An Open Label, Safety Study of Participants With Non-Small Cell Lung Cancer Receiving Second-Line Nivolumab Monotherapy in Asia
Phase: PHASE3
Conditions: Lung Cancer, Non-Small Cell Lung Cancer
Sponsor: Bristol-Myers Squibb

Official Title of Study: 
An Open Label, Safety Study of Participants with Non-Small Cell Lung Cancer Receiving 
Second-Line Nivolumab Monotherapy in Asia 
(CheckMate 870: CHECKpoint pathway and nivoluMAb clinical Trial Evaluation 870) 
 
NCT Number: NCT03195491 
Document Date (Date in which document was last revised): 25-Oct-2017 

Page:
1
Protocol Number:
CA209870
IND Number:
N/A
Ex US
Non-IND
EUDRACT Number
N/A
Date
23-Nov-2016
Revised Date:
25-Oct-2017
Clinical Protocol CA209870
An Open Label, Safety Study of Participants with Non-Small Cell Lung Cancer Receiving 
Second-Line Nivolumab Monotherapy in Asia
(CheckMate 870: CHECKpoint pathway and nivoluMAb clinical Trial Evaluation 870)
Revised Protocol Number: 02
Incorporates amendment(s): 02
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International: 
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Shanghai P.R. 200040 China
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organization will participate in and/or the performance of the proposed BMS sponsored 
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within your organization or to your independent ethics committee(s). Any other use, 
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Revised Protocol No: 02
Date: 25-Oct-2017
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copying, disclosure or dissemination of this information is strictly prohibited unless 
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that may be added to this document is also confidential and proprietary to BMS and must 
be kept in 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 
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protocol may apply to partners to which BMS has transferred obligations, eg, a Contract 
Research Organization (CRO).
Replace all previous version(s) of the protocol with this revised protocol and please provide a 
copy of this revised protocol to all study personnel under your supervision, and archive the 
previous versions.
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Revised Protocol No: 02
Date: 25-Oct-2017
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DOCUMENT HISTORY
Document
Date of Issue
Summary of Change
Revised Protocol 02
25-Oct-2017
Incorporates Amendment 02
Amendment 02
25-Oct-2017
Change the efficacy objective, endpoint, and analyses 
 
 to secondary classification.
Revised Protocol 01
20-Mar-2017
Incorporates Amendment 01
Amendment 01
20-Mar-2017
•
Treatment duration will have a 2-year stopping rule 
•
Number of EGFR mutation participants will be capped to 
40 participants
•
PD-L1 testing 
 will be 
evaluated in a central laboratory.
Original Protocol
23-Nov-2016
Not Applicable
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TABLE OF CONTENTS 
TITLE PAGE ................................................................................................................ 
DOCUMENT HISTORY .............................................................................................. 
TABLE OF CONTENTS .............................................................................................. 
1 SYNOPSIS ................................................................................................................. 
2. SCHEDULE OF ACTIVITIES................................................................................. 
3. INTRODUCTION .................................................................................................... 
3.1 Study Rationale ................................................................................................. 
3.1.1 Rationale for Participant Population with NSCLC ................................. 
3.1.2 Rationale for Flat Dosing of Nivolumab ................................................. 
3.1.3 Rationale for Two Year Duration for Nivolumab Treatment................... 
3.1.4 Rationale for Safety Data Collection in HBVsAg Positive Patients ........ 
3.1.5 Rationale for EGFR Mutation and ALK Translocation Patients ............. 
3.1.5.1 Rationale for Nivolumab 30 Minute Infusion ................................. 
3.1.5.2 Rationale for Biomarker Assessments ............................................ 
3.1.5.3 Rationale for Outcomes Research Assessments .............................. 
3.2 Background ....................................................................................................... 
3.3 Benefit/Risk Assessment .................................................................................. 
4. OBJECTIVES AND ENDPOINTS .......................................................................... 
5. STUDY DESIGN...................................................................................................... 
5.1 Overall Design .................................................................................................. 
5.1.1 Data Monitoring Committee and Other External Committees ................ 
5.2 Number of Participants ..................................................................................... 
5.3 End of Study Definition .................................................................................... 
5.4 Scientific Rationale for Study Design............................................................... 
5.5 Justification for Dose and Infusion Time .......................................................... 
5.5.1 Summary of Safety of Nivolumab in Metastatic Setting ........................... 
5.5.2 Rationale for Nivolumab Flat Dose Selection ......................................... 
5.5.3 Clinical Pharmacology Summary ............................................................ 
5.5.4 Rationale for 30-Minute Infusion ............................................................. 
6. STUDY POPULATION ........................................................................................... 
6.1 Inclusion Criteria .............................................................................................. 
6.2 Exclusion Criteria ............................................................................................. 
6.3 Lifestyle Restrictions ........................................................................................ 
6.4 Screen Failures .................................................................................................. 
6.4.1 Retesting During Screening or Lead-In Period ....................................... 
7. TREATMENT .......................................................................................................... 
7.1 Treatments Administered .................................................................................. 
7.2 Method of Treatment Assignment .................................................................... 
7.3 Blinding............................................................................................................. 
7.4 Dosage Modification ......................................................................................... 
7.4.1 Nivolumab Dosing ................................................................................... 
7.4.2 Dose Delay Criteria for Nivolumab ......................................................... 
7.4.3 Criteria to Resume Treatment .................................................................. 
7.4.4 Nivolumab Treatment beyond Disease Progression ................................ 
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7.4.5 Treatment of Nivolumab Related Infusion Reactions .............................. 
7.4.6 Protocol-Specific Recommendations for Management of Hepatic Events
.....................................................................................................................
7.4.7 Management Algorithms for Immuno-Oncology Agents ......................... 
7.5 Preparation/Handling/Storage/Accountability .................................................. 
7.5.1 Retained Samples for Bioavailability / Bioequivalence ........................... 
7.6 Treatment Compliance ...................................................................................... 
7.7 Concomitant Therapy........................................................................................ 
7.7.1 Prohibited and/or Restricted Treatments................................................. 
7.7.1.1 Permitted Therapy .......................................................................... 
7.7.1.2 Palliative Local Therapy................................................................. 
7.7.2 Other Restrictions and Precautions ......................................................... 
7.7.2.1 Imaging Restriction and Precautions ............................................. 
7.7.2.2 Surgical Resection Following Initial Response .............................. 
7.8 Treatment After the End of the Study ............................................................... 
8. DISCONTINUATION CRITERIA .......................................................................... 
8.1 Discontinuation from Study Treatment ............................................................ 
8.1.1 Post Study Treatment Study Follow-up.................................................... 
8.2 Discontinuation from the Study ........................................................................ 
8.3 Lost to Follow-Up ............................................................................................. 
9. STUDY ASSESSMENTS AND PROCEDURES .................................................... 
9.1 Efficacy Assessments ........................................................................................ 
9.1.1 Imaging Assessment for the Study............................................................ 
9.2 Adverse Events ................................................................................................. 
9.2.1 Time Period and Frequency for Collecting AE and SAE Information .... 
9.2.2 Method of Detecting AEs and SAEs ......................................................... 
9.2.3 Follow-up of AEs and SAEs ..................................................................... 
9.2.4 Regulatory Reporting Requirements for SAEs ......................................... 
9.2.5 Pregnancy ................................................................................................ 
9.2.6 Laboratory Test Result Abnormalities ..................................................... 
9.2.7 Potential Drug Induced Liver Injury (DILI) ............................................ 
9.2.8 Immune-mediated Adverse Events ........................................................... 
9.2.9 Other Safety Considerations .................................................................... 
9.3 Overdose ........................................................................................................... 
9.4 Safety ................................................................................................................ 
9.4.1 Physical Examinations ............................................................................. 
9.4.2 Vital Signs ................................................................................................ 
9.4.3 Clinical Safety Laboratory Assessments .................................................. 
9.4.4 Imaging Safety Assessment ...................................................................... 
9.5 Pharmacokinetic ................................................................................................ 
9.6 Pharmacodynamics ........................................................................................... 
9.7 Pharmacogenomics ........................................................................................... 
9.8 Biomarkers ........................................................................................................ 
9.10 Patient Reported Outcomes ............................................................................. 
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10. STATISTICAL CONSIDERATIONS ................................................................... 
10.1 Sample Size Determination ............................................................................. 
10.2 Populations for Analyses ................................................................................ 
10.3 Statistical Analyses ......................................................................................... 
10.3.1 Efficacy Analyses ................................................................................... 
10.3.1.1 Efficacy Analysis in Subgroups: ................................................... 
10.3.2 Safety Analyses....................................................................................... 
10.3.3 Other Analyses ....................................................................................... 
10.3.3.1 Patient Reported Outcomes .......................................................... 
10.3.4 Interim Analyses ..................................................................................... 
11. REFERENCES ....................................................................................................... 
12 APPENDICES ......................................................................................................... 
APPENDIX 1 ABBREVIATIONS AND TRADEMARKS ........................................ 
 
APPENDIX 2 STUDY GOVERNANCE CONSIDERATIONS ................................. 
 
APPENDIX 3 ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS: 
DEFINITIONS AND PROCEDURES FOR RECORDING, EVALUATING, 
FOLLOW UP AND REPORTING ......................................................................... 
 
APPENDIX 4 WOMEN OF CHILDBEARING POTENTIAL DEFINITIONS AND 
METHODS OF CONTRACEPTION ..................................................................... 
 
APPENDIX 5 PERFORMANCE STATUS ................................................................. 
 
APPENDIX 6 RECIST 1.1 GUIDELINES .................................................................. 
 
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1
SYNOPSIS
Protocol Title: An Open Label, Safety Study of Participants with Non-Small Cell Lung 
Cancer Receiving Second-Line Nivolumab Monotherapy in Asia
Study Phase: 3b
Rationale: Non-small cell lung cancer (NSCLC) second line (2L) will be launched in China in 
July, 2018 based on the results of the CA209-078 study, an open-label randomized multinational 
phase 3 trial of nivolumab versus docetaxel in previously treated participants with advanced or 
metastatic NSCLC. NSCLC 2L treatment in the study used weight-based dosing and will be the 
first indication for nivolumab in China. In CA209078 study weight based dosing with a 60 
minutes infusion time was used. The study excluded patients with tumors harboring EGFR 
activating mutation or ALK rearrangement in order to control potential confounding OS 
outcomes due to subsequent use of new generation TKI. Additionally, the study used 
conventional eligibility criteria for phase 3 trials and limited enrollment of patients such as those 
with HBV infection, which is more frequently found in clinical practice in Asia. However, 
modeling and simulation, as well as preliminary PK data support the use of flat dose as well and 
a shorter 30 minute infusion time in this study. As flat based dosing will be the future nivolumab 
dosing for NSCLC patients and a 30 minute infusion time is more convenient for participants, 
this study will gather safety and efficacy data on these subjects.
With the NSCLC 2L indication for nivolumab, important clinical practice questions and 
regulatory issues remain to be answered. 
1) EGFR-mutation and ALK translocation subset data gap: A data gap exists in patients in 
China regarding EGFR mutation and ALK translocation patients, as they were excluded in 
CA209-078 study 
2) HBV-infection subset data gap: CA209-078 study excludes participants with positive 
results of hepatitis B virus surface antigen (HBV sAg). The HBV prevelence is 7.18% among 
Chinese population from 1 to 59 years old based on the natioanl epidemiological serosurvey 
of hepatitis B in China in 2006. Recent data from Shanghai Chest Hospital shows that 
approximately 15% of lung cancer patients are HBV sAg positive, indicating a huge data gap 
in these patients.
3) Benefit of shorter infusion time benefit gap: The risk/benefit profile for nivolumab has 
been characterized primarily using a 60 minute infusion. Longer infusion times place an 
additional burden on patients and treatment cnistered using shorter infusion times will 
diminish some of this burden. 
4) Flat Dose: Nivolumab 240mg every 2 weeks flat dose will be more convinient than 3mg/kg 
every 2 weeks (weight-based dosing) in clinical practice. Evaluating the flat fose will 
demonstrate that nivolumab can be safely administered using flat dose and will diminish 
some of this burden of weight-based dosing.
5)
 Patient Reported Outcomes
(PRO) data gap: Nivolumab will be the first approved immunoncology drug in China and 
no comprehensive data set exists on patient reported outcomes (PROs) 
 data 
from patients diagnosed with NSCLC. PRO 
 data are needed demonstrate the 
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high-value of these innovative drugs and to support policy decision making. This study will 
collect a robust data set for broader patient population, as compared to study CA209078. 
Notably, this study will collect data on patients who are EGFR or ALK positive and HBV 
infected. Additionally, this study will evaluate shorter infusion times and impact on quality 
of life and is of interest. 
6) Future Post-Approval Committment: The China Food and Drug Administration (CFDA) 
strongly indicated that of a future requirement of PAC (post-approval-commitment) study to 
collect nivolumab safety data in Chinese cohort. Thus, team proposes to author the Chinese 
cohort safety study in advance of successful global launch. 
Study Population: This open label, phase 3b trial will include participants with advanced or 
metastatic NSCLC.
Objectives and Endpoints:
Objectives
Endpoints
Primary
• To evaluate safety and tolerability in non-
HBV infected participants with advanced or 
metastatic NSCLC who have progressed 
during or after one prior systemic therapy and 
are treated with nivolumab monotherapy with 
an infusion duration of 30 min
• Incidence and severity of high grade 
(combined CTCAE v4 Grade 3-4 and 
Grade 5) treatment-related select adverse 
events in non-HBV infected participants.
Secondary
• To assess safety and tolerability in HBV 
infected participants with advanced or 
metastatic NSCLC who have progressed 
during or after one prior systemic therapy and 
are treated with nivolumab monotherapy with 
an infusion duration of 30 min 
• Incidence and severity of all high grade 
(combined CTCAE v4 Grade 3-4 and Grade 
5) treatment-related select adverse events in 
HBV participants
• To assess safety and tolerability in all 
participants 
• Incidence and severity of AEs and specific 
laboratory abnormalities in all treated 
subjects
• To evaluate efficacy in participants with 
advanced or metastatic NSCLC who have 
progressed during or after one prior systemic 
therapy and are treated with nivolumab 
monotherapy
• Collection of overall survival (OS), time to 
treatment failure (TTF), progression free 
survival (PFS), objective response rate
(ORR) , duration of tumor response (DOR)
by tumor histology (SQ or NSQ), tumor PD-
L1 expression level (PD-L1 negative or PD-
L1 positive), by infection status (HBV 
infection or non-HBV infection), and by 
molecular type (EGFR mutation, ALK 
translocation, or WT).
• Exploratory
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Objectives
Endpoints
• To assess overall health status and health 
utility 
• The 3-level version of the EQ-5D 
(EQ-5D-3L) visual analog scale (VAS) and 
utility index, respectively
• To evaluate the proportion of participants 
exhibiting disease-related symptom 
deterioration at week 12 and by week 24
• Lung Cancer Symptoms Scale (LCSS) will 
use disease-related symptom deterioration 
rate at week 12 and week 24 and is defined 
as the proportion of treated subjects who 
had 10 points or more increase from 
baseline in Average Symptom Burden 
Index (ASBI) score at any time between 
first dosing and at week 12 and week 24.
Overall Design: This single arm, open label, phase 3b clinical trial will enroll participants with 
advanced or metastatic NSCLC.
Number of Participants: Approximately 400 treated participants
Treatment Arms and Duration: The primary analysis of safety will be conducted after a 
minimum of six months after last patient first treatment (LPFT). This study will end when 
analysis of the primary endpoint is complete. The study will close after the LPFT completes 2
year follow-up.
Study treatment: 
Study Drug for CA209870
Medication 
Potency 
IP/Non-IP 
nivolumab
100 mg (10 mg/mL and 40 mg/4 mL)
IP
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Study Schematic for CA209870
A Enrolled patients without EGFR mutation and ALK-positive are restricted to have only 1 prior systemic therapies. 
Patients with EGFR mutation or ALK-positive should be treated with prior 2 systemic treatment including TKI 
and chemotherapy. With a large percentage of NSCLC of patients with EGFR mutation (approximately 30% 
incidence), this population will be capped to 40 participants in the CA209870 study.
B HBsAg+ participants (estimated 15%) must be on antiviral therapy based on China anti-HBV guideline. Patients 
with HBV infection will be capped to 60 participants.
C Treatment until progression or unacceptable toxicity. Nivolumab treatment will be given up to 24 months in the 
absence of disease progression or unacceptable toxicity. Treatment with nivolumab could be reinitiated as per the 
initial schedule for subsequent disease progression and administered for up to 1 additional year.
D Participants may receive nivolumab treatment beyond progression as defined in protocol. The decision to continue 
treatment beyond initial progression should be discussed with the BMS Medical Monitor and documented in the 
study records.
Eligible participants will receive nivolumab (BMS-936558) administered IV with a flat dose of 
240 mg q2 weeks as a 30-minute IV infusion on Day 1 of each treatment cycle. Participants will 
be treated until progression, unacceptable toxicity, withdrawal of consent, or when the study 
ends, whichever occurs first. Nivolumab treatment will be given up to 24 months in the absence 
of disease progression or unacceptable toxicity. Treatment with nivolumab could be reinitiated as 
per the initial schedule for subsequent disease progression and administered for up to 1 
additional year. The total duration of the study is expected to be approximately 3 years from the 
time of first visit of the first participant to the last participant last visit. Efficacy will be evaluated 
using RECIST 1.1 response criteria.
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2.
SCHEDULE OF ACTIVITIES
Table 2-1:
Screening Procedural Outline
Procedure
Screening
Visit
Notes
Eligibility Assessments
Informed consent
X
Inclusion/Exclusion criteria
X
All inclusion/exclusion criteria should be assessed at screening and confirmed prior to first dose.
Medical history
X
Including smoking history. 
In addition, mutational status of EGFR, ALK, ROS, MET, KRAS and BRAF should be collected, if 
available. 
If mutational status is not available in the medical history of participants with non-squamous 
histology, EGFR and ALK mutational status must be determined as specified in inclusion criteria
Safety Assessments
Pregnancy test 
X
WOCBP only: Serum or urine to be done at screening visit and repeated within 24 hours of first dose 
of study therapy. Pregnancy testing must use same method throughout study.
Concomitant medications
X
Within 14 days prior to treatment
Physical examination
X
Includes height, weight, baseline EKG, and a focused physical exam is to be performed at screening. 
C1D1 weight is to be used as baseline weight. 
Vital signs
X
Temperature, BP, HR, RR, O2 saturation by pulse oximetry at rest. 
Monitor amount of supplemental oxygen, if applicable.
Obtain vital signs at screening visit and within 72 hours of treatment
Performance Status
X
Within 14 days prior to treatment.
Serious Adverse Event Assessment
X
Serious Adverse Events from time of consent
Adverse Events
X
Adverse Events from time of consent
Assessment of signs and symptoms
X
Within 14 days prior to treatment
Laboratory Tests
Hematology and chemistry
X
Laboratory assessments will be performed locally within 14 days prior to treatment. 
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Table 2-1:
Screening Procedural Outline
Procedure
Screening
Visit
Notes
See Section 9.4.3 Clinical Safety Laboratory Assessments
Hepatitis B and hepatitis C testing
X
Hepatitis B and C testing (HBV sAg and HCV Ab or HCV RNA). Within 28 days prior to treatment:
HIV Testing
X
Testing for HIV must be performed. Within 28 days prior to treatment:
Thyroid function testing
X
Thyroid panel including TSH, free T3, and free T4 within 14 days prior to treatment
Tissue collection
PD-L1 testing and molecular testing
X
Mandatory tumor tissues may be archival or recent sample.
One formalin-fixed paraffin embedded tumor tissue block (< 1 year old) or 10 minimum FFPE
unstained slides (< 6 months old) must be submitted. A copy of the original pathology report must be 
submitted with the tissue sample. Additional testing will include EGFR mutation, ALK translocation, 
.
Tissue samples from different biopsy procedures are to be submitted if available with each matching 
pathology report and biopsy date.
Efficacy Assessments
Radiographic tumor assessment
X
•
Solid Tumor: CT with IV contrast of chest/abdomen/pelvis and all other known/suspected sites of 
disease should be imaged during the screening period. If CT iodinated contrast is contraindicated, 
CT without IV contrast of chest and MRI with contrast of abdomen and pelvis may be obtained. 
•
Brain MRI without and with contrast should be performed during screening in participants with 
known history of treated brain metastases or suspected CNS involvement to rule out active brain 
metastases.
•
Radiographic tumor assessment must be performed within 28 days prior to first treatment. 
IRT/Clinical Drug Supplies
Contact IRT
X
IRT contact must occur as follows:
•
For participant number assignment at the time informed consent is obtained.
•
Before dosing for study drug vial assignment 
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Table 2-2:
On-Treatment Assessment CA209870
Procedure
Cycle 1
Day 1
(Q2 weeks)
Subsequent 
cycles
(Q2 weeks)
Notes
Safety Assessments
Pregnancy test 
X
X
WOCBP only: Serum or urine (for WOCBP only) test to be performed within 24 
hours prior to first dose. Serum or urine pregnancy test to be done every 4 weeks 
(± 1 week) regardless of dosing schedule. Pregnancy testing must use same 
method as screening/baseline.
Physical examination 
X
Including height and weight within 3 days prior to treatment.
C1D1 weight is to be used as baseline weight
Targeted physical examination
X
Targeted examination must be performed within 3 days prior to dosing and to 
include at a minimum the cardiovascular, gastrointestinal, and pulmonary body 
systems 
Vital signs
X
X
Temperature, BP, HR, RR, O2 saturation by pulse oximetry at rest. 
Monitor amount of supplemental oxygen, if applicable.
Performance status
X
X
See Appendix 5 for ECOG performance status
Concomitant medication
X
X
Serious Adverse Events assessment
Continuously
Adverse events and laboratory values will be graded according to the NCI-
CTCAE version 4.
Adverse Events assessment
Continuously
Adverse events and laboratory values will be graded according to the NCI-
CTCAE version 4.
Laboratory Assessments
Hematology and chemistry
X
X
Laboratory assessments will be performed locally and within 3 days prior to 
treatment. See Section 9.4.3 Clinical Safety Laboratory Assessments
Note: Cycle 1 Day 1 laboratory assessments do not need to be repeated if 
performed within 14 days prior to 1st dose.
Thyroid function testing
X
X
Thyroid function testing (TSH with free T3 and free T4) is to be done every 6 
weeks (every 3 infusions) 
Note: Cycle 1 Day 1 laboratory assessments do not need to be repeated if 
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Table 2-2:
On-Treatment Assessment CA209870
Procedure
Cycle 1
Day 1
(Q2 weeks)
Subsequent 
cycles
(Q2 weeks)
Notes
performed within 14 days prior to 1st dose.
Efficacy Assessments
Radiographic tumor assessment
X
X
First tumor assessment should first be performed at 8 weeks (±7 days) from 
treatment initiation
Tumor assessments will occur every 8 weeks (± 1 week). After 48 weeks, tumor 
assessments will occur every 12 weeks (± 1 week), until disease progression is 
documented or treatment is discontinued (whichever occurs later).
Tumor assessments must use same imaging method as was used at 
screening/baseline.
Participants with a history of brain metastasis should have surveillance MRI 
approximately every 8 weeks for first 48 weeks and every 12 weeks thereafter.
Assessments should include chest, pelvis and abdomen (with contrast) as well as 
any area that is being monitored.
Tumor assessments will use RECIST 1.1 criteria (Appendix 6)
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Table 2-2:
On-Treatment Assessment CA209870
Procedure
Cycle 1
Day 1
(Q2 weeks)
Subsequent 
cycles
(Q2 weeks)
Notes
Outcome Research Assessment
LCSS and EQ-5D questionnaires
X
X
For C1D1, PRO must be performed prior to first dose (day -3 to 1)
Assessments will be performed every 4 weeks on day 1 (±5 days) for the first 6 
months on study, then every 6 weeks for the remainder of the study.
At study visits, PRO assessments should be assessed prior to any study related 
procedures and treatment. See Table 9.10-1
Clinical Drug Supplies and Study Drug Administration
Nivolumab 240 mg Q2 weeks 
X
X
Within 3 days from vial allocation, the participant must receive the first dose of 
study medication. Participants may be dosed no less than 12 days between doses 
and within 3 days from the scheduled dose
Nivolumab treatment until disease progression, discontinuation due to 
unacceptable toxicity, withdrawal of consent, or study closure.
IRT/Clinical Drug Supplies
Contact IRT
X
X
Dosing must be performed within 3 days of study drug vial assignment
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nivolumab
Table 2-3:
Follow-up Assessments CA209870
Procedure
Follow-up Visits 
X01 (Day 35) (± 7 Days) 
and 
X02 (Day 100)a (± 7 Days) 
after Last Dose
Survival
Follow-up Visitsb
Every 12 Weeks
Notes
Safety Assessments
Targeted Physical Examination
X
Targeted examination must include the cardiovascular, 
gastrointestinal, and pulmonary body systems and 
examination to specific malignancy 
To assess for potential late emergent study drug related 
findings. 
Adverse Events assessment
X
All AEs and SAEs must be collected up to 100 days 
after study drug discontinuation. SAEs that relate to any 
later protocol specified procedure must be collected.
Any subsequent cancer treatment 
information
X
X
Vital signs
X
28 days from the date of last study treatment
Laboratory Tests
Hematology and chemistry
X
Laboratory assessments will be performed locally.
See Section 9.4.3
Thyroid function testing
X
TSH with free T3 and free T4 
Pregnancy test
X
WOCBP only: serum or urine
Outcome Research Assessment
LCSS and EQ-5D questionnaire
X
X
Both LCSS and EQ-5D will occur in FU Visits 1 & 2. 
During Survival Visits, the EQ-5D will be collected 
every 3 months (± 14 days) for the first year of Survival 
Phase, then every 6 months thereafter.
May be obtained through a telephone call or clinic visit. 
See Table 9.10-1
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Table 2-3:
Follow-up Assessments CA209870
Procedure
Follow-up Visits 
X01 (Day 35) (± 7 Days) 
and 
X02 (Day 100)a (± 7 Days) 
after Last Dose
Survival
Follow-up Visitsb
Every 12 Weeks
Notes
Efficacy Assessments
Radiographic tumor assessment
X
X
Only for participants without progression.
Use same imaging method as was used at 
screening/baseline.
Participant status
X
X
Every 3 months after X02; may be accomplished by visit 
or phone contact, to update survival information 
a Participants must be followed for at least 100 days after last dose of study treatment. Follow-up visit number one X01 (FU1) occurs approximately 35 days 
(± 7 days) after the last dose or coinciding with the date of discontinuation (± 7 days) if date of discontinuation is greater than 30 days after last dose. 
Follow-up visit X02 (FU2) occurs approximately 100 days (± 7 days) from last dose.
b Survival Follow-up visits to occur every 3 months from Follow-up Visit 2. First Survival visit to occur 3 months (±14 days) from Follow-up visit 2. BMS may 
request that survival data be collected on all treated participants outside of the protocol window. At the time of this request, each subject will be contacted to 
determine their survival status unless the subject has withdrawn consent for all contacts.
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3.
INTRODUCTION
3.1
Study Rationale
The main objective of the study is to collect additional safety data on the incidence rate of 
high-grade select AEs and their outcomes and supplement the growing safety database of 
nivolumab-treated participants. This study will treat approximately 400 participants in order to 
estimate the incidence of the rare high grade (CTCAE V4 Grades 3-4 and Grade 5) 
treatment-related select AEs with greater precision and characterize their outcome. Previous 
studies have shown an incidence per event type between 0 to 3% in NSCLC patients treated with 
nivolumab monotherapy.  
3.1.1
Rationale for Participant Population with NSCLC
Substantial monotherapy clinical activity has been observed in participants with heavily 
pretreated advanced NSCLC in the ongoing phase 1/2 study of nivolumab (CA209003). This 
study showed ORR of 17% which is greater than the historical ORR for docetaxel as second line 
therapy for advanced NSCLC (approximately 8 to 10%).1,2,3 Durable responses were observed in 
both squamous and non-squamous subtypes. In 3 mg/kg group, ORR in squamous and 
non-squamous subgroups was 22% and 26% respectively and 3mg/kg group had median OS of 
14.9 months. Whereas, the historical median OS for docetaxel was about 8 months. 4 , 5 , 6
Nivolumab phase 3 second-line studies with docetaxel as comparator. CA209017 for squamous 
NSCLC and CA209057 for non-squamous NSCLC demonstrated significant survival benefit of 
nivolumab with a better safety profile in nivolumab arm compared to the docetaxel arm.7,8
Therefore, CA209870 will test the safety and efficacy of nivolumab as monotherapy in
previously treated advanced or metastatic NSCLC in in Asia population.
3.1.2
Rationale for Flat Dosing of Nivolumab
The dose and schedule of nivolumab 3 mg/kg every 2 weeks was based upon a 24 February 2012 
analysis of safety, efficacy, and exposure-response data from the ongoing phase 1 study, 
MDX1106-03. Anti-tumor activity was observed in NSCLC participants at dose levels of 1, 3,
and 10 mg/kg every 2 weeks. Anti-tumor activity appeared to approach a plateau at dose levels 
of 3 mg/kg and above. Consistent with these observations, the results of exposure response 
analyses showed that the probability of a tumor response tended to approach a plateau for trough 
concentrations produced by 3 mg/kg and 10 mg/kg administered every 2 weeks. Nivolumab was 
adequately tolerated up to 10 mg/kg, the highest dose level tested, and no maximum tolerated 
dose (MTD) was identified. While the spectrum, frequency, and severity of nivolumab-related 
AEs were generally similar across the dose levels tested, the 10 mg/kg dose level had 
numerically higher rates of Grade 3/4 drug-related SAEs and AEs leading to discontinuation. 
Based on these observations, a dose of 3 mg/kg every 2 weeks was chosen for further studies.
Nivolumab monotherapy has been extensively studied in the NSCLC patient population in 
studies CA209003, CA209063, CA209017, and CA209057, with body weight normalized dosing 
(mg/kg). Nivolumab pharmacokinetics (PK) and exposures of participants in these studies have 
been characterized by population pharmacokinetic (PPK) analysis of data collected from these 
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studies, together with PK data from several phase 1, 2, and 3 clinical studies of nivolumab 
monotherapy in solid tumors. Nivolumab PK was determined to be linear, with dose proportional 
exposures over a dose range of 0.1 to 10 mg/kg. Nivolumab clearance and volume of distribution 
was found to increase with increasing body weight, but the increase was less than proportional, 
indicating that a mg/kg dose represents an over-adjustment for the effect of body weight on 
nivolumab PK.
Flat dosing offers several advantages over body weight normalized dosing, including reduced 
potential for dosing errors and shortened dosage preparation time. A flat dose of 240 mg every 
2 weeks is expected to produce the equivalent average exposure to 3 mg/kg every 2 weeks at the 
median body weight of ~80 kg in nivolumab-treated participants. A PPK model predicted overall 
nivolumab exposures across participants with a wide range of body weight (35 to 160 kg) for a 
240 mg every 2 weeks flat dose to be similar to that from 3 mg/kg every 2 weeks. Although the 
flat dose is expected to lead to higher exposure in lighter patients, relative to the exposure in 
heavier patients given the relationship between nivolumab PK and body weight, the predicted 
median and 95th percentile of exposures from these regimens are maintained well below those in 
10 mg/kg every 2 weeks, which was established as a safe and well-tolerated dose.
In addition, the relationship between nivolumab exposure produced by 3 mg/kg and efficacy has 
been found to be relatively flat. Taken together, the PK, safety, and efficacy data indicate that the 
safety and efficacy profile of 240 mg nivolumab dosing will be similar to that of 3 mg/kg 
nivolumab dosing.
3.1.3
Rationale for Two Year Duration for Nivolumab Treatment
The optimal duration of immunotherapy is currently unknown. However, because 
immunotherapy engages the immune system to control the tumor, continuous treatment as is 
required with targeted agents or cytotoxic therapy may not be necessary. Accumulating evidence 
from different clinical trials in different tumors types with nivolumab or nivolumab combined to 
ipilimumab indicates that most of the responses are generally occurring early, with a median 
time to response of 2-4 months including in patients with NSCLC9,10,11 and a recent analysis in a 
melanoma study suggests the majority of patients who discontinue nivolumab and/or ipilimumab 
for toxicity maintain disease control in the absence of further treatment.12
For these reasons, study CA209870 will treat participants with nivolumab for up to 24 months in 
the absence of disease progression or unacceptable toxicity. Treatment with nivolumab could be 
reinitiated as per the initial schedule for subsequent disease progression and administered for up 
to 1 additional year.
3.1.4
Rationale for Safety Data Collection in HBVsAg Positive Patients 
According to the data from Shanghai Chest Hospital, 15% Chinese lung cancer patients have 
HBV sAg positive results, therefore it is anticipated that approximately 60 HBV infected patients 
will enroll and receive nivolumab treatment. Safety will be evaluated in this population with 
great interest in hepatic safety and disease related issues. 
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Data to support inclusion of HBV patients (less than 500 IU/ml) is based on recent analysis of 
safety data from HBV infected patients with hepatocellular carcinoma in study CA 209040. 
Results of an interim analysis were published at ASCO 2016 (data on file). Among 214 patients 
enrolled in this phase 1/2 HCC study, there were 51 HBV-HCC patients. The most common 
treatment-related AEs TRAEs) were pruritus (22%), fatigue (14%) and rash (12%), which was 
consistent with that observed in cohorts of other etiology. To note, elevations of AST and ALT 
were the most frequent Grade 3-4 TRAEs and were more commonly observed in patients with 
HBV infection. In a total of 22 treated patients, HBV DNA > 100 IU/ml at any time points from 
the screening to the follow-up was observed. Among them, HBV DNA load was recorded 
< 500IU/ml in 16, and within 500-1000IU/ml in the other 6 patients. Among these patients, 5 had 
reported AEs related to abnormal liver function tests (LFT) with only 1 patient in whom Grade 1 
abnormal LFT was attributable to study drug according to the investigator. Therefore, no 
significant safety concern was observed so far in patients with detectable HBV DNA in 
CA209040.
3.1.5
Rationale for EGFR Mutation and ALK Translocation Patients 
Nivolumab is approved by FDA for metastatic NSCLC patients with EGFR or ALK genomic 
tumor aberrations who have had disease progression on FDA approved therapy for these 
aberrations.
Clinical benefit of nivolumab was shown in NSCLC patients with EGFR mutation in early phase 
studies CA209003 (phase 1/2) and CA209012 (phase 1) with objective response rate as 17% and 
14% respectively, the safety profile of patients with EGFR mutation is as good as the patients 
with EGFR wild type.13 In a second-line phase 3 trial for non-squamous NSCLC including 
patients with EGFR mutation (CA209057), the patients reported outcome based on EQ-5D and 
LCSS in nivolumab treated patients is better than the patients treated by docetaxel.
In addition, almost all patients who initially respond to EGFR TKI or ALK TKI will 
subsequently develop disease progression. Although part of the patients could get benefit from 
second and third generation TKIs overcoming resistance, it is still a population with highly 
unmet medical needs.
With a large percentage of NSCLC of patients with EGFR mutation (approximately 30% 
incidence), this population will be capped to 40 participants in the CA209870 study.
3.1.5.1
Rationale for Nivolumab 30 Minute Infusion 
Long infusion times place a burden on patients and treatment centers. Establishing that 
nivolumab can be safely administered using shorter infusion times of 30 minutes duration in 
subjects will diminish the burden provided no change in safety profile. The incidence rate of 
treatment related select high grade AE is 0.5 to 3% of nivolumab 3mg/kg every two weeks with 
infusion time no less than 30 minutes based on the Checkmate 153 study which published in 
ASCO 2016.14 Previous clinical studies show that nivolumab has been administered safely over 
60 minutes at doses ranging up to 10 mg/kg over long treatment duration. In Study CA209010 (a 
phase 2, randomized, double blinded, dose-ranging study of nivolumab in subjects with 
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advanced/metastatic clear cell RCC), a dose association was observed for infusion site reactions 
and hypersensitivity reactions (1.7% at 0.3 mg/kg, 3.7% at 2 mg/kg and 18.5% at 10 mg/kg). All 
the events were Grade 1 - 2 and were manageable. An infusion duration of 30 minutes for 240mg 
nivolumab (40% of the dose provided at 10 mg/kg in patients with a body weight expected to be 
on average around 60 kg) is not expected to present any safety concerns compared to the prior 
experience at 10 mg/kg nivolumab dose infused over a 60-minute duration. Overall, infusion 
reactions including high-grade hypersensitivity reactions have been uncommon across 
nivolumab clinical studies. A change in safety profile is not anticipated with 30-minute infusion 
of nivolumab.
3.1.5.2
Rationale for Biomarker Assessments
Aberrant expression of PD-L1 protein by tumor cells (retrospectively detected by IHC) has been
reported in a number of human malignancies, especially in relation to poor prognosis in multiple
tumor types, including squamous cell and non-squamous NSCLC.15,16,17,18,19,20,21These findings 
may be explained by the notion that high PD-L1 expression leads to immune evasion. This 
hypothesis is supported by separate studies demonstrating that PD-L1 expressed by tumor cells 
enhances apoptosis of activated tumor-specific T cells in vitro and that the expression of PD-L1 
protects tumor cells from the induction of apoptosis by effector T cells.22 In NSCLC, blocking 
PD-L1 allows for the increase of tumor-infiltrating CD8+ T cells and an increased production of 
IFN-γ but no difference noted in peripheral blood CD8+ T cells when subjects with NSCLC 
were compared with healthy controls. 23 These high levels of PD-L1 protein expression in 
NSCLC have also been significantly associated with poor prognosis and the presence of tumor 
infiltration by immature dendritic cells.24
Intriguingly, preliminary data indicate that PD-L1 protein expression in tumors may correlate
with nivolumab clinical activity. Archival tumor specimens from a limited subset (N = 30) of
subjects in MDX1106-03 were assessed for tumor PD-L1 protein expression measured by
immunohistochemistry (IHC). In this subset, 100% of subjects whose tumors lacked detectable
expression of PD-L1 protein (N = 13) did not have evidence of clinical benefit (response, stable
disease, or mixed response) to nivolumab, whereas subjects whose tumors were deemed 
PD-L1- positive (based on PD-L1 protein expression on a pre-defined threshold of tumor cells) 
were more likely to demonstrate clinical benefit. Despite the limited number of subjects 
evaluated in this initial study, our findings indicate that tumor PD-L1 protein expression status 
may have a profound impact on the likelihood of a patient to respond to nivolumab therapy. 
Because clinical benefit appeared to correlate with PD-L1 status measured in baseline, 
pre-treatment specimens, these data also suggest that PD-L1 expression could serve as a 
predictive biomarker for patient selection. As such, analysis of a larger number of samples is
warranted, and evaluation of additional patients (and their tumors) enrolled in the MDX1106-03 
study is ongoing.
In this trial, baseline tumor tissue will be collected for biomarker analyses. 
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3.1.5.3
Rationale for Outcomes Research Assessments 
The evaluation of health related quality of life is an increasingly important aspect of a clinical 
efficacy in oncology trials. Such data provides an understanding of the impact of treatment from 
the patient perspective and offers insights into the patient experience that may not be captured 
through physician reporting. 
 
 
3.2
Background
OPDIVO® (nivolumab), is a human programmed death receptor-1 (PD-1)25 blocking antibody 
approved for unresectable or metastatic melanoma, previously treated metastatic squamous 
NSCLC, advanced renal cell carcinoma, and classical Hodgkin lymphoma in the United States
and in Japan for unresectable melanoma, kidney cancer, and NSCLC, and is in clinical 
development for the treatment of other malignancies. Nivolumab has also demonstrated clinical 
activity as combination therapy with ipilimumab in melanoma, NSCLC, RCC, and Hodgkin
lymphoma. The majority of responses were durable and exceeded 6 months. 
The overall safety experience with nivolumab, as a monotherapy or in combination with other 
therapeutics, is based on experience in approximately 12,300 subjects treated to date. Overall, 
the safety profile of nivolumab monotherapy is manageable and generally consistent across 
completed and ongoing clinical trials with no maximum tolerated dose (MTD) reached at any 
dose tested up to 10 mg/kg. There was no pattern in the incidence, severity, or causality of AEs 
to nivolumab dose level. Most AEs were low grade (Grade 1 - 2) with relatively few related high 
grade (Grade 3 - 4) AEs. 
To characterize AEs of special clinical interest that are potentially associated with the use of 
nivolumab, Bristol-Myers Squibb has identified select AEs based on the following principles: 
AEs that may differ in type, frequency, or severity from AEs caused by therapies that are not 
immuno-modulating; AEs that may require immunosuppression (eg, corticosteroids) as part of 
their management; AEs whose early recognition and management may mitigate severe toxicity; 
AEs for which multiple event terms may be used to describe a single type of AE, thereby 
necessitating the pooling of terms for full characterization. 
Based on these principles and taking into account the types of AEs already observed across 
studies of nivolumab monotherapy, pneumonitis, interstitial nephritis, diarrhea/colitis, hepatitis, 
rash, endocrinopathies, and hypersensitivity/infusion reaction events are currently considered to 
be select AEs. The majority of these AEs have been managed successfully with supportive care 
and, in more severe cases, a combination of dose delay, permanent discontinuation, and/or 
initiation of systemic corticosteroids. 
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This protocol will generate safety and efficacy data on nivolumab monotherapy for advanced and 
metastatic NSCLC.
Mechanism of action of nivolumab: Cancer immunotherapy rests on the premise that tumors 
can be recognized as foreign rather than as self and can be effectively attacked by an activated 
immune system. An effective immune response in this setting is thought to rely on immune 
surveillance of tumor antigens expressed on cancer cells that ultimately results in an adaptive 
immune response and cancer cell death. Meanwhile, tumor progression may depend upon 
acquisition of traits that allow cancer cells to evade immunosurveillance and escape effective 
innate and adaptive immune responses.26,27,28 Current immunotherapy efforts attempt to break 
the apparent tolerance of the immune system to tumor cells and antigens by either introducing 
cancer antigens by therapeutic vaccination or by modulating regulatory checkpoints of the 
immune system. T-cell stimulation is a complex process involving the integration of numerous 
positive as well as negative co-stimulatory signals in addition to antigen recognition by the T-cell 
receptor (TCR).29 Collectively, these signals govern the balance between T-cell activation and 
tolerance. 
PD-1 is a member of the CD28 family of T-cell co-stimulatory receptors that also includes 
CD28, CTLA 4, ICOS, and BTLA.30 PD-1 signaling has been shown to inhibit CD28-mediated 
upregulation of IL-2, IL-10, IL-13, interferon-γ, and Bcl-xL. PD-1 expression also been noted to 
inhibit T cell activation, and expansion of previously activated cells. Evidence for a negative 
regulatory role of PD-1 comes from studies of PD-1 deficient mice, which develop a variety of 
autoimmune phenotypes.31 These results suggest that PD-1 blockade has the potential to activate 
anti-self T-cell responses, but these responses are variable and dependent upon various host 
genetic factors. Thus, PD-1 deficiency or inhibition is not accompanied by a universal loss of 
tolerance to self-antigens.
In vitro, nivolumab (BMS-936558) binds to PD-1 with high affinity (EC50 0.39-2.62 nM), and 
inhibits the binding of PD-1 to its ligands PD-L1 and PD-L2 (IC50 ± 1 nM). Nivolumab binds 
specifically to PD-1 and not to related members of the CD28 family such as CD28, ICOS, 
CTLA-4 and BTLA. Blockade of the PD-1 pathway by nivolumab results in a reproducible 
enhancement of both proliferation and IFN-γ release in the mixed lymphocyte reaction (MLR). 
Using a CMV re stimulation assay with human PBMC, the effect of nivolumab on antigen 
specific recall response indicates that nivolumab augmented IFN-γ secretion from CMV specific 
memory T cells in a dose-dependent manner versus isotype-matched control. In vivo blockade of 
PD-1 by a murine analog of nivolumab enhances the anti-tumor immune response and result in 
tumor rejection in several immunocompetent mouse tumor models (MC38, SA1/N, and 
PAN02).32
A detailed description of the chemistry, pharmacology, efficacy, and safety of nivolumab is 
provided in the BMS-936558 (nivolumab) Investigator Brochure.33
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3.3
Benefit/Risk Assessment
Nivolumab has been studied in over 12,300 subjects and is widely approved in multiple
indications. Across multiple tumor types, nivolumab has demonstrated an acceptable benefit-risk 
ratio with clinical activity and tolerable AE profile, including advanced melanoma, HCC, CRC, 
NSCLC, and some lymphomas. 
Subjects with advanced NSCLC who progressed after first-line therapy represent a great unmet 
medical need. The clinical activity of nivolumab in this patient population shows significantly 
improved clinical outcomes as monotherapy compared with docetaxel in both squamous and 
non-squamous NSCLC.
Docetaxel has a well characterized adverse event profile as cytotoxic chemotherapy, including 
the potential of pancytopenia, fluid retention, peripheral neuropathies, diarrhea, nausea, and 
vomiting. In CA209017 and CA209057, nivolumab demonstrated improved safety profile 
compared with docetaxel. Immune mediated adverse events of nivolumab are consistent with its 
mechanism of action and include liver toxicities (eg, ALT or AST increase), endocrinopathies 
(eg, hypothyroidism), pulmonary toxicity (eg, pneumonitis), renal toxicity (eg, nephritis), skin 
toxicity (eg, rash), and gastrointestinal toxicity (eg, diarrhea). 
The data of CA209040 showed the safety profile of nivolumab is tolerable of the HCC patients 
with HBV infection, even the HBV DNA is more than 500IU/ml, so we choose HBV DNA 
<500IU/ml if HBVsAg positive. Based on the PPK modeling and CA209153 data, nivolumab 
240 mg and infusion time with 30 minutes are well tolerated. The majority of the immune 
mediated adverse events are of low grade. Guided by the established toxicity management 
algorithm immune mediated adverse events are well manageable. 
The manageable AEs profile observed with nivolumab, including the EGFR mutation and ALK 
rearrangment population, supports a phase 3b clinical trial of nivolumab monotherapy as 240 mg 
intravenous with the infusion time of 30 minutes every 2 weeks in second-line advanced or 
metastatic NSCLC without EGFR mutation or ALK translocation, and third-line advanced or 
metastatic NSCLC with EGFR mutation or ALK translocation.
To assure an ongoing favorable benefit-risk assessment for subjects enrolled onto CA209870, a 
delegated internal physician will monitor the activity and safety throughout the conduct of the 
trial. Additional details on the safety profile of nivolumab, including results from other clinical 
studies, are also available in the BMS-936558 (nivolumab) Investigator Brochure.33
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4.
OBJECTIVES AND ENDPOINTS
Objectives
Endpoints
Primary
• To evaluate safety and tolerability in non-
HBV infected participants with advanced or 
metastatic NSCLC who have progressed 
during or after one prior systemic therapy 
and are treated with nivolumab 
monotherapy with an infusion duration of 30 
min
• Incidence and severity of high grade 
(combined CTCAE v4 Grade 3-4 and 
Grade 5) treatment-related select adverse 
events in non-HBV infected patients.
Secondary
• To assess safety and tolerability in HBV
infected participants with advanced or 
metastatic NSCLC who have progressed 
during or after one prior systemic therapy 
and are treated with nivolumab 
monotherapy with an infusion duration of 30 
min 
• Incidence and severity of all high grade 
(combined CTCAE v4
Grade 3-4 and 
Grade 5) treatment-related select adverse 
events in HBV participants
• To assess safety and tolerability in all 
participants 
• Incidence and severity of AEs and specific 
laboratory abnormalities in all treated 
subjects
• To evaluate efficacy in participants with 
advanced or metastatic NSCLC who have 
progressed during or after one prior 
systemic therapy and are treated with 
nivolumab monotherapy
• Collection of overall survival (OS), time to 
treatment failure (TTF), progression free 
survival (PFS), objective response rate
(ORR) , duration of tumor response (DOR)
by tumor histology (SQ or NSQ), tumor 
PD-L1 expression level (PD-L1 negative or 
PD-L1 positive), by infection status (HBV 
infection or non-HBV infection), and by 
molecular type (EGFR mutation, ALK 
translocation, or WT).
• Exploratory
• To assess overall health status and health 
utility 
• The 3-level version of the EQ-5D 
(EQ-5D-3L) visual analog scale (VAS) and 
utility index, respectively
• To evaluate the proportion of participants 
exhibiting disease-related symptom 
deterioration by Week 12 and by Week 24
• Lung Cancer Symptoms Scale (LCSS) will 
use disease-related symptom deterioration 
rate at week 12 and week 24 and is defined 
as the proportion of treated subjects who 
had 10 points or more increase from 
baseline in Average Symptom Burden 
Index (ASBI) score at any time between 
first dosing and at week 12 and week 24.
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5.
STUDY DESIGN
5.1
Overall Design
In this safety study of nivolumab monotherapy, subjects will undergo screening evaluations to
determine eligibility within 28 days prior to first dose. Eligible subjects will be treated with
nivolumab administered intravenously over 30 minutes at 240 mg every two weeks. Each 2 week 
dosing period will constitute a cycle.
Study treatment can continue beyond initial investigator assessed progression, as specified in 
criteria presented in Section 7.4.4 Treatment beyond Disease Progression. The study will close 
after the last enrolled subject completes 2 year follow up. Details regarding the assessments to be 
performed during these phases are outlined in Section 2 Schedule of Activities. 
The study design schematic is presented in Figure 5.1-1.
Figure 5.1-1:
Study Design Schematic
A Enrolled patients without EGFR mutation and ALK-positive are restricted to have only 1 prior systemic therapies. 
Patients with EGFR mutation or ALK-positive should be treated with prior 2 systemic treatment including TKI 
and chemotherapy. With a large percentage of NSCLC of patients with EGFR mutation (approximately 30% 
incidence), this population will be capped to 40 participants in the CA209870 study.
B HBsAg+ participants (estimated 15%) must be on antiviral therapy based on China anti-HBV guideline. Patients   
with HBV infection will be capped to 60 participants.
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C Treatment until progression or unacceptable toxicity. Nivolumab treatment will be given up to 24 months in the 
absence of disease progression or unacceptable toxicity. Treatment with nivolumab could be reinitiated as per the 
initial schedule for subsequent disease progression and administered for up to 1 additional year.
D Participants may receive nivolumab treatment beyond progression as defined in protocol. The decision to continue 
treatment beyond initial progression should be discussed with the BMS Medical Monitor and documented in the 
study records.
Physical examinations, vital sign measurements, outcome questionnaires, 
 
and clinical laboratory evaluations will be performed at selected times throughout study 
participation. Participants will be closely monitored for AEs throughout the study. Blood 
samples will be collected for safety
 analysis. 
In this study, overall survival is a key endpoint of the study. Post study follow-up is of critical 
importance and is essential to preserving participant safety and the integrity of the study. 
Participants 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 8 until death or the conclusion 
of the study.
5.1.1
Data Monitoring Committee and Other External Committees
A Data Monitoring Committee (DMC) will not be used for this study, given the following:
1) This study is an open-label, single arm study.
2) Safety data will be closely monitored by BMS with real time review and assessment of SAEs 
as they are received, and periodic review safety signals.
BMS will assign a physician responsible for reviewing, on a systematic and continuous basis, the
safety of participants on this study. This includes a review of serious and non-serious adverse 
events, and all hematological and non-hematological events. In addition, BMS has a Medical
Surveillance Team (MST), independent from the clinical medical monitor. The MST has the
primary responsibility within Bristol-Myers Squibb for assessing emerging safety trends,
identifying potential safety signals, notifying appropriate stakeholders of relevant findings, and
implementing risk mitigation activities to ensure the safety of patients participating in BMS
trials. The MST is also responsible for reviewing data from all sources including non-clinical
studies and clinical trials, monitoring the progress of various nivolumab (BMS-936558) safety
support activities, and recommending and implementing necessary changes to the safety plan and
any other specific safety-related activities.
5.2
Number of Participants
Approximately 470 participants will be screened for the trial to enroll and treat approximately 
400 participants. Patients with HBV infection will be capped to 60 participants according to the 
prevalence of HBV infection in China (∼15% prevalence in China NSCLC population).
5.3
End of Study Definition
The start of the trial is defined as the first visit for the first participant screened. End of trial is
defined as the last visit or scheduled procedure shown in the Schedule of Activities for the last 
participant. Study completion is defined as the final date on which data for the primary endpoint 
was or is expected to be collected, if this is not the same
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5.4
Scientific Rationale for Study Design
The main objective of the study is to provide additional insight into the frequency of high-grade
select AEs and their outcome, and thus supplement the growing safety database of nivolumab 
treated Asian subjects. This study will treat approximately 400 Asian subjects in order to 
estimate the incidence of the rare high grade (CTCAE V4 Grade 3-4 and Grade 5) 
treatment-related select AEs with greater precision and characterize their outcome (between 
0 and 2% incidence per event type in NSCLC subjects treated with nivolumab monotherapy in 
previous studies). The safety assessment for the patient with HBV infection (HBV DNA 
< 500 IU/ml) is expected to be similar and limited to 60 treated subjects. These data will provide 
a larger data set to inform the risk/benefit profile of the use of nivolumab in Asian NSCLC 
patients and will help to further clarify the effectiveness of the current treatment algorithms for 
managing drug-mediated toxicities.
5.5
Justification for Dose and Infusion Time
Eligible subjects will be treated with nivolumab administered intravenously over 30 minutes at 
240 mg every two weeks. Each 2 week dosing period will constitute a cycle. The first dose of 
study drug is to be administered within 3 days of enrollment confirmation. All subjects will be 
monitored continuously for AEs while on study treatment. Treatment modifications (eg, dose 
delay, reduction, or discontinuation) will be based on specific laboratory and adverse event 
criteria, as described in Sections 7.4.
5.5.1
Summary of Safety of Nivolumab in Metastatic Setting
In clinical trials, nivolumab has demonstrated an acceptable benefit-risk across multiple tumor 
types, including advanced melanoma, RCC, NSCLC, and some lymphomas. The two clinical 
trials that have contributed the most to the clinical experiences of nivolumab monotherapy are 
CA209003 and CA209037. Overall, the safety profile is similar across these two studies and is 
discussed below. Therefore, no additional degree of safety risk is expected.
CA209003 is a completed phase 1 open label, multiple dose escalation study in 306 subjects with 
select previously treated advanced solid tumors, including melanoma, RCC, NSCLC, CRC, 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. A total of 
306 subjects were treated with nivolumab in the dose range of 0.1 to 10 mg/kg.
No maximal tolerated dose was identified in CA209003. The incidence, severity and relationship 
of adverse events (AEs) were generally similar across dose levels and tumor types. Nivolumab 
related AEs of any grade occurred in 75.2% of subjects. Of the 306 treated subjects, 303 (99.0%) 
subjects have at least 1 reported AE regardless of causality. The most frequently reported AEs 
were fatigue (54.9%), decreased appetite (35.0%), diarrhea (34.3%), nausea (30.1%), and cough 
(29.4%). Treatment-related AEs were reported in 230 (75.2%) of the 306 subjects. The most 
frequently reported treatment-related AEs were fatigue (28.1%), rash (14.7%), diarrhea (13.4%), 
and pruritus (10.5%). Most treatment-related AEs were low grade. Treatment-related high grade 
(Grade 3 - 4) AEs were reported in 52 (17.0%) subjects. The most common treatment-related 
high grade AEs were fatigue (2.3%) and diarrhea (1%). Drug-related SAEs occurred in 11.5% of 
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subjects. Grade 3 - 4 drug-related SAEs reported in at least 2 subjects included: diarrhea 
(3 subjects, 1.0%), pneumonitis (3 subjects, 1.0%), pneumonia (2 subjects, 0.7%) and lipase 
increased (2 subjects, 0.7%).
Select AE categories (events with a potential inflammatory mechanism requiring more frequent 
monitoring and/or unique intervention such as immunosuppressants and/or endocrine 
replacement therapy) include: GI AEs, pulmonary AEs, renal AEs, hepatic AEs, skin AEs, and 
endocrinopathies. In addition, select AEs include a category for infusion reaction. Each category 
is composed of a discrete set of preferred terms, including those of greatest clinical relevance. 
These select AEs are considered events of interest based on the mechanism of action and were 
previously referred to as immune-related AEs or immune-mediated AEs. Most high grade events 
resolved following the treatment guidelines for the treatment of pulmonary events, GI events, 
hepatic events, renal events, and endocrine events, respectively. Overall, the safety profile at 
3 mg/kg (n = 54) was similar to safety profile across the dose ranges from 0.1 mg/kg to 10 mg/kg 
(n = 306).
Table 5.5.1-1:
Treatment-related Select Adverse Events by Treatment - All CTC 
Grades Reported in at least 10 Treated Subjects in CA209003
Preferred Term
3 mg/kg N = 54
Total (0.1 to 10 mg/kg) N = 306
Any Grade
Grade 3 - 4
Any Grade
Grade 3 - 4
Any select AE
23 (43)
2 (4)
140 (46)
19 (6)
Anyendocrinopathies
4 (7)
0
29 (10)
3 (1)
Endocrinopathiesthyroid
4 (7)
0
26 (9)
2 (1)
Blood TSH increased
2 (4)
0
11 (4)
1 (0.3)
Hypothyroidism
1 (2)
0
11 (4)
1 (0.3)
Any skin AEs
12 (22)
0
75 (25)
1 (0.3)
Rash
5 (9)
0
45 (15)
0
Pruritus
3 (6)
0
32 (11)
1 (0.3)
Any GI AE
7 (13)
0
43 (14)
3 (1)
Diarrhea
6 (11)
0
41 (13)
3 (1)
Any hepatic AE
3 (6)
2 (4)
18 (6)
4 (1)
ALT increased
1 (2)
0
11 (4)
1 (0.3)
Any pulmonary AE
2 (4)
0
17 (6)
6 (2)
Pneumonitis
1 (2)
0
12 (4)
4 (1)
Other select AE
3 (6)
0
15 (5)
2 (1)
Infusion-relatedreaction
3 (6)
0
12 (4)
0
Abbreviations: AE, adverse event; ALT, alanine aminotransferase; GI, gastrointestinal; TSH, thyroid stimulating 
hormone Source: CA209003. Clinical data cut-off date: 18-Mar-2013
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Total includes subjects who also received 0.1 mg/kg (n = 17), 0.3 mg/kg (n = 18), 1 mg/kg (n = 86), and 10 mg/kg 
(n = 131) in addition to those illustrated at 3 mg/kg (n = 54).
Treatment-related AEs leading to discontinuation were reported in 32 (10.5%) of the
306 nivolumab treated subjects on CA209003. The most frequent of these were pneumonitis
(8 subjects; 2.6%) and colitis (3 subjects; 1.0%). There were 3 (1%) drug related deaths; each 
occurred after development of pneumonitis.
CA209037 is an ongoing phase 3, open-label study of nivolumab (3 mg/kg administered by 
intravenous [IV] infusion every 2 weeks [q2w]) vs investigator’s choice therapy in subjects with 
previously-treated advanced melanoma. As of 30-Apr-2014, 268 subjects have been treated with 
3 mg/kg IV nivolumab in CA209037 with safety results as outlined below that are consistent 
with the phase 1 experience of CA209003.
In CA209037, nivolumab related AEs of any grade occurred in 67.5% of subjects. Of the 
268 subjects treated with nivolumab, 255 (95.1%) subjects had at least 1 reported AE regardless 
of causality. The most frequently reported treatment-related AEs were fatigue (25.0%), pruritus 
(16.0%), diarrhea (11.2%), and nausea (9.3%). Most treatment-related AEs were low grade. 
Treatment -related high grade (Grade 3 - 4) AEs were reported in 24 (9.0%) of subjects. The 
most common treatment-related high grade AEs were fatigue (0.7 %), anemia (0.7%), diarrhea 
(0.4%), and vomiting (0.4%). Drug-related SAEs occurred in 4.5% of subjects. Grade 3 - 4 
drug related SAEs reported in at least 2 subjects included diarrhea (2 subjects, 0.7%). In 
addition, drug-related SAE of hyperglycemia occurred in 0.7%.
Select AE categories (events with a potential inflammatory mechanism requiring more frequent 
monitoring and/or unique intervention such
as immunosuppressants and/or endocrine 
replacement therapy) were:
•
Skin (29.1%) including pruritus (16.0%) and rash (9.3%)
•
GI (11.6%) including diarrhea (11.2%) and colitis (1.1%)
•
Endocrine (7.8%) including hypothyroidism (7.8%) and hyperthyroidism (1.9%)
•
Hepatic (4.5%) including AST increased (4.1%) and ALT increased (2.6%)
•
Pulmonary (2.2%) including pneumonitis (1.9%)
•
Hypersensitivity/infusion reaction (1.9%)
•
Renal (1.5%) including increased creatinine (0.7%), increased urea (0.4%), and 
tubulointerstitial nephritis (0.4%)
In general, these select AEs were considered by the investigator to be related to study drug, 
except for AEs in the hepatic and renal select AE categories. There were few high-grade select 
AEs (n = 20), and the majority of high-grade events (13 of 20) subsequently resolved, including 
those for which immunosuppressive therapy was not initiated.
Treatment-related AEs leading to discontinuation were reported in 6 (2.2%) of the 268 
nivolumab treated subjects in CA209037 including single events of colitis, pancreatitis, 
increased ALT, increased lipase, autoimmune neuropathy, and demyelination. In CA209037, one 
subject experienced drug-related grade 5 hypoxia, possibly pneumonitis, in the setting of 
lymphangitic spread and possible pneumonia.
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Taken together, these data from studies from CA209003 and CA209037 highlight the acceptable 
safety profile with similar trends in AEs in the 574 subjects treated with nivolumab in these 
2 studies. Additional details on the safety profile of nivolumab, including results from other 
clinical studies, are also available in the nivolumab Investigator Brochure (IB).33
5.5.2
Rationale for Nivolumab Flat Dose Selection
The nivolumab dose of 240 mg every 2 weeks (q2w) was selected based on clinical data and 
modeling and simulation approaches using population PK (PPK) and exposure-response analyses 
of data from studies in multiple tumor types (melanoma, NSCLC, and RCC) where body weight 
normalized dosing (mg/kg) has been used.
PPK analyses have shown that the PK of nivolumab is linear with proportional exposure over a 
dose range of 0.1 to 10 mg/kg, and no differences in PK across ethnicities and tumor types were 
observed. Nivolumab clearance and volume of distribution were found to increase as the body 
weight increases, but less than the proportional with increasing weight, indicating that mg/kg 
dosing represents an over-adjustment for the effect of body weight on nivolumab PK. The PPK 
model previously developed using data from NSCLC subjects has recently been updated, using 
data from 1,544 subjects from 7 studies investigating nivolumab in the treatment of melanoma, 
NSCLC, and RCC. In this dataset, the median (minimum - maximum) weight was 77 kg (35 to
160 kg) and thus, an approximately equivalent dose of 3 mg/kg for an 80 kg subject, nivolumab 
240 mg q2w was selected for future studies. To predict relevant summary exposures of 
nivolumab 240 mg q2w, the PPK model was used to simulate nivolumab 3 mg/kg q2w and 240 
mg q2w. In the simulations, the simulated patient populations consisted of 1,000 subjects per 
treatment arm randomly sampled from aforementioned pooled database of cancer subjects. 
Because no differences in PK were noted across ethnicities and tumor types, these simulated 
melanoma and NSCLC data will be applicable to subjects with other tumor types. The simulated 
measure of exposure of interest, time-averaged concentrations (Cavgss) for 240 mg q2w are 
predicted to be similar for all subjects in reference to 80 kg subjects receiving 3 mg/kg q2w.
Nivolumab is safe and well tolerated up to 10 mg/kg q2w dose level. AEs have been broadly 
consistent across tumor types following monotherapy and have not demonstrated clear 
dose-response or exposure-response relationships. Additionally, the simulated median and 95th 
prediction interval of nivolumab summary exposures across body weight range (35 - 160 kg) are 
predicted to be maintained below the corresponding observed highest exposure experienced in 
nivolumab ie, 95th percentile following nivolumab 10 mg/kg q2w from clinical study 
CA209003. Thus, while subjects in the lower body weight ranges would have greater exposures 
than 80 kg subjects, the exposures are predicted to be within the range of observed exposures at 
doses (up to 10 mg/kg q2w) used in the nivolumab clinical program, and are not considered to 
put subjects at increased risk. For subjects with greater body weights, the simulated ranges of 
exposures are also not expected to affect efficacy, because the exposures predicted following 
administration of a 240 mg q2w are on the flat part of the exposure-response curves for 
previously investigated tumors, melanoma and NSCLC. Given the similarity of nivolumab PK 
across tumor types and the similar exposures predicted following administration of 240 mg flat 
dose compared to 3 mg/kg, it is expected that the safety and efficacy profile of 240 mg 
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nivolumab will be similar to that of 3 mg/kg nivolumab. Thus nivolumab 240 mg every 2 weeks 
over 30 minutes will be recommended in this study.
5.5.3
Clinical Pharmacology Summary 
The pharmacokinetics (PK) of nivolumab were studied in subjects over a dose range of 0.1 to 
10 mg/kg administered as a single dose or as multiple doses of nivolumab every 2 or 3 weeks. 
The geometric mean (% CV%) clearance (CL) was 9.5 mL/h (49.7%), geometric mean volume 
of distribution at steady state (Vss) was 8.0 L (30.4%), and geometric mean elimination half-life 
(t1/2) was 26.7 days (101%). Steady-state concentrations of nivolumab were reached by 
12 weeks when administered at 3 mg/kg q2w, and systemic accumulation was approximately 3-
fold. The exposure to nivolumab increased dose proportionally over the dose range of 0.1 to 10 
mg/kg administered every 2 weeks. The clearance of nivolumab increased with increasing body 
weight. The PPK analysis suggested that the following factors had no clinically important effect 
on the CL of nivolumab: age (29 to 87 years), gender, race, baseline lactate dehydrogenase 
(LDH), PD-L1. A PPK analysis suggested no difference in CL of nivolumab based on age, 
gender, race, tumor type, baseline tumor size, and hepatic impairment.
Although ECOG status, baseline glomerular filtration rate (GFR), albumin and body weight had 
an effect on nivolumab CL, the effect was not clinically meaningful. When nivolumab is 
administered in combination with ipilimumab, the CL of nivolumab was increased by 24%, 
whereas there was no effect on the clearance of ipilimumab. Additionally, PPK and exposure 
response analyses have been performed to support use of 240 mg q2w dosing in addition to the 
3 mg/kg q2w regimen. Using the PPK model, exposure of nivolumab at 240 mg flat dose was 
identical to a dose of 3 mg/kg for subjects weighing 80 kg, which was the approximate median 
body weight in nivolumab clinical trials.
Full details on the clinical pharmacology aspects of nivolumab can be found in the BMS-936558 
(nivolumab) Investigator Brochure.33
5.5.4
Rationale for 30-Minute Infusion
Long infusion times place a burden on participants and treatment centers. Establishing that 
nivolumab can be safely administered using shorter infusion times of 30 minutes duration in 
participants will diminish the burden provided no change in safety profile. Previous clinical 
studies show that nivolumab has been administered safely over 60 minutes at doses ranging up to 
10 mg/kg over long treatment duration. In Study CA209010, (a phase 2, randomized, double 
blinded, dose-ranging study of nivolumab in participants with advanced/metastatic clear cell 
RCC) a dose association was observed for infusion site reactions and hypersensitivity reactions 
(1.7% at 0.3 mg/kg, 3.7% at 2 mg/kg and 18.5% at 10 mg/kg). All the events were Grade 
1 - 2 and were manageable. An infusion duration of 30 minutes for 240mg nivolumab (40% of 
the dose provided at 10 mg/kg in patients with a body weight expected to be on average around 
60 kg) are not expected to present safety concerns compared to the prior experience at 10 mg/kg 
nivolumab dose infused over a 60-minute duration. Overall, infusion reactions including 
high-grade hypersensitivity reactions have been uncommon across nivolumab clinical studies. A 
change in safety profile is not anticipated with 30-minute infusion of nivolumab.
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6.
STUDY POPULATION
For entry into the study, the following criteria MUST be met.
6.1
Inclusion Criteria
1) Signed Written Informed Consent
a) Participants must have signed and dated an IRB/IEC-approved written informed consent 
form in accordance with regulatory and local guidelines. This must be obtained before the 
performance of any protocol-related procedures that are not part of normal participant
care.
b) Participants must be willing and able to comply with scheduled visits, treatment schedule,
laboratory tests, and other requirements of the study.
2) Type of Participant and Target Disease Characteristics
a) Participants with histologically- or cytologically-documented NSCLC (SQ or NSQ) who 
present with Stage IIIB/Stage IV disease (according to version 8 of the International 
Association for the Study of Lung Cancer Staging Manual in Thoracic Oncology), or 
with recurrent or progressive disease following multimodal therapy (radiation therapy, 
surgical resection, or definitive chemo-radiotherapy for locally advanced disease).
i)
Participants must have experienced disease progression or recurrence after one 
systemic therapies for advanced or metastatic disease.
ii) Each subsequent line of therapy must be preceded by disease progression. A switch of 
an agent within a regimen in order to manage toxicity does not define the start of a
new line of therapy.
iii) Maintenance therapy following platinum doublet-based chemotherapy is not
considered as a separate regimen of therapy.
iv) Participants who received platinum-containing adjuvant, neoadjuvant or definitive
chemoradiation therapy given for locally advanced disease, and developed recurrent
(local or metastatic) disease within 6 months of completing therapy are eligible.
v) Participants with recurrent disease > 6 months after completing a platinum-containing
adjuvant, neoadjuvant or definitive chemoradiation therapy given for locally
advanced disease, who also subsequently progressed during or after a systemic
regimen given to treat the recurrence, are eligible.
(1).EGFR testing is not required if ALK or KRAS test is positive.
(2).ALK testing is not required if EGFR or KRAS test is positive.
b) Participants with non-squamous histology must be tested for EGFR mutations (including, 
but not limited to, deletions in exon 19 and exon 21 [L858R] substitution) and ALK 
rearrangement if tests have not been previously performed. Participants who are positive 
on sensitizing EGFR mutations (exon 19 deletion, exon 21 [L858R] substitution) or ALK 
rearrangement testing, are eligible to enroll after progression from first line tyrosine 
kinase inhibitor (TKI) regimen and one systemic therapies.
i)
Participants who are positive on non-sensitizing EGFR mutation are eligible to enroll
after two line of systemic therapy, which can be TKI and chemotherapy.
ii) Participants are eligible if genetic test results are indeterminate or if no tumor tissue is
available or accessible for testing as long as they have received one prior systemic
chemotherapy.
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iii) Experimental therapies when given as separate regimen are considered as separate
line of therapy. Participants with more than 1 line chemotherapy are not allowed in 
this study.
c) Eastern Cooperative Oncology Group (ECOG) Performance Status of ≤1
d) Participants must have measurable disease by CT or MRI per RECIST 1.1 criteria 
(radiographic tumor assessment performed within 28 days of first dose of study drug) or 
clinically apparent disease that the investigator can follow for response per RECIST 1.1.
e) Prior radiotherapy or radiosurgery must have been completed at least 2 weeks prior to 
starting study treatment
3) Age and Reproductive Status
a) Males and Females, ≥18 of age
b) Women of childbearing potential (WOCBP) must have a negative serum or urine 
pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 24 
hours prior to the start of study treatment.
c) Women must not be breastfeeding
d) WOCBP must agree to follow instructions for method(s) of contraception for the duration 
of study treatment with nivolumab and 5 months after the last dose of study treatment (ie, 
30 days [duration of ovulatory cycle] plus the time required for the investigational drug to 
undergo approximately five half-lives).
e) Males who are sexually active with WOCBP must agree to follow instructions for 
method(s) of contraception for the duration of study treatment with nivolumab and 
7 months after the last dose of study treatment {i.e., 90 days (duration of sperm turnover) 
plus the time required for the investigational drug to undergo approximately five 
half- lives.}
f)
Azoospermic males are exempt from contraceptive requirements. WOCBP who are 
continuously not heterosexually active are also exempt from contraceptive requirements, 
and still must undergo pregnancy testing as described in this section.
Investigators shall counsel WOCBP, and male participants who are sexually active with 
WOCBP, on the importance of pregnancy prevention and the implications of an unexpected 
pregnancy. Investigators shall advise on the use of highly effective methods of contraception, 
(Appendix 4) which have a failure rate of < 1% when used consistently and correctly.
6.2
Exclusion Criteria
1) Medical Conditions
a) Women with a positive pregnancy test at enrollment or prior to administration of study 
medication
b) Participants with active CNS metastases are excluded. Participants are eligible if the CNS 
metastases are adequately treated and participants 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, participants must be either off corticosteroids, or on a 
stable or decreasing dose of < 10 mg daily prednisone (or equivalent).
c) Participants with a condition requiring systemic treatment with either corticosteroids
(> 10 mg daily prednisone equivalent) or other immunosuppressive medications within
14 days of first dose of study drug. Inhaled or topical steroids, and adrenal replacement
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steroid doses > 10 mg daily prednisone equivalent, are permitted in the absence of active
autoimmune disease.
d) Participants with previous malignancies (except non-melanoma skin cancers, and the 
following in situ cancers: bladder, gastric, colon, endometrial, cervical/dysplasia, 
melanoma, or breast) 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.
e) Participants with carcinomatous meningitis.
f)
Participants with a history of interstitial lung disease (eg, sarcoidosis) that is symptomatic 
or may interfere with the detection or management of suspected drug-related pulmonary
toxicity. Participants with COPD whose disease is controlled at study entry are allowed.
g) Any serious or uncontrolled medical disorder that, in the opinion of the investigator, may 
increase the risk associated with study participation or study drug administration, impair 
the ability of the subject to receive protocol therapy, or interfere with the interpretation of 
study results.
h) Participants with an active, known or suspected autoimmune disease. Participants with 
type I diabetes mellitis, hypothyroidism only requiring hormone replacement, skin 
disorders (such as vitiligo, psoriasis, or alopecia) not requiring systemic treatment, or 
conditions not expected to recur in the absence of an external trigger are permitted to 
enroll.
i)
All toxicities attributed to prior anti-cancer therapy other than alopecia, fatigue, or 
peripheral neuropathy must have resolved to Grade 1 (NCI CTCAE version 4) or baseline 
before administration of study drug.
j)
Participants must have recovered from the effects of major surgery or significant 
traumatic injury at least 14 days before the first dose of study treatment.
k) Participants who have been previously treated with cell immunotherapy (eg, cytokine
induced killer [CIK] treatment). 
l)
Participants who participated in either arm of the following clinical trials CA209078 or 
received prior treatment with anti-PD-1 or anti-PDL1 experimental agents.
m) Participants who participated in other experimental therapies for NSCLC.
2) Prior/Concomitant Therapy
a) Participants who received prior treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2, 
anti-CD137, or anti-CTLA-4 antibody, or any other antibody or drug specifically 
targeting T-cell co-stimulation or checkpoint pathways
b) Participants with a history of screen failure to any PD1 or PDL1 antibody clinical trial 
due to PD-L1 status. Patients with undetermined status are allowed on study.
c) All toxicities attributed to prior anti-cancer therapy other than alopecia and fatigue must 
have resolved to Grade 1 (NCI CTCAE version 4) or baseline before administration of 
study drug. Participants with toxicities attributed to prior anti-cancer therapy which are 
not expected to resolve and result in long lasting sequelae, such as neuropathy after 
platinum based therapy, are permitted to enroll.
d) Treatment with any chemotherapy, radiation therapy, biologics for cancer, or 
investigational therapy within 28 days of first administration of study treatment 
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(participants with prior cytotoxic or investigational products < 4 weeks prior to treatment 
might be eligible after discussion between investigator and sponsor, if toxicities from the 
prior treatment have been resolved to Grade 1 (NCI CTCAE version 4).
e) Previous treatment with an investigational agent 
f)
Current or planned anti-cancer treatments
3) Physical and Laboratory Test Findings
a) Screening laboratory values must meet the following criteria (using CTCAE v4):
i)
WBC < 2000/uL
ii) Neutrophils < 1500/uL
iii) Platelets < 100 x103/uL
iv) Hemoglobin < 9.0 g/dL
v) Serum creatinine > 1.5 x ULN or calculated creatinine clearance < 40 mL/min (using 
the Cockcroft Gault formula)
Female CrCl = ([140 - age in years] x weight in kg x 0.85)/ (72 x serum creatinine in mg/dL)
Male CrCl = ([140 - age in years] x weight in kg x 1.00)/ (72 x serum creatinine in mg/dL)
vi) AST > 3.0 x ULN 
vii)ALT > 3.0 x ULN 
viii)
Total Bilirubin > 1.5 x ULN (except participants with Gilbert Syndrome who 
must have a total bilirubin level of < 3.0 x ULN). 
b) HBV DNA test for participants with HBsAg positive should > 500 IU/ml
c) Known history of positive test for human immunodeficiency virus (HIV) or known 
acquired immunodeficiency syndrome (AIDS). NOTE: Testing for HIV must be 
performed at sites where mandated locally.
d) Any positive test for Hepatitis C virus indicating acute or chronic infection.
4) Allergies and Adverse Drug Reaction
a) History of severe hypersensitivity reactions to other monoclonal antibodies
b) History of allergy or hypersensitivity to study drug components
5) Other Exclusion Criteria
a) Prisoners or participants who are involuntarily incarcerated. (Note: under certain specific 
circumstances a person who has been imprisoned may be included or permitted to 
continue as a participant. Strict conditions apply and Bristol-Myers Squibb approval is 
required.)
b) Participants who are compulsorily detained for treatment of either a psychiatric or 
physical (e.g., infectious disease) illness
Eligibility criteria for this study have been carefully considered to ensure the safety of the study 
participants and that the results of the study can be used. It is imperative that participants fully 
meet all eligibility criteria.
6.3
Lifestyle Restrictions
Not applicable. No restrictions are required.
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6.4
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study but are 
not subsequently entered in the study. A minimal set of screen failure information is required to 
ensure transparent reporting of screen failure participants, to meet the Consolidated Standards of 
Reporting Trials (CONSORT) publishing requirements, and to respond to queries from 
regulatory authorities. Minimal information includes date of consent, demography, screen failure 
details, eligibility criteria, and any serious AEs.
6.4.1
Retesting During Screening or Lead-In Period
Participant Re-enrollment: This study does not permit the re-enrollment of a participant that has 
discontinued the study as a pre-treatment failure.
7.
TREATMENT
Study treatment is defined as any investigational treatment(s), marketed product(s), placebo or 
medical device intended to be administered to a study participant according to the study 
treatment allocation.
Study treatment includes only Investigational [Medicinal] Product (IP/IMP).
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.
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.
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Table 7-1:
Study treatments for CA209870
Product Description 
/ Class and Dosage 
Form
Potency
IP/Non-IMP
Blinded or Open 
Label
Packaging / Appearance
Storage Conditions
(per label)
Nivolumab 
BMS-936558-01
Solution for Injection
100 mg
(10 mg/mL and 
40 mg/4 mL)
IP
Open Label
Clear to opalescent colorless to pale yellow 
liquid. May contain particles
240 mg kit contains: 2 x 100 mg vials 
(10 mL/vial) and 1 x 40 mg vial (4 mL/vial) or 
carton containing 5 vials of  100 mg
2° to 8°C. Protect 
from light and 
freezing
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7.1
Treatments Administered
The selection and timing of dose for each participant is as follows:
Table 7.1-1:
Selection and Timing of Dose
Study 
Treatment
Unit dose 
strength(s)/Dosage level(s)
Dosage formulation
Frequency of Administration
Route of Administration
Nivolumab
240 mg
Q2 weeks 
IV
7.2
Method of Treatment Assignment
All participants will be assigned to treatment using an Interactive Response Technology (IRT). 
Users will receive log in information and directions on how to access the IRT. Study treatment 
will be dispensed at the study visits as listed in Schedule of Activities (Section 2). 
7.3
Blinding
This is an open-label, single arm study and blinding procedures are not applicable.
7.4
Dosage Modification
7.4.1
Nivolumab Dosing
Participants should begin study treatment within 3 calendar days of treatment assignment. 
Participants should receive nivolumab at a dose of 240 mg as a 30 minute infusion on Day 1 of 
each treatment cycle until progression, unacceptable toxicity, withdrawal of consent, or study 
end, whichever occurs first. Nivolumab treatment will be given up to 24 months in the absence 
of disease progression or unacceptable toxicity. Treatment with nivolumab could be reinitiated as 
per the initial schedule for subsequent disease progression and administered for up to 1 
additional year.
Premedications are not recommended for the first dose of nivolumab. Participants should be 
carefully monitored for infusion reactions during nivolumab administration. If an acute infusion 
reaction is noted, participants should be managed according to Section 7.4.5 and Section 8.1.
There will be no dose escalations or reductions of nivolumab allowed. Participants may be dosed
within a ± 3-day window and no less than 12 days from the previous dose during q2w cycles. 
Doses of nivolumab may be interrupted, delayed, or discontinued depending on how well the 
subject tolerates the treatment. Dosing visits are not skipped, only delayed.
Nivolumab Injection, 100 mg/10 mL (10 mg/mL) and 40 mg/mL (10 mg/mL): nivolumab 
injection is to be administered as an IV infusion through a 0.2-micron to 1.2-micron pore size, 
low-protein binding in-line filter at the protocol-specified doses. It is not to be administered as an 
IV push or bolus injection. Nivolumab injection can be infused undiluted (10 mg/mL) or diluted 
with 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP to protein 
concentrations as low as 1 mg/mL. Instructions for dilution and infusion of nivolumab injection 
may be provided in the clinical protocol, pharmacy binder, or pharmacy reference sheet. Care 
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must be taken to assure sterility of the prepared solution as the product does not contain any 
antimicrobial preservative or bacteriostatic agent. 
Nivolumab infusions are compatible with polyvinyl chloride (PVC) or polyolefin containers and 
infusion sets, and glass bottles.
7.4.2
Dose Delay Criteria for Nivolumab
Doses of nivolumab may be interrupted, delayed, or discontinued depending on how well the 
participant tolerates the treatment. Dosing visits are not skipped, only delayed.
Nivolumab administration should be delayed for the following:
•
Grade 2 non-skin, drug-related adverse event, with the exception of fatigue
•
Grade 2 drug-related creatinine, AST, ALT and/or Total Bilirubin abnormalities
•
Grade 3 skin, drug-related adverse event
•
Grade 3 drug-related laboratory abnormality, with the following exceptions: 
o
Grade 3 lymphopenia or asymptomatic amylase or lipase does not require dose delay
•
Dose delay for changes in AST or ALT as follows:
o
If a subject has a baseline AST or ALT that is within normal limits, delay dosing for
drug-related Grade ≥2 toxicity (2 grade shift)
o
If a subject has baseline AST or ALT within the Grade 1 toxicity range, delay dosing 
for drug-related Grade ≥3 toxicity (2 grade shift)
o
If a subject has baseline AST or ALT within the Grade 2 toxicity range, delay dosing 
for a two-fold drug-related increase in AST or ALT or for AST or ALT values 8 x
ULN (whichever is lower).
•
Any adverse event, laboratory abnormality, or intercurrent illness which, in the judgment of 
the investigator, warrants delaying the dose of study medication.
Participants who require delay of nivolumab should be re-evaluated weekly or more frequently if 
clinically indicated and resume nivolumab dosing when re-treatment criteria are met.
7.4.3
Criteria to Resume Treatment
Participants may resume treatment with study drug when the drug-related AE(s) resolve to 
Grade ≤1 or baseline value, with the following exceptions:
•
Participants may resume treatment in the presence of Grade 2 fatigue
•
Participants who have not experienced a Grade 3 drug-related skin AE may resume treatment 
in the presence of Grade 2 skin toxicity
•
For participants with Grade 2 AST, ALT, or TBILI elevations, dosing may resume when 
laboratory values return to baseline and management with corticosteroids, if needed, is 
complete.
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•
Participants with combined Grade 2 AST/ALT AND total bilirubin values meeting 
discontinuation parameters (Section 8) should have treatment permanently discontinued. 
•
Drug-related pulmonary toxicity, diarrhea or colitis must have resolved to baseline before 
treatment is resumed. Participants with persistent Grade 1 pneumonitis after completion of a 
steroid taper over at least 1 month may be eligible for retreatment if discussed with and 
approved by BMS Medical Monitor.
Participants with drug-related endocrinopathies adequately controlled with only physiologic 
hormone replacement may resume treatment after consultation with the BMS Medical Monitor.
Adrenal insufficiency requires discontinuation regardless of control with hormone replacement.
7.4.4
Nivolumab Treatment beyond Disease Progression
Accumulating evidence indicates a minority of participants treated with immunotherapy may 
derive clinical benefit despite initial evidence of PD.34 Participants treated with nivolumab will 
be permitted to continue nivolumab treatment beyond initial study criteria defined PD or other 
hematologic criteria, assessed by the investigator, as long as they meet the following criteria:
•
Investigator-assessed clinical benefit without 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)
•
Participants provides written informed consent prior to receiving additional nivolumab 
treatment. All other elements of the main consent including description of reasonably 
foreseeable risks or discomforts, or other alternative treatment options will still apply.
The decision to continue treatment beyond initial progression should be discussed with the BMS
Medical Monitor and documented in the study records.
A radiographic assessment/ scan should be performed within 6 weeks of initial 
investigator-assessed progression to determine whether there has been a decrease in the tumor 
size or continued PD. The assessment of clinical benefit should be balanced by clinical judgment 
as to whether the participant is clinically deteriorating and unlikely to receive any benefit from 
continued treatment with nivolumab.
If the investigator feels that the participant continues to achieve clinical benefit by continuing 
treatment, the participant should remain on the trial and continue to receive monitoring according 
to the Schedule of Activities in Section 2.
For the participants who continue nivolumab study therapy beyond progression, further 
progression is defined as an additional 10% increase in tumor burden with a minimum 5 mm 
absolute increase from time of initial PD. This includes an increase in the sum of diameters of all 
target lesions and/ or the diameters of new measurable lesions compared to the time of initial PD. 
Nivolumab treatment should be discontinued permanently upon documentation of further 
progression.
New lesions are considered measureable at the time of initial progression if the longest diameter 
is at least 10 mm (except for pathological lymph nodes which must have a short axis of at least
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15 mm). Any new lesion considered non-measureable at the time of initial progression may 
become measureable and therefore included in the tumor burden if the longest diameter increases 
to at least 10 mm (except for pathological lymph nodes which must have a short axis of at least 
15 mm). In situations where the relative increase in total tumor burden by 10% is solely due to 
inclusion of new lesions which become measurable, these new lesions must demonstrate an
absolute increase of at least 5 mm.
7.4.5
Treatment of Nivolumab Related Infusion Reactions
As nivolumab contains only human immunoglobulin protein sequences, it is unlikely to be 
immunogenic and induce infusion or hypersensitivity reactions. However, if a reaction was to 
occur, it might manifest with fever, chills, rigors, headache, rash, pruritus, arthralgias, 
hypotension, hypertension, bronchospasm, or other allergic-like reactions. All Grade 3 or 4 
infusion reactions should be reported within 24 hours to the BMS Study Medical Monitor and 
reported as an SAE if it meets the criteria. Infusion reactions should be graded according to NCI 
CTCAE (Version 4) guidelines.
Treatment recommendations are provided below and may be modified based on local treatment 
standards and guidelines, as appropriate:
For Grade 1 symptoms: (mild reaction; infusion interruption not indicated; intervention not 
indicated):
•
Remain at bedside and monitor participant until recovery from symptoms. The following 
prophylactic premedications are recommended for future infusions: diphenhydramine 50 mg 
(or equivalent) and/or acetaminophen/paracetamol 325 to 1000 mg at least 30 minutes before 
additional nivolumab administration.
For Grade 2 symptoms: (moderate reaction required 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 participant 
with diphenhydramine 50 mg IV (or equivalent) and/or acetaminophen/paracetamol 325 to 
1000 mg; remain at bedside and monitor participant until resolution of symptoms. 
Corticosteroid and/or bronchodilator therapy may also be administered as appropriate. If the 
infusion is interrupted, then restart the infusion at 50% of the original infusion rate when 
symptoms resolve; if no further complications ensue after 30 minutes, the rate may be 
increased to 100% of the original infusion rate. Monitor participant closely. If symptoms 
recur, then nivolumab will be not be administered at that visit.
•
For future infusions, the following prophylactic premedications are recommended:
diphenhydramine 50 mg (or equivalent) and/or acetaminophen/paracetamol 325 to 1000 mg 
should be administered at least 30 minutes before nivolumab infusions. If necessary, 
corticosteroids (up to 25 mg of hydrocortisone or equivalent) may be used.
For Grade 3 or 4 symptoms: (severe reaction, Grade 3: prolonged [ie, not rapidly responsive to 
symptomatic medication and/or brief interruption of infusion]; recurrence of symptoms 
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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 participant as follows: Recommend bronchodilators, epinephrine 0.2 to 1 mg of a 
1:1000 solution for subcutaneous administration or 0.1 to 0.25 mg of a 1:10,000 solution 
injected slowly for IV administration, and/or diphenhydramine 50 mg IV with 
methylprednisolone 100 mg IV (or equivalent), as needed. Participant should be monitored 
until the Investigator is comfortable that the symptoms will not recur. Study drug will be 
permanently discontinued. Investigators should follow their institutional guidelines for the 
treatment of anaphylaxis. Remain at bedside and monitor participant until recovery of the 
symptoms.
In 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).
7.4.6
Protocol-Specific Recommendations for Management of Hepatic Events 
The nivolumab program has developed a standardized approach for the management of hepatic
events based on cumulative data across the program in subjects with normal hepatic function.
Across most nivolumab studies, the eligibility criteria for inclusion are based on a maximum 
AST or ALT < 3 x ULN; therefore, only subjects with normal to grade 1 LFTs have been
enrolled.
For CA209870, the upper limits for inclusion were therefore adjusted to account for baseline 
liver dysfunction. Subjects with AST or ALT elevations within the CTCAE Grade 2 range are 
eligible for inclusion. In contrast, the majority of subjects included in prior nivolumab studies 
have had no higher than a CTCAE grade 1 AST or ALT elevation. Criteria for dose delay, 
resumption, and discontinuation are in Section 7.4.2, Section 7.4.3, and Section 8.1, respectively. 
The protocol-specific approach for the management of hepatic events is as follows:
•
If AST or ALT levels do not improve with a dose delay of 3-5 days or if the levels worsen,
initiate steroid therapy at 0.5-2 mg/kg/day methylprednisolone or oral equivalent.
•
For ALT or AST levels > 8x ULN, initiate steroid therapy promptly at 1-2 mg/kg/day
methylprednisolone or oral equivalent.
•
For all subjects initiating steroids, consult the BMS Medical Monitor within 24 hours after
initiation of steroids. Gastroenterology consult is recommended.
•
If AST or ALT levels do not improve within 3-5 days or the levels worsen after the start of
steroid therapy, discuss with the BMS Medical Monitor the possibility of adding
mycophenolate mofetil at 1 g BID.
•
Tapering of steroids can start once AST or ALT levels have declined by 1 CTCAE grade.
Taper steroids slowly over no less than 1 month.
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As outlined in Section 7.4.3, nivolumab therapy may resume when AST or ALT have returned to 
near baseline unless the criteria for permanent discontinuation are reached (Section8.1).
7.4.7
Management Algorithms for Immuno-Oncology Agents
Immuno-oncology (I-O) agents, such as nivolumab are associated with AEs that can differ in 
severity and duration than AEs caused by other therapeutic classes. Early recognition and 
management of AEs associated with immuno-oncology agents may mitigate severe toxicity. 
Management algorithms have been developed to assist investigators in assessing and managing 
the following groups of AEs:
•
Gastrointestinal
•
Renal
•
Pulmonary
•
Hepatic
•
Endocrinopathy
•
Skin
•
Neurological
Treatment management algorithms are found in the BMS-936558 (nivolumab) Investigator 
Brochure.33
7.5
Preparation/Handling/Storage/Accountability
The investigational product should be stored in a secure area according to local regulations. It is 
the responsibility of the investigator to ensure that investigational product is only dispensed to 
study Participants. The investigational product must be dispensed only from official study sites 
by authorized personnel according to local regulations.
The product storage manager should ensure that the study treatment is stored in accordance with 
the environmental conditions (temperature, light, and humidity) as determined by BMS. If 
concerns regarding the quality or appearance of the study treatment arise, the study treatment
should not be dispensed and contact BMS immediately.
Study treatment not supplied by BMS will be stored in accordance with the package insert.
Investigational product documentation (whether supplied by BMS or not) must be maintained 
that includes all processes required to ensure drug is accurately administered. This includes 
documentation of drug storage, administration and, as applicable, storage temperatures, 
reconstitution, and use of required processes (e.g., required diluents, administration sets).
Further guidance and information for final disposition of unused study treatment are provided in 
CA209870 Study Reference Manual. 
7.5.1
Retained Samples for Bioavailability / Bioequivalence
Not Applicable.
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7.6
Treatment Compliance
Study treatment compliance will be periodically monitored by drug accountability. Drug 
accountability should be reviewed by the site study staff at each visit to confirm treatment 
compliance. Sites should discuss discrepancies with the participant at each on-treatment study 
visit.
7.7
Concomitant Therapy
7.7.1
Prohibited and/or Restricted Treatments
Prohibited and/or restricted medications taken prior to and during nivolumab treatment are 
described below. Medications taken within 2 weeks prior to study drug administration and 
medications taken during study must be recorded on the CRF.
1) Prior exposure to nivolumab (BMS-936558)
2) Immunosuppressive agents (except to treat a drug-related adverse event)
3) Immunosuppressive doses of systemic corticosteroids (except as stated in Section 7.7.1.1)
4) Any concurrent antineoplastic therapy (ie, chemotherapy, hormonal therapy, immunotherapy, 
extensive, non-palliative radiation therapy, or standard or investigational agents for treatment 
of cancer)
5) Exposure to any systemic treatment within 2 weeks of nivolumab administration. 
6) No concomitant medications (prescription, over-the-counter or herbal) are to be administered 
during study unless they are prescribed for treatment of specific clinical events. Any 
concomitant therapies must be recorded on the CRF.
7.7.1.1
Permitted Therapy
Participants are permitted the use of topical, ocular, intra-articular, intranasal and inhalation 
corticosteroids (with minimal system absorption). Adrenal replacement steroid doses > 10 mg 
daily prednisone are permitted. A brief (less than 3 weeks) course of corticosteroids for 
prophylaxis (eg, for contrast dye allergy) or for treatment of non-autoimmune conditions (eg, 
delayed-type hypersensitivity reaction caused by a contact allergen) is permitted. Prior palliative 
radiotherapy must have been completed at least 2 weeks prior to first dose.
7.7.1.2
Palliative Local Therapy
Palliative local therapy, including palliative radiation therapy- and palliative surgical resection, 
to symptomatic non-target bone lesions, skin lesions, or CNS lesions is permitted prior to 
discontinuation of study treatment for participants who do not have evidence of overall clinical 
or radiographic progression per study criteria. Palliative local therapy to lesions causing 
hemoptysis may also be permitted prior to discontinuation of study treatment in participants who 
do not have evidence of overall clinical or radiographic progression per study defined response 
criteria, provided that the lesions undergoing palliative local therapy are not the only sites of 
measurable disease and the case is discussed with and approved by the BMS Medical Monitor.
Participants requiring palliative local therapy should be evaluated for objective evidence of 
disease progression prior to the initiation of such therapy, particularly if the most recent tumor 
assessment was more than 4 weeks prior to the start of local therapy. If progression per study 
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defined response criteria is identified on any tumor assessments prior to the initiation of 
palliative local therapy, then participants must either discontinue study drug treatment or they 
must meet criteria to continue treatment beyond progression in order to resume immunotherapy 
after palliative local therapy.
The potential for overlapping toxicities with radiotherapy and nivolumab currently is not known; 
however, anecdotal data suggests that it is tolerable. As concurrent radiotherapy and nivolumab 
have not been formally evaluated, in cases where palliative radiotherapy is required for a tumor 
lesion, then nivolumab should be withheld for at least 1 week before, during, and 1 week after 
radiation. Participants should be closely monitored for any potential toxicity during and after 
receiving radiotherapy, and AEs should resolve to Grade ≤1 prior to resuming nivolumab.
7.7.2
Other Restrictions and Precautions
Participants with a condition requiring systemic treatment with either corticosteroids (> 10 mg 
daily prednisone equivalent) or other immunosuppressive medications within 14 days of
treatment are excluded. Inhaled or topical steroids, and adrenal replacement steroid doses 
> 10 mg daily prednisone equivalent, are permitted in the absence of active autoimmune disease.
7.7.2.1
Imaging Restriction and Precautions
It is the local imaging facility’s responsibility to determine, based on participant attributes (eg, 
allergy history, diabetic history and renal status), the appropriate imaging modality and contrast 
regimen for each participant. Imaging contraindications and contrast risks should be considered 
in this assessment. Participants with renal insufficiency should be assessed as to whether or not 
they should receive contrast and if so, what type and dose of contrast is appropriate. Specific to 
MRI, participants with severe renal insufficiency (ie, estimated glomerular filtration rate (eGFR) 
< 30 mL/min/1.73 m2) are at increased risk of nephrogenic systemic fibrosis. MRI contrast 
should not be given to this participant population. In addition, participants are excluded from 
MRI if they have tattoos, metallic implants, pacemakers, etc. The ultimate decision to perform 
MRI in an individual participant in this study rests with the site radiologist, the investigator and 
the standard set by the local Ethics Committee.
7.7.2.2
Surgical Resection Following Initial Response
In some clinical scenarios, investigators may choose to resect solitary lesions in participants with 
metastatic disease and render the patient free of macroscopic disease. Participants enrolled in this 
study may have lesions surgically resected only if confirmation of response is documented at 
least 4 weeks after previous scan and following consultation with the BMS Medical Monitor. If 
tumor shrinkage of the solitary lesion is noted on the re-staging assessment, it is highly 
encouraged that surgical resection be delayed until subsequent scans fail to demonstrate further 
shrinkage.
7.8
Treatment After the End of the Study
At the conclusion of the study, participants who continue to demonstrate clinical benefit will be 
eligible to receive BMS supplied study treatment. Study treatment will be provided via an 
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extension of the study, a rollover study requiring approval by responsible health authority and 
ethics committee or through another mechanism at the discretion of BMS.
BMS reserves the right to terminate access to BMS supplied study treatment if any of the 
following occur: a) the study is terminated due to safety concerns; b) the development of the
nivolumab is terminated for other reasons, including but not limited to lack of efficacy and/or not 
meeting the study objectives; c) the participant can obtain medication from a government 
sponsored or private health program. d) therapeutic alternatives become available in the local 
market. In all cases BMS will follow local regulations.
8.
DISCONTINUATION CRITERIA
8.1
Discontinuation from Study Treatment
Participants MUST discontinue investigational product for any of the following reasons:
•
Participant’s request to stop study treatment. Participants who request to discontinue study 
treatment will remain in the study and must continue to be followed for protocol specified 
follow-up procedures. The only exception to this is when a participant specifically withdraws 
consent for any further contact with him/her or persons previously authorized by participant 
to provide this information
•
Any clinical adverse event (AE), laboratory abnormality or intercurrent illness which, in the 
opinion of the investigator, indicates that continued participation in the study is not in the 
best interest of the participant
•
Termination of the study by 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.
Nivolumab treatment should be permanently discontinued for the following:
•
Any Grade 2 drug-related uveitis, eye pain or blurred vision that does not respond to topical 
therapy and does not improve to Grade 1 severity within the re-treatment period OR requires 
systemic treatment 
•
Any Grade 3 non-skin, drug-related adverse event lasting > 7 days or recurs, with the 
following exceptions for laboratory abnormalities, drug-related uveitis, pneumonitis, 
bronchospasm, hypersensitivity reactions, infusion reactions, and endocrinopathies:
o
Grade 3 drug-related uveitis, pneumonitis, bronchospasm,
hypersensitivity 
reaction, or infusion reaction of any duration requires discontinuation
o
Grade 3 drug-related endocrinopathies adequately controlled with only 
physiologic hormone replacement do not require discontinuation
o
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

Grade ≥3 drug-related AST, ALT or total bilirubin requires 
discontinuation* 

Concurrent AST or ALT > 3 x ULN and total bilirubin > 2x ULN
*In most cases of Grade 3 AST or ALT elevation, study drug(s) will be permanently 
discontinued. If the investigator determines a possible favorable benefit/risk ratio that warrants 
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continuation of study drug(s), a discussion between the investigator and the BMS Medical 
Monitor/designee must occur.
•
Any Grade 4 drug-related adverse event or laboratory abnormality (including but not limited 
to creatinine, AST, ALT, or Total Bilirubin), except for the following events which do not 
require discontinuation:
o
Grade 4 neutropenia ≤7 days
o
Grade 4 lymphopenia or leukopenia
o
Isolated Grade 4 amylase or lipase abnormalities that are not associated with 
symptoms or clinical manifestations of pancreatitis.  
o
Isolated Grade 4 electrolyte imbalances/abnormalities that are not associated with 
clinical sequelae and are corrected with supplementation/appropriate management 
within 72 hours of their onset
o
Grade 4 drug-related endocrinopathy AEs, such as adrenal insufficiency, ACTH 
deficiency, hyper- or hypothyroidism, or glucose intolerance, which resolve or are 
adequately controlled with physiologic hormone replacement (corticosteroids, 
thyroid hormones) or glucose-controlling agents, respectively, may not require 
discontinuation after discussion with and approval from the BMS Medical 
Monitor.
•
Any event that leads to delay in dosing lasting > 6 weeks from the previous dose requires 
discontinuation, with the following exceptions:
o
Dosing delays to allow for prolonged steroid tapers to manage drug-related AEs 
are allowed. Prior to re-initiating treatment in a participant with a dosing delay 
lasting > 6 weeks from the previous dose, the BMS Medical Monitor must be 
consulted. Tumor assessments should continue as per protocol even if dosing is
delayed. Periodic study visits to assess safety and laboratory studies should also 
continue every 6 weeks or more frequently if clinically indicated during such 
dosing delays.
o
Dosing delays lasting > 6 weeks from the previous dose that occur for 
non-drug-related reasons may be allowed if approved by the BMS Medical 
Monitor. 
Prior to re-initiating treatment in a participant with a dosing delay lasting > 6 weeks, the BMS 
Medical Monitor must be consulted. Tumor assessments should continue as per protocol even if 
dosing is delayed. Periodic study visits to assess safety and laboratory studies should also 
continue every 6 weeks or more frequently if clinically indicated during such dosing delays.
•
Any adverse event, laboratory abnormality, or intercurrent illness which, in the judgment of 
the Investigator, presents a substantial clinical risk to the participant with continued 
nivolumab dosing.
Discontinuation of the study treatment for abnormal liver tests should be considered by the 
investigator when a participant meets one of the conditions outlined in BMS-936558 
(nivolumab) Investigator Brochure33 or if the investigator believes that it is in best interest of the 
participant.
Refer to the Section 2 Schedule of Activities for data to be collected at the time of treatment 
discontinuation and follow-up and for any further evaluations that can be completed
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In the case of pregnancy, the investigator must immediately notify the BMS Medical 
Monitor/designee of this event. In the event a normal healthy female participant becomes 
pregnant during a clinical trial, the study treatment must be discontinued immediately. In most 
cases, the study treatment will be permanently discontinued in an appropriate manner (eg, dose 
tapering if necessary for participant safety). Please call the BMS Medical Monitor within 24 
hours of awareness of the pregnancy. If the investigator determines a possible favorable 
benefit/risk ratio that warrants continuation of study treatment, a discussion between the 
investigator and the BMS Medical Monitor/designee must occur.
All participants who discontinue study treatment should comply with protocol specified follow-
up procedures as outlined in Section 2 Schedule of Activities. The only exception to this 
requirement is when a participant withdraws consent for all study procedures including post-
treatment study follow-up or loses the ability to consent freely (ie, is imprisoned or involuntarily 
incarcerated for the treatment of either a psychiatric or physical illness).
If study treatment is discontinued prior to the participant’s completion of the study, the reason 
for the discontinuation must be documented in the participant’s medical records and entered on 
the appropriate case report form (CRF) page.
8.1.1
Post Study Treatment Study Follow-up
Overall survival is a key endpoint of the study. Post treatment follow-up is of critical importance 
and is essential to preserving participant safety and the integrity of the study. Participants who 
discontinue study treatment must continue to be followed for collection of outcome and/or 
survival follow-up data as required and in line with Section 5 until death or the conclusion of the 
study. 
BMS may request that survival data be collected on all treated/randomized participants outside 
of the protocol defined window (see Schedule of Activities Table 2.3). At the time of this 
request, each participant will be contacted to determine their survival status unless the participant 
has withdrawn consent for all contacts or is lost to follow-up.
8.2
Discontinuation from the Study
Participants who request to discontinue study treatment will remain in the study and must 
continue to be followed for protocol specified follow-up procedures. The only exception to this 
is when a participant specifically withdraws consent for any further contact with him/her or 
persons previously authorized by participant to provide this information. 
•
Participants should notify the investigator of the decision to withdraw consent from future 
follow-up in writing, whenever possible.
•
The withdrawal of consent should be explained in detail in the medical records by the 
investigator, as to whether the withdrawal is from further treatment with study treatment only 
or also from study procedures and/or post treatment study follow-up, and entered on the 
appropriate CRF page.
•
In the event that vital status (whether the participant is alive or dead) is being measured, 
publicly available information should be used to determine vital status only as appropriately 
directed in accordance with local law.
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•
If the participant withdraws consent for disclosure of future information, the sponsor may 
retain and continue to use any data collected before such a withdrawal of consent.
BMS may request the survival data be collected on all treated/randomized participants outside of 
the protocol defined window (see Table 2-3).  At the time of this request, each participant will be 
contacted to determine their survival status unless the participant has withdrawn consent for all 
contacts or is lost to follow-up.
8.3
Lost to Follow-Up
•
All reasonable efforts must be made to locate participants to determine and report their 
ongoing status. This includes follow-up with persons authorized by the participant.
•
Lost to follow-up is defined by the inability to reach the participant after a minimum of three
documented phone calls, faxes, or emails as well as lack of response by participant to one 
registered mail letter. All attempts should be documented in the participant’s medical 
records.
•
If it is determined that the participant has died, the site will use permissible local methods to 
obtain date and cause of death.
•
If investigator’s use of third-party representative to assist in the follow-up portion of the 
study has been included in the participant’s informed consent, then the investigator may use a 
Sponsor retained third-party representative to assist site staff with obtaining participant’s 
contact information or other public vital status data necessary to complete the follow-up 
portion of the study. 
•
The site staff and representative will consult publicly available sources, such as public health 
registries and databases, in order to obtain updated contact information.
•
If after all attempts, the participant remains lost to follow-up, then the last known alive date 
as determined by the investigator should be reported and documented in the participant’s 
medical records.
9.
STUDY ASSESSMENTS AND PROCEDURES
•
Study procedures and timing are summarized in the Schedule of Activities. 
•
Protocol waivers or exemptions are not allowed.
•
All immediate safety concerns must be discussed with the Sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or discontinue 
treatment.
•
Adherence to the study design requirements, including those specified in the Schedule of 
Activities, is essential and required for study conduct.
•
All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria before treatment. The investigator will maintain a 
screening log to record details of all participants screened and to confirm eligibility or record 
reasons for screening failure, as applicable.
•
Procedures conducted as part of the participant’s routine clinical management (eg, blood 
count) and obtained before signing of informed consent may be utilized for screening or 
baseline purposes provided the procedure meets the protocol-defined criteria and has been 
performed within the timeframe defined in the Schedule of Activities.
•
Additional measures, including non-study required laboratory tests, should be performed as 
clinically indicated or to comply with local regulations. Laboratory toxicities (eg, suspected 
drug induced liver enzyme evaluations) will be monitored during the follow-up phase via on 
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site/local labs until all study drug related toxicities resolve, return to baseline, or are deemed 
irreversible.
•
If a subject shows pulmonary-related signs (hypoxia, fever) or symptoms (eg. dyspnea, 
cough, fever) consistent with possible pulmonary adverse events, the subject should be 
immediately evaluated to rule out pulmonary toxicity, according to the suspected pulmonary 
toxicity management algorithm in the BMS-936558 (nivolumab) Investigator Brochure.33
•
Some of the assessments referred to in this section may not be captured as data in the eCRF. 
They are intended to be used as safety monitoring by the treating physician. Additional 
testing or assessments may be performed as clinically necessary or where required by 
institutional or local regulations.
9.1
Efficacy Assessments
Duration of response and progression-free survival will be evaluated by local investigator using 
RECIST v1.1.
9.1.1
Imaging Assessment for the Study
The imaging assessment schedule is provided in Table 9.1.1-1.
Table 9.1.1-1:
Imaging Assessment Schedule
Study Day
Event Relative to Dosing
Tumor Assessment
Screening
N/A
X
Week 9
N/A
X
Every 8 weeks for 48 weeks
N/A
X
Every 12 weeks after 48 weeks
N/A
X
Note: Screening assessments should be performed within 28 days of treatment.
Study evaluations (tumor assessments) will take place in accordance with the Section 2 Schedule 
of Activities.
For solid tumors, CT with oral and intravenous contrast or contrast-enhanced MRI are the 
preferred imaging modalities for assessing radiographic tumor response. If a participant has a 
known allergy to contrast material, please use local prophylaxis standards to obtain the 
assessment with contrast if at all possible, or use the alternate modality. In cases where contrast 
is strictly contraindicated, a non-contrast scan will suffice. 
Screening assessments should be performed within 28 days of treatment. Brain MRI without and 
with contrast is the preferred imaging method for evaluating CNS metastasis, and assessment is 
required during screening in participants with a known history of treated brain metastases. All 
known or suspected sites of disease (including CNS) 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 the appropriate response criteria
should be used when recording data, and should again be used for all subsequent assessments. 
Bone scan, PET scan, or ultrasound are not adequate for assessment of RECIST response. In 
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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 target disease or 
when progression in bone is suspected. Previously treated CNS metastases are not considered 
measurable lesions for purposes of RECIST determined response. Participants with a history of 
brain metastasis should have surveillance MRI approximately every 8 weeks for the first 48 
weeks, every 12 weeks thereafter, or sooner if clinically indicated. Radiographic tumor 
assessments will be conducted until disease progression, lost to follow-up, or withdrawal of 
study consent. Participants treated beyond progression should continue radiographic tumor 
assessments until discontinuation of study therapy or start of subsequent therapy as defined in 
Section 8.1.1 for disease progression.
Tumor assessments for all participants should continue as per protocol even if dosing is 
interrupted. Tumor assessment should be made by the same investigator or radiologist for each 
assessment whenever possible. Changes in tumor sizes and tumor responses to guide ongoing 
study treatment decisions will be assessed by the investigator using appropriate response criteria.
(See Section 7.7.2 regarding additional precautions).
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 participant’s medical 
record and should not be provided to BMS, unless specifically requested. Sites should be trained 
prior to scanning the first study participant. 
9.2
Adverse Events
The definitions of an AE or serious adverse event (SAE) can be found in Appendix 3.
AEs will be reported by the participant (or, when appropriate, by a caregiver, surrogate, or the 
participant's legally authorized representative). 
The investigator and any designees are responsible for detecting, documenting, and reporting 
events that meet the definition of an AE or SAE and remain responsible for following up AEs 
that are serious, considered related to the study treatment or the study, or that caused the 
participant to discontinue before completing the study. 
Contacts for SAE reporting specified in Appendix 3.
9.2.1
Time Period and Frequency for Collecting AE and SAE Information
The collection of nonserious AE information should begin at initiation of study treatment for a 
minimum of 100 days following discontinuation of study treatment and at the timepoints 
specified in the Schedule of Activities (Section 2). Nonserious AE information should also be 
collected from the start of a placebo lead-in period or other observational period intended to 
establish a baseline status for the participants.
Sections 5.6.1 and 5.6.2 in the Investigator Brochure (IB) represent the Reference Safety 
Information to determine expectedness of serious adverse events for expedited reporting. 
Following the participant’s written consent to participate in the study, all SAEs, whether related 
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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 the 
last dose of study treatment. For participants assigned to treatment and never treated with study 
drug, SAEs should be collected for 30 days from the date of treatment assignment.
The investigator must report any SAE that occurs after these time periods and that is believed to 
be related to study drug or protocol-specified procedure.
•
Medical occurrences that begin before the start of study treatment but after obtaining 
informed consent will be recorded on the appropriate section of the eCRF section.
•
All SAEs will be recorded and reported to Sponsor or designee within 24 hours, as indicated 
in Appendix 3. 
•
The investigator will submit any updated SAE data to the sponsor within 24 hours of this 
being available.
Investigators are not obligated to actively seek AEs or SAEs in former study participants. 
However, if the investigator learns of any SAE, including a death, at any time after a participant 
has been discharged from the study, and he/she considers the event reasonably related to the 
study treatment or study participation, the investigator must promptly notify the sponsor.
The method of evaluating, and assessing causality of AEs and SAEs and the procedures for 
completing and reporting/transmitting SAE reports are provided in Appendix 3.
9.2.2
Method of Detecting AEs and SAEs
Adverse events can be spontaneously reported or elicited during open-ended questioning, 
examination, or evaluation of a subject. (In order to prevent reporting bias, participants should 
not be questioned regarding the specific occurrence of one or more AEs.)
9.2.3
Follow-up of AEs and SAEs
•
Nonserious AEs should be followed to resolution or stabilization, or reported as SAEs if they 
become serious (see Section Appendix 3).
•
Follow-up is also required for nonserious AEs that cause interruption or discontinuation of 
study treatment and for those present at the end of study treatment as appropriate.
•
 All identified nonserious AEs must be recorded and described on the nonserious AE page of 
the CRF (paper or electronic). Completion of supplemental CRFs may be requested for AEs 
and/or laboratory abnormalities that are reported/identified during the course of the study.
After the initial AE/SAE report, the investigator is required to proactively follow each participant 
at subsequent visits/contacts. All SAEs, and non-serious AEs of special interest (as defined in 
Section 9.2 will be followed until resolution, until the condition stabilizes, until the event is 
otherwise explained, or until the participant is lost to follow-up (as defined in Section 8.3).
Further information on follow-up procedures is given in Appendix 3.
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9.2.4
Regulatory Reporting Requirements for SAEs
•
Prompt notification by the investigator to the Sponsor of SAEs is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of a 
product under clinical investigation are met.
•
An investigator who receives an investigator safety report describing SAEs or other specific 
safety information (eg, summary or listing of SAEs) from the Sponsor will file it along with 
the Investigator’s Brochure and will notify the IRB/IEC, if appropriate according to local 
requirements.
Sponsor or designee will be reporting adverse events to regulatory authorities and ethics 
committees according to local applicable laws including European Directive 2001/20/EC and 
FDA Code of Federal Regulations 21 CFR Parts 312 and 320. A SUSAR (Suspected, 
Unexpected Serious Adverse Reaction) is a subset of SAEs and will be reported to the 
appropriate regulatory authorities and investigators following local and global guidelines and 
requirements.
All SAEs must be collected that occur during the screening period and within 100 days of the 
last dose of study treatment. For participants randomized/assigned to treatment and never treated 
with study drug, SAEs should be collected for 30 days from the date of treatment assignment.
9.2.5
Pregnancy
If, following initiation of the study treatment, it is subsequently discovered that a participant is 
pregnant or may have been pregnant at the time of study exposure, including during at least 
5 half-lives after product administration, the investigator must immediately notify the BMS 
Medical Monitor/designee of this event and complete and forward a Pregnancy Surveillance 
Form to BMS Designee within 24 hours of awareness of the event and in accordance with SAE 
reporting procedures described in Appendix 3
In most cases, the study treatment will be permanently discontinued in an appropriate manner 
(e.g., dose tapering if necessary for participant safety). Please call the BMS Medical Monitor 
within 24 hours of awareness of the pregnancy.
Follow-up information regarding the course of the pregnancy, including perinatal and neonatal 
outcome and, where applicable, offspring information must be reported on the Pregnancy 
Surveillance Form.
Any pregnancy that occurs in a female partner of a male study participant should be reported to 
Sponsor or designee. In order for Sponsor or designee to collect any pregnancy surveillance 
information from the female partner, the female partner must sign an informed consent form for 
disclosure of this information. Information on this pregnancy will be collected on the Pregnancy 
Surveillance Form.
9.2.6
Laboratory Test Result Abnormalities
The following laboratory test result abnormalities should be captured on the nonserious AE CRF 
page or SAE Report Form electronic, as appropriate. Paper forms are only intended as a back-up 
option when the electronic system is not functioning.
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•
Any laboratory test result that is clinically significant or meets the definition of an SAE 
•
Any laboratory test result abnormality that required the participant to have study treatment
discontinued or interrupted
•
Any laboratory test result abnormality that required the participant to receive specific 
corrective therapy
It is expected that wherever possible, the clinical rather than laboratory term would be used by 
the reporting investigator (eg, anemia versus low hemoglobin value).
9.2.7
Potential Drug Induced Liver Injury (DILI)
Wherever possible, timely confirmation of initial liver-related laboratory abnormalities should 
occur prior to the reporting of a potential DILI event. All occurrences of potential DILIs, 
meeting the defined criteria, must be reported as SAEs (see Section 9.2 and Appendix 3 for 
reporting details).
Potential drug induced liver injury is defined as: 
1) AT (ALT or AST) elevation > 3 times upper limit of normal (ULN)
AND
2) Total bilirubin > 2 times ULN, without initial findings of cholestasis (elevated serum alkaline 
phosphatase),
AND
3) No other immediately apparent possible causes of AT elevation and hyperbilirubinemia, 
including, but not limited to, viral hepatitis, pre-existing chronic or acute liver disease, or the 
administration of other drug(s) known to be hepatotoxic.
9.2.8
Immune-mediated Adverse Events
Immune-mediated adverse events (IMAEs) are AEs consistent with an immune-mediated 
mechanism or immune-mediated component for which non-inflammatory etiologies (eg, 
infection or tumor progression) have been ruled out. IMAEs can include events with an alternate 
etiology which were exacerbated by the induction of autoimmunity. Information supporting the 
assessment will be collected on the subject’s case report form.
9.2.9
Other Safety Considerations
Any 
significant 
worsening 
noted 
during 
interim 
or 
final 
physical 
examinations, 
electrocardiogram, x-ray filming, any other potential safety assessment required or not required 
by protocol should also be recorded as a nonserious or serious AE, as appropriate, and reported 
accordingly.
9.3
Overdose
An overdose is defined as the accidental or intentional administration of any dose of a product 
that is considered both excessive and medically important. All occurrences of overdose must be 
reported as an SAE (see Section 9.2).
In the event of an overdose the investigator should:
1) Contact the BMS Medical Monitor immediately
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2) Closely monitor the participant for AEs/SAEs and laboratory abnormalities 
3) Document the quantity of the excess dose as well as the duration of the overdosing in the 
CRF.
Decisions regarding dose interruptions or modifications will be made by the investigator in 
consultation with the BMS Medical Monitor based on the clinical evaluation of the participant.
9.4
Safety
Planned time points for all safety assessments are listed in the Schedule of Activities.
9.4.1
Physical Examinations
Refer to Schedule of Activities.
9.4.2
Vital Signs
Refer to Schedule of Activities.
9.4.3
Clinical Safety Laboratory Assessments
Investigators must document their review of each laboratory safety report.
Hematology
Hemoglobin
Hematocrit
Total leukocyte count, including differential
Platelet count
Serum Chemistry
Aspartate aminotransferase (AST)
Alanine aminotransferase (ALT)
Total bilirubin
Alkaline phosphatase
Lactate dehydrogenase (LDH)
Blood urea nitrogen (BUN) or serum 
creatinine level
Calcium
Sodium
Potassium
Chloride
Phosphate
Glucose 
Serology
Serum for hepatitis B and C testing (HBV sAg and HCV Ab or HCV RNA).
Serum for HIV testing where locally mandated
Other Analyses
Thyroid function testing (including TSH, free T3, and free T4) 
9.4.4
Imaging Safety Assessment
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. 
9.5
Pharmacokinetic
Not applicable.
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9.6
Pharmacodynamics
Pharmacodynamic parameters are not evaluated in this study.
9.7
Pharmacogenomics
Not applicable.
9.8
Biomarkers
Table 9.8-1:
Biomarker Tissue 
 Sample Collection
Study Day
Archival Tumor or Fresh Biopsy Tissue
Screening
X
PD-L1 testing 
 testing: Archival or fresh formalin-fixed paraffin-
embedded (FFPE) tumor tissue collected within one year (block) or within 6 months (sectioned 
slide) must be submitted to central laboratory for PD -L1 IHC testing prior to the treatment 
assignment. All samples will be stained and scored for PD-L1 expression using the PD-L1 IHC 
28-8 pharmDx kit (Dako). Stained tissue samples will be assessed by the pathologist who has 
been trained by the Sponsor and scored as PD-L1 expressing if membrane staining is observed in
≥1% tumor cells among a minimum of 100 evaluable tumor cells.
All analyses will be completed retrospectively and within the scope of informed consent.
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9.10
Patient Reported Outcomes
LCSS (Lung Cancer Symptom Scale) is designed as a site-specific measure of quality of life 
(QL), particularly for use in clinical trials. It evaluates six major symptoms associated with lung 
malignancies and their effect on overall symptomatic distress, functional activities, and global 
QL. It captures in detail those dimensions most likely to be influenced by therapeutic 
interventions and evaluates other dimensions globally. It consists of two scales: one completed 
by the patient and an optional one for health care professionals ("counterpart observer") to 
provide context.35 LCSS remains popular and has been used in clinical trials for assessing quality 
of life. 36 It comprises two different scales, one rated by the patient and the other by the 
physician. The patient scale contains nine items, including three summation and six symptom 
items. Each item is marked on a VAS of 100 mm length, with zero denoting the lowest rating 
and 100 the highest. The mean of six main symptoms is used to calculate the ‘average symptom 
burden’ of the patient. The physician scale consists of six items pertaining to the main lung 
cancer symptoms. These are rated as 0, 25, 50, 75, and 100 depending on symptom severity.37
EQ-5D is the one of the generic preference-based instruments which are advantageous in that 
they facilitate calculation of QALYs for subsequent application to cost-utility analysis (CUA) as 
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well as allow for comparison of HR-QOL across different conditions. EQ-5D is widely used and 
simple to administer and score. 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 3.38 Thus, the vectors 
11111 and 33333 represent the best health state and the worst health state, respectively, 
described by the EQ-5D. Altogether, the instrument describes 35 = 243 health states. Empirically 
derived weights can be applied to an individual’s responses to the EQ-5D 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 Japan, UK, US, Spain, Germany, and even in China. 
In addition, the EQ-5D includes a visual analog scale that allows respondents to rate their own 
current health on a 101-point scale ranging from “best imaginable” to “worst imaginable” health.
In addition to the aforementioned patient-reported outcomes
 
 will be collected for all participants using an internal case report form. The 
CRF will record information about hospital admissions, including number of days spent in 
various wards, discharge diagnosis, and medical services item and cost received while inpatient, 
as well as outpatient visits related to lung cancer therapy, including date of visit, reason for visit, 
type of visit and medical services item and cost. 
 
Table 9.10-1:
Timepoints and Windows for EORTC-QLQ-C30 and EuroQoL 
EQ-5D Assessments
Nominal Timepoint
Time Window
Baseline
3 days of C1D1 dosing and prior to any study procedures
Every 4 Weeks for 6 months
Every 4 weeks (within 5 days of C1D1) for 6 months
Every 6 Weeks 
Every 6 weeks (within 5 days of C1D1) for remainder of study
Follow-Up 1
If assessment is post last dose and within 76 days of last dose (if date of 
discontinuation is within 35 day after last dose)
If assessment is post last dose and within 40 days of date of discontinuation 
(if date of discontinuation is greater  than 35 days after last dose)
Follow-Up 2
If assessment is post 76 days of last dose(if date of discontinuation is within 
35 day after last dose)
If assessment is  post 40 days of date of discontinuation (if date of 
discontinuation is greater  than 35 days after last dose)
10.
STATISTICAL CONSIDERATIONS
10.1
Sample Size Determination 
The incidence rate of treatment related select high grade AE is 0.5-3% of nivolumab 3mg/kg 
every two weeks with infusion time no less than 30 minutes based on the Checkmate 153 study 
which published in ASCO 2016,39 and a PPK model predicted overall nivolumab exposures 
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across participants with a wide range of body weight (35-160 kg) for a 240 mg every 2 weeks 
flat dose to be similar to that from 3 mg/kg every 2 weeks, so we assume that the incidence rate 
of  treatment related select high grade AE is similar in both 3 mg/kg every 2 weeks and 240mg 
every 2 weeks. 
In order to further characterize the frequency and outcome of the rather infrequent treatment 
related select adverse of high grade (Grade 3-5), the current study will treat approximately 400 
participants (assuming 340 non-HBV infected participants and 60 HBV infected participants)
with nivolumab. The 95% confidence intervals of the incidence rate of high grade (grade 3-5) 
treatment related select adverse events were listed as below table. With the screen failure rate of 
15%, totally 470 participants will be screened. 
Table 10.1-1 shows the CI using Clopper Pearson methods for a sample size of 340 non-HBV 
infected participants and all treated participants.
Table 10.1-1:
95% Confidence Intervals of Adverse Event Rate
AE Incidence Rate 
Non-HBV (340 participants)
Overall (400 participants)
0.5% 
0.07%, 2.11%
0.06%, 1.79%
1%
0.32%, 2.98%
0.27%, 2.54%
3%
1.63%, 5.71%
1.56%,5.18%
10.2
Populations for Analyses
The following defined population will apply to pooled tumor types and individual tumor 
histology and molecular genotype, unless otherwise specified:
Population
Description
Enrolled participants
All participants who signed an informed consent form and were 
registered into the IRT.
Treated participants
All enrolled participants who received at least one dose of study 
drug.
All response evaluable 
participants
All treated participants who have baseline and at least one on-
study evaluable tumor measurement.
Non-HBV infected 
participants
All treated participants with HBVsAg negative by serum testing.
HBV infected participants
All treated participants with HBVsAg positive by serum testing.
Biomarker participants
All treated participants with available tissue/blood samples.
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10.3
Statistical Analyses
Statistical analyses will be performed for pooled for each histology and molecular genotype type 
unless otherwise specified.
Demographic and baseline laboratory results will be summarized using descriptive statistics for 
all treated participants. Baseline characteristics, including demographics (age, gender, 
geographic location, race/ethnicity) and clinical characteristics (date of diagnosis, disease stage, 
liver function status, performance status, co-morbidity/prognostic indicators, location of 
metastases) will be collected at the time of treatment initiation for each cohort. General 
descriptive statistics, including mean and standard deviation (SD) for continuous variables, count 
and percentage for categorical variables will be used extensively to examine these variables.
The statistical analysis plan will be developed and finalized before database lock, will describe 
all planned analyses, and procedures for accounting for missing, unused, and spurious data. A
summary of planned statistical analyses of the primary and secondary endpoints is in Section 
10.3.1 and Section 10.3.2.
10.3.1
Efficacy Analyses
Endpoint Definition
Statistical Analysis Methods
Primary
Not applicable
Secondary
Overall Survival (OS) is defined as the time 
from the first dosing date to the date of 
death. Participants without documentation of 
death will be censored on the last date the 
participant was known to be alive.
Time to event distribution will be estimated 
using Kaplan Meier techniques. Median OS 
along with 95% CI will be constructed based 
on a log-log transformed CI for the survivor 
function. OS Rates at fixed timepoints (6, 12, 
18, and 24 months) will be derived from the 
Kaplan Meier estimate and corresponding 
confidence interval will be derived based on 
Greenwood formula for variance derivation 
and on log-log transformation applied on the 
survivor function.
Time to Treatment Failure (TTF)
is 
defined as the minimum of the time from 
treatment assignment to disease progression 
(determined by investigator assessments 
using RECIST 1.1), death or last dose date if 
a subject progressed, died or discontinued 
from treatment for any reasons other than 
“maximum 
clinical 
benefit” 
and
Time to event distribution will be estimated 
using Kaplan Meier techniques. Median TTF
along with 95% CI will be constructed based 
on a log-log transformed CI for the survivor 
function. 
Sensitivity analysis will be conducted to 
censor TTF for discontinuations due to patient 
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Endpoint Definition
Statistical Analysis Methods
“administrative reasons by sponsor”. TTF is 
censored at the last dose date for subjects 
who 
continued 
on 
treatment 
without
progression (per RECIST 1.1) or death at the 
time of the database lock.
preference.
Progression-Free Survival (PFS) is defined 
as the time from first dose date to the date of 
the first documented tumor progression (per 
RECIST 1.1) or death due to any cause. 
Subjects who die without a reported prior 
progression will be considered to have 
progressed on the date of their death. 
Subjects who did not progress or die will be 
censored on the date of their last evaluable 
tumor assessment. Subjects who did not 
have any on study tumor assessments and 
did not die will be censored on their first 
dose date. Subjects who started any 
subsequent anti-cancer therapy without a 
prior reported progression will be censored 
at the last evaluable tumor assessment prior 
to initiation of the subsequent anti-cancer 
therapy.
Time to event distribution will be estimated 
using Kaplan Meier techniques. Median PFS
along with 95% CI will be constructed based 
on a log-log transformed CI for the survivor 
function. 
Objective Response Rate (ORR) is defined 
as the proportion of all treated subjects 
whose best overall response (BOR) from 
baseline is either a CR or PR per RECIST 
1.1 criteria. BOR is determined by the best 
response designation recorded between the 
first dose date and the date of objectively 
documented progression or the date of 
subsequent anti-cancer therapy, whichever 
occurs first. For subjects without 
documented progression or subsequent anti-
cancer therapy, all available response 
designations will contribute to the BOR 
determination. For subjects who continue 
nivolumab beyond progression, the BOR 
should be determined based on response 
designations recorded at the time of the 
ORR will be summarized by binomial 
response rates and their corresponding two-
sided 95% exact CIs using Clopper-Pearson 
method.
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initial RECIST 1.1 defined progression.
Duration of Response (DOR) is defined as 
the time between the date of first confirmed 
response to the date of the first documented 
tumor progression (per RECIST 1.1) or 
death due to any cause. Subjects who neither 
progress nor die will be censored on the date 
of their last assessment. The censoring 
algorithm for DOR will be the same as used 
for PFS definition. This endpoint will only 
be evaluated for participants with BOR of 
CR or PR.
The DOR will be summarized for all treated 
participants who achieve confirmed PR or CR 
using the Kaplan-Meier (KM) product-limit 
method. Median values of DOR, along with 
two-sided 95% CI using Brookmeyer and 
Crowley method, will also be calculated.
10.3.1.1
Efficacy Analysis in Subgroups:
The efficacy analyses methods for OS, TTF, PFS, ORR, and DOR will also be evaluated in 
different subgroups, including squamous and non-squamous subgroups, PD-L1 positive and 
PD-L1 negative protein expression subgroups, non-HBV infected and HBV infected subgroups, 
and EGFR mutation, ALK positive and WT subgroups. The analyses methods described above 
for OS, ORR, and PFS will be repeated for each of the subgroup.
10.3.2
Safety Analyses
Endpoint Definition
Statistical Analysis Methods
Primary and Secondary
Safety and tolerability
Descriptive statistics of safety will be presented using NCI CTCAE 
version 4. All on-study AEs and SAEs and drug-related AEs and 
SAEs will be tabulated using worst grade per NCI CTCAE v.4 
criteria by system organ class and MedDRA preferred term. 
On-study lab parameters including hematology, chemistry, liver 
function, thyroid function, and renal function will be summarized 
using worst grade per NCI CTCAE v.4 criteria.
10.3.3
Other Analyses
Exploratory analyses for 
 health outcomes
 
 will be described in the statistical analysis plans finalized 
before database lock. These analyses will be presented separately from the main clinical study 
report.
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10.3.3.1
Patient Reported Outcomes
The LCSS and EQ-5D completion rates, defined as the proportion of questionnaires actually 
received out of the expected number will be calculated and summarized at each assessment 
point. The EQ-5D (with two essential components: the EQ-5D descriptive system and the EQ 
visual analogue scale (EQ VAS) will be used to assess the subject’s overall health status.
Proportion of subjects reporting problems for the 5 EQ-5D dimensions at each assessment time 
point will be summarized by level of problem. Percentages will be based on number of subjects 
assessed at assessment time point. Value set for Chinese population37 will be used to get utility 
values for each individual. The baseline and change from baseline of the EQ-5D and LCSS 
scores at each assessment point will be summarized using descriptive statistics. The disease-
related symptom deterioration rate at week 12 and week 24 as measured by LCSS and its 
corresponding 95% CI will also be calculated by Clopper-Pearson method. All summaries for 
LCSS and EQ-5D will be done for all treated participants, and also by tumor histology (SQ or 
NSQ), by PD-L1 expression (PD-L1 negative or PD-L1 positive), by infection status (HBV 
infection or non-HBV infection), and by molecular type (EGFR mutation, ALK translocation, or 
WT).
10.3.4
Interim Analyses
Not applicable.
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11.
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first-line treatment for advanced non-small-cell lung cancer (CheckMate 012): results of an 
open-label, phase 1, multicohort study. Lancet Oncol. 2017; 18:31-41.
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(MEL) who discontinued treatment with nivolumab (NIVO) plus ipilimumab (IPI) due to 
toxicity in a phase III trial (CheckMate 067). 2016 Annual Meeting of the European 
Association of Dermato-Oncology; August 31-September 3, 2016; Vienna, Austria
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13 Sweeney C, Chen Y-H, Carducci MA et al Impact on overall survival (OS) with 
chemohormonal therapy versus hormonal therapy for hormone-sensitive newly metastatic 
prostate cancer (mPrCa): An ECOG-led phase III randomized trial. J Clin Oncol 32:5s, 2014
14 Waterhouse DM, Horn L, Reynolds CH, et al. Safety profile of nivolumab administered as 
30-minute (min) infusion: Analysis of data from CheckMate 153. 2016 ASCO Annual 
Meeting. J Clin Oncol 34, 2016 (suppl; abstr 3059)
15 Dong H, chen L. B7-H1 pathway and its role in the evasion of tumor immunity. J Mol Med. 
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cells and its relationship with tumor-infiltrating lymphocytes and their PD-1 expression. Clin 
Cancer Res. 2004; 10: 5094-10.
17 Thompson RH, Gillett MD, Cheville JC, et al. Costimulatory B7-H1 in renal cell carcinoma 
subjects; indicator of tumor aggressiveness and potential therapeutic target. Proc Natl Acad 
Sci USA. 2004; 101: 17174-9.
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contribute to poor prognosis and tumor cells immune escape through suppressing tumor 
infiltrating dendritic cells maturation. Med Oncol. 2011; 28:682–688.
19 Ohigashi Y, Sho M, Yamada Y, et al. Clinical significance of programmed death-1ligand-1 
and programmed death-1 ligand-2 expression in human esophageal cancer. Clin Cancer Res. 
2005; 11: 2947-53.
20 Tsushima F, Tanaka K, Otsuki N, et al. Predominant expression of B7-H1 and its 
immunoregulatory roles in oral squamous cell carcinoma. Oral Oncol. 2006; 42: 268-74.
21 Nishimura H, Honjo T. PD-1: an inhibitory immunoreceptor involved in peripheral tolerance. 
Trends Immunol. 2001; 22: 265-8.
22 Azuma T, Yao S, Zhu G, et al. B7-H1is a ubiquitous antiapoptotic receptor on cancer cells. 
Blood. 2008; 111: 3635-43.
23 Zhang Y, Huang S, Gong D, et al. Programmed death-1 upregulation is correlated with 
dysfunction of tumor infiltrating CD8+ T lymphocytes in human non-small cell lung cancer. 
Cell and Mol Immunol. 2010; 7: 389-95.
24 Mu C.-Y, Huang J.-A, Chen Y, et al. High expression of PD-L1 in lung cancer may 
contribute to poor prognosis and tumor cells immune escape through suppressing tumor 
infiltrating dendritic cells maturation. Med Oncol. 2011; 28:682–688.
25 OPDIVO [package insert]. Princeton, NJ: Bristol-Myers Squibb Company; 2016.
26 Pardoll D. Does the immune system see tumors as foreign or self? Annu Rev Immunol. 
2003;21:807-39.
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27 Zitvogel L, Tesniere A, Kroemer G. Cancer despite immunosurveillance: immunoselection 
and immunosubversion. Nat Rev Immunol. 2006;6:715-27.
28 Dunn GP, Bruce AT, Ikeda H, et al. Cancer immunoediting: from immunosurveillance to 
tumor escape. Nat Immunol. 2002;3:991-8.
29 Greenwald RJ, Freeman GH, Sharpe AH. The B7 family revisited. Annu Rev Immunol. 
2004;23:515-48.
30 Freeman FJ, Long AJ, Iwai Y, et al. Engagement of the PD-1 immunohibitory receptor by a 
novel B7 family member leads to negative regulation of lymphocyte activation. J Exp Med 
2000; 192(7): 1027-34.
31 Sharpe AH, Wherry EJ, Ahmed R, et al. The function of programmed cell death 1 and its 
ligands in regulating autoimmunity and infection. Nature Immunol. 2007;8:237-45
32 Wolchok JD, Hoos A, O’Day S, et al. Guidelines for the evaluation of immune therapy 
activity in solid tumors: immune related response criteria. Clin Cancer Res. 2009;15:7412-
20.
33 Nivolumab (BMS-936558) Investigator Brochure Version no. 15. Bristol-Myers Squibb. 
Version date: 24-Jun-2016 
34 Wolchok JD, Hoos A, O’Day S, et al. Guidelines for the evaluation of immune therapy 
activity in solid tumors: immune related response criteria. Clin Cancer Res. 2009;15:7412-
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35 http://www.lcss-ql.com/index.htm 
36 Klastersky J, Paesmans M, Response to chemotherapy, quality of life benefits and survival in 
advanced non-small cell lung cancer: review of literature results. Lung Cancer 2011; 34:S95-
101.
37 Hollen, P.J., Gralla, R.J., Kris, M.G., & Cox, C. (1994). Quality of life during clinical trials: 
Conceptual model for the Lung Cancer Symptom Scale (LCSS). Supportive Care in Cancer, 
2, 213-222
38 EuroQol EQ-5D website http://www.euroqol.org/ 
39 Waterhouse DM, Horn L, Reynolds CH, et al. Safety profile of nivolumab administered as 
30-minute (min) infusion: Analysis of data from CheckMate 153. 2016 ASCO Annual 
Meeting. J Clin Oncol 34, 2016 (suppl; abstr 3059)
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APPENDICES
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APPENDIX 1
ABBREVIATIONS AND TRADEMARKS
Term
Definition
AE
adverse event
ALT
alanine aminotransferase
AST
aspartate aminotransferase
AT
aminotransaminases
BMS
Bristol-Myers Squibb
BP
blood pressure
BUN
blood urea nitrogen
C
Celsius
Ca
calcium
CBC
complete blood count
CBR
clinical benefit rate
CFR
Code of Federal Regulations 
CI
confidence interval
C1-
chloride
CLcr
creatinine clearance
CRF
case report form, paper or electronic
CT
computerized tomography
CTCAE
Common Terminology Criteria for Adverse Events
dL
deciliter
DMC
Data monitoring committee
DNA
Deoxynucleic acid
DOR
duration of response
ECOG
Eastern Cooperative Oncology Group
EDC
electronic data capture
EORTC
European Organization for Research and Treatment of Cancer 
eg
exempli gratia (for example)
FDG
fluorodeoxyglucose
FSH
follicle stimulating hormone
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Term
Definition
GCP
Good Clinical Practice
GFR
glomerular filtration rate
h
hour
HBsAg
hepatitis B surface antigen
HBV
hepatitis B virus
HCV
hepatitis C virus
HCO3-
bicarbonate
HIV
human immunodeficiency virus
HR
heart rate
ICH
International Conference on Harmonisation 
IHC
immunohistochemistry
ie
id est (that is)
IEC
Independent Ethics Committee
IHC
immunohistochemistry
IMP
investigational medicinal products
IND
Investigational New Drug Exemption
IRB
Institutional Review Board
IRC
Independent Review Committee
IRT
Interactive Response Technology
IU
International Unit
IV
intravenous
K+
potassium
kg
kilogram
L
liter
LDH
lactate dehydrogenase
mg
milligram
Mg++
magnesium
min
minute
mL
milliliter
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Term
Definition
MRI
magnetic resonance imaging
N
number of subjects or observations
Na
sodium
N/A
not applicable
NCI
National Cancer Institute
NIMP
non-investigational medicinal products 
ORR
objective response rate
OS
overall survival
PD
pharmacodynamics
PET 
positron emission tomography
PFS
progression free survival
PK
pharmacokinetics
QOL
quality of life
RECIST
Response Evaluation Criteria in Solid Tumors
RBC
red blood cell
SAE
serious adverse event
SD
standard deviation
SOP
Standard Operating Procedures
t
temperature
T
time
TSH
thyroid stimulating hormone
WBC
white blood cell
WHO
World Health Organization
WOCBP
women of childbearing potential
WNOCBP
women not of childbearing potential
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APPENDIX 2
STUDY GOVERNANCE CONSIDERATIONS
The term ‘Participant’ is used in the protocol to refer to a person who has consented to participate 
in the clinical research study.  The term ‘Subject’ used in the eCRF is intended to refer to a person 
(Participant) who has consented to participate in the clinical research study.
REGULATORY AND ETHICAL CONSIDERATIONS
GOOD CLINICAL PRACTICE
This study will be conducted in accordance with:
•
Good Clinical Practice (GCP), 
•
as defined by the International Council on Harmonisation (ICH)
•
in accordance with the ethical principles underlying European Union Directive 2001/20/EC
•
United States Code of Federal Regulations, Title 21, Part 50 (21CFR50) 
•
applicable local requirements.
The study will be conducted in compliance with the protocol. The protocol and any amendments 
and the participant informed consent will receive approval/favorable opinion by Institutional 
Review Board/Independent Ethics Committee (IRB/IEC), and regulatory authorities according to 
applicable local regulations prior to initiation of the study.
All potential serious breaches must be reported to Sponsor or designee immediately. A serious 
breach is a breach of the conditions and principles of GCP in connection with the study or the 
protocol, which is likely to affect, to a significant degree, the safety or physical or mental integrity 
of the subjects of the study or the scientific value of the study.
Personnel involved in conducting this study will be qualified by education, training, and 
experience to perform their respective tasks.
This study will not use the services of study personnel where sanctions have been invoked or where 
there has been scientific misconduct or fraud (e.g., loss of medical licensure, debarment). 
INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS COMMITTEE
Before study initiation, the investigator must have written and dated approval/favorable opinion 
from the IRB/IEC for the protocol, consent form, participant recruitment materials (e.g., 
advertisements), and any other written information to be provided to subjects. The investigator or 
BMS should also provide the IRB/IEC with a copy of the Investigator Brochure or product labeling 
information to be provided to subjects and any updates. 
The investigator, Sponsor or designee should provide the IRB/IEC with reports, updates and other 
information (e.g., expedited safety reports, amendments, and administrative letters) according to 
regulatory requirements or institution procedures.
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COMPLIANCE WITH THE PROTOCOL AND PROTOCOL REVISIONS
The investigator should not implement any deviation or change to the protocol without prior 
review and documented approval/favorable opinion of an amendment from the IRB/IEC (and if 
applicable, also by local health authority) except where necessary to eliminate an immediate 
hazard(s) to study subjects. 
If a deviation or change to a protocol is implemented to eliminate an immediate hazard(s) prior to 
obtaining relevant  approval/favorable opinion(s) the deviation or change will be submitted, as 
soon as possible to:
•
IRB/IEC for 
•
Regulatory Authority(ies), if applicable by local regulations (per national requirements)
Documentation of approval/favorable opinion signed by the chairperson or designee of the 
IRB(s)/IEC(s) and if applicable, also by local health authority must be sent to BMS.
If an amendment substantially alters the study design or increases the potential risk to the 
participant: (1) the consent form must be revised and submitted to the IRB(s)/IEC(s) for review 
and approval/favorable opinion; (2) the revised form must be used to obtain consent from subjects 
currently enrolled in the study if they are affected by the amendment; and (3) the new form must 
be used to obtain consent from new subjects prior to enrollment.
If the revision is done via an administrative letter, investigators must inform their IRB(s)/IEC(s).
FINANCIAL DISCLOSURE
Investigators and sub-Investigators will provide the Sponsor with sufficient, accurate financial 
information in accordance with local regulations to allow the Sponsor to submit complete and 
accurate financial certification or disclosure statements to the appropriate health authorities. 
Investigators are responsible for providing information on financial interests during the course of 
the study and for 1 year after completion of the study.
INFORMED CONSENT PROCESS
Investigators must ensure that subjects are clearly and fully informed about the purpose, potential 
risks, and other critical issues regarding clinical studies in which they volunteer to participate. 
In situations where consent cannot be given to subjects, their legally acceptable representatives (as 
per country guidelines) are clearly and fully informed about the purpose, potential risks, and other 
critical issues regarding clinical studies in which the participant volunteers to participate. 
Sponsor or designee will provide the investigator with an appropriate (i.e., Global or Local) sample 
informed consent form which will include all elements required by ICH, GCP and applicable 
regulatory requirements. The sample informed consent form will adhere to the ethical principles 
that have their origin in the Declaration of Helsinki.
Investigators must:
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•
Provide a copy of the consent form and written information about the study in the language 
in which the participant is most proficient prior to clinical study participation. The language 
must be non-technical and easily understood. 
•
Allow time necessary for participant or participant's legally acceptable representative to 
inquire about the details of the study.
•
Obtain an informed consent signed and personally dated by the participant or the 
participant's legally acceptable representative and by the person who conducted the 
informed consent discussion. 
•
Obtain the IRB/IEC’s written approval/favorable opinion of the written informed consent 
form and any other information to be provided to the subjects, prior to the beginning of the 
study, and after any revisions are completed for new information.
If informed consent is initially given by a participant’s legally acceptable representative or legal 
guardian, and the participant subsequently becomes capable of making and communicating his or 
her informed consent during the study, consent must additionally be obtained from the participant.
Revise the informed consent whenever important new information becomes available that is 
relevant to the participant's consent. The investigator, or a person designated by the investigator, 
should fully inform the participant or the participant's legally acceptable representative or legal 
guardian, of all pertinent aspects of the study and of any new information relevant to the 
participant's willingness to continue participation in the study. This communication should be 
documented. 
The confidentiality of records that could identify subjects must be protected, respecting the privacy 
and confidentiality rules applicable to regulatory requirements, the subjects' signed ICF and, in the 
US, the subjects’ signed HIPAA Authorization.
The consent form must also include a statement that BMS and regulatory authorities have direct 
access to participant records. 
The rights, safety, and well-being of the study subjects are the most important considerations and 
should prevail over interests of science and society.
SOURCE DOCUMENTS
The Investigator is responsible for ensuring that the source data are accurate, legible, 
contemporaneous, original and attributable, whether the data are hand-written on paper or entered 
electronically. If source data are created (first entered), modified, maintained, archived, retrieved, 
or transmitted electronically via computerized systems (and/or any other kind of electronic 
devices) as part of regulated clinical trial activities, such systems must be compliant with all 
applicable laws and regulations governing use of electronic records and/or electronic signatures. 
Such systems may include, but are not limited to, electronic medical/health records (EMRs/EHRs), 
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adverse event tracking/reporting, protocol required assessments, and/or drug accountability 
records).
When paper records from such systems are used in place of electronic format to perform regulated 
activities, such paper records should be certified copies. A certified copy consists of a copy of 
original information that has been verified, as indicated by a dated signature, as an exact copy 
having all of the same attributes and information as the original. 
STUDY TREATMENT RECORDS
Records for study treatments (whether supplied by BMS, its vendors, or the site) must substantiate 
study treatment integrity and traceability from receipt, preparation, administration, and through 
destruction or return. Records must be made available for review at the request of BMS/designee 
or a Health Authority.
If
Then
Supplied by BMS (or its vendors):
Records or logs must comply with applicable 
regulations and guidelines and should include:
•
amount received and placed in storage 
area
•
amount currently in storage area
•
label identification number or batch 
number
•
amount dispensed to and returned by each 
participant, including unique participant
identifiers
•
amount transferred to another area/site for 
dispensing or storage
•
nonstudy disposition (e.g., lost, wasted) 
•
amount destroyed at study site, if 
applicable
•
amount returned to BMS
•
retain samples for 
bioavailability/bioequivalence, if 
applicable 
•
dates and initials of person responsible for 
Investigational Product 
dispensing/accountability, as per the 
Delegation of Authority Form.
Sourced by site, and not supplied by BMS or 
its vendors (examples include IP sourced from 
the sites stock or commercial supply, or a 
specialty pharmacy)
The 
investigator 
or 
designee 
accepts 
responsibility for documenting traceability and 
study drug integrity in accordance with 
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If
Then
requirements applicable under law and the 
SOPs/standards of the sourcing pharmacy.   
These records should include:
•
label identification number or batch 
number 
•
amount dispensed to and returned by each 
participant, including unique participant
identifiers
•
dates and initials of person responsible for 
Investigational Product 
dispensing/accountability, as per the 
Delegation of Authority Form.
BMS or designee will provide forms to facilitate inventory control if the investigational site does not have an 
established system that meets these requirements.
CASE REPORT FORMS
An investigator is required to prepare and maintain adequate and accurate case histories designed 
to record all observations and other data pertinent to the investigation on each individual treated 
or entered as a control in the investigation. Data that are derived from source documents and 
reported on the CRF must be consistent with the source documents or the discrepancies must be 
explained. Additional clinical information may be collected and analyzed in an effort to enhance 
understanding of product safety. CRFs may be requested for AEs and/or laboratory abnormalities
that are reported or identified during the course of the study.
For sites using the Sponsor or designee electronic data capture tool, electronic CRFs will be 
prepared for all data collection fields except for fields specific to SAEs and pregnancy, which will 
be reported on the electronic SAE form and Pregnancy Surveillance form, respectively.  If 
electronic SAE form is not available, a paper SAE form can be used. 
The confidentiality of records that could identify subjects must be protected, respecting the privacy 
and confidentiality rules in accordance with the applicable regulatory requirement(s).
The investigator will maintain a signature sheet to document signatures and initials of all persons 
authorized to make entries and/or corrections on CRFs. 
The completed CRF, SAE/pregnancy CRFs, must be promptly reviewed, signed, and dated by the 
investigator or qualified physician who is a subinvestigator and who is delegated this task on the 
Delegation of Authority Form. Subinvestigators in Japan may not be delegated the CRF approval 
task The investigator must retain a copy of the CRFs including records of the changes and 
corrections.
Each individual electronically signing electronic CRFs must meet Sponsor or designee training 
requirements and must only access the BMS electronic data capture tool using the unique user 
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account provided by Sponsor or designee. User accounts are not to be shared or reassigned to other 
individuals
MONITORING
Sponsor or designee representatives will review data centrally to identify potential issues to 
determine a schedule of on-site visits for targeted review of study records. 
Representatives of BMS must be allowed to visit all study site locations periodically to assess the 
data quality and study integrity. On site they will review study records and directly compare them 
with source documents, discuss the conduct of the study with the investigator, and verify that the 
facilities remain acceptable. Certain CRF pages and/or electronic files may serve as the source 
documents.
In addition, the study may be evaluated by Sponsor or designee internal auditors and government 
inspectors who must be allowed access to CRFs, source documents, other study files, and study 
facilities. BMS audit reports will be kept confidential.
The investigator must notify BMS promptly of any inspections scheduled by regulatory authorities, 
and promptly forward copies of inspection reports to Sponsor or designee. 
RECORDS RETENTION
The investigator (or head of the study site in Japan) must retain all study records and source 
documents for the maximum period required by applicable regulations and guidelines, or 
institution procedures, or for the period specified by BMS or designee, whichever is longer. The 
investigator (or head of the study site in Japan) must contact BMS prior to destroying any records 
associated with the study.
BMS or designee will notify the investigator (or head of the study site in Japan) when the study 
records are no longer needed.
If the investigator withdraws from the study (e.g., relocation, retirement), the records shall be 
transferred to a mutually agreed upon designee (e.g., another investigator, study site, IRB). Notice 
of such transfer will be given in writing to BMS or designee. 
RETURN OF STUDY TREATMENT
For this study, study treatments (those supplied by BMS, a vendor or sourced by the investigator) 
such as partially used study treatment containers, vials and syringes may be destroyed on site. 
If..
Then
Study treatments supplied by BMS (including 
its vendors
Any unused study treatments supplied by BMS 
can only be destroyed after being inspected 
and reconciled by the responsible Study 
Monitor unless study treatments containers 
must be immediately destroyed as required for 
safety, or to meet local regulations (e.g., 
cytotoxics or biologics).
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If study treatments will be returned, the return 
will be arranged by the responsible Study 
Monitor.
Study treatments sourced by site, not supplied 
by BMS (or its vendors) (examples include 
study treatments sourced from the sites stock 
or 
commercial 
supply, 
or 
a 
specialty 
pharmacy)
It 
is 
the 
investigator’s 
or 
designee’s 
responsibility to dispose of all containers 
according to the institutional guidelines and 
procedures.
It is the investigator’s or designee’s responsibility to arrange for disposal, provided that procedures 
for proper disposal have been established according to applicable federal, state, local, and 
institutional guidelines and procedures, and provided that appropriate records of disposal are kept. 
The following minimal standards must be met:
•
On-site disposal practices must not expose humans to risks from the drug.
•
On-site disposal practices and procedures are in agreement with applicable laws and 
regulations, including any special requirements for controlled or hazardous substances.
•
Written procedures for on-site disposal are available and followed. The procedures must 
be filed with the site’s SOPs and a copy provided to BMS upon request.
•
Records are maintained that allow for traceability of each container, including the date 
disposed of, quantity disposed, and identification of the person disposing the containers. 
The method of disposal, i.e., incinerator, licensed sanitary landfill, or licensed waste 
disposal vendor must be documented.
•
Accountability and disposal records are complete, up-to-date, and available for the Monitor 
to review throughout the clinical trial period.
It is the investigator’s or designee’s responsibility to arrange for disposal of all empty containers.
If conditions for destruction cannot be met the responsible Study Monitor will make arrangements 
for return of study treatments provided by BMS (or its vendors). Destruction of non- study 
treatments sourced by the site, not supplied by BMS, is solely the responsibility of the investigator 
or designee.
CLINICAL STUDY REPORT AND PUBLICATIONS
A Signatory Investigator must be selected to sign the clinical study report. 
For this protocol, the Signatory Investigator will be selected as appropriate based on the following 
criteria:
•
External Principal Investigator designated at protocol development
The data collected during this study are confidential and proprietary to Sponsor or designee. Any 
publications or abstracts arising from this study must adhere to the publication requirements set 
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forth in the clinical trial agreement (CTA) governing [Study site or Investigator] participation in 
the study. These requirements include, but are not limited to, submitting proposed publications to 
Sponsor or designee at the earliest practicable time prior to submission or presentation and 
otherwise within the time period set forth in the CTA.
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APPENDIX 3
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS: 
DEFINITIONS AND PROCEDURES FOR RECORDING, 
EVALUATING, FOLLOW UP AND REPORTING
ADVERSE EVENTS
Adverse Event Definition:
An Adverse Event (AE) is defined as any new untoward medical occurrence or worsening of a 
preexisting medical condition in a clinical investigation participant administered study drug 
and that does not necessarily have a causal relationship with this treatment. 
An AE can therefore be any unfavorable and unintended sign (such as an abnormal laboratory 
finding), symptom, or disease temporally associated with the use of study drug, whether or not 
considered related to the study drug.
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SERIOUS ADVERSE EVENTS
Serious Adverse Event (SAE) is defined as any untoward medical occurrence that, at any 
dose:
Results in death
Is life-threatening (defined as an event in which the participant was at risk of death at the time 
of the event; it does not refer to an event which hypothetically might have caused death if it 
were more severe)
Requires inpatient hospitalization or causes prolongation of existing hospitalization (see 
NOTE below)
NOTE: 
The following hospitalizations are not considered SAEs in BMS clinical studies: 
o
a visit to the emergency room or other hospital department < 24 hours, that 
does not result in admission (unless considered an important medical or life-
threatening event)
o
elective surgery, planned prior to signing consent
o
admissions as per protocol for a planned medical/surgical procedure
o
routine health assessment requiring admission for baseline/trending of health 
status (e.g., routine colonoscopy)
o
medical/surgical admission other than to remedy ill health and planned prior to 
entry into the study. Appropriate documentation is required in these cases
o
admission encountered for another life circumstance that carries no bearing on 
health status and requires no medical/surgical intervention (e.g., lack of 
housing, economic inadequacy, caregiver respite, family circumstances, 
administrative reason)
o
admission for administration of anticancer therapy in the absence of any other 
SAEs (applies to oncology protocols)
Results in persistent or significant disability/incapacity
Is a congenital anomaly/birth defect
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is an important medical event (defined as a medical event(s) that may not be immediately life-
threatening or result in death or hospitalization but, based upon appropriate medical and 
scientific judgment, may jeopardize the participant or may require intervention [e.g., medical, 
surgical] to prevent one of the other serious outcomes listed in the definition above.) Examples 
of such events include, but are not limited to, intensive treatment in an emergency room or at 
home for allergic bronchospasm; blood dyscrasias or convulsions that do not result in 
hospitalization.) Potential drug induced liver injury (DILI) is also considered an important 
medical event. (See Section 9.2.7 for the definition of potential DILI.) 
Suspected transmission of an infectious agent (e.g., pathogenic or nonpathogenic) via the study 
treatment is an SAE. 
Although pregnancy, overdose, cancer, and potential drug induced liver injury (DILI) are not 
always serious by regulatory definition, these events must be handled as SAEs. (See Section 
9.2.5 for reporting pregnancies).
Any component of a study endpoint that is considered related to study therapy should be reported 
as SAE (e.g., death is an endpoint, if death occurred due to anaphylaxis, anaphylaxis must be 
reported).
EVALUATING AES AND SAES
Assessment of Causality
The causal relationship to study drug is determined by a physician and should be used to 
assess all adverse events (AE). The causal relationship can be one of the following:
Related: There is a reasonable causal relationship between study drug 
administration and the AE.
Not related: There is not a reasonable causal relationship between study drug 
administration and the AE. 
The term "reasonable causal relationship" means there is evidence to suggest a causal 
relationship. 
Follow-up of AEs and SAEs
If only limited information is initially available, follow-up reports are required. (Note: 
Follow-up SAE reports must include the same investigator term(s) initially reported.) 
If an ongoing SAE changes in its intensity or relationship to study drug or if new 
information becomes available, the SAE report must be updated and submitted within 24 
hours to BMS (or designee) using the same procedure used for transmitting the initial 
SAE report.
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All SAEs must be followed to resolution or stabilization.
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 discontinuation of study treatment. 
Every adverse event must be assessed by the investigator with regard to whether it is 
considered immune-mediated. For events which are potentially immune-mediated, 
additional information will be collected on the participant’s case report form.
REPORTING OF SAES TO SPONSOR OR DESIGNEE
•
SAEs, whether related or not related to study drug, and pregnancies must be 
reported to BMS (or designee) within 24 hours of awareness of the event.
•
SAEs must be recorded on the SAE Report Form; pregnancies on a Pregnancy 
Surveillance Form (electronic or paper forms).
•
The preferred method for SAE data reporting collection is through the eCRF.
•
The paper SAE/pregnancy surveillance forms are only intended as a back-up 
option when the eCRF system is not functioning.
o
In this case, the paper forms are to be transmitted via email or confirmed 
facsimile (fax) transmission to:
SAE Email Address: Refer to Contact Information list.
SAE Facsimile Number: Refer to Contact Information list.
For studies capturing SAEs through electronic data capture (EDC), electronic submission 
is the required method for reporting. In the event the electronic system is unavailable for 
transmission, paper forms must be used and submitted immediately. When paper forms 
are used, the original paper forms are to remain on site.
SAE Telephone Contact (required for SAE and pregnancy reporting): Refer to Contact 
Information list
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APPENDIX 4
WOMEN OF CHILDBEARING POTENTIAL DEFINITIONS AND 
METHODS OF CONTRACEPTION
DEFINITIONS
Woman of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming post-menopausal unless 
permanently sterile. Permanent sterilization methods include hysterectomy, bilateral 
salpingectomy, and bilateral oophorectomy.
Women in the following categories are not considered WOCBP
•
Premenarchal
•
Premenopausal female with 1 of the following:
−
Documented hysterectomy
−
Documented bilateral salpingectomy
−
Documented bilateral oophorectomy
Note: Documentation can come from the site personnel’s review of the participant’s medical 
records, medical examination, or medical history interview.
•
Postmenopausal female
−
A postmenopausal state is defined as 12 months of amenorrhea in a woman over age 45 
years in the absence of other biological or physiological causes. In addition, females under 
the age of 55 years must have a serum follicle stimulating hormone, (FSH) level > 40 
mIU/mL to confirm menopause.
CONTRACEPTION GUIDANCE FOR FEMALE PARTICIPANTS OF CHILD BEARING 
POTENTIAL
One of the highly effective methods of contraception listed below is required during study duration 
and until the end of relevant systemic exposure, defined as 5 months after the end of study 
treatment. 
Local laws and regulations may require use of alternative and/or additional contraception methods.
Highly Effective Contraceptive Methods That Are User Dependent 
Failure rate of <1% per year when used consistently and correctly.a
•
Combined (estrogen- and progestogen-containing) hormonal contraception associated with 
inhibition of ovulationb 
−
oral 
−
intravaginal 
−
transdermal 
•
Progestogen-only hormonal contraception associated with inhibition of ovulationb 
−
oral 
−
injectable 
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Highly Effective Methods That Are User Independent
•
Implantable progestogen-only hormonal contraception associated with inhibition of 
ovulation b
•
Hormonal methods of contraception including oral contraceptive pills containing a 
combination of estrogen and progesterone, vaginal ring, injectables, implants and 
intrauterine hormone-releasing system (IUS)c
•
Intrauterine device (IUD)c
•
Bilateral tubal occlusion
•
Vasectomized partner 
A vasectomized partner is a highly effective contraception method provided that the partner 
is the sole male sexual partner of the WOCBP and the absence of sperm has been confirmed. 
If not, an additional highly effective method of contraception should be used. 
•
Sexual abstinence
Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study drug. The 
reliability of sexual abstinence needs to be evaluated in relation to the duration of the study 
and the preferred and usual lifestyle of the participant.
•
It is not necessary to use any other method of contraception when complete abstinence is 
elected. 
•
WOCBP participants who choose complete abstinence must continue to have pregnancy 
tests, as specified in Section 2. 
•
Acceptable alternate methods of highly effective contraception must be discussed in the 
event that the WOCBP participants chooses to forego complete abstinence 
NOTES: 
a Typical use failure rates may differ from those when used consistently and correctly. Use should be consistent 
with local regulations regarding the use of contraceptive methods for participants participating in clinical studies. 
b Hormonal contraception may be susceptible to interaction with the study drug, which may reduce the efficacy 
of the contraceptive method.  Hormonal contraception is permissible only when there is sufficient evidence that 
the IMP and other study medications will not alter hormonal exposures such that contraception would be 
ineffective or result in increased exposures that could be potentially hazardous.  In this case, alternative methods 
of contraception should be utilized. 
c Intrauterine devices and intrauterine hormone releasing systems are acceptable methods of contraception in the 
absence of definitive drug interaction studies when hormone exposures from intrauterine devices do not alter 
contraception effectiveness
Unacceptable Methods of Contraception
•
Male or female condom with or without spermicide.  Male and female condoms cannot be 
used simultaneously
•
Diaphragm with spermicide
•
Cervical cap with spermicide
•
Vaginal Sponge with spermicide
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•
Progestogen-only oral hormonal contraception, where inhibition of ovulation is not the 
primary mechanism of action
•
Periodic abstinence (calendar, symptothermal, post-ovulation methods)
•
Withdrawal (coitus interruptus).
•
Spermicide only
•
Lactation amenorrhea method (LAM)
CONTRACEPTION GUIDANCE FOR MALE PARTICIPANTS WITH PARTNER(S) OF 
CHILD BEARING POTENTIAL.
Male participants with female partners of childbearing potential are eligible to participate if they 
agree to the following during the treatment and until the end of relevant systemic exposure.
•
Inform any and all partner(s) of their participation in a clinical drug study and the need to 
comply with contraception instructions as directed by the investigator.
•
Male participants are required to use a condom for study duration and until end of relevant 
systemic exposure defined as 7 months after the end of study treatment.
•
Female partners of males participating in the study to consider use of effective methods of 
contraception until the end of relevant systemic exposure, defined as 7 months after the end of 
treatment in the male participant.
•
Male participants with a pregnant or breastfeeding partner must agree to remain abstinent from 
penile vaginal intercourse or use a male condom during each episode of penile penetration 
during the treatment and until 7 months after the end of study treatment.
•
Refrain from donating sperm for the duration of the study treatment and until 7 months after 
the end of study treatment.
COLLECTION OF PREGNANCY INFORMATION
Guidance for collection of Pregnancy Information and outcome of pregnancy on the Pregnancy 
Surveillance Form is provided in Section 9.2.5 and the Appendix for Adverse Events and Serious 
Adverse Events Definitions and procedures for Evaluating, Follow-up and Reporting
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APPENDIX 5
PERFORMANCE STATUS
1
ECOG PERFORMANCE STATUS
Table 1:
ECOG Performance Status
Grade 
ECOG 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or 
sedentary nature, e.g., light house work, office work 
2 
Ambulatory and capable of all selfcare but unable to carry out any work activities. Up and about 
more than 50% of waking hours 
3 
Capable of only limited selfcare, confined to bed or chair more than 50% of waking hours 
4 
Completely disabled. Cannot carry on any selfcare. Totally confined to bed or chair 
5 
Dead 
Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, Carbone PP. Toxicity and Response Criteria 
of the Eastern Cooperative Oncology Group. Am J Clin Oncol 5:649-655, 1982.
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APPENDIX 6
RECIST 1.1 GUIDELINES
1
EVALUATION OF LESIONS
At baseline, tumor lesions/lymph nodes will be categorized measurable or non-measurable as 
follows:
1.1
Measurable
Tumor lesions: Must be accurately measured in at least one dimension (longest diameter in the 
plane of measurement is to be recorded) with a minimum size of:
1. 10 mm by CT scan (CT scan slice thickness no greater than 5 mm)
2. 10 mm caliper measurement by clinical exam (lesions which cannot be accurately measured 
with calipers should be recorded as non-measurable)
3. 20 mm by chest x-ray
Malignant lymph nodes: To be considered pathologically enlarged and measurable, a lymph node 
must be ≥15 mm in short axis when assessed by CT scan (CT scan slice thickness recommended 
to be no greater than 5 mm).
Lymph nodes merit special mention since they are normal anatomical structures which may be 
visible by imaging even if not involved by tumor. Pathological nodes which are defined as 
measurable and may be identified as target lesions must meet the criterion of a short axis of 
≥15 mm by CT scan. Only the short axis of these nodes will contribute to the baseline sum. The 
short axis of the node is the diameter normally used by radiologists to judge if a node is involved 
by solid tumor. Nodal size is normally reported as two dimensions in the plane in which the image 
is obtained (for CT scan this is almost always the axial plane; for MRI the plane of acquisition 
may be axial, saggital or coronal). The smaller of these measures is the short axis. For example, 
an abdominal node which is reported as being 20 mm x 30 mm has a short axis of 20 mm and 
qualifies as a malignant, measurable node. In this example, 20 mm should be recorded as the node 
measurement. All other pathological nodes (those with short axis ≥10 mm but < 15 mm) should 
be considered non-target lesions. Nodes that have a short axis < 10 mm are considered 
non-pathological and should not be recorded or followed.
1.2
Non-Measurable
All other lesions are considered non-measurable, including small lesions (longest diameter 
< 10mm or pathological lymph nodes with ≥10 to < 15 mm short axis) as well as truly 
non-measurable lesions. Lesions considered truly non-measurable include: leptomeningeal 
disease, ascites, pleural or pericardial effusion, inflammatory breast disease, lymphangitic 
involvement of skin or lung, abdominal masses/abdominal organomegaly identified by physical 
exam that is not measurable by reproducible imaging techniques.
1.3
Baseline Documentation Of ‘Target’ And ‘Non-Target’ Lesions
When more than one measurable lesion is present at baseline all lesions up to a maximum of five 
lesions total (and a maximum of two lesions per organ) representative of all involved organs should 
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be identified as target lesions and will be recorded and measured at baseline (this means in 
instances where patients have only one or two organ sites involved a maximum of two and four 
lesions respectively will be recorded).
Target lesions should be selected on the basis of their size (lesions with the longest diameter), be 
representative of all involved organs, but in addition should be those that lend themselves to 
reproducible repeated measurements. It may be the case that, on occasion, the largest lesion does 
not lend itself to reproducible measurement in which circumstance the next largest lesion which 
can be measured reproducibly should be selected.
A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target 
lesions will be calculated and reported as the baseline sum diameters. If lymph nodes are to be 
included in the sum, then as noted above, only the short axis is added into the sum. The baseline 
sum diameters will be used as reference to further characterize any objective tumor regression in 
the measurable dimension of the disease.
All other lesions (or sites of disease) including pathological lymph nodes should be identified as 
non-target lesions and should also be recorded at baseline. Measurements are not required and 
these lesions should be followed as ‘present’, ‘absent’, or in rare cases ‘unequivocal progression’ 
(more details to follow). In addition, it is possible to record multiple nontarget lesions involving 
the same organ as a single item on the case record form (eg, ‘multiple enlarged pelvic lymph nodes’ 
or ‘multiple liver metastases’).
2.
RESPONSE CRITERIA
2.1
Evaluation of Target Lesions
Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes 
(whether target or non-target) must have reduction in short axis to < 10 mm.
Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, taking 
as reference the baseline sum diameters.
Progressive Disease (PD): At least a 20% increase in the sum of diameters of target lesions, taking 
as reference the smallest sum on study (this includes the baseline sum if that is the 
smallest on study). In addition to the relative increase of 20%, the sum must also 
demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or 
more new lesions is also considered progression).
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest sum diameters while on study.
2.1.1
Special Notes on the Assessment of Target Lesions
2.1.1.1
Lymph nodes
Lymph nodes identified as target lesions should always have the actual short axis measurement 
recorded (measured in the same anatomical plane as the baseline examination), even if the nodes 
regress to below 10 mm on study. This means that when lymph nodes are included as target lesions, 
the ‘sum’ of lesions may not be zero even if complete response criteria are met, since a normal 
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lymph node is defined as having a short axis of < 10 mm. Case report forms or other data collection 
methods may therefore be designed to have target nodal lesions recorded in a separate section 
where, in order to qualify for CR, each node must achieve a short axis < 10 mm. For PR, SD and 
PD, the actual short axis measurement of the nodes is to be included in the sum of target lesions.
2.1.1.2
Target lesions that become ‘too small to measure’
While on study, all lesions (nodal and non-nodal) recorded at baseline should have their actual 
measurements recorded at each subsequent evaluation, even when very small (eg, 2 mm). 
However, sometimes lesions or lymph nodes which are recorded as target lesions at baseline 
become so faint on CT scan that the radiologist may not feel comfortable assigning an exact 
measure and may report them as being ‘too small to measure’. When this occurs it is important 
that a value be recorded on the case report form. If it is the opinion of the radiologist that the lesion 
has likely disappeared, the measurement should be recorded as 0 mm. If the lesion is believed to 
be present and is faintly seen but too small to measure, a default value of 5 mm should be assigned 
(Note: It is less likely that this rule will be used for lymph nodes since they usually have a definable 
size when normal and are frequently surrounded by fat such as in the retroperitoneum; however, 
if a lymph node is believed to be present and is faintly seen but too small to measure, a default 
value of 5 mm should be assigned in this circumstance as well). This default value is derived from 
the 5 mm CT slice thickness (but should not be changed with varying CT slice thickness). The 
measurement of these lesions is potentially non-reproducible, therefore providing this default 
value will prevent false responses or progressions based upon measurement error. To reiterate, 
however, if the radiologist is able to provide an actual measure, that should be recorded, even if it 
is below 5 mm.
2.1.1.3
Lesions that split or coalesce on treatment
When non-nodal lesions ‘fragment’, the longest diameters of the fragmented portions should be 
added together to calculate the target lesion sum. Similarly, as lesions coalesce, a plane between 
them may be maintained that would aid in obtaining maximal diameter measurements of each 
individual lesion. If the lesions have truly coalesced such that they are no longer separable, the 
vector of the longest diameter in this instance should be the maximal longest diameter for the 
‘coalesced lesion’.
2.2
Evaluation of Non-Target Lesions
This section provides the definitions of the criteria used to determine the tumor response for the 
group of non-target lesions. While some non-target lesions may actually be measurable, they need 
not be measured and instead should be assessed only qualitatively at the time points specified in 
the protocol.
Complete Response (CR): Disappearance of all non-target lesions and normalization of tumor 
marker level. All lymph nodes must be non-pathological in size (< 10mm short axis). 
Non-CR/Non-PD: Persistence of one or more non-target lesion(s) and/or maintenance of tumor 
marker level above the normal limits.
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Progressive Disease (PD): Unequivocal progression (see comments below) of existing non-target 
lesions. (Note: the appearance of one or more new lesions is also considered 
progression).
2.2.1
Special Notes on Assessment of Progression of Non-Target Disease
The concept of progression of non-target disease requires additional explanation as follows:
2.2.1.1
When the patient also has measurable disease
In this setting, to achieve ‘unequivocal progression’ on the basis of the non-target disease, there 
must be an overall level of substantial worsening in non-target disease such that, even in presence 
of SD or PR in target disease, the overall tumor burden has increased sufficiently to merit 
discontinuation of therapy (see examples in Appendix 2 and further details below). A modest 
‘increase’ in the size of one or more non-target lesions is usually not sufficient to qualify for 
unequivocal progression status. The designation of overall progression solely on the basis of 
change in non-target disease in the face of SD or PR of target disease will therefore be extremely 
rare.
2.2.1.2
When the patient has only non-measurable disease
This circumstance arises in some trials when it is not a criterion of study entry to have measurable 
disease. The same general concepts apply here as noted above, however, in this instance there is 
no measurable disease assessment to factor into the interpretation of an increase in non-measurable 
disease burden. Because worsening in non-target disease cannot be easily quantified (by definition: 
if all lesions are truly non-measurable) a useful test that can be applied when assessing patients for 
unequivocal progression is to consider if the increase in overall disease burden based on the change 
in non-measurable disease is comparable in magnitude to the increase that would be required to 
declare PD for measurable disease: ie, an increase in tumor burden representing an additional 73% 
increase in ‘volume’ (which is equivalent to a 20% increase diameter in a measurable lesion). 
Examples include an increase in a pleural effusion from ‘trace’ to ‘large’, an increase in 
lymphangitic disease from localized to widespread, or may be described in protocols as ‘sufficient 
to require a change in therapy’. If ‘unequivocal progression’ is seen, the patient should be 
considered to have had overall PD at that point. While it would be ideal to have objective criteria 
to apply to non-measurable disease, the very nature of that disease makes it impossible to do so; 
therefore the increase must be substantial.
2.2.2
New Lesions
The appearance of new malignant lesions denotes disease progression; therefore, some comments 
on detection of new lesions are important. There are no specific criteria for the identification of 
new radiographic lesions; however, the finding of a new lesion should be unequivocal: ie, not 
attributable to differences in scanning technique, change in imaging modality or findings thought 
to represent something other than tumor (for example, some ‘new’ bone lesions may be simply 
healing or flare of pre-existing lesions). This is particularly important when the patient’s baseline 
lesions show partial or complete response. For example, necrosis of a liver lesion may be reported 
on a CT scan report as a ‘new’ cystic lesion, which it is not.
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A lesion identified on a follow-up study in an anatomical location that was not scanned at baseline 
is considered a new lesion and will indicate disease progression. An example of this is the patient 
who has visceral disease at baseline and while on study has a CT or MRI brain ordered which 
reveals metastases. The patient’s brain metastases are considered to be evidence of PD even if 
he/she did not have brain imaging at baseline.
If a new lesion is equivocal, for example because of its small size, continued therapy and follow-up 
evaluation will clarify if it represents truly new disease. If repeat scans confirm there is definitely 
a new lesion, then progression should be declared using the date of the initial scan. While FDG-
PET response assessments need additional study, it is sometimes reasonable to incorporate the use 
of FDG-PET scanning to complement CT scanning in assessment of progression (particularly 
possible ‘new’ disease). New lesions on the basis of FDG-PET imaging can be identified according 
to the following algorithm:
1. Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of PD based 
on a new lesion.
2. No FDG-PET at baseline and a positive FDG-PET at follow-up: If the positive FDG-PET at 
follow-up corresponds to a new site of disease confirmed by CT, this is PD. If the positive 
FDG-PET at follow-up is not confirmed as a new site of disease on CT, additional follow-up 
CT scans are needed to determine if there is truly progression occurring at that site (if so, the 
date of PD will be the date of the initial abnormal FDG-PET scan). If the positive FDG-PET 
at follow-up corresponds to a pre-existing site of disease on CT that is not progressing on the 
basis of the anatomic images, this is not PD.
2.3
Response Assessment
2.3.1
Evaluation of Best Overall Response
The best overall response is the best response recorded from the start of the study treatment until 
the end of treatment taking into account any requirement for confirmation. The patient’s best 
overall response assignment will depend on the findings of both target and non-target disease and 
will also take into consideration the appearance of new lesions. Furthermore, depending on the 
nature of the study and the protocol requirements, it may also require confirmatory measurement.
2.3.2
Time Point Response
It is assumed that at each protocol specified time point, a response assessment occurs. Table 2.3.2-
1 provides a summary of the overall response status calculation at each time point for patients who 
have measurable disease at baseline. When patients have non-measurable (therefore non-target) 
disease only, Table 2.3.2-2 is to be used. 
Table 2.3.2-1:
Time Point Response: Patients With Target (+/- Non-Target) 
Disease
Target Lesions
Non-Target Lesions
New Lesions
Overall Response
CR
CR
No
CR
CR
Non-CR/non-PD
No
PR
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Table 2.3.2-1:
Time Point Response: Patients With Target (+/- Non-Target) 
Disease
Target Lesions
Non-Target Lesions
New Lesions
Overall Response
CR
Not evaluated
No
PR
PR
Non-PD or not all 
evaluated
No
PR
SD
Non-PD or not all 
evaluated
No
SD
Not all evaluated
Non-PD
No
NE
PD
Any
Yes or No
PD
Any
PD
Yes or No
PD
Any
Any
Yes
PD
CR = complete response, PR = partial response, SD = stable disease, PD = progressive disease and NE = inevaluable
Table 2.3.2-2:
Time Point Response: Patients with Non-target Disease Only
Non-Target Lesions
New Lesions
Overall Response
CR
No
CR
Non-CR/non-PD
No
Non-CR/non-PDa
Not all evaluated
No
NE
Unequivocal PD
Yes or No
PD
Any
Yes
PD
CR = complete response, PD = progressive disease and NE = inevaluable
a Non-CR/non-PD is preferred over SD for non-target disease since SD is increasingly used as endpoint for 
assessment of efficacy in some trials so to assign this category when no lesions can be measured is not advised.
2.3.3
Best Overall Response 
Best response determination of complete or partial response requires confirmation: Complete or 
partial responses may be claimed only if the criteria for each are met at a subsequent time point of 
≥4 weeks later. In this circumstance, the best overall response can be interpreted as in Table 2.3.3-
1.
Special note on response assessment: When nodal disease is included in the sum of target lesions 
and the nodes decrease to ‘normal’ size (< 10 mm), they may still have a measurement reported 
on scans. This measurement should be recorded even though the nodes are normal in order not to 
overstate progression should it be based on increase in size of the nodes. As noted earlier, this 
means that patients with CR may not have a total sum of ‘zero’ on the case report form (CRF).
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Table 2.3.3-1:
Best Overall Response (Confirmation of CR&PR Required)
Overall Response 
First Time Point
Overall Response 
Subsequent Time Point
BEST Overall Response
CR
CR
CR
CR
PR
SD, PD OR PRa
CR
SD
SD provided minimum criteria for SD durationb met, 
otherwise, PD
CR
PD
SD provided minimum criteria for SD durationb met, 
otherwise, PD
CR
NE
SD provided minimum criteria for SD durationb met, 
otherwise, NE
PR
CR
PR
PR
PR
PR
PR
SD
SD
PR
PD
SD provided minimum criteria for SD durationb met, 
otherwise, PD
PR
NE
SD provided minimum criteria for SD duration bmet, 
otherwise, NE
NE
NE
NE
CR = complete response, PR = partial response, SD = stable disease, PD = progressive disease, and 
NE = inevaluable
a If a CR is truly met at first time point, then any disease seen at a subsequent time point, even disease meeting PR 
criteria relative to baseline, makes the disease PD at that point (since disease must have reappeared after CR). Best 
response would depend on whether minimum duration for SD was met. However, sometimes ‘CR’ may be claimed 
when subsequent scans suggest small lesions were likely still present and in fact the patient had PR, not CR at the 
first time point. Under these circumstances, the original CR should be changed to PR and the best response is PR.
b Minimum criteria for SD duration is 6 weeks.
2.3.4
Confirmation Scans
Verification of Response: To be assigned a status of CR or PR, changes in tumor measurements 
must be confirmed by consecutive repeat assessments that should be performed no less than 
28 days after the criteria for response are first met. For this study, the next scheduled tumor 
assessment can meet this requirement.
Verification of Progression: Progression of disease should be verified in cases where progression 
is equivocal. If repeat scans confirm PD, then progression should be declared using the date of the 
initial scan. If repeat scans do not confirm PD, then the subject is considered to not have 
progressive disease.
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