable. 
ix) As of Amendment 03, this criterion is not applicable.
x) As of Amendment 03, this criterion is not applicable.
xi) As of Amendment 03, this criterion is not applicable.
3. Age and Reproductive Status
a) Men and women, aged 18 years
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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 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 with study drug (s)  nivolumab plus 5 half-lives of study drug nivolumab (5 
times the half-life = 125 days) plus 30 days (duration of ovulatory cycle) for a total of 155 
days or 23 weeks post-treatment completion.
e) Men who are sexually active with WOCBP must agree to follow instructions for method(s) 
of contraception for the duration of treatment with study drug nivolumab plus 5 half-lives 
of the study drug (125 days) plus 90 days (duration of sperm turnover) for a total of  31 
weeks post-treatment completion.
f)
Azoospermic males and WOCBP who are continuously not heterosexually active are 
exempt from contraceptive requirements. However, WOCBP subjects 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% per year when used consistently and correctly.
At a minimum, subjects must agree to the use of two methods of contraception, with one method 
being highly effective and the other method being either highly effective or less effective as 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 or 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. 

Nonhormonal IUDs, such as ParaGard

Tubal ligation 

Vasectomy

Complete abstinence
NOTE: Complete abstinence is defined as complete avoidance of heterosexual 
intercourse and is an acceptable form of contraception for all study drugs. Subjects who 
choose complete abstinence are not required to use a second method of contraception, 
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but female subjects must continue 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.
LESS EFFECTIVE METHODS OF CONTRACEPTION

Diaphragm with spermicide

Cervical cap with spermicide

Vaginal sponge

Male condom without spermicide

Progestin only pills by WOCBP subject or  male subject’s WOCBP partner 

Female condom
NOTE: A male and female condom must not be used together. 
3.3.2
Exclusion Criteria
1. Target Disease Exceptions
a) As of Amendment 02, this criterion is no longer applicable. 
b) Patients with untreated, symptomatic CNS metastases are excluded
2. Medical History and Concurrent Diseases
a) As of Amendment 03, this criterion is not applicable. 
b) Patients with a condition requiring systemic treatment with either corticosteroids (>10 mg 
daily prednisone equivalent) or other immunosuppressive medications within 14 days of 
study drug administration. Inhaled or topical steroids and adrenal replacement steroid doses 
> 10 mg daily prednisone equivalent are permitted in the absence of active autoimmune 
disease. 
c) Patients with previous malignancies (except non-melanoma skin cancers, in situ bladder 
cancer, gastric or colon cancers, cervical cancers/dysplasia or breast carcinoma in situ) are 
excluded unless a complete remission was achieved at least 2 years prior to study entry and 
no additional therapy is required or anticipated to be required during the study period
d) Any serious or uncontrolled medical disorder or active infection that, in the opinion of the 
investigator, may increase the risk associated with study participation, study drug 
administration, or would impair the ability of the patient to receive protocol therapy
e) Any treatment in a BMS-sponsored, interventional nivolumab trial or ipilimumab trial 
f)
Known drug or alcohol abuse
3. Physical and Laboratory Test Findings
a) Any positive test for hepatitis B virus or hepatitis C virus indicating acute or chronic 
infection
b) Positive test for HIV
4. Allergies and Adverse Drug Reaction
a) History of severe hypersensitivity reactions to other monoclonal antibodies
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b) History of allergy or intolerance (unacceptable adverse event) to study drug components 
or Polysorbate-80-containing infusions.
c) As of Amendment 02, this criterion is no longer applicable. 
5. Sex and Reproductive Status
a) WOCBP who are pregnant or breastfeeding
b) Women with a positive pregnancy test at enrollment or prior to administration of study 
medication
c) Women treated with ORAL hormone replacement therapy (HRT) are to be excluded unless 
the oral replacement therapy was stopped by investigator’s discretion at least 4 weeks prior 
to screening and was changed to other contraception method.
6. As of Amendment 02, this criterion is no longer applicable
a)
As of Amendment 02, this criterion is no longer applicable
b) As of Amendment 02, this criterion is no longer applicable
c) As of Amendment 02, this criterion is no longer applicable
d) As of Amendment 02, this criterion is no longer applicable
7. 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 
(eg, infectious disease) illness
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
A woman of childbearing potential (WOCBP) is defined as any female who has experienced 
menarche and who has not undergone surgical sterilization (hysterectomy or bilateral 
oophorectomy) and is not postmenopausal. Menopause is defined as 12 months of amenorrhea in 
a woman over age 45 years in the absence of other biological or physiological causes. In addition, 
females under the age of 55 years must have a serum follicle stimulating hormone, (FSH) level > 
40 mIU/mL to confirm menopause.
Females treated with hormone replacement therapy (HRT) are likely to have artificially suppressed 
FSH levels and may require a washout period in order to obtain a physiologic FSH level. The 
duration of the washout period is a function of the type of HRT used. The duration of the washout 
period below are suggested guidelines and the investigators should use their 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.
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. 
3.5
Discontinuation of Subjects Following Any Treatment with Study Drug
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 adverse event (AE), laboratory abnormality or intercurrent illness which, in the 
opinion of the investigator, indicates that continued participation in the study is not in the best 
interest of the subject

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 (eg, infectious disease) illness

Maximum of 24 months  treatment period from first administration of nivolumab

Disease progression without investigator-assessed clinical benefit (See Section 4.6.5, 
Treatment Beyond Disease Progression)

Additional protocol-specified reasons for discontinuation (See Section 4.6.4)
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 (ie, is imprisoned or involuntarily incarcerated for the treatment 
of either a psychiatric or physical illness).
If study treatment 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 
appropriate case report form (CRF) page.
3.6
Post Study Drug Study Follow up
Subjects who discontinue study drug may continue to be followed. In this study, safety and survival 
are key endpoints of the study. Post study follow-up is of critical importance and is essential to 
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preserving subject safety and the integrity of the study. Subjects who discontinue study drug must 
continue to be followed for collection of outcome and/or survival follow-up data as required and 
in line with Section 5--Study Assessments and Procedures--until death or the conclusion of the 
study.
The patients will be followed up for select AEs beyond 100 days from the last dose of study 
therapy, for ongoing drug-related AEs until resolved, return to baseline or deemed irreversible, or 
until lost to follow-up or withdrawal of study consent.
One of the endpoints is overall survival, and every attempt will be made to obtain survival status 
in accordance with Table 5.1-3 until death, lost to follow-up, or withdrawal of study consent.
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.
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. The site staff and 
representative will consult publicly available sources, such as public health registries and 
databases, in order to obtain updated contact information. If after all attempts, the 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.
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4
STUDY DRUG
4.1
Study Treatments
Study drug includes both Investigational [Medicinal] Product (IP/IMP) and Non-investigational 
[Medicinal] Product (Non-IP/Non-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, and 

Other drugs administered as part of the study that are critical to claims of efficacy 
(eg, 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.
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Table 4.1-1:
Study Drugs for CA209172
Product Description / 
Class and Dosage Form
Potency
IP/Non-IMP
Blinded or Open 
Label
Packaging/ 
Appearance
Storage Conditions
(per label)
Nivolumab  Solution for 
Injection a
100 mg     (10 mg/mL)
IP
10 or 5 vials per carton/ 
Open-label
10 mL per vial/ Open-
label; Clear to 
opalescent, colorless to 
pale yellow liquid, light 
(few) particulates may 
be present.
Store at 2-8C (36-
46F). Protect from 
light and freezing.
a Nivolumab is labeled as BMS-936558-01 Solution for Injection
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4.2
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, the investigational product is nivolumab.
4.3
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 products are not applicable.
4.4
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.
Study drug not supplied by BMS will be stored in accordance with the package insert.
Investigational product documentation (whether supplied by BMS or not) must be maintained that 
includes all processes required to ensure drug is accurately administered. This includes 
documentation of drug storage, administration and, as applicable, storage temperatures, 
reconstitution, and use of required processes (eg, required diluents, administration sets).
4.5
Method of Assigning Subject Identification
After the subject’s eligibility is established and informed consent has been obtained, the subject 
will be enrolled, and a 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.
4.6
Selection and Timing of Dose for Each Subject
Patients will be treated with 3 mg/kg of nivolumab as a 60-minute (5 minutes) IV infusion on 
Day 1 of a treatment cycle every 2 weeks (14 days) for a maximum of 24 months. No 
premedications are recommended for initiation of dosing. Dosing calculations should be based on 
the body weight assessed at each visit as per Table 5.1-2. It is not necessary to re-calculate 
subsequent doses if the patient’s weight is within 10% of the weight used to calculate the previous 
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dose. All doses should be rounded to the nearest milligram per institutional standard. The screening 
body weight may be used for dosing of Cycle 1. There will be no nivolumab escalations or 
reductions permitted. Patients may be dosed no less than 12 days from the previous dose. 
Patients will be monitored continuously for AEs while on study. Treatment and modifications (eg, 
dose delay or discontinuation) will be based on specific laboratory and adverse event criteria.  
4.6.1
Nivolumab Dose Delay Criteria
Nivolumab administration should be delayed for the following:

Grade 2 non-skin, drug-related adverse events with the following exceptions:

Grade 2 drug-related fatigue or laboratory abnormalities do not require a treatment delay

Any Grade 3 skin, drug-related AE

Any Grade 3 drug-related laboratory abnormalities with the following exceptions for 
lymphopenia, leukopenia, AST, ALT, or total bilirubin

Grade 3 lymphopenia or leukopenia does not require dose delay

If a patient has a baseline AST, ALT, or total bilirubin that is within normal limits, delay 
dosing for drug-related Grade 2 toxicity

If a patient has baseline AST, ALT, or total bilirubin within the Grade 1 toxicity range, 
delay dosing for drug-related Grade 3 toxicity

Any adverse event, laboratory abnormalities, or undercurrent illness which in the judgment of 
the investigator, warrants delaying the dose of study medication. 
4.6.1.1
Management Algorithms for Immuno-Oncology Agents
Immuno-oncology (I-O) agents are associated with adverse events that can differ in severity and 
duration from adverse events caused by other therapeutic classes. Nivolumab is considered an 
immuno-oncology agent in this protocol. Early recognition and management of adverse events 
associated with immuno-oncology agents may mitigate severe toxicity. Management algorithms 
can be found in the Investigator’s Brochure and have been developed to assist investigators in 
assessing and managing the following groups of adverse events:

Pulmonary toxicity

Gastrointestinal toxicity (diarrhea or colitis)

Endocrinopathies

Hepatotoxicity (including asymptomatic LFT elevations)

Renal toxicity

Skin toxicity

Neurological toxicity
For patients expected to require 4 weeks of corticosteroids or other immunosuppressants to manage 
the adverse event, consider recommendations provided in the Investigator’s Brochure.
Tumor assessments for all patients should continue as per protocol even if dosing is interrupted.
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4.6.2
Nivolumab Modifications
Nivolumab dose reductions and escalations are not permitted.
4.6.3
Criteria to Resume Treatment with Nivolumab
Patients may resume treatment with nivolumab when the drug-related AEs resolve to Grade 1 or 
baseline value with the following exceptions:

Patients may resume treatment in the presence of Grade 2 fatigue

Patients who have not experienced a Grade 3 drug-related skin AE may resume treatment in 
the presence of Grade 2 skin toxicity

Patients 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 or ALT OR total bilirubin.

Drug-related pulmonary toxicity, diarrhea, or colitis must have resolved to baseline before 
treatment is resumed

Drug-related endocrinopathies adequately controlled with only physiologic hormone 
replacement may resume treatment

If treatment is delayed > 6 weeks, the patient may be permanently discontinued from study 
therapy, except as specified in Section 3.5. 
4.6.4
Discontinuation Criteria for Nivolumab
BMS-936558 (nivolumab) treatment should be permanently discontinued for the following 
reasons:

Any Grade 2 drug-related uveitis or eye pain or blurred vision that does not respond to topical 
therapy and does not improve to Grade 1 severity within the re-treatment period OR requires 
systemic treatment 

Any Grade 3 non-skin, drug-related adverse event lasting > 7 days, with the following 
exceptions for laboratory abnormalities, drug-related uveitis, pneumonitis, bronchospasm, 
hypersensitivity reactions, and infusion reactions:

Grade 3 drug-related uveitis, pneumonitis, 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 > 7 days or associated with bleeding requires 
discontinuation
Any drug-related liver function test (LFT) abnormality that meets the following criteria 
require discontinuation: 
o
AST or ALT > 5-10x ULN for > 2 weeks
o
AST or ALT > 10x ULN
o
Total bilirubin > 5x ULN
o
Concurrent AST or ALT > 3x ULN and total bilirubin > 2x ULN
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
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

Any dosing interruption lasting > 6 weeks with the following exceptions:

Dosing interruptions to allow for prolonged steroid tapers to manage drug-related adverse 
events are allowed. Prior to re-initiating treatment in a patient with a dosing interruption 
lasting > 6 weeks, the BMS Medical Monitor must be consulted. Tumor assessments should 
continue as per protocol even if dosing is interrupted. 

Dosing interruptions > 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 patient with a 
dosing interruption lasting > 6 weeks, the BMS Medical Monitor must be consulted. Tumor 
assessments should continue as per protocol even if dosing is interrupted.

Any adverse event, laboratory abnormality, or intercurrent illness which, in the judgment of 
the Investigator, presents a substantial clinical risk to the patient with continued nivolumab 
dosing
4.6.5
Treatment Beyond Disease Progression
As described in Section 1.1.2, accumulating evidence indicated a minority of patients treated with 
immunotherapy may derive clinical benefit despite initial evidence of progressive disease.37
Patients treated with nivolumab will be permitted to continue treatment beyond initial Investigator-
assessed progressive disease as long as they meet the following criteria:

Investigator-assessed clinical benefit and do not have rapid disease progression

Tolerance of study drug

Stable performance status

Treatment beyond progression will not delay an imminent intervention to prevent serious 
complications of disease progression (eg, CNS metastases)

Patient provides written informed consent prior to receiving additional nivolumab treatment 
using an ICF describing any reasonably foreseeable risk or discomforts or other alternative 
treatment options

The assessment of clinical benefit should be balanced by clinical judgment as to whether the 
patient is clinically deteriorating and unlikely to receive any benefit from continued treatment 
with nivolumab
If the investigator feels that the nivolumab patient continues to achieve clinical benefit by 
continued treatment, the patient should remain on the trial and continue to receive monitoring 
according to the Time and Events Schedule in Table 5.1-2.
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Global deterioration of health status requiring discontinuation of treatment without objective 
evidence of disease progression at the time should be reported as symptomatic deterioration. Every 
effort should be made to document objective progression (ie, radiographic confirmation) even after 
discontinuation of treatment. 
The assessment of clinical benefit should take into account whether the patient is clinically 
deteriorating and unlikely to receive further benefit from continued treatment. All decisions to 
continue treatment beyond initial progression must be discussed in the study records.
4.6.6
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, arthralgias, hypo- or 
hypertension, bronchospasm, or other symptoms. All Grade 3 or 4 infusion reactions should be 
reported within 24 hours to the BMS Medical Monitor and reported as an SAE if criteria are met. 
Infusion reactions should be graded according to NCI CTCAE (version 4.0) 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 patient until recovery from symptoms. The following prophylactic 
premedications are recommended for future infusions: diphenhydramine 50 mg (or equivalent) 
and/or paracetamol 325 to 1000 mg (acetaminophen) at least 30 minutes before additional 
nivolumab administrations.
For Grade 2 symptoms (moderate reaction requires therapy or infusion interruption but responds
promptly to symptomatic treatment [eg, antihistamines, non-steroidal anti-inflammatory drugs, 
narcotics, corticosteroids, bronchodilators, IV fluids], prophylactic medications indicated for 24 
hours):
Stop the nivolumab infusion, begin an IV infusion of normal saline, and treat the patient with 
diphenhydramine 50 mg IV (or equivalent) and/or paracetamol 325 to 1000 mg (acetaminophen); 
remain at bedside and monitor patient until resolution of symptoms. Corticosteroid or 
bronchodilator therapy may also be administered as appropriate. If the infusion is interrupted, then 
restart the infusion at 50% of the original infusion rate when symptoms resolve; if no further 
complications ensue after 30 minutes, the rate may be increased to 100% of the original infusion 
rate. Monitor patient closely. If symptoms recur then no further nivolumab will be administered at 
that visit. Administer diphenhydramine 50 mg IV and remain at bedside and monitor the patient
until resolution of symptoms. The amount of study drug infused must be recorded on the electronic 
case report form (eCRF). The following prophylactic medications are recommended for future 
infusions: diphenhydramine 50 mg (or equivalent) and/or paracetamol 325 to 1000 mg 
(acetaminophen) should be administered at least 30 minutes before additional nivolumab 
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administration. If necessary, corticosteroids (recommended dose: up to 25 mg of IV 
hydrocortisone or equivalence) may be used. 
Grade 3 or 4 symptoms (severe reaction, Grade 3 prolonged [ie not rapidly responsive to 
symptomatic medication and/or brief interruption or infusion]; recurrence of symptoms following 
initial improvement; hospitalization indicated for other clinical sequelae [eg, renal impairment, 
pulmonary infiltrates]). Grade 4: (life-threatening, pressor or ventilatory support indicated):
Immediately discontinue infusion of nivolumab. Begin an IV infusion of normal saline and treat 
the patient as follows: recommend bronchodilators, epinephrine 0.2 to 1 mg of 1:1,000 solution 
for subcutaneous administration or 0.1 to 0.25 mg of 1:10,000 solution injected slowly for IV 
administration, and/or diphenhydramine 50 mg IV with methylprednisolone 100 mg IV (or 
equivalent) as needed. Nivolumab will be permanently discontinued. Investigators should follow 
their institutional guidelines for the treatment of anaphylaxis. Remain at bedside and monitor 
patients until recovery from symptoms. In the case of late-occurring hypersensitivity symptoms 
(eg, appearance of a localized or generalized pruritus within 1 week after treatment), symptomatic 
treatment may be given (eg, oral antihistamine or corticosteroids). 
4.7
Blinding/Unblinding
Not applicable.
4.8
Treatment Compliance
Treatment compliance will be monitored by drug accountability as well as the patient’s medical 
record and eCRF. 
4.9
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 Study Monitor unless study drug containers must be immediately destroyed as required 
for safety, or to meet local regulations (eg, 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, ie, incinerator, licensed sanitary landfill, or licensed waste disposal vendor 
must be documented.

Accountability and disposal records are complete, up-to-date, and available for the Monitor to 
review throughout the clinical trial period.
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If conditions for destruction cannot be met the responsible 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.
4.10
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 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. 
Arrangements for the return of study drug will be made by the responsible Study Monitor. 
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5
STUDY ASSESSMENTS AND PROCEDURES
5.1
Flow Chart/Time and Events Schedule
Table 5.1-1:
Screening Procedural Outline (CA209172)
Procedure
Screening 
Visita
Visit 1
Notes
Eligibility Assessments
Informed Consent
X
Inclusion/Exclusion 
Criteria
X
Assessed prior to first dose
Medical History
X
Documentation of mutation status (BRAF, NRAS, cKIT) if known.
Safety Assessments
HIV testing (Germany 
only)
X
To be performed within 28 days of the first dose.
Physical Examination
X
X
Included height, weight, ECOG Performance Status. Focused physical exam performed at 
screening, if clinically indicated. 
ECOG Performance Status
X
X
Cohort : PS 0-1
Cohort 2: PS 2
Vital Signs and Oxygen 
Saturation
X
X
Temperature, BP, HR, RR, O2 saturation by pulse oxymetry at rest (also monitor amount of 
supplement oxygen if applicable). Obtain vital signs at screening visit and within 72 hours of 
first dose. 
Serious Adverse Events 
Assessment
X
X
Adverse Events 
Assessment
X
X
Assessment of Signs and 
Symptoms
X
After obtaining Informed Consent, assess all signs and symptoms within 14 days of first dose, 
prior to study treatment initiation
 
Laboratory Tests
X
Serum chemistry tests performed locally within 14 days prior to first dose (unless otherwise 
specified): CBC with differential, serum chemistry (BUN or serum urea level, serum 
creatinine, sodium, calcium, phosphate, chloride, and glucose), AST, ALT, total bilirubin, 
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Table 5.1-1:
Screening Procedural Outline (CA209172)
Procedure
Screening 
Visita
Visit 1
Notes
alkaline phosphatase, albumin, LDH, TSH, free T3, freeT4, and lipase. Within 28 days prior 
to first dose, hepatitis B surface antigen (HBsAg) and hepatitis C antibody (HCV Ab).
Pregnancy Tests 
X
Xb
Performed within 24 hours prior to first dose for WOCBP only (serum or urine as required by 
the standard of care at the site). See Section 3.3.3 for the definition of Women of 
Childbearing Potential. 
Additional Assessments 
EORTC QLQ-C30
X
Patient to complete
EQ-5D-3L
X
Patient to complete
Efficacy Assessments
Screening/Baseline Tumor 
Assessments
------see notes------
Chest, abdomen, pelvis, brain, and other known sites of disease within 6 weeks prior to first 
dose of study therapy. Patients must have evaluable disease by CT or MRI per RECIST 1.1 
criteria (radiographic tumor assessment performed within 6 weeks prior to first dose of study) 
or clinically apparent disease that the investigator can follow for response. 
ALT = Alanine aminotransferase; AST = Aspartate aminotransferase; BP = blood pressure; BUN = blood urea nitrogen; CBC = complete blood count; HBsAg 
= hepatitis B surface antigen; HCV Ab = hepatitis C antibody; HR = heart rate; LDH = lactate dehydrogenase; O2 = oxygen; PS = Performance Status; RR = 
respiratory rate; TSH, thyroid stimulating hormone; WOCBP = women of child bearing potential
a Within 6 weeks before start of nivolumab
b Within 24 hours prior to the start of nivolumab (Day 1). An extension up to 72 hours prior to the start of nivolumab is permissible in situations where results 
cannot be obtained within the standard 24 hour window
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Table 5.1-2:
CA209172 On-Treatment Assessments
Procedure
Each Cycle 
(every 2 weeks)
(2 days) 
Every 2 Cycles 
(every 4 weeks)
(2 days)
Every 3 Cycles 
(every 6 weeks)
(2 days)
Notes
Safety Assessments
Physical Measurements 
(including PS)
X
Collect weight and ECOG PS within 72 hours prior to dosing. Focused 
physical exams should be performed as clinically indicated.
Vital Signs and 
Oxygen Saturation
X
Within 72 hours prior to dosing, tests include temperature, BP, HR, RR, 
O2 saturation by pulse oxymetry at rest (also monitor amount of 
supplemental oxygen if applicable) prior to dosing and at any time a 
patient has any new or worsening respiratory symptoms.
Serious Adverse Event 
Assessments
X
Assessed using NCI CTCAE v 4.0. 
For patients with known immune-related, Grades 3-4 adverse events 
during treatment with an anti-CLTA-4 antibody, weekly telephone calls 
or in-person visits are recommended. 
Adverse Event 
Assessment
X
Assessed using NCI CTCAE V 4.0.
For patients with known immune-related, Grades 3-4 adverse events 
during treatment with an anti-CTLA-4 antibody, weekly telephone calls 
or in-person visits are recommended.
 
Laboratory Tests
X
X (TFTs only)
CBCs with differential,a Serum chemistry tests,b liver function testsc
and lipase should be checked every cycle, and the results should be 
obtained prior to dosing. TFTsd should be checked every 3 cycles 
(every 6 weeks) starting with Cycle 1. May be completed more 
frequently if required by local standards. Laboratory tests should be 
completed 72 hours prior to dosing, and the results must be available 
prior to dosing. See footnote b regarding availability of lipase results 
prior to dosing. 
Pregnancy Test
X
Completed every 2 cycles, starting with Cycle 1. May be completed 
more frequently if required by local standards
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Table 5.1-2:
CA209172 On-Treatment Assessments
Procedure
Each Cycle 
(every 2 weeks)
(2 days) 
Every 2 Cycles 
(every 4 weeks)
(2 days)
Every 3 Cycles 
(every 6 weeks)
(2 days)
Notes
Efficacy Assessments
Tumor Scans
---see notes---
Mandatory initial tumor assessment is to be completed at Week 12 (5 
days). If known or new CNS metastases are detected during screening, a 
brain scan is required at the mandatory tumor assessment at Week 12 
(5 days). Further tumor assessments are recommended to be 
completed as required by local standards of care or at the investigator’s 
discretion and are recommended every 8 weeks. The assessment of 
clinical benefit should be balanced by clinical judgment as to whether 
the patient is clinical deteriorating and unlikely to receive any benefit 
from continued treatment with nivolumab.
Survival 
X
Outcomes 
Assessments 
EQ-5D-3L
X
Every 2 cycles (4 weeks) for 4 months starting with Cycle 1, then every 
4 cycles (8 weeks) after first administration of nivolumab prior to any 
study procedures and treatments 
EORTC QLQ-C30
X
Every 2 cycles (4 weeks) for 4 months starting with Cycle 1, then every 
4 cycles (8 weeks) after first administration of nivolumab prior to any 
study procedures and treatments
Clinical Drug 
Supplies
Administration of 
Study Drug
X
BP = blood pressure; CBC = complete blood count; HR = heart rate; LDH = lactate dehydrogenase; LFT = liver function test; NCI CTCAE = National Cancer 
Institute Common Terminology Criteria for AEs; O2 = oxygen; PS = Performance Status; RR = respiratory rate; TFT, thyroid function test.
a CBCs with differential includes white blood cell count, lymphocyte count, absolute neutrophil count, hemoglobin, hematocrit, and platelet count. Results to be 
obtained prior to dosing on infusion days
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b Serum chemistry tests include blood urea nitrogen [BUN] or serum urea level, serum creatinine, sodium, calcium, chloride, lipase, and glucose. Amylase should 
be performed in addition to lipase in cases where lipase results are not available prior to dosing. 
c Liver function tests include AST, ALT, total bilirubin, alkaline phosphatase, albumin.
d Thyroid function testing including TSH (free T3 and free T4 if abnormal results for TSH).
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Table 5.1-3:
Off-Treatment Follow-Up Assessments:CA209172
Procedure
Every 4 Weeks
FU-X01 (30 days 
7 days)
FU-X02 
(70-84 days 
after FU-
X01 7 
days
Follow-Up 
After X01
and X02. 
Every 3 
months.
(7 days)
Notes
Safety 
Assessments
. 
Physical 
Examinations
X
X
Collect weight and ECOG PS. Focused physical examination may 
be performed if clinically indicated.
Vital Signs 
and Oxygen 
Saturation
X
X
Temperature, BP, HR, RR, O2 saturation by pulse oximetry at rest 
(also monitor amount of supplemental oxygen if applicable) prior to 
dosing and at any time a patient has any new or worsening 
respiratory symptoms. 
Adverse 
Events 
Assessments
X
X
Beyond 100 days from the last dose of study therapy, patients 
followed for ongoing drug-related adverse events until resolved, 
symptoms return to baseline or are deemed irreversible, lost to 
follow-up, or withdrawal of study consent. 
 
 
 
Laboratory 
Tests
X
X
Serum chemistry tests and TFTs should be checked at FU1 and 
FU2.
Pregnancy 
Test
X
X
X
Pregnancy testing may be performed at home if an in-office visit is 
otherwise not required.
Efficacy 
Assessments 
Tumor Scans
-------see notes------
Tumor progression scans are recommended to be completed as 
required by local standards of care or at the investigator’s 
discretion.
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Table 5.1-3:
Off-Treatment Follow-Up Assessments:CA209172
Procedure
Every 4 Weeks
FU-X01 (30 days 
7 days)
FU-X02 
(70-84 days 
after FU-
X01 7 
days
Follow-Up 
After X01
and X02. 
Every 3 
months.
(7 days)
Notes
Survival 
Follow-up
X
X
Xa
Outcomes 
Assessments
EQ-5D-3L
X
X
Xa
The EQ-5D-3L can be completed by mail, e-mail, or telephone call 
(using the telephone version) when a clinical visit is not otherwise 
required. When a clinical visit is required, the questionnaire should 
be completed at the clinic.
BP = blood pressure; CBC = complete blood count; HR = heart rate; LDH = lactate dehydrogenase; LFT = liver function test; NCI CTCAE = National Cancer 
Institute Common Terminology Criteria for AEs; O2 = oxygen; PS = Performance Status; RR = respiratory rate; TFT, thyroid function test.
a For subjects who have discontinued treatment before the end of the 2-year treatment period. Per Amendment 08, follow up begins when the decision to 
discontinue a patient from study therapy is made (no further treatment with nivolumab) and continues from first dose of study therapy up to 2 years or until 
death, withdrawal of study consent, or lost-to-follow-up.
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5.1.1
Retesting During Screening or Lead-in Period
Retesting of laboratory parameters and/or other assessments within any single Screening or Lead-
in period will be permitted (in addition to any parameters that require a confirmatory value).
Any new result will override the previous result (ie, the most current result prior to first dose) and 
is the value by which study inclusion will be assessed, as it represents the patient’s most current 
clinical state.
5.2
Study Materials
The site will provide all required materials for the tests performed locally (ie, relevant to clinical 
laboratory tests). The site will have available a well-calibrated scale for recording body weight, a 
calibrated sphygmomanometer, and thermometer for temperature. The site will have a validated 
temperature-controlled refrigerator. The site will provide all materials required for accurate source 
documentation of study activities. 
BMS will provide a BMS-approved protocol and any amendments or administrative letters (if 
required). Case report forms (electronic or hard copy) will be provided by BMS. Nivolumab will 
be supplied by BMS. BMS will also provide the Investigator Brochure and the EORTC QLQ-C30
and EQ-5D-3L.
5.3
Safety Assessments
Only data for the procedures and assessments specified in this protocol should be submitted to 
BMS on a case report form. Additional procedures and assessments may be performed as part of 
standard of care; however, data for these assessments should remain in the patient’s medical record 
and should not be provided to BMS unless specifically requested. NCI CTCAE version 4.0 will be 
the criteria used to assess severity of AEs.
During the 100 days after the last dose of study treatment, patients will have 2 additional follow-
up visits as described in Table 5.1-3. 
The following assessments should be monitored starting on Cycle 1 Day 1 and will continue as 
per the schedule in the Time and Events Tables at the specified frequency until discontinuation 
from study therapy:

Adverse events continuously throughout the study

Physical examination and physical measurements including weight and ECOG PS 

Complete blood count with differential, including white blood cells, lymphocyte count, 
absolute neutrophil count, hemoglobin, hematocrit, and platelet count. Results to be obtained 
prior to dosing on infusion days.

Serum chemistry tests (blood urea nitrogen or serum urea level, serum creatinine, sodium, 
calcium, phosphate, chloride, glucose, lipase, and LDH). Results to be obtained prior to dosing 
on infusion days. Amylase should be performed in addition to lipase in cases where lipase 
results are not available prior to dosing. 

Liver function tests including AST, ALT, total bilirubin, alkaline phosphatase, and albumin. 
Results to be obtained prior to dosing on infusion days.
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
Thyroid function testing including thyroid stimulating hormone (free T3 and free T4 if 
abnormal results for TSH)
5.3.1
Imaging Assessment for the Study
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
Vital Signs and Physical Examinations
Vital signs (seated blood pressure and heart rate), physical measurements, and physical 
examinations should be performed at program visits. 
A full physical examination should be performed prior to the start of treatment. A targeted physical 
examination may be performed by a qualified professional guided by the examiner’s observations 
and/or patient complaints on new or changed conditions, symptoms, or concerns. Targeted 
physical exam includes assessment of heart, lungs, and abdomen.
5.3.3
Pregnancy Testing
Pregnancy testing must be completed for WOCBP every 4 weeks while receiving the program 
drugs and during the follow-up period of 100 days, which includes Follow-up Visits 1 and 2.
Pregnancy testing may be performed at home if an in-office visit is otherwise not required. 
Telephone contacts are required to obtain results for all patients who perform post-treatment at-
home pregnancy testing. Although testing may be performed with home pregnancy testing kits, 
any positive result must be confirmed by serum pregnancy testing at the program site.
5.4
Efficacy Assessments
Efficacy assessments include initial mandatory tumor assessment at Week 12 (5 days). Further 
tumor assessments to be completed as required by local standards of care or at the investigator’s 
discretion and are recommended every 8 weeks, as discussed in Table 5.1-2.
Study evaluations will take place in accordance with Table 5.1-2 and should be performed 
according to RECIST 1.1 criteria. 
High resolution CT with oral or IV contrast or contrast-enhanced MRI are the preferred imaging 
modalities for assessing radiographic tumor response. If a patient has a known allergy to contrast 
material, please use local prophylaxis standards to obtain the assessment with contrast if at all 
possible or use an alternate modality. In cases where contrast is strictly contraindicated, a non-
contrast scan will suffice. Screening assessments should be performed within 6 weeks prior to first 
dose of study drug. Brain MRI is the preferred imaging method for evaluating CNS metastasis, 
and an assessment is required during screening. If known or new CNS metastases are detected 
during screening, a brain scan is required at the mandatory tumor assessment at Week 12 (5 days). 
Furthermore, all known or suspected sites of disease should be assessed at screening and at 
subsequent assessments using the same imaging method and technique. If more than one method 
is used at screening, then the most accurate method according to RECIST 1.1 should be used when 
recording data and should again be used for all subsequent assessments. Bone scan, PET scan, or 
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ultrasound is not adequate for assessment of RECIST response. In selected circumstances where 
such modalities are the sole modality used to assess certain non-target organs, those non-target 
organs may be evaluated less frequently. For example, bone scans may need to be repeated only 
when complete response is identified in the target disease or when progression in bone is suspected. 
Previously treated CNS metastases are not considered measurable lesions for purposes of RECIST 
determined response.
Tumor measurements should be made by the same investigator or radiologist for each assessment 
whenever possible. Changes in tumor measurements and tumor responses to guide ongoing study 
treatment decisions should be assessed by the investigator using RECIST 1.1 at Week 12 and using 
investigator-assessed response thereafter.
Per Amendment 08, patients or their caregivers will be contacted following progression every 
3 months either by direct contact or via telephone until death, withdrawal of consent, or lost to 
follow up for up to 2 years from the start of their treatment with nivolumab. Overall survival will 
be followed continuously while patients are on the study drug and at follow up visits 1 and 2 as 
well as every 3 months after discontinuation, or progression, for up to 2 years following the start 
of therapy either by direct contact (office visits) or via telephone contact, until death, withdrawal 
of study consent, or lost to follow-up. Overall survival is defined as the time between the start of 
treatment and the date of death due to any cause. See Table 5.1-3 for further clarification.
Per Amendment 08, survival will be followed after progression either by direct contact (office 
visits) or via telephone contact until death, withdrawal of study consent, or lost to follow-up for 
2 years following start of therapy.
5.5
Pharmacokinetic Assessments
Not applicable.
5.6
Biomarker Assessments
Not applicable.
5.7
Outcomes Research Assessments
Quality-of-life data will be measured using the EORTC QLQ-C30 and EQ-5D-3L questionnaires. 
The EORTC QLQ C-30 will be collected in order to assess cancer-specific, health-related quality 
of life. The EORTC QLQ-C30 is one of the most commonly used QoL instruments in oncology 
studies and has been assessed in previous studies assessing health-related quality of life in patients 
with melanoma. The EORTC QLQ-C30 is a 30-item instrument comprising six functional scales 
(physical functioning, cognitive functioning, emotional functioning, social functioning and global 
quality of life) as well as nine symptom scales (fatigue, pain, nausea/vomiting, dyspnea, insomnia, 
appetite loss, constipation, diarrhea, and financial difficulties). Except for the overall health status 
and global quality of life items, responses for all items are 4-point categorical scales ranging from 
0 (not at all) to 4 (very much). The overall health status and quality of life responses are 7-point 
Likert scales. 
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The EQ-5D-3L comprises 5 dimensions (mobility, self-care, usual activities, pain/discomfort and 
anxiety) and a visual analog rating scale (VAS).
5.8
Other Assessments
Not applicable. 
5.9
Results of Central Assessments
Not applicable. All assessments will be on site.  
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 causal relationship can be one of the following:
Related: There is a reasonable causal relationship between study drug administration and 
the AE.
Not related: There is not a reasonable causal relationship between study drug 
administration and the AE. 
The term "reasonable causal relationship" means there is evidence to suggest a causal relationship. 
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.)
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)

requires inpatient hospitalization or causes prolongation of existing hospitalization (see NOTE
below)

results in persistent or significant disability/incapacity

is a congenital anomaly/birth defect 

is an important medical event (defined as a medical event(s) that may not be immediately life-
threatening or result in death or hospitalization but, based upon appropriate medical and 
scientific judgment, may jeopardize the subject or may require intervention [eg, medical, 
surgical] to prevent one of the other serious outcomes listed in the definition above.) Examples 
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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 (eg, 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 6.1.1
for reporting pregnancies).
Any component of a study endpoint that is considered related to study therapy (eg, death is an 
endpoint, if death occurred due to anaphylaxis, anaphylaxis must be reported) should be reported 
as SAE (see Section 6.1.1 for reporting details).
NOTE: 
The following hospitalizations are not considered SAEs in BMS clinical studies: 

a visit to the emergency room or other hospital department < 24 hours, that does not result 
in admission (unless considered an important medical or life-threatening event)

elective surgery, planned prior to signing consent

admissions as per protocol for a planned medical/surgical procedure

routine health assessment requiring admission for baseline/trending of health status (eg, 
routine colonoscopy)

medical/surgical admission other than to remedy ill health and planned prior to entry into 
the study. Appropriate documentation is required in these cases

admission encountered for another life circumstance that carries no bearing on health status 
and requires no medical/surgical intervention (eg, lack of housing, economic inadequacy, 
caregiver respite, family circumstances, administrative reason).

Admission for administration of anticancer therapy in the absence of any other SAEs 
(applies to oncology protocols)
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 and within 
100 days of discontinuation of dosing (within 30 days of last visit for enrollment/screening 
failures).
The investigator should 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 should be completed for any event where doubt exists regarding its seriousness. 
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If the investigator believes that an SAE is not related to study drug, but is potentially related to the 
conditions of the study (such as withdrawal of previous therapy or a complication of a study 
procedure), the relationship should be specified in the narrative section of the SAE Report Form.
SAEs, whether related or not related to study drug, and pregnancies must be reported to BMS (or 
designee) within 24 hours. SAEs must be recorded on the SAE Report Form; pregnancies on a 
Pregnancy Surveillance Form (electronic or paper forms). The preferred method for SAE data 
reporting collection is through the eCRF.  The paper SAE/pregnancy surveillance forms are only 
intended as a back-up option when the eCRF system is not functioning.  In this case, the paper 
forms are to be transmitted via email or confirmed facsimile (fax) transmission to:
SAE Email Address: Refer to Contact Information list.
SAE Facsimile Number:  Refer to Contact Information list.
For studies capturing SAEs through electronic data capture (EDC), electronic submission is the 
required method for reporting. 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. All 
nonserious adverse events (not only those deemed to be treatment-related) should be collected 
continuously during the treatment period and for a minimum of 100 days following the last dose 
of study treatment.
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 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.
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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 (eg, anemia versus low hemoglobin value).
6.4
Pregnancy
If, following initiation of the study drug, it is subsequently discovered that a study subject is 
pregnant or may have been pregnant at the time of study exposure, including during at least 5 half 
lives after product administration, the investigator must immediately notify the BMS Medical 
Monitor/designee of this event and complete and forward a Pregnancy Surveillance Form to BMS 
Designee within 24 hours 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).
In the rare event that the benefit of continuing study drug is thought to outweigh the risk, after 
consultation with BMS, the pregnant subject may continue study drug after a thorough discussion 
of benefits and risk with the subject.
Protocol-required procedures for study discontinuation and follow-up must be performed on the 
subject unless contraindicated by pregnancy (eg, x-ray studies). Other appropriate pregnancy 
follow-up procedures should be considered if indicated.
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.
6.5
Overdose
All occurrences of overdose must be reported as SAEs (see Section 6.1.1 for reporting details).
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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.
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
The Scientific Steering Committee (SSC) will closely review the safety data throughout the study 
to evaluate the risk/benefit ratio in general and for the separate prospective cohorts following a 
predefined Safety Management Plan.
8
STATISTICAL CONSIDERATIONS
The study will include patients with histologically confirmed stage III (unresectable) or stage IV 
melanoma and progression after prior treatment containing an anti-CTLA-4 monoclonal antibody 
treated with nivolumab (BMS-936558) at a dose of 3 mg/kg every 2 weeks. Patients will be treated 
with 3 mg/kg of nivolumab IV every 2 weeks for a maximum of 24 months. 
Based on the Performance Status of the patients, there are 2 pre-defined cohorts: Cohort 1, 
enrolling patients with progression after prior treatment containing an anti-CTLA-4 monoclonal 
antibody and Performance Status 0-1 (n is at least 640, 85% of the minimum of the 735 screened) 
and Cohort 2, enrolling patients with progression after prior treatment containing an anti-CTLA-4 
monoclonal antibody and Performance Status 2 (n is at the most 160, 85% of the maximum of the 
185 screened; a minimum of 50 patients will be enrolled). 
A patient who meets the screening criteria will be treated for a maximum of 24 months with safety 
follow-up at 30 [7] and 70-84 [7] days from first follow-up visit post-treatment. With an 
expected screening failure rate of 15%, a maximum total of about 800 patients (640 PS1 and 160 
PS2) will be treated. 
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The number and percentage of patients with high-grade, treatment-related, select adverse events 
and their characteristics will be reported overall and by subgroups and during and off-treatment. 
Overall survival is defined as the time between the start of treatment and the date of death due to 
any cause. A patient who has not died will be censored at last known date alive. OS will be 
followed up while patients are on the study drug and every 3 months via in-person visits or phone 
contact after patients discontinue study drug. 
8.1
Sample Size Determination
Currently, there is only little reliable data describing the percentage of patients with melanoma 
progressing after prior therapy containing treatment with an anti-CTLA-4 monoclonal antibody, 
presenting with Performance Status 2, and eligible for nivolumab treatment. It is estimated that a 
minimum of 20% of the potential study population will initially present with PS2. Given that 20% 
of the 920 patients screened is 185 patients, it is expected that the full complement of 160 patients 
will be enrolled into the PS2 cohorts and treated.
With an approximate 15% screening failure rate, a cohort of 735 enrolled PS1 patients is projected 
to a yield 640 treated patients. With n = 640 patients, about 3 will experience a rare adverse event 
with 0.5% true cumulative event rate with a rate estimated within 95% confidence interval (CI) 
(0.1%-1.4%). Approximately 2 patients with events and a 95% CI of (0%-1.1%) for assumed true 
event rate of 0.3% are projected.
8.2
Populations for Analyses

The safety analysis set comprises patients who received at least 1 dose of nivolumab. The 
analysis of safety, OS, and QoL data will be based on the safety analysis set.

The response evaluable analysis set comprises patients who received at least 1 dose of 
nivolumab and have both baseline and at least 1 post-baseline tumor scan. 
8.3
Endpoints
8.3.1
Primary Endpoint(s)
The primary endpoint is the incidence for high-grade (CTCAE v4.0 Grade 3 or higher), treatment-
related, select adverse events.
Select adverse events are defined in Section 4.6.1.1.
8.3.2
Secondary Endpoint(s)
The secondary endpoints include:

Incidence of all high-grade (Grades 3 and higher), select adverse events 

Median time to onset and median time to resolution (Grades 3-4) of select adverse events

OS is defined as the time from first dosing date to the date of death. A patient who has not died 
will be censored at last known date alive. OS will be followed continuously while patients are 
on treatment and every 3 months via in-person or phone contact after patients discontinue the 
study drug.
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
Investigator-assessed ORR. ORR is defined as the number and percentage of patients with a 
best overall response (BOR) of confirmed CR or PR. ORR as assessed by the investigator will 
be reported.
 
 
 
 
  
8.4
Analyses
The analysis of primary, secondary (excluding ORR), 
 will be reported 
for the full safety analysis set and by cohorts based on ECOG PS. ORR will be reported for the 
response evaluable analysis set and by PS. OS and ORR will be further presented by initial 
investigator-assessed objective response under treatment with an anti-CTLA-4 monoclonal 
antibody.
Additional details regarding statistical analyses performed in the study are provided in the 
Statistical Analysis Plan (SAP), which will be finalized before data base lock.
8.4.1
Demographics and Baseline Characteristics
The demographic characteristics, medical history, and baseline assessments of patients will be 
reported as counts and percentages. The number and percentage of patients by cohorts and 
subgroups based on types of melanoma (with BRAF-mutated melanoma, uveal melanoma, 
mucosal melanoma), patients with CNS metastases, patients with known autoimmune disease, and 
patients who experienced immune-related adverse events during treatment with an anti-CLTA-4 
antibody will be presented.
Study participation status including completion and discontinuation of treatment will be reported. 
Reasons for discontinuation will be summarized.
8.4.2
Safety Analyses
8.4.2.1
Primary Analyses 
The evidence for the research hypothesis of this clinical trial that high-grade (CTCAE v4.0 Grade 
3 or higher), treatment-related select adverse events occur with a low frequency in patients with 
advanced (unresectable or metastatic) melanoma will be presented in terms of the number, 
percentage of patients, and 95% confidence intervals for the percentage with these select adverse 
events during and off-treatment overall and by cohort.
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8.4.2.2
Secondary Analyses
Adverse events from date of enrollment up to last contact with patients will be presented for the 
full study duration and separately for events that occur on- or post-treatment. In particular, safety 
data will be summarized and listed for all treated patients using the NCI CTCAE version 4.0. All 
on-study AEs, drug-related AEs, SAEs, and drug-related SAEs will be tabulated using worst grade 
per NCI CTCAE v4.0 criteria by system organ class and MedDRA preferred term. On-study 
laboratory parameters including hematology, chemistry, liver function, thyroid function, and renal 
function will be summarized using worst grade per NCI CTCAE v4.0 criteria.
In addition to reporting number and percentages of patients with adverse events, incidence density 
rates may be reported for repeated adverse events that vary by duration of study participation. 
Reporting of 95% confidence intervals for incidence density rates will be based on the Poisson 
distribution.
 
 
 
 
 
 
 
8.4.3
Efficacy Analyses
Overall survival is defined as the time between the start of treatment and the date of death due to 
any cause. A patient who has not died will be censored at last known date alive. 
OS will be summarized using Kaplan-Meier (KM) product-limit method and associated statistics. 
Median values of OS, if estimable, along with 2-sided 95% CI using the Brookmeyer and Crowley 
method will be calculated. Overall survival rates at selected time points, including survival rates 
at Years 1 and 2, together with their 95% CIs will also be estimated using KM estimates on the 
OS curves. Associated 2-sided 95% CIs will be calculated using the Greenwood formula. OS 
summary statistics by subgroups will also be reported. In particular, OS post-treatment will be 
reported by investigator-reported ORR under treatments with anti-CTLA-4 monoclonal antibody.
ORR is defined as the number and percentage of patients with a best overall response (BOR) of 
confirmed CR or PR. ORR as assessed by the investigator will be reported.
8.4.4
Pharmacokinetic Analyses
Not applicable. 
8.4.5
Biomarker Analyses
Not applicable. 
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8.4.6
Outcomes Research Analyses
The patients’ self-report of their quality of life at baseline and change in their QoL in subsequent 
visits as recorded in the EORTC QLQ-C30 and EQ-5D-3L questionnaires will be summarized at 
each time point for the full safety analysis set. In addition, EORTC QLQ-C30 mean domain score 
and mean change from baseline in domain score will be reported. The overall global health score 
and domain score (functional and symptom score) for each patient will be calculated using the 
EORTC QLQ-C30 scoring algorithm.  A mixed effects random model may be fitted for the mean 
change from baseline with time as the main factor and patient level characteristics like age, sex, 
Performance Status, and other patient characteristics as covariates. 
Additionally, the EQ-5D-3L assessment will be performed. The EQ-5D-3L comprises 5 
dimensions (mobility, self-care, usual activities, pain/discomfort and anxiety) and a visual analog 
rating scale). The responses to the EQ-5D-3L domains will be converted to health status index 
based on the European scoring algorithm.  
8.4.7
Other Analyses
Not applicable. 
8.5
Interim Analyses
Several interim analyses will be performed ad hoc and as necessary to address queries from the 
regulatory authorities.  
9
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 and Regulatory Authorities, if required by local regulations, 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 
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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
BMS representatives will review data centrally to identify potential issues to determine a schedule 
of on-site visits for targeted review of study records. 
Representatives of BMS must be allowed to visit all study site locations periodically to assess the 
data quality and study integrity. On site they will review study records and directly compare them 
with source documents, discuss the conduct of the study with the investigator, and verify that the 
facilities remain acceptable. Certain CRF pages and/or electronic files may serve as the source 
documents.
In addition, the study may be evaluated by 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 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.
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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 to include investigational product. 
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

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.
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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:

External Principal Investigator designated at protocol development

National Coordinating Investigator 

Study Steering Committee chair or their designee

Subject recruitment (eg, among the top quartile of enrollers)

Involvement in trial design

Regional representation (eg, among top quartile of enrollers from a specified region or 
country)

Other criteria (as determined by the study team)
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The data collected during this study are confidential and proprietary to BMS. Any publications or 
abstracts arising from this study require approval by BMS prior to publication or presentation and 
must adhere to BMS’s publication requirements as set forth in the approved clinical trial agreement 
(CTA). All draft publications, including abstracts or detailed summaries of any proposed 
presentations, must be submitted to BMS at the earliest practicable time for review, but at any 
event not less than 30 days before submission or presentation unless otherwise set forth in the 
CTA. BMS shall have the right to delete any confidential or proprietary information contained in 
any proposed presentation or abstract and may delay publication for up to 60 days for purposes of 
filing a patent application.
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GLOSSARY OF TERMS
Term
Definition
Complete Abstinence
If one form of contraception is required, 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 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.
If two forms of contraception is required, Complete 
abstinence is defined as complete avoidance of heterosexual 
intercourse and is an acceptable form of contraception for all 
study drugs. Subjects who choose complete abstinence are 
not required to use a second method of contraception, but 
female subjects must continue 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.
Expanded definition Complete abstinence as defined as 
complete avoidance of heterosexual intercourse is an 
acceptable form of contraception for all study drugs. This 
also means that abstinence is the preferred and usual lifestyle 
of the patient. This does not mean periodic abstinence (e.g., 
calendar, ovulation, symptothermal, profession of abstinence 
for entry into a clinical trial, post-ovulation methods) and 
withdrawal, which are not acceptable methods of 
contraception. Subjects who choose complete abstinence are 
not required to use a second method of contraception, but 
female subjects must continue 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
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LIST OF ABBREVIATIONS
Term
Definition
AE
adverse event
ALT
alanine aminotransferase
ANC
absolute neutrophil count
ANOVA
analysis of variance
AST
aspartate aminotransferase
AT
aminotransaminases
AUC
area under the concentration-time curve
BMS
Bristol-Myers Squibb
BUN
blood urea nitrogen
CFR
Code of Federal Regulations 
CRF
Case Report Form, paper or electronic
eCRF
Electronic Case Report Form
EDC
Electronic Data Capture
FDA
Food and Drug Administration
FSH
follicle stimulating hormone
GCP
Good Clinical Practice
HRT
hormone replacement therapy
ICH
International Conference on Harmonisation 
ie
id est (that is)
IEC
Independent Ethics Committee
IMP
investigational medicinal products
IND
Investigational New Drug Exemption
IRB
Institutional Review Board
IU
International Unit
IV
intravenous
mg
milligram
MTD
maximum tolerated dose
g
microgram
N
number of subjects or observations
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Term
Definition
N/A
not applicable
NIMP
non-investigational medicinal products 
PTT
partial thromboplastin time
SAE
serious adverse event
SD
standard deviation
TAO
Trial Access Online, the BMS implementation of an EDC capability
WBC
white blood cell
WHO
World Health Organization
WOCBP
women of childbearing potential
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SAP_000.pdf: 
Official Title of Study: 
A Single-Arm, Open-Label, Multicenter Clinical Trial with Nivolumab (BMS-936558) for 
Subjects with Histologically Confirmed Stage III (unresectable) or Stage IV Melanoma 
Progressing After Prior Treatment Containing an Anti-CTLA-4 Monoclonal Antibody 
 
NCT Number:  NCT02156804 
 
Document Date (Date in which document was last revised): June 13, 2019 


STATISTICAL ANALYSIS PLAN
FOR CLINICAL STUDY REPORT
A SINGLE-ARM, OPEN-LABEL, MULTICENTER CLINICAL TRIAL WITH 
NIVOLUMAB (BMS-936558) FOR SUBJECTS WITH HISTOLOGICALLY CONFIRMED 
STAGE III (UNRESECTABLE) OR STAGE IV MELANOMA PROGRESSING AFTER 
PRIOR TREATMENT CONTAINING AN ANTI-CTLA-4 MONOCLONAL ANTIBODY
CheckMate 172: CHECKpoint pathway and nivoluMAb clinical Trial Evaluation 172
PROTOCOL CA209-172
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TABLE OF CONTENTS
STATISTICAL ANALYSIS PLAN FOR CLINICAL STUDY REPORT ...................................1
TABLE OF CONTENTS............................................................................................................2
LIST OF TABLES......................................................................................................................3
LIST OF FIGURES ....................................................................................................................4
2
STUDY DESCRIPTION ..........................................................................................6
2.1
Study Design ............................................................................................................6
2.2
Treatment Assignment..............................................................................................8
2.3
Blinding and Unblinding...........................................................................................8
2.4
Protocol Amendments...............................................................................................9
2.5
Scientific Steering Committee ................................................................................11
3
OBJECTIVES ........................................................................................................11
3.1
Primary...................................................................................................................11
3.2
Secondary...............................................................................................................11
4
ENDPOINTS..........................................................................................................12
4.1
Primary Endpoint....................................................................................................12
4.2
Secondary Endpoints ..............................................................................................12
4.2.1
Incidence of all High-grade, Select AEs..................................................................12
4.2.2
Median Time to Onset and Resolution of Select AEs ...............................................13
4.2.3
Overall Survival (OS) .............................................................................................13
4.3.1
Safety Endpoints.....................................................................................................13
4.3.2
Overall Survival .....................................................................................................13
4.3.3
Outcomes Research Assessments ............................................................................13
4.3.3.1
EORTC QLQ-C30 ..................................................................................................13
4.3.3.2
EuroQoL EQ-5D-3L...............................................................................................15
5
SAMPLE SIZE AND POWER...............................................................................16
6
STUDY PERIODS, TREATMENT REGIMENS AND POPULATIONS 
FOR ANALYSES ..................................................................................................16
6.1
Study Period...........................................................................................................16
6.2
Treatment Regimens...............................................................................................16
6.3
Populations for Analyses ........................................................................................16
6.4
Subpopulations for Analyses...................................................................................17
7
STATISTICAL ANALYSES..................................................................................17
7.1
General Methods ....................................................................................................17
7.2
Study Conduct........................................................................................................18
7.2.1
Accrual...................................................................................................................18
7.2.2
Relevant Protocol Deviations..................................................................................18
7.3
Study Population ....................................................................................................19
7.3.1
Subject Disposition.................................................................................................19
7.3.2
Demography and Subject Characteristics ...............................................................19
7.3.3
Medical History......................................................................................................20
7.3.4
Disease Characteristics ..........................................................................................20
7.3.5
Prior Therapy.........................................................................................................20
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7.3.6
Baseline Examinations............................................................................................21
7.4
Extent of Exposure .................................................................................................21
7.4.1
Administration of Study Therapy.............................................................................21
7.4.2
Interruption or Delay of Study Therapy ..................................................................22
7.4.4
Subsequent Therapy................................................................................................22
7.5
Efficacy..................................................................................................................22
7.5.1
Overall Survival and Overall Response Rate at Week 12 ........................................22
7.5.2
Subject Follow-up for OS........................................................................................23
7.5.3
Subgroups Analyses................................................................................................23
7.6
Safety.....................................................................................................................24
7.6.1
Primary Analysis ....................................................................................................24
7.6.1.1
High-grade (CTCAE v4.0 Grade 3 or higher) Treatment-Related, Select 
Adverse Events. ......................................................................................................24
7.6.2
Secondary Analysis.................................................................................................24
7.6.2.1
High-grade (CTCAE v4.0 Grade 3 or higher) Select Adverse Events ......................24
7.6.2.2
Select Adverse Events .............................................................................................24
7.6.3
Other Safety Analysis..............................................................................................24
7.6.4
Immunogenicity Analysis ........................................................................................25
7.8
Outcomes Research Analyses .................................................................................25
7.8.1
EORTC QLQ-C30 ..................................................................................................25
7.8.2
EuroQoL Five Dimensions Questionnaire...............................................................26
8
CONVENTIONS....................................................................................................26
8.1
Baseline..................................................................................................................26
8.2
Duration, On-study Event calculations....................................................................26
8.3
Conventions for Partial/Missing Dates....................................................................27
8.4
Missing Data ..........................................................................................................28
9
CONTENT OF REPORTS .....................................................................................28
APPENDIX 1
SELECT ADVERSE EVENTS DEFINITION AND 
CONVENTIONS....................................................................................29
DOCUMENT HISTORY..........................................................................................................37
REFERENCES
37
LIST OF TABLES
Table 1:
Subject Cohorts ........................................................................................7
Table 2:
Protocol Amendments ..............................................................................9
Table 3:
Time Windows for Assessments.............................................................15
Table 4:
Derivation of Clustered Select AE..........................................................30
Table 5:
Select Adverse Events ............................................................................31
Table 6:
Document History ..................................................................................37
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LIST OF FIGURES
Figure 1:
Study Design Schematic...........................................................................8
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Research Hypothesis: 
High-grade (CTCAE v4.0 Grade 3 or higher), treatment-related, select adverse events occur with 
a low frequency in subjects with histologically confirmed stage III (unresectable) or stage IV 
melanoma treated and progression after prior treatment containing an anti-CTLA-4 monoclonal 
antibody with nivolumab monotherapy.
Schedule of Analyses:
Several interim analysis will be conducted ad-hoc and as necessary to address queries from 
regulatory authorities.
The Scientific Steering Committee (SSC) will closely review the safety data throughout the study 
to evaluate the risk/benefit ratio in general and for the separate prospective subgroups following a 
predefined Safety Management Plan.
The final analysis will be conducted only after subjects who have met the screening criteria have 
been treated for a maximum of 24 months with safety follow-up at 30 [±7] and 70-84 [±7] days 
from first follow-up visit post-treatment.
2
STUDY DESCRIPTION
2.1
Study Design
The study will include subjects with histologically-confirmed stage III (unresectable) or stage IV 
advanced melanoma who have documented progression after treatment containing an anti-CTLA-
4 monoclonal antibody. Subjects will be treated with 3 mg/kg of nivolumab IV every 2 weeks for 
a maximum of 24 months. Subjects will undergo screening evaluations to determine eligibility 
within 6 weeks prior to the first dose following the signing of an informed consent. Each 14-day 
dosing period will constitute a cycle. 
The Scientific Steering Committee will evaluate the clinical risk/benefit ratio closely following a 
defined Safety Management Plan.
Subjects will undergo screening evaluations to determine eligibility prior to first dose following 
signed informed consent. Subject’s demographic data will be collected: date of birth, gender, 
disease stage, date of diagnosis, previous treatments, comorbidities, performance status, lactate 
dehydrogenase (LDH) level, type of melanoma (mucosal, uveal), and mutation status if known 
(BRAF, NRAS, cKIT).
Safety, including adverse events and physical examination, should be monitored continually, and 
safety assessments are discussed in Tables 5.1-1 and 5.1-2 of the protocol. 
Mandatory initial tumor assessments are to be done at Week 12 (+/-7 days). Further tumor 
assessments should be performed according to institutional standard of care and are recommended 
every 8 weeks until: 

disease progression 

a concurrent malignancy requires treatment

the subject is lost to follow up

the subject withdraws study consent 

completed 24 months of treatment 
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Subjects will not be permitted to continue their treatment beyond initial Investigator-assessed 
progressive disease unless they meet the following criteria:

Investigator-assessed clinical benefit 

Subject is tolerating study drug
The investigator should use his or her clinical judgment to assess clinical benefit by considering 
whether the subject is clinically deteriorating and unlikely to receive any benefit from continued 
treatment with nivolumab.
Follow up begins when the decision to discontinue a subject from study therapy is made (no further 
treatment with nivolumab) and continues up to 5 years from first dose of study therapy until death, 
withdrawal of study consent, or lost-to-follow-up.
The cohorts are described in Table 1.
Table 1:
Subject Cohorts
(Cohort Number)
Disease Criteria
Cohort 1: Advanced Melanoma (unresectable 
stage III or stage IV) (N > 735)

ECOG Performance Status 0 to 1

Progressing after prior therapy containing 
treatment 
with 
an 
anti-CTLA-4 
monoclonal antibody
Cohort 2: Advanced Melanoma (unresectable 
stage III or stage IV) (50≤N≤185)

ECOG Performance Status 2

Progressing after prior therapy containing 
treatment 
with 
an 
anti-CTLA-4 
monoclonal antibody
Enrollment of new subjects on the study will stop at the time of marketing authorization approval. 
In those countries where nivolumab may not be immediately available upon marketing 
authorization, enrollment will remain open for a maximum of 1 year after marketing authorization 
is granted or nivolumab becomes commercially available within the country, whichever occurs 
sooner.
For those subjects enrolled on the study, BMS will continue to provide drug per the timelines 
defined in the protocol.
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The study design schematic is presented in Figure 1.
Figure 1:
Study Design Schematic
2.2
Treatment Assignment
Because this is an open label study with everyone receiving the same treatment, no treatment 
assignment is needed. Subjects will be enrolled into study cohorts (see Table 1) based on their 
disease characteristics at screening.
Enrolled subjects will be assigned a unique identification number. The subject number will be
assigned through an interactive voice response system (IVRS) once the subject has signed the
informed consent form and is registered. Every subject that signs the informed consent form must 
be assigned a subject number in IVRS. Specific instructions for using IVRS will be provided to 
that investigational site in a separate document.
2.3
Blinding and Unblinding
Not applicable. This is an open-label study.
Treat until progression* 
or unacceptable 
toxicities.  Safety is 
followed continuously. 
Subjects followed for 
ongoing drug-related 
AEs until resolution, 
symptoms return to 
baseline, AE deemed 
irreversible, lost to 
follow up/death, disease 
progression,* or 
withdrawal of consent.
*Subjects may be treated 
beyond progression 
under protocol-defined 
circumstances. 
N = approximately 920 
subjects
Study Population:
Subjects with 
histologically-
confirmed stage III 
(unresectable) or 
stage IV melanoma 
who  have 
documented 
progression after 
prior treatment 
containing an anti-
CTLA-4 monoclonal 
antibody
Intervention:
Assuming a 14.7% screening 
failure rate, N = ~800 treated with 
nivolumab 3 mg/kg as a 60-minute 
IV infusion every 2 weeks for a 
maximum of 24 months.
Study Cohorts:

Progression after anti-CTLA-
4 therapy, ECOG PS 0-1) (n 
=~ 735 )

Progression after anti-CTLA-
4 therapy, ECOG PS2 
(minimum of 50, maximum of 
185)
Safety assessments every 2 weeks. 
First mandatory tumor assessments 
are at Week 12.  
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.
Endpoints: Safety, OS, 
EORTC QLQ-C30, and 
EQ-5D
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2.4
Protocol Amendments
There are currently 6 approved amendments. Table 2 shows the history of protocol amendments 
including the dates and change history to the protocol.
Table 2:
Protocol Amendments
Document
Date
Summary of Changes
Revised Protocol 
05
08-Dec-2015

Incorporates Amendment 06
Amendment 06
08-Dec-2015

Adds dosing windows to the Time and Events 
Schedule
Revised Protocol 
04
28-Oct-2015

Incorporates 
Administrative 
Letter 
05 
and 
Amendment 05
Amendment 05
28-Oct-2015

To provide further clarity on the requirements for 
lipase testing

To provide clarity on dose calculations

To allow the EQ-5D-3L to be completed without an 
office visit if one is not otherwise needed.
Administrative 
Letter 05
23-Jul-2015

The of expectations when lipase results are not 
available prior to dosing

Aligning the footnotes of Table 5.1-2 and Section 
5.3, Safety Assessments with the requirements for 
lipase described in Table 5.1-2.

Assessments allowed to be done according to 
standard of care

At what cycle assessments should start and 
assessment windows

When RECIST 1.1 criteria must be used.

NOTE: Administrative Letter 04 was not finalized 
because it was considered to not be needed. 
However, Administrative Letter 05 was created and 
finalized with the mistaken understanding that 
Administrative Letter 04 was finalized.
Revised protocol 
03
02-Jun-2015

Incorporates Amendment 04
Amendment 04
02-Jun-2015

Decreases sample size
Revised Protocol 
02
19-Mar-2015

Incorporates Amendment 03
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Table 2:
Protocol Amendments
Document
Date
Summary of Changes
Amendment 03
19-Mar-2015

This Amendment removes the inclusion of the 
treatment-naïve subjects, also referred to as the first-
line cohort.
Revised Protocol 
01
16-Jan-2015

Incorporates Amendment 02 and Administrative 
Letter 03.
Amendment 02
16-Jan-2015

The inclusion criteria have been expanded and the 
exclusion criteria have been minimized. 

 
. 

The options for palliative local therapy have also 
been expanded to meet the needs of the current 
subject populations. 

The EORTC QLQ-C30 has been eliminated from the 
subject follow up. 

The time points and frequency of assessments have 
been updated. 

The subjects in Cohort 2 will now be analyzed at the 
same frequency to Cohort 1, so the separate Time 
and Events Schedule for Cohort 2 was removed. 

The statistical section has been reformatted to aid 
understanding of the analyses to support the 
respective primary, secondary, and 
 
objectives. 

The timing and frequency of all assessments have 
been removed from sections of the protocol outside 
of the Time and Events tables. 

The endpoints are more representative of the data 
that will be collected in support of the objectives. 

The requirement for electrocardiograms has been 
removed.
Administrative 
Letter 03
02-Oct-2014

Correct the tables in Section 5.1, Flow Chart/Time 
and Events Schedule so that the information in these 
tables is consistent with the text in the protocol.
Revised Protocol 
01a
04-Jun-2014

Incorporates 
Administrative 
Letter 
01, 
Administrative Letter 02, and Amendment 01.
Amendment 01
04-Jun-2014

Revisions aim to comply with the Health Authority 
requirements in Germany
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Table 2:
Protocol Amendments
Document
Date
Summary of Changes
Administrative 
Letter 02
21-May-2014

A number was missing from Exclusion Criterion 
4cviii. This letter is to provide you with the missing 
number. This is an administrative protocol change 
and does not significantly affect the safety of 
subjects, study scope, or scientific quality of a Phase 
Iib. 
Accordingly, 
it 
may 
be
implemented 
immediately.
Administrative 
Letter 01
12-May-2014

The title of this protocol has been modified for 
consistency with the BMS conventions for protocols 
in the nivolumab program. This is an administrative 
protocol change and does not significantly affect the 
safety of subjects, study scope, or scientific quality 
of a Phase II or III protocol. Accordingly, it may be 
implemented immediately.
Original Protocol
18-Apr-2014
Original Protocol
2.5
Scientific Steering Committee 
The Scientific Steering Committee (SSC) will closely review the safety data throughout the study 
to evaluate the risk/benefit ratio in general and for the separate prospective subgroups following a 
predefined Safety Management Plan
3
OBJECTIVES
3.1
Primary
The primary objective of this study is:

To determine the incidence of high-grade (CTCAE v4.0 Grade 3 or higher), treatment-related, 
select adverse events in subjects with histologically confirmed stage III (unresectable) or stage 
IV melanoma and progression after prior treatment containing an anti-CTLA-4 monoclonal 
antibody treated.
3.2
Secondary
The secondary objectives of this study are:

To determine the incidence and to characterize the outcome of all high-grade (CTCAE v4.0 
Grade 3 or higher), select adverse events in subjects with histologically confirmed stage III 
(unresectable) or stage IV melanoma and progression after prior treatment containing an anti-
CTLA-4 antibody;

To estimate OS in all treated subjects.
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
 
 
 
 
 
 
 
4
ENDPOINTS
4.1
Primary Endpoint
The primary endpoint is the incidence for high-grade (CTCAE v4.0 Grade 3 or higher), treatment-
related, select adverse events.  The select Adverse Events consist of a list of preferred terms 
grouped by specific category as follows:

Pulmonary toxicity

Gastrointestinal toxicity (diarrhea or colitis)

Endocrinopathies

Hepatotoxicity (including asymptomatic LFT elevations)

Renal toxicity

Skin toxicity

Hypersensitivity/Infusion site reaction
4.2
Secondary Endpoints
The secondary endpoints include the incidence of all high-grade (Grades 3 and higher) select 
adverse events, the median time to onset and median time to resolution (Grades 3-4) of select 
adverse events, the and overall survival (OS) of subjects.
4.2.1
Incidence of all High-grade, Select AEs
The incidence for high-grade (CTCAE v4.0 Grade 3 or higher), select adverse events.  The select 
Adverse Events consist of a list of preferred terms grouped by specific category as follows:

Pulmonary toxicity

Gastrointestinal toxicity (diarrhea or colitis)

Endocrinopathies

Hepatotoxicity (including asymptomatic LFT elevations)

Renal toxicity

Skin toxicity

Hypersensitivity/Infusion site reaction
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4.2.2
Median Time to Onset and Resolution of Select AEs
The median time to onset and the median time to resolution will be calculated for the list of select 
AEs defined in section 4.2.1.  The time to onset is defined as the time from treatment start (first 
dose, first cycle) to AE start for each individual AE.  The time to resolution is defined as the time 
from AE start to AE stop for each individual AE.
4.2.3
Overall Survival (OS)
Overall survival (OS) is defined as the time from the date of first dose until the date of death. For 
those subjects who have not died, OS will be censored on the last date the subject was known to
be alive. OS will be followed continuously while subjects are on treatment and every 3 months via 
in-person or phone contact after subjects discontinue the study drug.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Table 3:
Time Windows for Assessments
Nominal Time-Point
Time Window
Week 1 (Baseline)
Prior to first dose on Day 1 
Week 5
Day 2 thru Day 55, inclusive
Every 4 weeks up to Week 13
Nominal day (+26 days/-2 days, inclusive)
Week 17
Nominal day 113 (+54 days/-2 days, inclusive)
Every 8 weeks thereafter
Nominal day (+54 days/-2 days, inclusive)
Follow-up 1 (EQ-5D-3L only)
If assessment is post last dose and within 30 days of last dose 
(+68-82 days/-2 days, inclusive)
Follow-up 2 (EQ-5D-3L only)
If assessment is post 70-84 days of Follow-up 1 (+89 days/-2 
days, inclusive)
Every 3 months thereafter (EQ-5D-3L only)
If assessment is after Follow-up 1 and Follow-up 2 (+89 days/-2 
days, inclusive)
4.3.3.2
EuroQoL EQ-5D-3L
Subjects’ reports of general health status will be assessed using the EuroQoL Group’s EQ-5D-3L. 
EQ-5D-3L essentially has 2 components: the descriptive system and the visual analogue scale 
(VAS).
The instrument’s descriptive system consists of 5 dimensions: mobility, self-care, usual activities, 
pain/discomfort, and anxiety/depression. Each dimension has 3 levels, reflecting "no health 
problems," "moderate health problems," and "extreme health problems." A dimension for which 
there are no problems is said to be at level 1, while a dimension for which there are extreme 
problems is said to be at level 3. Thus, the vectors 11111 and 33333 represent the best health state 
and the worst health state, respectively, described by the EQ-5D-3L. Altogether, the instrument 
describes 35 = 243 health states. Empirically derived weights can be applied to an individual’s 
responses to the EQ-5D-3L descriptive system to generate an index measuring the value to society 
of his or her current health. Such preference-weighting systems have been developed for the UK, 
US, Spain, Germany, and numerous other populations. For this study, EQ-5D-3L utility index 
values will be computed using a scoring algorithm based on the United Kingdom Time-Trade-Off 
(UK TTO) value set2
In addition, the EQ-5D-3L includes a VAS, which allows respondents to rate their own current 
health on a 101-point scale ranging from 0=”worst imaginable” health to 100=“best imaginable” 
health state3.
A change from baseline of 0.08 for the EQ-5D-3L utility index score and of 7 for the EQ-5D-3L 
VAS are considered minimally important differences for the EQ-5D-3L4.
All questionnaires completed at baseline and on-study will be assigned to a time-point according 
to the windowing criteria in Table 3 and included in the analysis. In case a subject has two on-
study assessments within the same window, the assessment closest to the time-point will be used. 
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And, in the case of two assessments at a similar distance to the time-point, the latest one will be 
chosen. In the event where the subject has no assessment at all in a specific window, the 
observation will be treated as missing for that time-point.
5
SAMPLE SIZE AND POWER
Currently, there is only little reliable data describing the percentage of subjects with melanoma 
progressing after prior therapy containing treatment with an anti-CTLA-4 monoclonal antibody, 
presenting with Performance Status 2, and eligible for nivolumab treatment. It is estimated that a 
minimum of 20% of the potential study population will initially present with PS2. Given that 
approximately 20% of the 920 subjects screened is 185 subjects, it is expected that the full 
complement of 160 subjects will be enrolled and treated in the PS2 cohort.
With an approximate 15% screening failure rate, a cohort of 735 screened PS1 subjects is projected 
to yield 640 treated subjects. With n = 640 subjects, about 3 will experience a rare adverse event 
with 0.5% true cumulative event rate with a rate estimated within 95% confidence interval (CI) 
(0.1%-1.4%). Approximately 2 subjects with events and a 95% CI of (0%-1.1%) for assumed true 
event rate of 0.3% are projected.
6
STUDY PERIODS, TREATMENT REGIMENS AND POPULATIONS FOR 
ANALYSES
6.1
Study Period
See Section 6.1 of the Core Safety SAP.
6.2
Treatment Regimens
Subjects will be treated with 3 mg/kg of nivolumab as a 60-minute (+/-5 minutes) IV infusion on 
Day 1 of a treatment cycle every 2 weeks (14 days) for a maximum of 24 months. No 
premedications are recommended for initiation of dosing. Dosing calculations should be based on 
the body weight assessed at each visit. It is not necessary to re-calculate subsequent doses if the 
subject’s weight is within 10% of the weight used to calculate the previous dose. All doses should 
be rounded to the nearest milligram per institutional standard. The screening body weight may be 
used for dosing of Cycle 1. There will be no nivolumab escalations or reductions permitted. 
Subjects may be dosed no less than 12 days from the previous dose.
6.3
Populations for Analyses
The following analysis populations are defined for this study:

All Enrolled analysis set: All subjects who signed an informed consent form and were 
registered into the IVRS.

All Treated analysis set: All enrolled subjects who received at least 1 dose of nivolumab

Response evaluable analysis set: All enrolled subjects who received at least 1 dose of 
nivolumab and have both baseline and at least 1 post-baseline tumor scans.
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6.4
Subpopulations for Analyses
The study will include several analyses performed according to subpopulations (cohorts). These 
subpopulations are summarized below. Except where otherwise stated, all analyses will be 
performed for all treated subjects, as overall and for each subpopulation defined in this section.

Mucosal population: Subjects have their baseline type of melanoma as mucosal.

Cutaneous population: Subjects have their baseline type of melanoma as cutaneous.

Ocular/Uveal population: Subjects have their baseline type of melanoma as ocular/uveal.

Acral: Subjects have their baseline type of melanoma as acral. 

Other subtype of melanoma: Subjects have their baseline type of melanoma as other.

ECOG PS 2 population: Subjects have their baseline ECOG PS grade of 2.

CNS metastasis population: Subjects will be classified into this group based on the 
evidence of brain metastasis at baseline. Subjects with CNS metastasis are those who 
answered “MIC WITH BRAIN METASTASES” on the “M Status” question of the 
“Initial/Current Disease Diagnosis” form of the CRF (Yes). 

BRAF Mutation population: Subjects have their baseline BRAF mutation status with 
Mutant defined as all mutations of V600 (e.g., V600, V600E, V600K, V600D, or V600R) 
and all remaining (no mutation or non-V600 mutations) defined as Wildtype.

Autoimmune disease population: Subjects will be classified into this group if they report a
history of autoimmune disease at baseline.

Experience of immune-related AE during treatment with an anti-CTLA-4 antibody: 
Subjects will be classified into this group based on subject’s experience of Grade 3-4
immune-related AE during treatment with an anti-CTLA-4 antibody (Yes).
7
STATISTICAL ANALYSES
7.1
General Methods
In the analysis described below (except where noted), counts and percentages will be reported for 
discrete variables with inclusion of unknown or missing values as a separate category. The mean, 
standard deviation, median, range (minimum and maximum), and number of non-missing values 
will be reported for each continuous measure.
Adverse events and medical history will be coded according to the most recent Medical Dictionary 
for Regulatory Activities (MedDRA). Previous and 
 will be coded using 
the WHO Drug Dictionary. 
The time to event distribution (i.e. overall survival) will be estimated using Kaplan Meier 
techniques. Median for time to event endpoints along with 95% confidence interval (CI) will be 
constructed based on 95% CI using the Brookmeyer and Crowley1 method. Overall survival rates 
at selected time points, including survival rates at Years 1 and 2, together with their 95% Cis will 
also be estimated using KM estimates on the OS curves. Associated 2-sided 95% Cis will be 
calculated using the Greenwood formula.
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All data summaries, unless otherwise noted, will be presented by subpopulations. A total column 
will be included in each summary.

Mucosal

Cutaneous

Ocular/Uveal

Acral

Other

ECOG PS2

CNS Metastasis

Autoimmune disease

Grade 3-4 irAEs with anti-CTLA-4
Tables that will be presented by baseline LDH, BRAF mutation and type of autoimmune disorder 
should have the following presentation order:

Baseline LDH: < ULN, > ULN, and > 2*ULN

BRAF status: Mutant, Wildtype, and Not reported, if no BRAF genetic mutation results 
are available.

Type of autoimmune disorder: Endocrine, Gastrointestinal, Hepatic, Skin, and Other
Further, general methods information for the safety analysis, including general methods for 
adverse events and laboratory tests can be found in Section 7.1 of the CA209 Core Safety SAP 
version 4. Statistical analyses will be carried out using SAS software (SAS Institute, Cary, North 
Carolina, USA), unless otherwise noted.
7.2
Study Conduct
7.2.1
Accrual
The accrual pattern will be summarized per country, investigational site, and per month for all 
treated subjects. Informed consent date, first dosing date, country, and investigational site will be 
presented in a by subject listing of accrual.
7.2.2
Relevant Protocol Deviations
Relevant deviations from the study protocol will be summarized and listed by subjects on the 
population of all treated subjects.
At entrance:

Subjects with baseline ECOG Performance Status > 2.

Subjects with no prior systemic anti-cancer therapy.

Subjects with no histologically documented stage III or IV melanoma.

Subjects without measurable disease at baseline.

Subjects who have not received anti-CTLA-4 therapy or have not progressed on or after 
anti-CTLA-4 therapy.
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On study:

Subjects receiving concurrent anti-cancer therapy.
Each subject’s data will be examined for deviation from protocol criteria (including violation of 
eligibility criteria, discrepancies between enrolled and treatment received and on-study 
deviations). 
7.3
Study Population
7.3.1
Subject Disposition
Number of subjects enrolled but not treated along with the reason will be tabulated. This analysis 
will be performed on the enrolled analysis set.
Study participation status including completion and discontinuation of treatment will be reported
using the all treated analysis set. Reasons for discontinuation will be summarized and listed.
A subject listing will be provided showing the subject’s off study date and reason for going off-
study. A subject listing of subjects not treated will also be provided.
7.3.2
Demography and Subject Characteristics
The demographic characteristics, physical measurements, and other baseline characteristics of 
subjects will be reported using the all treated analysis set, overall and by subpopulations.
The following demographic characteristics,
physical measurements, and other baseline 
characteristics will be summarized. The age of a subject will be defined as the truncated difference 
in years between the date of the informed consent and the date of birth, plus 1 day (e.g. 
((DD/MM/YYYY2 – DD/MM/YYYY1)+1/365.25) = result in years to 1 decimal place (xx.x)).
Frequency and percentage will be reported, unless otherwise noted.
Demographics characteristics:

Age (< 65; > 65 and < 75; > 75 and < 85; > 65; > 75; > 85; summary statistics) (years)

Sex (Male, Female)

Race (White, Black or African American, American Indian or Alaska Native, Asian, Native 
Hawaiian or Other Pacific Islander, Other, Not Reported)

Ethnicity (Hispanic/Latino, Not Hispanic/Latino, Not Reported)
Physical measurements summary:

Baseline weight (summary statistics) (kg)

Baseline height (summary statistics) (cm)

Baseline BMI (summary statistics) (kg/m2)

ECOG Performance Status (0-1, 2, Not Reported)
Other baseline characteristics:
Subtype of Melanoma (Mucosal, Cutaneous, Acral, Ocular/Uveal, Other)
BRAF Mutation status (Wild type, Mutant, Not Reported) 
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Current disease stage (Stage III, Stage IV, Unknown)  
M-stage at study entry (M0, M1A, M1B, M1C, Unknown)
Brain metastasis (Yes, No)  
Treatment status of CNS metastasis (Treated, Untreated, Leptomeningeal) 
Number of prior therapies (1, 2, >=3) 
Baseline LDH (<=ULN, >ULN, <=2*ULN, >2*ULN) 
Type of autoimmune disorder (Endocrine, Gastrointestinal, Hepatic, Skin, and Other)
Condition of autoimmune disorder (Active, Not Active)
A subject listing of demography and subject characteristics will be produced on the all treated 
analysis set.
A summary of demographic characteristics, physical measurements, and other baseline 
characteristics will also be presented by baseline LDH, BRAF status, and type of autoimmune 
disorder.
7.3.3
Medical History
A subject listing of general medical history will be produced for all subjects in the treated analysis 
set.
7.3.4
Disease Characteristics
The following baseline disease characteristics will be summarized using the all treated analysis set
by subpopulations:

Time (in months) from initial pathological diagnosis to first dose of study therapy (summary 
statistics)

Baseline tumor assessments (subjects with at least 1 lesion, site of disease, number of disease 
sites) 

Baseline BRAF, NRAS and cKIT status
A subject listing will be produced on all treated analysis set.
7.3.5
Prior Therapy
The following information will be summarized using the all treated analysis set by subpopulations:

Prior maintenance therapy (Yes, No, Not Reported)

On study line of therapy for advance metastatic disease (Second line, Third line, Other)

Type of prior systemic therapy received (Chemotherapy, Immunotherapy)

Prior systemic therapy regimen setting (Adjuvant, Neo-adjuvant, Metastatic)

Best response to most recent prior systemic therapy regimen (CR or PR, SD, PD, Not 
Reported)

Time from completion of most recent prior systemic therapy regimen to enrollment (< 3 
months, 3-6 months, > 6 months, Not Reported)
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
Time from completion of prior adjuvant/neoadjuvant therapy to enrollment (<6 months, >= 6 
months, Not Reported)

Prior surgery related to cancer (Yes, No)

Prior Radiotherapy (Yes, No)
A listing will be provided using the all treated analysis set. A separate listing will be created for 
the prior anti-CTLA-4 therapy.
7.3.6
Baseline Examinations
Subjects with abnormal baseline physical exam result will be tabulated by examination criteria 
(e.g. neck, cardiovascular) using the all treated analysis set by subpopulations. 
A listing will be provided using the all treated set.
7.4
Extent of Exposure
The analyses of study drug exposure will focus on the on-study period. The first dosing day 
corresponds to the day of first administration of any nivolumab. Throughout this analysis plan, 
dose level will refer to the actual dose rather than the planned dose. 
Nivolumab dose reductions and escalations are not permitted.
The nivolumab dose delay and interruption of a subject will be evaluated.
A dose interruption refers to an interruption of the infusion of nivolumab, whether or not the 
infusion is resumed. If a subject is unable to start a cycle because of unacceptable toxicity related 
to nivolumab, therapy may be held for up to 6 weeks. 
Dose delay, up to 6 weeks, is also allowed for study drug so toxicities return to Grade 1 or 
baseline.
If a cycle is delayed, the reason for the delay will be ascertained from the “dosing changes” section 
of the dosing CRFs.
7.4.1
Administration of Study Therapy
The following parameters will be summarized using the all treated analysis set by subpopulations:

Number of doses received (1, 2, 3, 4, >4. Summary statistics)

Cumulative dose (summary statistics)
The cumulative dose is the sum of the doses (mg/kg) administered to a subject during the 
treatment period. Dose (mg/kg) is derived based on dose (mg) divided by the most recent body 
weight (kg) that is collected in the CRF.

Relative dose intensity (>= 100%, 90% to < 100%, 70% to < 90%, 50% to < 70%, <50%, Not 
Reported)
The relative dose intensity is derived as :
[Cumulative dose (mg/kg) /( (Last dose date – Start dose date + 14) x 3/14] x 100

Duration of therapy (> 3 months, > 6 months, > 9 months, >12 months, summary statistics). A 
Kaplan-Meier curve will also be presented where the last dose date is the event date for those 
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subjects who are off study treatment. Median duration of treatment and associated 95% CI will 
be provided. Subjects who are still on study therapy will be censored on their last dose date.
7.4.2
Interruption or Delay of Study Therapy
The following parameters will be summarized using the all treated analysis set by subpopulations, 
according to the general methods:

Dose interruption (number of subjects with at least one interrupted dose, number of infusion 
interrupted per subject, reason for interruption, total number of interruptions).
The dose 
interruption information will be retrieved from the CRF dosing pages.

Dose delay (subjects with at least one delayed dose, number of dose delay per subjects, length 
of delay: 4-7 days, 8-24 days, 25-42 days, and > 42 days, reason for dose delay, total number 
of dose delays,). A dose will be considered as delayed if the delay is exceeding 3 days (i.e 
greater than or equal to 4 days from scheduled dosing date).

Dose infusion rate reduction (number of subjects with at least one infusion with IV rate 
reduced, number of infusion with IV rate reduced per subject, reason for IV rate reduction, 
total number of IV rate reduced). The dose infusion rate reduction information will be retrieved 
from the CRF dosing pages.
A listing will be provided using the all treated analysis set.
 
 
 
 
 
7.4.4
Subsequent Therapy
Subsequent therapy will be summarized using the treated analysis set by subpopulations. 

Number of subjects with any subsequent therapy

Number of subjects who received subsequent radiotherapy

Number of subjects who received subsequent surgery

Number of subjects who received subsequent systemic therapy. 
7.5
Efficacy
7.5.1
Overall Survival and Overall Response Rate at Week 12
Overall survival is defined as the time between the start of treatment and the date of death due to 
any cause. A subject who has not died will be censored at last known date alive. 
Overall survival will be summarized using Kaplan-Meier (KM) product-limit method and 
associated statistics in the all treated analysis set by subpopulations. Median values of OS, if 
estimable, along with 2-sided 95% CI using the Brookmeyer and Crowley method will be 
calculated. If medians are not estimable, other percentiles (e.g., 10th and 25th) may be reported. OS 
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rates at selected time points, including survival rates at 6 months, 12 months, 18 months, and 24 
months, together with their 95% CIs will also be estimated using KM estimates on the OS curves. 
Minimum follow-up must be longer than the timepoint of interest to generate the OS rate for that 
particular timepoint. For example, if the timepoint of interest is 6 months and the interval of 
enrollment date and last patient last visit is less than 6 months, then, the minimum follow-up is not 
reached and OS rate is not generated. Associated 2-sided 95% CIs will be calculated using the 
Greenwood formula. 
A swimming plot showing the response, progression, duration of therapy and death will be 
presented using the all treated analysis set, overall and by ECOG PS 2, Ocular/Uveal, and Mucosal 
subpopulations only.
The overall response rate is defined as the number of subjects with a complete response (CR) or 
partial response (PR) at week 12 divided by the number of subjects treated. The overall response 
will be summarized by binomial response rates and their corresponding two-sided 95% exact CIs 
using the Clopper-Pearson method. A by subject listing will be provided.
A summary of overall response will also be presented by baseline LDH, BRAF status, and type of 
autoimmune disorder.
7.5.2
Subject Follow-up for OS
Overall Survival probabilities for each subpopulations will be estimated and plotted using the 
Extent of follow-up defined as the time between first dose date and last known date alive (for 
subjects who are alive) or death date (for subjects who died) will be summarized descriptively 
(median, min, max) for all subjects treated.
The currentness of follow-up, defined as the time between last OS contact (ie, last known date 
alive or death date) and data cut-off date, will be summarized by subpopulations. Subjects who 
died before data cut-off date will automatically have zero value for currentness of follow-up. For 
subjects with last known date alive after data cut-off date, they will have zero value for currentness 
of follow-up as well. The currentness of follow-up will be categorized into the following 
categories: 0 days, 1-30 days, 31-60 days, 61-90 days, 91-120 days, 121-150 days, 151 or more 
days. 
7.5.3
Subgroups Analyses
OS among treated population will also be summarized within subsets at baseline (with two-sided 
95% CI for the medians calculated via log-log transformation.).

Age (< 65, 65)

Gender (male, female) 

M-Stage at diagnosis

Number of lines of prior systemic treatment in metastatic setting (add footnote for only 
metastatic setting)

Baseline LDH (<= ULN, >ULN, >2xULN)
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7.6
Safety
Unless otherwise specified, safety results will be presented using the all treated analysis set 
subjects by subpopulations. See Core Safety SAP for more details on safety analysis.
7.6.1
Primary Analysis
7.6.1.1
High-grade (CTCAE v4.0 Grade 3 or higher) Treatment-Related, Select Adverse 
Events.
The number and percentage of subjects who report high-grade (CTCAE v4.0 Grade 3 or higher), 
treatment-related, select adverse events pulmonary, gastrointestinal, skin, renal, hepatic, 
pancreatic, neurologic, endocrine) will be summarized using the all treated analysis set by system 
organ class and Medical Dictionary for Regulatory (MedDRA) preferred term. In addition, the 
number, percentage of subjects, 95% CI for the percentage of subjects with these select AEs will 
also be presented by subpopulations.
7.6.2
Secondary Analysis
7.6.2.1
High-grade (CTCAE v4.0 Grade 3 or higher) Select Adverse Events
The number and percentage of subjects who report high-grade (CTCAE v4.0 Grade 3 or higher), 
select adverse events will be summarized using the all treated analysis set by system organ class 
and Medical Dictionary for Regulatory (MedDRA) preferred term.
7.6.2.2
Select Adverse Events
Select adverse events will be summarized according to their incidence, as well as their time to 
onset and resolution as described in Section 7.6.6 of the Core Safety SAP.
7.6.3
Other Safety Analysis
Other safety analysis will be conducted as below as specified in the Core Safety SAP, according 
to the general methods:

Deaths

Serious adverse events

Adverse events leading to discontinuation of study therapy

Adverse events leading to dose modification

Adverse events

Multiple adverse events

Laboratory parameters

Vital signs

Pregnancy

Adverse events by demographic subgroups
A summary by type of autoimmune disorder will be presented for the following adverse events 
tables.
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
Any adverse events

Drug-related adverse events

Drug-related serious adverse events

Drug-related adverse events leading to discontinuation

Drug-related select adverse events

Drug-related select adverse events leading to discontinuation

Any adverse events that required immune modulating medications

Time to resolution of drug-related select adverse events

Time to resolution of drug-related select adverse events where immune modulating 
medications was initiated

Time to onset of drug-related select adverse events
A subject listing of prior immune modulating medications (subjects with any prior immune 
modulating medication, subjects by medication class and generic term) will be presented. This 
would include immune modulating medications taken on or before first dose of study therapy.
7.6.4
Immunogenicity Analysis
Not applicable
 
7.8
Outcomes Research Analyses
Outcomes research (Quality-of-life) data will be measured using the EORTC QLQ-C30 and EQ-
5D-3L questionnaires. The analysis of EORTC QLQ-C30 and EQ-5D-3L will be restricted to 
treated subjects who have an assessment at baseline and at least one post-baseline assessment.
7.8.1
EORTC QLQ-C30
For EORTC QLQ-C30, all scales and single items are scored on categorical scales and linearly 
transformed to 0-to-100 scales with higher scores for a functional scale representing higher levels 
of functioning, higher scores for the global health status/quality of life scale representing higher 
levels of global health status/quality of life and higher scores for a symptom scale representing 
higher level of symptoms. A score difference of 10 is used as an estimate of a clinically important 
difference for the scales of the EORTC QLQ-C305.
The following descriptive analyses will be conducted: 

EORTC QLQ-C30 questionnaire completion rate, defined as the proportion of questionnaires 
actually received out of the expected number (i.e., number of subjects on treatment or in follow 
up) will be calculated and summarized for each assessment time point by treatment group.
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
Mean score and mean change from baseline in EORTC QLQ-C30 global health status, 
functional scales and symptom scales will be summarized using descriptive statistics (N, mean 
with SD and 95% CI, median, first and third quartiles, minimum, maximum) for all scales at 
each assessment time point. 

A line graph summarizing the mean changes from baseline will be produced for all scales.
7.8.2
EuroQoL Five Dimensions Questionnaire
The following descriptive analyses will be conducted: 

EQ-5D-3L questionnaire completion rate, defined as the proportion of questionnaires actually 
received out of the expected number (i.e. number of subjects on treatment or in follow up), will 
be calculated and summarized for each assessment time point by treatment group. 

A by-subject listing of the level of problems in each dimension, corresponding to EQ-5D-3L 
health state (i.e., 5-digit vector), EQ-5D-3L utility index score, and EQ-5D-3L VAS score will 
be provided.

Proportion of subjects reporting problems for the 5 EQ-5D-3L dimensions at each assessment 
time point will be summarized by level of problem and by treatment group. Percentages will 
be based on number of subjects assessed at assessment time point.

For the EQ-5D-3L utility index and VAS scores, separately:

Mean score and mean change from baseline at each assessment time point will be 
summarized by treatment group using descriptive statistics (N, mean with SD and 95% CI, 
median, first and third quartiles, minimum, maximum).

A line graph summarizing the mean changes from baseline will be produced.
8
CONVENTIONS
Unless otherwise noted, the following conventions should be understood to apply. Further 
conventions may be detailed in the Data Presentation Plan (DPP).
8.1
Baseline
Baseline results will be the last non-missing result occurring prior to the first dose of treatment 
medication.
8.2
Duration, On-study Event calculations
The duration between two dates will be calculated as [later date] – [earlier date] + 1 day. Study 
Day 1 or first dose date is the date of first study medication. Study day associated with an 
assessment will be calculated as [assessment date] – [first dose date (or enrollment date for non-
treated subjects)], if the assessment is before first dose/enrollment; [assessment date] – [first dose 
date (enrollment for non-treated subjects] + 1, if the assessment is on or after first dose/enrollment.
Events will be considered as occurring within X days (e.g., deaths within 30 days, deaths and AEs 
within 90 days) of last dose of study medication if [event date] – [last dosing date] X. 
The following factors will convert days to months or years: 1 month = 30.4375 days, 1 year = 
365.25 days.
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8.3
Conventions for Partial/Missing Dates
Unless specified otherwise the following conventions will be used for imputing partial dates:

If only the day of the month is missing, the 15th of the month will be used to replace the missing 
day.

If both the day and the month are missing, “July 1” will be used to replace the missing 
information.

If a date is completely missing, it will be considered as missing.
For date of death:

If only the day of the month is missing, the 1st of the month will be used to replace the missing 
day*. 

If both the day and the month are missing, “Jan 1” will be used to replace the missing 
information*.

If date is missing, death date will be imputed as the last known alive date.
*
The imputed death date will be compared with the last known alive date (date of censoring 
for survival). If the death date is not equal to the date of censoring for survival then the 
maximum of the (imputed death date, date of censoring for survival) will be considered as 
the date of death.
For date of progression:

If only the day of the month is missing, the 1st of the month will be used to replace the missing 
day*. 

If the day and month are missing or a date is completely missing, it will be considered as 
missing.
*
In case, the date of death is present (complete date), the imputed progression date will be 
compared with the date of death. The minimum of the (imputed progression date, date of 
death) will be considered as the date of progression.
For date of last tumor assessment:

If only the day of the month is missing, the 1st of the month will be used to replace the missing 
day* 

If the day and month are missing or a date is completely missing, it will be considered as 
missing.
*
In case, the date of death is present (complete date), the imputed date will be compared 
with the date of death. The minimum of the (imputed date, date of death) will be considered 
as the date of last tumor assessment.
For adverse events of special interest onset date:

If only the day of the month is missing, the first of the month will be used to replace the missing 
day.

If the day and month are missing or a date is completely missing, it will be considered as 
missing.
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For adverse events of special interest resolution date:

If only the day of the month is missing, the last of the month will be used to replace the missing 
day.

If the day and month are missing or a date is completely missing, it will be considered as 
missing.
Otherwise, missing values will not in general be imputed.
8.4
Missing Data 
No imputation method will be implemented for any missing items. The planned outcomes research 
analyses will be based on all available data points collected during the course of the study.
For the EORTC QLQ-C30, values will be imputed for missing items by using values equal to the 
average of the non-missing items for any scale in which at least half the items are completed. A 
scale in which fewer than half of the items are completed will be treated as missing.
Once instrument data are scored, no imputation will be used to handle missing data. In the 
longitudinal model, imputing missing data may lead to underestimating the variance of treatment 
effects over time and unintentional biasing of estimates. Once the type and source of missing data 
observed is evaluated (e.g., missing at random [MAR], missing completely at random [MCAR], 
missing not at random [MNAR]), appropriate measure will be taken to handle missing data. 
Recommended statistical approaches to handling missing data particularly for longitudinal studies
involve generalized linear mixed models when the data are MAR or MCAR. Realistically, since 
once cannot rule out MNAR in clinical trial longitudinal data, a pattern mixture model will be 
employed to investigate the possibility of MNAR. Mixed models are seen as an unbiased estimate 
under MAR conditions, and pattern mixture models are a method for identifying missing data as 
MAR or MNAR, as well as meaning behind the missing data. If the worst case analysis provides 
similar results to the model with no missing data imputed, then the results from the original model 
are likely robust to missing data.
9
CONTENT OF REPORTS
Study reports will be written corresponding to the final analyses of OS. The table, figure and listing 
outputs that will be produced will be described in the Data Presentation Plan for the study.
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APPENDIX 1
SELECT ADVERSE EVENTS DEFINITION AND CONVENTIONS
The select Adverse Events (select AEs) consist of a list of preferred terms grouped by specific 
category (e.g. pulmonary events, gastrointestinal events categories) and by subcategory (e.g. 
pituitary disorders, diabetes, thyroid disorders, adrenal disorders subcategories). These categories 
and subcategories are defined by the Sponsor and the list that is most current at the time of analysis 
will be used. Also, changes may be made to this list with each new version of MedDRA.
For information, the select adverse events defined at the time of finalization of the first version of 
the document are listed in Table 5 using MedDRA version 18.1.  The final list used for the clinical 
study report will be included in an Appendix of the CSR.
Time-to onset definition
Time-to onset of select AE (any grade) for a specific category (i.e. pulmonary events, 
gastrointestinal events, endocrine adverse event, hepatic adverse event, hypersensitivity/infusion 
reaction, renal adverse event, skin adverse event) is defined as the time between the day of the first 
dose of study treatment and the onset date of the earliest select AE (of any grade) in this category.
If the subject did not experience a select AE (of any grade) in the category, time-to onset will be 
censored at the maximum follow-up time of all subjects in their respective treatment group (i.e.
for subjects without an event, follow-up time is defined from first dosing date up to last dosing 
date +30 days (or 100 days depending on the analysis) if subjects are off treatment and followed 
for at least  30 days (or 100 days depending on the analysis) , otherwise it is defined up to the last 
known alive date). The resulting Kaplan-Meier plot will represent the cumulative rate of the select 
AE (any grade) in the category over time.
Time-to onset of select AE (grade 3-5) for a specific category is defined similarly but restricted to 
grade 3-5 select AEs.
Time-to onset of drug-related (grade 3-5 or any grade) select AE for a specific category is defined 
similarly but restricted to drug-related select AEs.
Time-to onset for a specific subcategory is defined similarly but restricted to event of this 
subcategory.
Time-to resolution definition
In order to derive the time-to resolution, overlapping or contiguous select AEs within a specific 
category (defined in Table 5) will be collapsed into what will be termed “clustered” select AEs. 
For example, if a subject (without pre-treatment AE) experienced an AE from 1st to 5th January, 
another AE (with different PT but within same category) from 6th to 11th January and same AE 
from 10th to 12th January, these will be collapsed into one clustered select AE from 1st to 12th
January. Table 4 is summarizing key derivation steps for each type of clustered select AEs.
Time-to resolution of select AE (any grade) for a specific category is defined as the longest time 
from onset to complete resolution or improvement to the grade at baseline among all clustered 
select AEs in this category experienced by the subject. Events which worsened into grade 5 events 
(death) or have a resolution date equal to the date of death are considered unresolved. If a clustered 
select AE is considered as unresolved, the resolution date will be censored to the last known date 
alive. Improvement to the grade at baseline implies that all different AE events in the clustered 
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select adverse event should at least have improved to the corresponding (i.e with same preferred 
term) baseline grade. This measure is defined only for subjects who experienced at least one select 
AE in the specific category.
The time-to resolution of select AE (grade 3-5) for a specific category is defined similarly with an 
onset date corresponding to a grade 3-5 select AE.
Time-to resolution of drug-related select AE (any grade or grade 3-5) is defined similarly but 
restricted to drug-related select AE.
The time-to resolution of select AE (any grade or grade 3-5, drug-related or all) where immune 
modulating medication was initiated is defined similarly with the additional condition that the 
subject started an immune modulating medication during the longest select AE resolution period.
Time-to resolution for a specific subcategory is defined similarly but restricted to event of this 
subcategory.
Table 4:
Derivation of Clustered Select AE
Type of clustered select AE
Derivation
Any grade

Collapse any on-treatment select AE from the same 
category
Drug-related of any grade

Collapse any on-treatment drug-related select AE from the 
same category
Grade 3-5

Collapse any on-treatment select AE from the same 
category.

Resolution will be based on the onset date of the earliest 
grade 3-5 records  (if no grade 3-5 record, clustered select 
AE is excluded)
Drug-related of Grade 3-5

Collapse any on-treatment drug-related select AE from the 
same category

Resolution will be based on the onset date of  the earliest 
grade 3-5 record (if no Grade 3-5 record, clustered select 
AE is excluded)
The algorithm for collapsing select adverse event records is using the following conventions:
For each subject and specified category, the corresponding adverse event records will be collapsed 
when:
1) Multiple adverse event records have the same onset date.
2) The onset date of an event record is either the same day or 1 day later than the resolution date 
of a preceding event record (contiguous events).
3) The onset date of an event record is after the onset date and prior to or on the resolution date of 
a preceding event record (overlapping events).
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Table 5:
Select Adverse Events
Category
Subcategory
Preferred Term
ENDOCRINE ADVERSE EVENT
ADRENAL DISORDER
ADRENAL INSUFFICIENCY
ADRENAL SUPPRESSION
ADRENOCORTICAL INSUFFICIENCY ACUTE
BLOOD CORTICOTROPHIN DECREASED
BLOOD CORTICOTROPHIN INCREASED
HYPOTHALAMIC PITUITARY ADRENAL AXIS SUPPRESSION
SECONDARY ADRENOCORTICAL INSUFFICIENCY
DIABETES
DIABETES MELLITUS
DIABETIC KETOACIDOSIS
FULMINANT TYPE 1 DIABETES MELLITUS
LATENT AUTOIMMUNE DIABETES IN ADULTS
TYPE 1 DIABETES MELLITUS
PITUITARY DISORDER
HYPOPHYSITIS
HYPOPITUITARISM
LYMPHOCYTIC HYPOPHYSITIS
THYROID DISORDER
ATROPHIC THYROIDITIS
AUTOIMMUNE HYPOTHYROIDISM
AUTOIMMUNE THYROIDITIS
BASEDOW’S DISEASE
BLOOD THYROID STIMULATING HORMONE DECREASED
BLOOD THYROID STIMULATING HORMONE INCREASED
HYPERTHYROIDISM
HYPOTHYROIDISM
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Table 5:
Select Adverse Events
Category
Subcategory
Preferred Term
PRIMARY HYPERTHYROIDISM
PRIMARY HYPOTHYROIDISM
THYROID FUNCTION TEST ABNORMAL
THYROID HORMONES DECREASED
THYROID HORMONES INCREASED
THYROIDITIS
THYROIDITIS ACUTE
THYROXINE DECREASED
THYROXINE FREE DECREASED
THYROXINE FREE INCREASED
THYROXINE INCREASED
TRI-IODOTHYRONINE UPTAKE INCREASED
GASTROINTESTINAL ADVERSE 
EVENT
AUTOIMMUNE COLITIS
COLITIS
COLITIS ULCERATIVE
DIARRHOEA
ENTERITIS
ENTEROCOLITIS
FREQUENT BOWEL MOVEMENTS
GASTROINTESTINAL PERFORATION
HEPATIC ADVERSE EVENT
ACUTE HEPATIC FAILURE
ACUTE ON CHRONIC LIVER FAILURE
ALANINE AMINOTRANSFERASE INCREASED
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Table 5:
Select Adverse Events
Category
Subcategory
Preferred Term
ASPARTATE AMINOTRANSFERASE INCREASED
AUTOIMMUNE HEPATITIS
BILIRUBIN CONJUGATED INCREASED
BLOOD ALKALINE PHOSPHATASE INCREASED
BLOOD BILIRUBIN INCREASED
DRUG-INDUCED LIVER INJURY
GAMMA-GLUTAMYLTRANSFERASE INCREASED
HEPATIC ENZYME INCREASED
HEPATIC FAILURE
HEPATITIS
HEPATITIS ACUTE
HEPATOTOXICITY
HYPERBILIRUBINAEMIA
LIVER DISORDER
LIVER FUNCTION TEST ABNORMAL
LIVER FUNCTION TEST INCREASED
LIVER INJURY
TRANSAMINASES INCREASED
HYPERSENSITIVITY/INFUSION 
REACTION
ANAPHYLACTIC REACTION
ANAPHYLACTIC SHOCK
BRONCHOSPASM
HYPERSENSITIVITY
INFUSION RELATED REACTION
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Table 5:
Select Adverse Events
Category
Subcategory
Preferred Term
PULMONARY ADVERSE EVENT
ACUTE RESPIRATORY DISTRESS SYNDROME
ACUTE RESPIRATORY FAILURE
INTERSTITIAL LUNG DISEASE
LUNG INFILTRATION
PNEUMONITIS
RENAL ADVERSE EVENT
ACUTE KIDNEY INJURY
AUTOIMMUNE NEPHRITIS
BLOOD CREATININE INCREASED
BLOOD UREA INCREASED
CREATININE RENAL CLEARANCE DECREASED
HYPERCREATININAEMIA
NEPHRITIS
NEPHRITIS ALLERGIC
PARANEOPLASTIC GLOMERULONEPHRITIS
RENAL FAILURE
RENAL TUBULAR NECROSIS
TUBULOINTERSTITIAL NEPHRITIS
URINE OUTPUT DECREASED
SKIN ADVERSE EVENT
AUTOIMMUNE DERMATITIS
BLISTER
DERMATITIS
DERMATITIS ALLERGIC
DERMATITIS EXFOLIATIVE
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Table 5:
Select Adverse Events
Category
Subcategory
Preferred Term
DRUG ERUPTION
ECZEMA
ERYTHEMA
ERYTHEMA MULTIFORME
EXFOLIATIVE RASH
FIXED DRUG ERUPTION
NODULAR RASH
PALMAR-PLANTAR ERYTHRODYSAESTHESIA SYNDROME
PHOTOSENSITIVITY REACTION
PRURITUS
PRURITUS ALLERGIC
PRURITUS GENERALISED
PSORIASIS
RASH
RASH ERYTHEMATOUS
RASH GENERALISED
RASH MACULAR
RASH MACULO-PAPULAR
RASH MORBILLIFORM
RASH PAPULAR
RASH PRURITIC
RASH VESICULAR
SKIN EXFOLIATION
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Table 5:
Select Adverse Events
Category
Subcategory
Preferred Term
SKIN HYPOPIGMENTATION
SKIN IRRITATION
STEVENS-JOHNSON SYNDROME
TOXIC EPIDERMAL NECROLYSIS
TOXIC SKIN ERUPTION
URTICARIA
VITILIGO
Source: MedDRA version 18.1
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