An Open-label, Single-arm Phase II Safety Study of Nivolumab in Participants With Advanced or Metastatic Non-small Cell Lung Cancer Who Have Progressed During or After Receiving at Least One Prior Systemic Regimen (CheckMate 907: CHECKpoint Pathway and nivoluMAb Clinical Trial Evaluation 907)
Phase: PHASE2
Conditions: Non-Small Cell Lung Cancer
Sponsor: Bristol-Myers Squibb

Official Title of Study: 
AN OPEN-LABEL, SINGLE-ARM PHASE II SAFETY STUDY OF NIVOLUMAB IN 
PARTICIPANTS WITH ADVANCED OR METASTATIC NON-SMALL CELL LUNG 
CANCER WHO HAVE PROGRESSED DURING OR AFTER RECEIVING AT LEAST 
ONE PRIOR SYSTEMIC REGIMEN 
 
NCT Number: NCT03090737 
Document Date (Date in which document was last revised): July 10, 2020 

Page:
1
Protocol Number:
CA209907
IND Number:
100,052
EUDRACT Number
2016-003731-37
Date
10-Nov-2016
Revised Date
10-Jul-2020
Clinical Protocol CA209907
An Open-label, Single-arm Phase II Safety Study of Nivolumab in Participants with Advanced or 
Metastatic Non-small Cell Lung Cancer Who Have Progressed During or After Receiving at 
Least One Prior Systemic Regimen
(CheckMate 907: CHECKpoint pathway and nivoluMAb clinical Trial Evaluation 907)
Revised Protocol Number: 02
Incorporates Administrative Letters 03, 05, 06, and 07
24-hr Emergency Telephone Number
Bristol-Myers Squibb Research and Development
3401 Princeton Pike
Lawrence Township, NJ 08648
This document is the confidential and proprietary information of Bristol-Myers Squibb 
Company and its global affiliates (BMS). By reviewing this document, you agree to keep it 
confidential and to use and disclose it solely for the purpose of assessing whether your 
organization will participate in and/or the performance of the proposed BMS sponsored 
study. Any permitted disclosures will be made only on a confidential "need to know" basis 
within your organization or to your independent ethics committee(s). Any other use, 
copying, disclosure or dissemination of this information is strictly prohibited unless 
expressly authorized in writing by BMS. Any supplemental information (e.g., amendments) 
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 
to BMS or promptly destroy it. All other rights reserved. References to BMS in this 
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BMS-936558
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Revised Protocol No.: 02
Date: 10-Jul-2020
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protocol may apply to partners to which BMS has transferred obligations, e.g., a Contract 
Research Organization (CRO).
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DOCUMENT HISTORY
Document
Date of Issue
Summary of Change
Revised Protocol 02
10-Jul-2020
•
Extended follow-up radiographic tumor assessment 
collection and survival follow-up to a maximum 
duration of 5 years after first dose.
•
Updated Appendix 4 and Appendix 6 to bring in line 
with current nivolumab and BMS protocol standards.
Administrative Letter 
07
23-Oct-2018
•
Nivolumab dosing information updated to be consistent 
with IB v17.
•
Study personnel information updated.
Administrative Letter 
06
16-Jul-2018
Study personnel information updated.
Administrative Letter 
05
09-Jul-2018
Nivolumab dosing information updated to be consistent 
with IB v16.
Administrative Letter 
03
26-Feb-2018
Study personnel information updated.
Revised Protocol 01
26-Jan-2018
•
Increased number of participants in study and sample 
size determination in statistical section 
•
Included additional language for nivolumab program 
level updates
•
Incorporated Administrative Letters 01 and 02.
Administrative Letter 
02
26-Oct-2017
Added the IND Number to Protocol Title Page
Administrative Letter 
01
17-Jul-2017
Updated information for Study Director and Medical 
Monitor
Original Protocol
10-Nov-2016
Not Applicable
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OVERALL RATIONALE FOR REVISED PROTOCOL 02:
The study was revised to allow for collection of efficacy data beyond 2 years for analyses.
SUMMARY OF KEY CHANGES FOR REVISED PROTOCOL 02
Section Number & Title
Description of Change
Brief Rationale
2, Schedule of Activities 
Table 2-3: Follow up and 
survival procedures (All 
Participants)
Modified follow-up 
radiographic tumor 
assessment collection and 
survival follow-up to a 
maximum duration of 5 years 
after first dose
To collect efficacy data 
beyond 2 years for analyses
5.1, Overall Design
Modified follow-up 
radiographic tumor 
assessment collection and 
survival follow-up to a 
maximum duration of 5 years 
after first dose and specified 
that participants who 
discontinue treatment for 
reasons other than disease 
progression or completed 2 
years of treatment will 
continue to have tumor 
assessments and be followed 
for survival.
To collect efficacy data 
beyond 2 years for analyses
Figure 5.1-1 Study Design 
Schematic
Modified footnote for 
survival follow-up to a 
maximum duration of 5 years 
after first dose and specified 
that participants who 
discontinue treatment for 
reasons other than disease 
progression or completed 2 
years of treatment will 
continue to be followed for 
survival.
To collect efficacy data 
beyond 2 years for analyses
5.3, End of Study Definition
Extension of study to a 
maximum of 5 years
To collect efficacy data 
beyond 2 years for analyses
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SUMMARY OF KEY CHANGES FOR REVISED PROTOCOL 02
Section Number & Title
Description of Change
Brief Rationale
9.1.1: Imaging Assessment for 
the study
Added text: Participants who 
discontinue earlier than 2 
years or completed 2 years of 
treatment but achieve 
SD/PR/CR at the end of 
Follow-up Visit 2 will have 
imaging scans every 3 
months (12 weeks ± 7 days) 
until documented 
radiographic disease 
progression or up to a 
maximum duration of 5 years 
after first dose.
To collect efficacy data 
beyond 2 years for analyses
10.3.1, Efficacy Analyses
Extended the PFS/OS rate 
timing intervals out to the 
maximum duration of 60 
months (5 years)
To collect efficacy data 
beyond 2 years for analyses
Appendix 4, Management 
Algorithms
Algorithms updated
Bring in line with nivolumab 
and BMS protocol standards
Appendix 6, Study 
Governance Considerations
Updates to potential serious
breach language
Addition of the word
participants.
Update to drug traceability
language under Study
Treatment Records.
Additional of information
about Scientific Publications
Bring in line with nivolumab 
and BMS protocol standards
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TABLE OF CONTENTS
TITLE PAGE................................................................................................................
DOCUMENT HISTORY ..............................................................................................
OVERALL RATIONALE FOR REVISED PROTOCOL 02:.....................................
SUMMARY OF KEY CHANGES FOR REVISED PROTOCOL 02.........................
TABLE OF CONTENTS..............................................................................................
1. SYNOPSIS................................................................................................................
2. SCHEDULE OF ACTIVITIES.................................................................................
3. INTRODUCTION ....................................................................................................
3.1 Study Rationale.................................................................................................
3.1.1 Research Hypothesis ................................................................................ 
3.2 Background.......................................................................................................
3.2.1 Non-Small Cell Lung Cancer (NSCLC) Background .............................. 
3.2.2 Nivolumab Mechanism of Action ............................................................. 
3.2.3 Nivolumab in NSCLC ............................................................................... 
3.2.4 Rationale for Nivolumab Dose and Schedule .......................................... 
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........................................................................................
5.5.1 Rationale for 480 mg Every 4 Week ........................................................ 
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..................................................................................
7.1.1 Nivolumab Dosing ................................................................................... 
7.2 Method of Treatment Assignment ....................................................................
7.3 Blinding.............................................................................................................
7.4 Dosage Modification.........................................................................................
7.4.1 Nivolumab Dose Delay Criteria .............................................................. 
7.4.2 Treatment of Nivolumab Related Infusion Reactions .............................. 
7.4.3 Management Algorithms for Immuno-Oncology Agents ......................... 
7.4.4 Nivolumab Treatment Beyond Disease Progression ............................... 
7.5 Preparation/Handling/Storage/Accountability..................................................
7.5.1 Retained Samples for Bioavailability / Bioequivalence ........................... 
7.6 Treatment Compliance......................................................................................
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7.7 Concomitant Therapy........................................................................................
7.7.1 Prohibited and/or Restricted Treatments................................................. 
7.7.2 Other Restrictions and Precautions ......................................................... 
7.7.3 Permitted Therapy ................................................................................... 
7.7.3.1 Imaging Restriction and Precautions ............................................. 
7.8 Treatment After the End of the Study...............................................................
8. DISCONTINUATION CRITERIA ..........................................................................
8.1 Discontinuation from Study Treatment ............................................................
8.1.1 Nivolumab Dose Discontinuation ............................................................ 
8.1.2 Criteria to Resume Treatment .................................................................. 
8.1.3 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 .... 
9.2.1.1 Adverse Events of Special Interest .................................................. 
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 Other Safety Considerations .................................................................... 
9.3 Overdose ...........................................................................................................
9.4 Safety ................................................................................................................
9.4.1 Clinical Safety Laboratory Assessments .................................................. 
9.4.2 Imaging Safety Assessment ...................................................................... 
9.6 Pharmacodynamics ...........................................................................................
9.7 Pharmacogenomics ...........................................................................................
9.9 Health Economics OR Medical Resource Utilization and Health Economics .
10. STATISTICAL CONSIDERATIONS ...................................................................
10.1 Sample Size Determination .............................................................................
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10.2 Populations for Analyses ................................................................................
10.3 Statistical Analyses.........................................................................................
10.3.1 Efficacy Analyses ................................................................................... 
10.3.2 Safety Analyses....................................................................................... 
10.3.3 Other Analyses ....................................................................................... 
10.3.3.1 Pharmacokinetic Analyses ............................................................ 
10.3.4 Additional Exploratory Analysis ............................................................ 
10.3.5 Interim Analyses ..................................................................................... 
10.3.6 Final Analyses ........................................................................................ 
11. REFERENCES .......................................................................................................
12. APPENDICES ........................................................................................................
APPENDIX 1 ABBREVIATIONS AND TRADEMARKS ........................................
APPENDIX 2 PERFORMANCE STATUS SCALES .................................................
APPENDIX 3 RECIST 1.1 GUIDELINES ..................................................................
APPENDIX 4 MANAGEMENT ALGORITHIMS .....................................................
APPENDIX 5 WOMEN OF CHILDBEARING POTENTIAL DEFINITIONS AND
METHODS OF CONTRACEPTION.....................................................................
APPENDIX 6 STUDY GOVERNANCE CONSIDERATIONS .................................
APPENDIX 7 ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS:
DEFINITIONS AND PROCEDURES FOR RECORDING, EVALUATING,
FOLLOW UP AND REPORTING.........................................................................
APPENDIX 8 REVISED PROTOCOL SUMMARY OF CHANGE HISTORY........
 
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Nivolumab
1.
SYNOPSIS
Protocol Title: An Open-label, Single-arm Phase II Safety Study of Nivolumab in 
Participants with Advanced or Metastatic Non-small Cell Lung Cancer Who Have 
Progressed During or After Receiving at Least One Prior Systemic Regimen
Study Phase:
Phase 2
Rationale:
A less frequent administration of nivolumab has the potential for improved convenience for 
patients and reduce administrative burden. A flat dosing is expected to reduce prescription 
dosing errors, shorten pharmacy preparation time, and improve ease of administration. Extending 
the dosing interval to 4 weeks would provide increased flexibility between clinical visits, as 
compared to Q2W dosing schedule.
A dose of 480 mg Q4W was selected based on equivalence to the approved 3 mg/kg every 
2 weeks at the median body weight of ~80 kg in nivolumab-treated participants. A PPK model 
predicted overall nivolumab average exposures across participants with a wide range of body 
weight from 480 mg Q4W to be similar to that from 3 mg/kg Q2W. 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 are maintained below those in 10 mg/kg every 2 weeks, which was 
established as a safe and well-tolerable dose across multiple tumor types. There was no clinical 
meaningful relationship between nivolumab exposure or body weight and frequency or severity 
of AEs. Therefore, a 480 mg Q4W is expected to be safe and tolerable in those patients.
Research Hypothesis
There is no formal hypothesis. The safety profile of less frequent dosing regimen of 480 mg of 
nivolumab every 4 weeks is expected to be similar to that of 3 mg/kg of nivolumab every 
2 weeks in participants with advanced or metastatic NSCLC. The analyses to summarize 
incidence of treatment-related select adverse events will be descriptive.
Study Population:
Participants ≥ 18 years old with advanced or metastatic non-small cell lung cancer who have 
progressed during, or after, receiving at least 1 prior systemic regimen.
Key Inclusion:
•
ECOG Performance Status ≤ 1
•
Participants with histologically documented NSCLC (SQ or NSQ) who present with Stage 
IIIB/Stage IV disease (according to version 7 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).
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•
All participants with non-squamous histology must have been tested for EGFR mutation 
status; use of regulatory -approved test is strongly encouraged. ALK mutation testing is not 
required for this study. 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). Participants who are positive on sensitizing EGFR mutations should have 
received EGFR inhibitors prior to study entry. 
•
Participants must be naïve to IO therapy.
•
Participants must have at least 1 lesion with measurable disease as defined by RECIST v1.1 
criteria for solid tumors response assessment. Participants with lesions in a previously 
irradiated field as the sole site of measurable disease will be permitted to enroll, provided the 
lesion(s) have demonstrated clear progression and can be measured accurately.
1) Key Exclusion Criteria
•
Active brain metastases or leptomeningeal metastases. Participants with brain metastases are 
eligible if these have been treated there is no magnetic resonance imaging (MRI)  - evidence 
of progression for at least 8 weeks after treatment is complete and within 28 days prior to 
first dose of study drug administration. When MRI is contraindicated, the results of the CT 
scan with IV contrast is acceptable.
•
There must also be no requirement for immunosuppressive doses of systemic corticosteroids 
(> 10 mg/day prednisone equivalents) for at least 2 weeks prior to study drug administration.
Objectives and Endpoints:
Table 1:
Objectives and Endpoints
Objective
Endpoint
Primary: 
To characterize the safety of nivolumab 
480 mg IV over 30 minutes every 4 weeks
•
The number and percentage of participants who 
experience high-grade (Grades 3-4 and Grade 5), 
treatment-related select Adverse Events.
•
The select Adverse Events (select AEs) consist of a list 
of preferred terms grouped by specific category (eg,
pulmonary events, gastrointestinal events, hepatic 
events, renal events, skin events, endocrine events 
categories). These categories are defined by the Sponsor 
and the list that is most current at the time of analysis 
will be used. Also changes may be made to this list with 
each new version of MedDRA.
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Table 1:
Objectives and Endpoints
Objective
Endpoint
Secondary:
To estimate the efficacy of nivolumab 
480 mg IV over 30 minutes every 4 weeks
•
Progression-free survival (PFS) defined as the time 
from first dosing date to the date of the first documented 
tumor progression, as determined by investigators (per 
RECIST v1.1), or death due to any cause, whichever 
occurs first.
•
Objective Response Rate (ORR) defined as the number 
and percentage of participants with a best overall 
response (BOR) of confirmed complete response (CR) 
or partial response (PR). Best overall response (BOR) is 
defined as the best response designation, recorded 
between the date of first dose and the date of the initial 
objectively documented tumor progression per RECIST 
v1.1 or the date of subsequent therapy, whichever 
occurs first.
•
Overall survival (OS), defined as the time from first 
dosing date to the date of death.
•
Duration of Response (DOR) 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, whichever occurs first.
Overall Design:
This will be an open-label, single arm Phase 2 safety study of less frequent flat dose 
administration of 
nivolumab in participants ≥ 18 years old with advanced or metastatic 
non-small cell lung cancer who have progressed during or after receiving at least 1 prior 
systemic regimen. Nivolumab 480 mg will be administered every 4 weeks. Each 28-day dosing 
period will constitute a cycle. Participants will receive treatment with nivolumab every 4 weeks 
until progression, unacceptable toxicity, withdrawal of consent, death or a maximum of 2 years, 
whichever occurs first. Treatment beyond initial investigator-assessed RECIST 1.1-defined 
progression will be considered in participants experiencing investigator assessed clinical benefit 
and tolerating study therapy. The post-treatment follow-up begins when the decision to 
discontinue a participant from treatment is made. Participants who discontinue treatment for 
reasons other than disease progression will continue to have tumor assessments (if clinically 
feasible) according to the schedule.
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Participants will be followed for drug-related toxicities until these toxicities resolve, return to 
baseline or are deemed irreversible. All adverse events will be documented for a minimum of 
100 days after the last dose of study medication.
BMS may request that survival data be collected on all treated participants outside of the 
Protocol defined window as detailed in the Section 2 (Schedule of Assessments: Follow-up 
Assessments). At the time of this request, each participant will be contacted to determine their 
survival status unless the participant has withdrawn consent for all contact. The study will end 
once survival follow-up has concluded.
The study design schematic is presented in Figure 1. 
Figure 1:
Study Design Schematic
* Nivolumab to be administered as a flat dose, 480 mg every 4 weeks, until progression, unacceptable toxicity, 
withdrawal of consent, or a maximum treatment duration of 2 years, whichever comes first. 
** Participants discontinuing treatment earlier than 2 years or completed 2 years of treatment will continue to be 
followed for survival follow up every 3 months until death, lost to follow-up, withdrawal of study consent, or up to 
a maximum duration of 5 years after the first dose.
Number of Participants: 
The present study will treat approximately 120 participants. 
Treatment Arms and Duration:
Participants will receive treatment 480 mg nivolumab every 4 weeks until progression, 
unacceptable toxicity, withdrawal of consent, death, or a maximum of 2 years, whichever occurs 
first.
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Study treatment: 
Study Drug for CA209907
Medication 
Potency 
IP/Non-IP 
BMS-936558-01
Solution for Injection/ Nivolumaba
10 mg/mL
IP
a May be labeled as either “BMS-936558-01” or “nivolumab”
STATISTICAL CONSIDERATIONS
Sample Size Determination 
Approximately 200 participants will be enrolled in order to treat up to 120 participants. This 
number of treated participants was chosen to provide descriptive analysis to estimate incidence 
rate of high-grade (Grades 3-4 or Grade 5), drug-related, select AE and rate of immune-mediated 
adverse events in all treated participants with nivolumab alternate dosing schedule. Overall, the 
safety profile of nivolumab monotherapy is manageable and generally consistent across 
completed and ongoing clinical trials with no MTD reached at any dose tested up to 10 mg/kg. 
Most AEs were low-grade (Grade 1 to 2) with relatively few related high-grade (Grades 3 to 4) 
AEs. Rates of high-grade (Grades 3-4 or Grade 5), drug-related, select AE and rate of 
immune-mediated adverse events by category observed in 2L NSCLC CheckMate 063, 017 and 
057 were low and <7%. Nivolumab monotherapy has been extensively studied in multiple tumor 
types, including melanoma, NSCLC, RCC, cHL, Head and Neck and UC with body weight 
normalized dosing (mg/kg). PPK modelling predicted median and 95th percentile of exposures 
are maintained below those in 10 mg/kg every 2 weeks, which was established as a safe and 
well-tolerable dose across multiple tumor types. There was no clinical meaningful relationship 
between nivolumab exposure or body weight and frequency or severity of AEs. Therefore, a 
480 mg Q4W is expected to be safe and tolerable in those patients.
The table below shows the 95% Confidence Intervals for different AE rates for a sample size of 
120 participants. 
Table 2:
95% Confidence Intervals for different AE rates for a sample size 
of 120
Number of participants with AE (%)
Exact 95% CI around proportion
0/120 (0%)
0%-3.0%
1/120 (0.8%)
0.8%-4.6%
2/120 (1.7%)
0.2%-5.9%
3/120 (2.5%)
0.5%-7.1%
4/120 (3.3%)
0.9%-8.3%
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Table 2:
95% Confidence Intervals for different AE rates for a sample size 
of 120
Number of participants with AE (%)
Exact 95% CI around proportion
5/120 (4.2%)
1.4%-9.5%
6/120 (5.0%)
1.9%-10.6%
With a sample size of 120, the chance of observing at least one participant with the event is 
greater than 80% for true probabilities of events higher than 1.3%.
•
If true probability of event is 1%, the chance of observing at least 1 participant with event 
among 120 treated participant s is 70%.
•
If true probability of event is 2%, the chance of observing at least 1 participant with event 
among 120 treated participant s is 91%.
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2.
SCHEDULE OF ACTIVITIES
Table 2-1:
Screening Assessments (All Participants)
Procedure
Screening Visit
(≤ 28 days)
Notes:
To occur within 28 days of first dose, unless otherwise specified.
EligibilityAssessments
Informed Consent
X
Register in Interactive Response system to obtain participant numbers
Inclusion/Exclusion Criteria
X
All inclusion/exclusion criteria should be reassessed prior to first dose
Medical History
X
Medical history will include smoking history. In addition, mutational status 
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 mutational status must be determined. 
Includes risk factors (eg, pleural effusion and pneumonitis). Include any 
toxicities or allergy to previous treatment.
Prior Systemic Cancer Therapies
X
SAFETY ASSESSMENTS
PhysicalMeasurements/Physical Examination, Vital 
Signs, and Performance Status
X
Include height and weight, Performance Status (Appendix 2), BP, HR, RR,
temperature within 72 hours prior to first dose. Complete physical examination 
within 14 days prior to first dose.
Assessment of Baseline Signs and Symptoms
X
Assess within 14 days prior to first dose.
Serious Adverse Event Assessments
X
SAEs present from time of consent. See Section 9.2.
Concomitant Medication Collection
X
Collect within 14 days prior to first dose through the study treatment period.
Pregnancy Test (WOCBP only)
X
Serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent 
units of HCG) to be done at screening visit and within 24 hours of first dose of 
study therapy on Day 1. 
LaboratoryTests
X
Must be performed within 14 days prior to first dose of study therapy:
•
CBC w/differential and platelets
•
Chemistry panel including AST, ALT, ALP, T Bili, BUN or serum urea
level, creatinine, phosphate, Ca, Na, K, Cl, LDH, Glucose, albumin
•
Thyroid panel including TSH, free T3 and free T4
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Table 2-1:
Screening Assessments (All Participants)
Procedure
Screening Visit
(≤ 28 days)
Notes:
To occur within 28 days of first dose, unless otherwise specified.
•
Serology: Hep B surface antigen and Hep C antibody (if Hep C antibody is 
positive reflex Hep C RNA) or Hep C RNA.
•
Follicle stimulating hormone (FSH)-only required to confirm menopause in 
women < age 55
Note: Testing for HIV-1 and HIV-2 must be performed at sites where 
mandated by local requirements.
ECG (12-lead)
X
Obtained only for participants who have met all eligibility criteria.
EFFICACY ASSESSMENTS
Radiographic Tumor Assessments(chest, abdomen, 
pelvis, brain)
X
Performed within 28 days prior to first dose.
CT of Chest, Abdomen, Pelvis and all known or suspected sites of disease 
should be imaged at the screening visit. MRI of brain without and with 
gadolinium is required for those with known or suspected brain metastases.
Tumor assessments will be according to RECIST 1.1 (Appendix 3)
BIOMARKER ASSESSMENTS
Mandatory Archived Tumor Tissue or Recent Tumor 
Biopsy
X
Fresh or archival sample from the primary site of the disease, obtained 
preferably within 6 months prior to enrollment. If the tissue from the primary 
site is unobtainable or unsuitable, tissue from a metastasis site is acceptable if 
its pathology report matches a pathology report from the primary tumor. 
Submission of archival tissue from time of diagnosis may be acceptable in 
some circumstances following a discussion with the BMS Study Director (or 
Medical Monitor). If archived slides are to be submitted, they must not have
been cut > 6 months prior to submission, as the sample may have degraded. 
One formalin-fixed paraffin embedded tumor tissue block or a minimum of 10
unstained tumor slides are required. Submission of fewer than 10 unstained 
slides may be acceptable in some circumstances following discussion with the 
BMS Study Director (or Medical Monitor).
Tissue samples are to be submitted with each matching pathology report and 
biopsy date. If there is inadequate tissue, BMS will contact the site for 
additional tissue. Criterion 2m in Section 6.1 discusses acceptable and 
unacceptable methods of collection. 
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Table 2-1:
Screening Assessments (All Participants)
Procedure
Screening Visit
(≤ 28 days)
Notes:
To occur within 28 days of first dose, unless otherwise specified.
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Table 2-2:
On Treatment Assessments (All Participants)a
Procedure
Cycle 1 
Day 1b
Each 
Subsequent 
Cycle Day 1b
EOTc
Notes
For purposes of this table, a cycle refers to 4 weeks (28 days) of 
treatment.
If a dose is delayed, the procedures scheduled for that same 
time point (with the exception of tumor assessments) should 
also be delayed to coincide with when that time point’s dosing 
actually occurs.
SAFETY ASSESSMENTS
Targeted PhysicalExamination, Vital 
Signs, Performance Status
X
(see note)
X
X
Weight, BP, HR, RR, temperature within 72 hours prior to dosing, 
and Performance Status. 
Note: C1D1 Targeted Physical Examination, Vital Signs, and 
Performance Status do not need to be repeated if Screening 
Physical Measurements/Physical Examination, Vital Signs, and 
Performance Status were performed within 72 hours of first dose.  
Adverse Event Assessments
Continuously during the study
SAEs should be approved within 5 days from entry. For AE 
reporting, see Section 9.2 and Appendix 7.
Review of Concomitant Medications
Continuously during the study
LaboratoryTests
X
X
X
•
CBC w/ differential and platelets
•
Chemistry panel including AST, ALT, ALP, T. Bili, BUN or 
serum urea level, creatinine, phosphate, Ca, Na, K, Cl, LDH, 
glucose, albumin
•
TSH panel including reflex Free T4 and Free T3
•
Within 72 hours prior to dosing.
Note: C1D1 labs do not need to be repeated if they were performed
within 14 days of dosing.
Pregnancy Test (WOCBP only)
X
X
X
To be evaluated at least every 4 weeks.
EFFICACY ASSESSMENTS
Radiographic Tumor Assessment
Repeat CT/MRI of chest/ abdomen with or 
without pelvis is required for participants 
See notes 
First assessment to occur at Week 8 (±  7 days) and then every 
8 weeks (±  7 days) until documented radiographic disease 
progression for a maximum of 2 years from the first dose.
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Table 2-2:
On Treatment Assessments (All Participants)a
Procedure
Cycle 1 
Day 1b
Each 
Subsequent 
Cycle Day 1b
EOTc
Notes
For purposes of this table, a cycle refers to 4 weeks (28 days) of 
treatment.
If a dose is delayed, the procedures scheduled for that same 
time point (with the exception of tumor assessments) should 
also be delayed to coincide with when that time point’s dosing 
actually occurs.
with metastases in those areas at baseline, 
or if clinically indicated.)
*Participants with a history of brain metastasis must have 
surveillance MRI approximately every 12 weeks from the date of 
first dose, or sooner if clinically indicated.
Participants being treated beyond progression tumor assessment 
continues per protocol specified schedule until the participant 
comes off study or for a maximum duration of 2 years from first 
dose.
CLINICAL DRUG SUPPLIES
IRT Vial Assignment
X 
X 
Within 3 calendar days prior to first dosing
Nivolumab 480 mg
X 
X 
a 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.
b If a dose is delayed, the procedures scheduled for that same timepoint should also be delayed to coincide with when that timepoint’s dosing actually occurs.
c EOT (end of treatment) is defined as the visit where the decision is made to discontinue the participants from treatment. For participants who complete all the 
scheduled cycles of therapy for a maximum of 2 years duration from first dose, the EOT will be the most recent on-treatment visit. For participants who 
discontinue from the study earlier than the maximum duration of 2 years from first dose , the EOT will be the most recent on-treatment visit (with all available 
safety and response data) and does not need to be repeated and will be considered the start of the week 1 safety follow up visit.
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Table 2-3:
Follow-up and Survival Procedures (All Participants)a
Procedure
Follow-Upb
Visits 1 & 2
Survival ,c
Follow-up Visits
Notes
SAFETY ASSESSMENTS
Physical Examination
X
To assess for potential late emergent study drug related issues.
Vital Signs
X
Including BP, HR, RR and temperature.
Adverse Event Assessment
X
SAEs should be approved within 5 days from entry. Beyond 100 days
from the last dose of study drug, participants will be followed for ongoing
drug-related adverse events until resolved, return to baseline or deemed
irreversible, or until lost to follow-up, withdrawal of study consent, or
start of subsequent therapy.
Review of Concomitant Medications
X
LaboratoryTests
X
Required at Visit 1. Repeat at Visit 2 only if study drug related toxicity
persists.
Pregnancy Test (WOCBP only)
X
EFFICACY ASSESSMENTS
Radiographic Tumor Assessment
(CT chest and known sites of disease.
Repeat CT/MRI of abdomen with or
without pelvis is required for
participants with metastases in those
areas at baseline, or if clinically
indicated.)
X*
X**
An unconfirmed PR or unconfirmed CR must be confirmed at least 
4 weeks after initial assessment
*Radiographic assessments for participants who have not experienced
PD must be obtained every 8 weeks (± 7 days) and not delayed until
Follow-up Visits 1 & 2.
**Participants who discontinue earlier than 2 years or completed 2 years 
of treatment but achieve SD/PR/CR at the end of Follow-up Visit 2 will 
have imaging scans every 3 months (12 weeks ± 7 days) until 
documented radiographic disease progression or up to maximum 
duration of 5 years after first dose 
Collection of Survival Status and
Subsequent TherapyInformation
X
X
Collect every 3 months in Survival Visits until death, lost to follow-up, 
withdrawal of study consent, or up to a maximum duration of 5 years 
after the first dose. May be performed by phone contact or office visit.
aSome 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.
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bParticipants must be followed for at least 100 days after last dose of study treatment. Follow-up Visit 1 (FU1) should occur 30 days from the last dose (± 7) days 
or can be performed on the date of discontinuation if that date is greater than 42 days from last dose. Follow-up Visit 2 (FU2) occurs approximately 100 days 
(± 7 days) from last dose of study drug. Both Follow-up Visits should be conducted in person.
c After completion of Follow-up Visit 1 and 2, all participants will enter Survival/ Response Follow-Up phase to occur approximately every 3 months from 
Follow-Up Visit 2 until death, lost to follow up, withdrawal of consent, or up to maximum duration of 5 years after the first dose, whichever comes first.
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3.
INTRODUCTION
Nivolumab (OPDIVO®) was approved in the United States (US) to treat patients with metastatic 
squamous cell NSCLC with progression on or after platinum-based chemotherapy. The approval 
was based on the results of Study CA209017, a randomized trial of nivolumab versus docetaxel. 
The median overall survival (OS) for participants in the nivolumab arm was 9.2 months versus 
6 months for those in the docetaxel arm (hazard ratio [HR] = 0.59). Improvement in survival was 
observed for nivolumab regardless of PD-L1 expression; however, there was a trend for better 
efficacy for those with PD-L1-positive tumors. A single-arm trial (Study CA209063) of 
117 participants with metastatic squamous cell NSCLC, with progression after platinum-based 
chemotherapy and at least 1 additional systemic regimen, showed a 15% overall response rate 
(ORR); 59% of these participants had response durations of 6 months or longer. A second Phase 3 
study, Study CA209057 demonstrating superior OS of nivolumab versus docetaxel in participants 
with previously-treated non squamous NSCLC with a 27% reduction in risk of death (HR = 0.73; 
P = 0.0015). Interaction P-values reported for PD-L1 expression subgroups by each of the 
predefined expression levels suggested a clinically important signal of a predictive association. 
Nivolumab also significantly improved ORR versus docetaxel (P = 0.0246), with ORR as high as 
36% in participants with PD-L1-expressing tumors. OS approximately doubled with nivolumab 
versus docetaxel across the PD-L1 expression continuum. In contrast, no difference in OS was 
seen between nivolumab and docetaxel when PD-L1 was not expressed in the tumor.
In general, nivolumab has been well tolerated to date, with a favorable safety profile consistent 
with anticipated toxicities based on an immunostimulatory mechanism of action. Nivolumab has 
been studied and is widely approved in multiple indications. Extensive details on the safety profile 
of nivolumab are available in the Investigator Brochure.
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. Most AEs were low-grade (Grade 1 to 2) with relatively few 
related high-grade (Grade 3 to 4) AEs. There was no pattern in the incidence, severity, or causality 
of AEs with respect to nivolumab dose level. Additional details on the safety profile of nivolumab, 
including results from other clinical studies, are also available in the nivolumab IB.
Decreasing the frequency of administration of nivolumab has the potential for improved 
convenience for patients and to reduce administrative burden. A flat dosing is expected to reduce 
prescription dosing errors, shorten pharmacy preparation time, and improve ease of administration. 
Extending the dosing interval to 4 weeks would provide increased flexibility between clinical 
visits, as compared to Q2W dosing schedule. The development of nivolumab is ongoing to provide 
additional data on the optimal dose and frequency of nivolumab administration that balances
quality of life and compliance for patients in addition to efficacy and safety. This study will
evaluate the safety profile of a less frequent dose administration. 
3.1
Study Rationale
Nivolumab has been studied and is widely approved in multiple indications and has been well 
tolerated to date, with a favorable safety profile. An unmet need was identified to characterize the 
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safety of less frequent dosing regimen 480 mg flat dose dosing regimen of nivolumab
monotherapy.
A less frequent administration of nivolumab has the potential for improved convenience for 
patients and reduce administrative burden. A flat dosing is expected to reduce prescription dosing 
errors, shorten pharmacy preparation time, and improve ease of administration. Extending the 
dosing interval to 4 weeks would provide increased flexibility between clinical visits as compared 
to Q2W dosing schedule
3.1.1
Research Hypothesis
There is no formal hypothesis. The safety profile of less frequent dosing regimen of 480 mg of 
nivolumab every 4 weeks is expected to be similar to that of 3 mg/kg of nivolumab every 2 weeks 
in participants with advanced or metastatic NSCLC. The analyses to summarize incidence of drug 
related select adverse events will be descriptive.
3.2
Background
3.2.1
Non-Small Cell Lung Cancer (NSCLC) Background
Lung cancer is the leading cause of cancer and cancer-related deaths globally, accounting for 
1.8 million new cases and 1.6 million deaths worldwide in 2012.1 Between 2004 and 2010, 
according to the SEER database, the overall 5-year survival rate was 21.4%.2 The majority of 
patients were diagnosed with advanced or metastatic disease. Prognosis for these patients remains 
dismal, with 5-year survival rates of < 5%. Approximately 85% of lung cancer is NSCLC, and of 
these, approximately 80% are non-squamous, and 20% are squamous histology. The use of 
platinum-based chemotherapy doublets, given for up to 6 cycles, is standard-of-care for patients 
with newly diagnosed advanced or metastatic NSCLC who do not have EGFR mutation or ALK 
translocation. 3 Current first-line chemotherapy doublets include cisplatin or carboplatin in 
combination with antimicrotubule agents, gemcitabine, or pemetrexed. Overall response rates with 
these platinum doublets is approximately 30-35%. Progression-free survival (PFS) has remained 
about 4 to 5.5 months, with an overall survival (OS) of about 9 to 11 months.4
In early clinical trials, the immunotherapeutic agent, nivolumab, has demonstrated activity in 
several tumor types, including melanoma, renal cell cancer, and NSCLC.5 Tumors may modulate 
and evade the host immune response through a number of mechanisms, including down regulation 
of tumor-specific antigen expression and presentation, secretion of anti-inflammatory cytokines, 
and upregulation of inhibitory ligands. T cell checkpoint regulators such as CTLA-4 and 
programmed death-1 (PD-1, CD279) are cell surface molecules that, when engaged by their 
cognate ligands, induce signaling cascades down-regulating T cell activation and proliferation. 
One proposed model by which therapeutic T cell checkpoint inhibitors derive antitumor activity is 
through breaking of immune tolerance to tumor cell antigens.
Nivolumab (BMS-936558) is a fully human, IgG4 (kappa) isotype mAb that binds PD-1 on 
activated immune cells and disrupts engagement of the receptor with its ligands PD-L1 
(B7-H1/CD274) and PD-L2 (B7-DC/CD273), thereby abrogating inhibitory signals and 
augmenting the host antitumor response.
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Nivolumab (Opdivo®) has recently been approved in the United States (US) to treat patients with 
advanced (metastatic) squamous cell and nonsquamous cell lung cancer whose disease has 
progressed during or after platinum-based chemotherapy. Approval of nivolumab in advanced 
NSCLC was based on 2 Phase 3 trials (CheckMate 017 and CheckMate 057) which demonstrated 
survival benefit over docetaxel across histologies. The approval in squamous NSCLC was based 
on the results of CA209017, a randomized trial of nivolumab versus docetaxel. The median OS 
for patients in the nivolumab arm was 9.2 months versus 6 months for those in the docetaxel arm 
(HR = 0.59). Improvement in survival was observed for nivolumab regardless of PD-L1 
expression, though there was a trend toward better efficacy for those with PD-L1 expressing 
tumors. A single-arm trial (CA209063) of 117 patients with metastatic squamous NSCLC with 
progression after platinum-based chemotherapy and at least 1 additional systemic regimen showed 
a 15% objective response rate (ORR); 59% of participants with an ORR had response durations of 
6 months or longer.
The approval of nivolumab for the treatment of non-squamous NSCLC is based on a second Phase 
3 study, CA209057, which met its primary endpoint of superior OS of nivolumab versus docetaxel 
in patients with previously treated non-squamous NSCLC at a preplanned interim analysis. 
Patients in the nivolumab arm had a 27% reduction in risk of death (HR = 0.73; P = 0.0015). 
Interaction P values, reported for PD L1 expression subgroups by each of the predefined 
expression levels, suggested a clinically important signal of a predictive association. Nivolumab 
also significantly improved ORR vs docetaxel (P=0.0246), with ORR as high as 36% in patients 
with PD-L1 expressing tumors. OS approximately doubled with nivolumab vs docetaxel at 1%, 
5% and 10% PD-L1 expression level. In contrast, no statistically significant difference in OS was 
seen between nivolumab and docetaxel when PD-L1 was not expressed in the tumor, although 
these patients also experienced durable responses, and the safety profile was more favorable for 
nivolumab vs docetaxel.6
In general, nivolumab is well tolerated, with a favorable safety profile relative to anticipated 
toxicities based on an immunostimulatory mechanism of action. Nivolumab is currently in Phase 3 
development in the first-line metastatic and the early stage NSCLC settings. A detailed description 
of the chemistry, pharmacology, efficacy, and safety of nivolumab is provided in the Investigator’s 
Brochure and local package insert.
3.2.2
Nivolumab Mechanism of Action
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. 7,8,9
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 
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involving the integration of numerous positive as well as negative co-stimulatory signals in 
addition to antigen recognition by the T-cell receptor (TCR).10 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. 11 PD-1 signaling has been shown to inhibit CD-28-mediated 
upregulation of IL-2, IL-10, IL-13, interferon-γ (IFN-γ) and Bcl-xL. PD-1 expression 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.12 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 
restimulation 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 results in tumor rejection in 
several immunocompetent mouse tumor models (MC38, SA1/N, and PAN02).13
3.2.3
Nivolumab in NSCLC
PD-1 is a 55 kD type I transmembrane protein primarily expressed on activated T cells, B cells, 
myeloid cells, and antigen presenting cells (APC).14 Binding of PD-1 to PD-L1 and PD-L2 has 
been shown to down-regulate T-cell activation in both murine and human systems.15,16,17,18 In 
particular, PD-L1 has been shown to be upregulated on several cancers types including NSCLC 
and, in some cases, correlated to negative prognosis.19,20,21,22,23 PD-1/PD-L interactions may also 
indirectly modulate the response to tumor antigens through T-cell/APC interactions. Therefore, 
PD-1 engagement may represent one means by which tumors evade immunosurveillance and 
clearance. 24 Blockade of the PD-1 pathway by nivolumab has been studied in a variety of 
preclinical in vitro assays, and antitumor activity using a murine analog of nivolumab has been 
shown in a number of immunocompetent mouse cancer models. Based on these and other 
preclinical data, PD-1 blockade by nivolumab has been pursued as a promising therapeutic strategy 
to reverse immune tolerance and enhance T-cell effector function in several tumor types including 
NSCLC.11
3.2.4
Rationale for Nivolumab Dose and Schedule
Nivolumab monotherapy has been extensively studied in multiple tumor types, including 
melanoma, NSCLC, RCC, cHL, Head and Neck, and UC with body weight normalized dosing 
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(mg/kg). 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 mg/kg 
dose represents an over-adjustment for the effect of body weight on nivolumab PK. A flat dosing 
is expected to reduce prescription dosing errors, shorten pharmacy preparation time, and improve 
ease of administration. Extending the dosing interval to 4 weeks provided numerous benefits to 
patients as they would have increased flexibility between clinical visits, as compared to Q2W 
dosing schedule. 
A 480 mg Q4W regimen was selected based on equivalence to the approved 3 mg/kg every 
2 weeks at the median body weight of ~80 kg in nivolumab-treated participants. A PPK model 
predicted overall nivolumab average exposures across participants with a wide range of body 
weight from 480 mg Q4W to be similar to that from 3 mg/kg Q2W. 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 are maintained below those in 10 mg/kg every 2 weeks, which was
established as a safe and well-tolerable dose across multiple tumor types. The simulated median 
and 95th prediction interval of nivolumab summary exposures across body weight range (35 to
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 participants in the lower body weight ranges would have greater 
exposures than 80 kg participants, 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 participants at increased risk. There was no clinical meaningful relationship 
between nivolumab exposure or BW and frequency or severity of AEs. Therefore, a 480 mg Q4W 
is expected to be safe and tolerable in those patients. In terms of efficacy, 480 mg Q4W is expected 
to result in similar efficacy given a flat exposure-response relationship and same dose intensity. 
Overall, the benefit-risk profile of nivolumab 480 mg Q4W is expected to be similar to approved 
regimen 3 mg/kg Q2W, and it is recommended for further investigation in this study.
3.3
Benefit/Risk Assessment
Participants with advanced or metastatic NSCLC who progress with first-line therapy represent a 
great unmet need. The clinical activity of nivolumab observed to date in NSCLC suggests the 
potential for improved clinical outcomes as monotherapy. A flat dosing is expected to reduce 
prescription dosing errors, shorten pharmacy preparation time, and improve ease of administration. 
Extending the dosing interval to 4 weeks provided numerous benefits to patients as they would 
have increased flexibility between clinical visits, as compared to Q2W dosing schedule. 
Overall, the safety profile of nivolumab monotherapy is manageable and generally consistent 
across completed and ongoing clinical trials with no MTD reached at any dose tested up to 
10 mg/kg. Most AEs were low-grade (Grade 1 to 2) with relatively few related high-grade (Grade 3 
to 4) AEs. There was no pattern in the incidence, severity, or causality of AEs with respect to 
nivolumab dose level.
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A pattern of immune-related adverse events has been defined, for which management algorithms 
have been developed; these are provided in Appendix 4. Most high-grade events were manageable 
with the use of corticosteroids or hormone replacement therapy (endocrinopathies) as instructed 
in these algorithms. 
Additional details on the safety profile of nivolumab, including results from other clinical studies, 
are also available in the nivolumab IB.
4.
OBJECTIVES AND ENDPOINTS
Table 4.-1:
Objectives and Endpoints
Objective
Endpoint
Primary: 
To characterize the safety of nivolumab 
480 mg IV over 30 minutes every 4 weeks
•
The number and percentage of participants who experience 
high-grade (Grades 3-4 and Grade 5), treatment-related select 
Adverse Events 
The select Adverse Events (select AEs) consist of a list of 
preferred terms grouped by specific category (eg, pulmonary 
events, gastrointestinal events, hepatic events, renal events, 
skin events, endocrine events categories). These categories are 
defined by the Sponsor and the list that is most current at the 
time of analysis will be used. Also changes may be made to this 
list with each new version of MedDRA.
Secondary:
To estimate the efficacy of nivolumab 
480 mg IV over 30 minutes every 4 weeks
•
Progression-free survival (PFS) defined as the time from first 
dosing date to the date of the first documented tumor 
progression, as determined by investigators (per RECIST 
v1.1), or death due to any cause, whichever occurs first.
•
Objective Response Rate (ORR) defined as the number and 
percentage of participants with a best overall response (BOR) 
of confirmed complete response (CR) or partial response 
(PR). Best overall response (BOR) is defined as the best 
response designation, recorded between the date of first dose 
and the date of the initial objectively documented tumor 
progression per RECIST v1.1 or the date of subsequent 
therapy, whichever occurs first.
•
Overall survival (OS) defined as the time from first dosing 
date to the date of death.
•
Duration of Response (DOR) 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, whichever occurs first.
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5.
STUDY DESIGN
5.1
Overall Design
This will be an open-label, single arm Phase 2 safety study of less frequent flat dose administration 
of nivolumab in participants ≥18 years old with advanced or metastatic non-small cell lung cancer 
who have progressed during or after receiving at least 1 prior systemic regimen.
The study will consist of 3 phases: screening, treatment, and follow-up.
Screening Phase
Begins by establishing the participant’s initial eligibility and signing of the informed consent 
(ICF). The participant will be enrolled using an interactive response technology (IRT). The 
screening period will last for 28 days. All screening assessments and procedures must be 
performed within 28 days prior to treatment. 
Treatment Phase
Eligible participants will be assigned by IRT. Participants will receive treatment with nivolumab 
every 4 weeks until progression, unacceptable toxicity, withdrawal of consent, or a maximum 
treatment duration 2 years. 
Tumor assessment will be performed every 8 weeks (± 7 days). Assessment of partial assessment 
response (PR) and complete response (CR) must be confirmed at least 4 weeks following initial 
assessment. Tumor response assessment will be assessed using RECIST 1.1 (Appendix 3).
•
Treatment beyond initial investigator-assessed RECIST 1.1-defined progression will be 
considered in participants experiencing investigator assessed clinical benefit and tolerating 
study therapy as per Section 7.4.4. Such participants must discontinue therapy when further 
progression is documented. Study assessments are to be collected as outlined in Table 2-2. 
Upon end of treatment participants will enter the Follow-up Phase. The post-treatment follow-
up begins when the decision to discontinue a participant from all treatment is made.
Follow-up Phase
Upon completion of the study, participants will enter the Follow-up Phase including in Safety 
Follow-up and Response/Survival Follow-up. 
•
Safety follow-up: Upon completion of the study, participants will enter the safety follow-up 
period lasting approximately 100 days from the last treatment. After the end of the treatment 
(EOT visit), participants will be followed for drug-related toxicities until these toxicities 
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resolve, return to baseline, or are deemed irreversible. All adverse events will be documented 
for a minimum of 100 days after the last dose of study medication. Participants must complete 
the 2 clinical safety follow-up visits regardless of whether they start new anticancer therapy.
•
Response/Survival follow-up: Participants who discontinue treatment for reasons other than 
disease progression or completed 2 years of treatment will continue to have tumor assessments 
(if clinically feasible) according to the schedule. In follow-up period, participants with ongoing 
SD, PR or CR at the EOT visit will enter response follow-up period. These participants will 
continue to have radiological and clinical tumor assessment every 3 months (12 weeks) until 
disease progression, death, lost to follow-up, withdrawal of study consent, or up to a maximum 
duration of 5 years after the first dose.
•
In addition, all participants who are discontinued from treatment earlier than 2 years or 
completed 2 years of treatment will be followed for survival every 3 months (12 weeks) until 
death, lost to follow up, withdrawal of consent, or up to a maximum duration of 5 years after 
the first dose.
The study design schematic is presented in Figure 5.1-1.
Figure 5.1-1:
Study Design Schematic
* Nivolumab to be administered as a flat dose, 480 mg every 4 weeks, until progression, unacceptable toxicity, 
withdrawal of consent, or a maximum treatment duration of 2 years, whichever comes first. 
** Participants discontinuing treatment earlier than 2 years or completed 2 years of treatment will continue to be 
followed for survival follow up every 3 months until death, lost to follow-up, withdrawal of study consent, or up to 
a maximum duration of 5 years after the first dose.
5.1.1
Data Monitoring Committee and Other External Committees
The Sponsor of this study will not utilize an independent data safety monitoring board (DSMB). 
BMS will assign a physician responsible for reviewing, on a systematic and continuous basis, the 
safety of participants in this study. This includes a review of serious and non-serious adverse events 
Intervention
Nivolumab 
480 mg every 
4 weeks
Study population
N= 120
Participants with 
advanced or metastatic 
NSCLC Who Have 
Progressed During or 
After Receiving At 
Least One Prior 
Systemic Regimen
SQ or Non-SQ
ECOG PS 0-1
Endpoints
Primary Endpoint 
•
Safety: Measuring the incidence 
for high grade (Grades 3-4 and 
Grade 5) treatment related select 
adverse events
Secondary Endpoints
•
ORR, PFS, DOR, OS
Screening Phase
-28 Days
Treatment Phase
Maximum Duration 
of 2 Years *
Follow-up Phase
(Safety Follow-up and 
Response/Survival Follow-up) **
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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 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
The present study plans to treat approximately 120 participants. 
5.3
End of Study Definition
The start of the trial is defined as the first screening visit for the first participant. End of trial is 
defined as last participant last follow-up visit, or up to a maximum of 5 years from last participant’s 
first dosing.
5.4
Scientific Rationale for Study Design
This is an open-label, single-arm, Phase 2 safety study of nivolumab that will provide additional 
safety data to support the alternate less frequent dosing regimen for nivolumab monotherapy. An 
open-label design will ensure that immune-mediated AEs are promptly identified and managed. 
The study will consist of 3 phases: screening, treatment, and follow-up.
5.5
Justification for Dose
5.5.1
Rationale for 480 mg Every 4 Week
Details regarding dose rationale are provided in Section 3.2.4.
6.
STUDY POPULATION
Males and female participants ≥18 years old with advanced or metastatic non-small cell lung 
cancer who have progressed during or after receiving at least 1 prior systemic regimen will be 
included in this population. 
For entry into the study, the following criteria MUST be met.
6.1
Inclusion Criteria
1) Signed Written Informed Consent
a) Participants must be able to give self-consent and then sign and date an IRB/IEC-approved 
written informed consent in accordance with regulatory and institutional guidelines. This 
must be obtained before the performance of any protocol-related procedures that are not 
considered part of normal patient care.
b) Participants must be willing and able to comply with scheduled visits, treatment schedule, 
laboratory testing, and other requirements of the study.
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2) Type of Participant and Target Disease Characteristics
a) ECOG Performance Status ≤1
b) Participants with histologically documented NSCLC (SQ or NSQ) who present with Stage 
IIIB/Stage IV disease (according to version 7 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 during or after at 
least 1 systemic therapy for advanced or metastatic disease.
(1) 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.
(2) Maintenance therapy following platinum doublet-based chemotherapy is not 
considered as a separate regimen of therapy.
c) Participants who received platinum-containing adjuvant, neoadjuvant or definitive 
chemo-radiation therapy given for locally advanced disease, and developed recurrent (local 
or metastatic) disease within 6 months of completing therapy are eligible.
d) Participants with recurrent disease > 6 months after completing a platinum-containing 
adjuvant, neoadjuvant or definitive chemo-radiation therapy given for locally advanced 
disease, who also subsequently progressed during or after a systemic regimen given to treat 
the recurrence, are eligible.
e) All participants with non-squamous histology must have been tested for EGFR mutation 
status; use of regulatory-approved test is strongly encouraged. ALK mutation testing is not 
required for this study. 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). Participants who are positive on sensitizing EGFR mutations should have 
received EGFR inhibitors prior to study entry.
f)
Experimental therapies when given as separate regimen are considered as separate line of 
therapy.
i)
Participants must be naïve to IO therapy. Should not have 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.
g) Participants must have a life expectancy of at least 3 months following their most recent 
chemotherapy.
h) Participants receiving prior palliative radiotherapy to a non-central nervous system (CNS). 
Lesion must have completed that therapy at least 2 weeks prior to the first dose of study 
drug.
i)
Participants with symptomatic tumor lesions at baseline who may require palliative 
radiotherapy within 4 weeks of the first dose of study drug are strongly encouraged to 
receive palliative radiotherapy prior to enrollment. Lesions which have received or are 
anticipated to receive palliative RT may not be designated as target or non-target lesions 
in the baseline tumor assessment.
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j)
Evaluable disease by CT or MRI; radiographic tumor assessment performed within 28 days 
of start of study treatment.
k) Participants must have at least 1 lesion with measurable disease as defined by RECIST 
v1.1 criteria for solid tumors response assessment. Participants with lesions in a previously 
irradiated field as the sole site of measurable disease will be permitted to enroll, provided 
the lesion(s) have demonstrated clear progression and can be measured accurately.
l)
Participants with toxicity from any prior anti-cancer therapy must have their toxicity 
returned to Grade ≤1 (NCI Common Terminology Criteria for Adverse Events [CTCAE] 
Version 4.03) or baseline before administration of study drug.
i)
Participants Grade ≥2 with toxicities attributed to prior anti-cancer therapy that are not 
expected to resolve and result in long-lasting sequela, such as neuropathy after a 
platinum-based therapy, are eligible.
ii)
Grade >1 alopecia is permitted.
m) Participants must have tissue submitted prior to study start
i)
Either a formalin-fixed, paraffin-embedded (FFPE) tissue block or unstained tumor 
tissue sections, with an associated pathology report, must be submitted for biomarker 
evaluation prior to treatment assignment. The tumor tissue sample may be fresh or 
archival if obtained preferably within 6 months prior to enrollment. Submission of 
archival tissue from time of diagnosis may be acceptable in some circumstances following 
a discussion with the BMS Study Director (or Medical Monitor).
ii) Tissue must be a core needle biopsy, excisional, or incisional biopsy. Fine needle 
biopsies or drainage of pleural effusions with cytospins are not considered adequate for 
biomarker review. Biopsies of bone lesions that do not have a soft tissue component or 
decalcified bone tumor samples are also not acceptable.
iii) Samples collected via other procedures, including, but not limited to, Endobronchial 
Ultrasound (EBUS) guided biopsy, transbronchial lung biopsy (TBLB) may be 
approved by the BMS MM/SD on a case by case basis.
3) Age and Reproductive Status
a) Males and Females, ages 18 or age of majority 
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) Women of childbearing potential (WOCBP) must agree to follow instructions for 
method(s) of contraception during treatment and for a period of 5 months after the last dose 
of nivolumab (ie, 30 days for duration of ovulatory cycle plus the time required for 
nivolumab to undergo five half-lives).
e) Males who are sexually active with WOCBP must agree to follow instructions for 
method(s) of contraception during treatment and for a period of 7 months after the last dose 
of nivolumab (ie, 90 days for duration of sperm turnover plus the time required for the 
investigational drug to undergo five half-lives).
f)
Azoospermia males are exempt from contraceptive requirements. 
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g) 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 5),
which have a failure rate of < 1% when used consistently and correctly.
6.2
Exclusion Criteria
1) Target Disease Exceptions
a) Active brain metastases or leptomeningeal metastases. Participants with brain metastases 
are eligible if these have been treated there is no magnetic resonance imaging (MRI) -
evidence of progression for at least 8 weeks after treatment is complete and within 28 days 
prior to first dose of study drug administration. When MRI is contraindicated, the results 
of the CT scan with IV contrast is acceptable.
b) There must also be no requirement for immunosuppressive doses of systemic 
corticosteroids (> 10 mg/day prednisone equivalents) for at least 2 weeks prior to study 
drug administration. 
2) Medical Conditions
a) Participants must have recovered from the effects of major surgery or significant traumatic 
injury at least 14 days prior to treatment.
b) Participants with previous malignancies (except non-melanoma skin cancers, and in situ 
cancers such as the following: bladder, gastric, colon, cervical/dysplasia, melanoma, or 
breast) are excluded unless a complete remission was achieved at least 3 years prior to 
treatment and no additional therapy is required or anticipated to be required during the 
study period.
c) Other active malignancy requiring concurrent intervention.
d) Participants with an active, known or suspected autoimmune disease. Participants with type 
I diabetes mellitus, hypothyroidism only requiring hormone replacement, skin disorders 
(such as vitiligo, psoriasis, or alopecia) not requiring systemic treatment, or conditions not 
expected to recur in the absence of an external trigger are permitted to enroll.
e) 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. Inhaled or topical steroids, and adrenal replacement steroid > 10 mg 
daily prednisone equivalent, are permitted in the absence of active autoimmune disease.
f)
Participants with interstitial lung disease that is symptomatic or may interfere with the 
detection or management of suspected drug-related pulmonary toxicity.
g) Known history of testing positive for human immunodeficiency virus (HIV) or known 
acquired immunodeficiency syndrome (AIDS). NOTE: Testing for HIV must be performed 
at sites where mandated locally.
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h) Any positive test result for hepatitis B virus or hepatitis C virus indicating the presence of 
virus, eg, Hepatitis B surface antigen (HBsAg, Australia antigen) positive, or Hepatitis C 
antibody (anti-HCV) positive (except if HCV-RNA negative).
i)
Known medical condition that, in the investigator’s opinion, would increase the risk 
associated with study participation or study drug administration or interfere with the 
interpretation of safety results.
3) Prior/Concomitant Therapy
a) 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) Treatment with botanical preparations (eg herbal supplements or traditional Chinese 
medicines) intended for general health support or to treat the disease under study within 4 
weeks prior to first treatment.
4) Physical and Laboratory Test Findings
a) WBC < 2000/μL
b) Neutrophils < 1500/μL
c) Platelets < 100 x 103/μL
d) Hemoglobin < 9.0 g/dL
e) Serum creatinine > 1.5 x ULN, unless creatinine clearance ≥ 40 mL/min (measured or 
calculated using the Cockroft-Gault formula)
f)
AST/ALT: > 3.0 x ULN
g) Total bilirubin > 1.5 x ULN (except participants with Gilbert Syndrome who must have a 
total bilirubin level of < 3.0 x ULN)
5) Allergies and Adverse Drug Reaction
a) History of allergy or hypersensitivity to study drug components. 
6) 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 
(eg, infectious disease) illness
c) Any other serious or uncontrolled medical disorder, active infection, physical exam 
finding, laboratory findings, altered mental status, or psychiatric condition that, in the 
opinion of the investigator, would limit a participant’s ability to comply with the study 
requirements, substantially increase risk to the participant, or impact the interpretability of 
study results. 
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.
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6.3
Lifestyle Restrictions
Not applicable. No restrictions are required
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 permits the re-enrollment of a participant that has 
discontinued the study as a pre-treatment failure (ie, participant has not been randomized / has not 
been treated). If re-enrolled, the participant must be re-consented
Retesting of laboratory parameters and/or other assessments within any single Screening period 
will be permitted (in addition to any parameters that require a confirmatory value).
The most current result prior to Randomization is the value by which study inclusion will be 
assessed, as it represents the participant’s most current, clinical state.
Laboratory parameters and/or assessments that are included in Table 2-1, Screening Procedural 
Outline may be repeated in an effort to find all possible well-qualified participants. Consultation 
with the Medical Monitor may be needed to identify whether repeat testing of any particular 
parameter is clinically relevant.
7.
TREATMENT
Study treatment is defined as any investigational treatment(s), marketed product(s), placebo or 
medical device intended to be administered to a study participant according to the study treatment 
allocation
Study 
treatment
includes 
both 
Investigational 
[Medicinal] 
Product 
(IP/IMP) 
and 
Non-investigational [Medicinal] Product (Non-IP/Non-IMP) and can consist of the following:
•
Nivolumab as 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 CA209907
Product Description / 
Class and Dosage 
Form
Potency
IP/Non-IMP
Blinded or Open 
Label
Packaging / 
Appearance
Storage Conditions
(per label)
BMS-936558-01
Solution for Injection/ 
Nivolumab a
10 mg/mL
IP
Open-label
Clear to opalescent, 
colorless to pale yellow 
liquid. May contain 
particles.
2° to 8° C. Protect form 
light, and freezing.
a May be labeled as either “BMS-936558-01” or “nivolumab”
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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/Dosage level
Dosage formulation
Frequency of 
Administration
Route of Administration
Nivolumab
10 mg/mL/ 480 mg
Every 4 weeks
IV Infusion
7.1.1
Nivolumab Dosing
Participants should receive nivolumab at a dose of 480 mg as a 30-minute infusion on Day 1 of 
each treatment cycle until progression, unacceptable toxicity, withdrawal of consent, death, or for 
maximum treatment duration of 2 years, whichever occurs first. Participants should begin study 
treatment within 3 days of treatment assignment. 
There will be no dose escalations or reductions of nivolumab allowed. Participants may be dosed 
no less than 25 days from the previous dose during cycles. For every 4 week dosing cycles, 
participants may be dosed within a ± 3 day window. 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 7.4.2.
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 Injection, 10 mg/mL 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 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.
7.2
Method of Treatment Assignment
Study using Interactive Response Technology (IRT): All participants will be assigned using an 
Interactive Response Technology (IRT). Before the study is initiated, each user will receive log-in 
information and directions on how to access the IRT.
Study treatment will be dispensed at the study visits as listed in Schedule of Activities (Section 2). 
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7.3
Blinding
Not applicable.
7.4
Dosage Modification
Dose reductions or modification of nivolumab are not permitted. 
7.4.1
Nivolumab Dose Delay Criteria  
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: 
−
Grade 3 lymphopenia or asymptomatic amylase or lipase does not require dose delay
−
Grade ≥3 AST, ALT, Total Bilirubin will require dose discontinuation (see Section 8.1.1)
•
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.
7.4.2
Treatment of Nivolumab Related Infusion Reactions
Since nivolumab contains only human immunoglobulin protein sequences, it is unlikely to be 
immunogenic and induce infusion or hypersensitivity reactions. However, if such a reaction were 
to occur, it might manifest with fever, chills, rigors, headache, rash, pruritus, arthralgias, 
hypotension, hypertension, bronchospasm, or other allergic-like reactions. All Grade 3 or 4 
infusion reactions should be reported within 24 hours to the study medical monitor and reported 
as an SAE if it meets the criteria. Infusion reactions should be graded according to NCI CTCAE 
(Version 4.0) guidelines.
Treatment recommendations are provided below and may be modified based on local treatment 
standards and guidelines, as appropriate:
For Grade 1 symptoms: (Mild reaction; infusion interruption not indicated; intervention not 
indicated).
•
Remain at bedside and monitor 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 administrations.
For Grade 2 symptoms: (Moderate reaction requires therapy or infusion interruption but 
responds promptly to symptomatic treatment [eg, antihistamines, non-steroidal anti-
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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 no further nivolumab will be administered at that visit.
•
For future infusions, the following prophylactic premedications are recommended: 
diphenhydramine 50 mg (or equivalent) and/or acetaminophen/paracetamol 325 to 1000 mg 
should be administered at least 30 minutes before nivolumab infusions. If necessary, 
corticosteroids (up to 25 mg of SoluCortef or equivalent) may be used.
For Grade 3 or 4 symptoms: (Severe reaction, Grade 3: prolonged [ie, not rapidly responsive 
to symptomatic medication and/or brief interruption of infusion]; recurrence of symptoms 
following initial improvement; hospitalization indicated for other clinical sequelae [eg, renal 
impairment, pulmonary infiltrates]. Grade 4: Life-threatening; pressor or ventilatory 
support indicated).
•
Immediately discontinue infusion of nivolumab. Begin an IV infusion of normal saline and 
treat the participant as follows: Recommend bronchodilators, epinephrine 0.2 to 1 mg of a 
1:1000 solution for subcutaneous administration or 0.1 to 0.25 mg of a 1:10,000 solution 
injected slowly for IV administration, and/or diphenhydramine 50
mg IV with 
methylprednisolone 100 mg IV (or equivalent), as needed. Participant should be monitored 
until the Investigator is comfortable that the symptoms will not recur. Nivolumab will be 
permanently discontinued. Investigators should follow their institutional guidelines for the 
treatment of anaphylaxis. Remain at bedside and monitor participant until recovery 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).
7.4.3
Management Algorithms for Immuno-Oncology Agents
Immuno-oncology (I-O) agents are associated with AEs that can differ in severity and duration 
than AEs caused by other therapeutic classes. Nivolumab and ipilimumab are considered 
immuno-oncology agents in this protocol. 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
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•
Renal
•
Pulmonary
•
Hepatic
•
Endocrinopathy
•
Skin
•
Neurological
The above algorithms are found in the nivolumab Investigator Brochure, as well as in Appendix 4. 
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. Participants will be permitted to continue 
study treatment beyond initial RECIST 1.1 defined PD as long as the following criteria are met:
1) Investigator-assessed clinical benefit
2) Tolerance of study drug
3) Stable performance status
4) Treatment beyond progression will not delay an imminent intervention to prevent serious
complications of disease progression (eg, CNS metastases)
5) Participant provides written informed consent prior to receiving additional study treatment, 
using an ICF describing any reasonably foreseeable risks or discomforts, or other alternative 
treatment options.
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 8 weeks of original PD 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 Time and Events Schedule (Section 2).
For the participants who continue study therapy beyond progression, further progression is defined 
as an additional 10% increase in tumor burden volume from time of initial PD. This includes an 
increase in the sum of all target lesions and/ or the development of new measurable lesions. 
Treatment should be discontinued permanently upon documentation of further disease 
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 
15 mm). Any new lesion considered non-measureable at the time of initial progression may 
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become measureable and therefore included in the tumor burden volume 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).
Participants with global deterioration of health status (as determined by the investigator) who 
require discontinuation of treatment without objective evidence of disease progression at the time 
of treatment discontinuation should be reported as ‘symptomatic deterioration.’ Every effort 
should be made to document objective progression (ie, radiographic confirmation) even after 
discontinuation of treatment.
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 (eg, required diluents, administration sets).
Further guidance and information for final disposition of unused study treatment are provided in
Appendix 6 (study governance).
7.5.1
Retained Samples for Bioavailability / Bioequivalence
Not Applicable.
7.6
Treatment Compliance
Treatment compliance will be monitored by drug accountability as well as the participant’s 
medical record and eCRF.
7.7
Concomitant Therapy
7.7.1
Prohibited and/or Restricted Treatments
The following medications are prohibited during the study (unless utilized to treat a drug-related
adverse event):
•
Immunosuppressive agents
•
Immunosuppressive doses of systemic corticosteroids (except as stated in Section 7.7.3)
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•
Any concurrent anti-neoplastic therapy (ie, chemotherapy, hormonal therapy, immunotherapy, 
extensive, non-palliative radiation therapy, or standard or investigational agents for treatment 
of NSCLC)
•
Any botanical preparation (eg herbal supplements or traditional Chinese medicines) intended 
to treat the disease under study or provide supportive care. Use of marijuana and its derivatives 
for treatment of symptoms related to cancer or cancer treatment are permitted if obtained by 
medical prescription or if its use (even without a medical prescription) has been legalized 
locally
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
assignment 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.
7.7.3
Permitted Therapy
Participants are permitted the use of topical, ocular, intra-articular, intranasal, and inhalational 
corticosteroids (with minimal systemic absorption). Adrenal replacement steroid doses > 10 mg 
daily prednisone are permitted. A brief (less than 3 weeks) course of corticosteroids for 
prophylaxis (eg, contrast dye allergy) or for treatment of non-autoimmune conditions (eg, 
delayed-type hypersensitivity reaction caused by a contact allergen) is permitted.
Pre-enrollment palliative radiotherapy must have been completed at least 2 weeks prior to first 
dose and all signs of toxicity must have remitted. Lesions which have received or are anticipated 
to receive palliative RT may not be designated as target or non-target lesions in the baseline tumor 
assessment.  Concomitant medications are recorded at baseline and throughout the treatment phase 
of the study in the appropriate section of the case report form (CRF). All medications (prescriptions 
or over the counter medications) continued at the start of the study or started during the study and
different from the study drug must be documented in the concomitant therapy section of the CRF.
Supportive care for disease-related symptoms may be offered to all participants on the trial.
Palliative (limited-field) radiation therapy and palliative surgical resection are permitted if the
following criteria are met:
1) The lesion being considered for palliative therapy is not a target lesion or a non-target lesion 
used for tumor assessment.
2) The case is discussed with the BMS Medical Monitor (including discussion of whether 
progression has occurred).
7.7.3.1
Imaging Restriction and Precautions
If a participant has a known allergy to contrast material, local prophylaxis standards may be used 
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. Should a participant 
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have a contraindication for CT IV contrast, a non-contrast CT chest and a contrast enhanced MRI 
of the abdomen and pelvis may be obtained.
Study-related MRI imaging will be performed per the frequency specified in the protocol. 
Investigators may obtain additional follow-up MRI scans as medically indicated. For other locally 
performed imaging, 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 < 30 mL/min/1.73 m2) are at increased risk of nephrogenic systemic 
fibrosis. MRI contrast should not be given to this participant population, who should be excluded 
from the study. In addition, participants with surgically implanted devices (pacemaker, deep brain 
stimulator, metallic implants, etc) that are incompatible with MRI should not undergo such 
imaging techniques. The local imaging facility and investigator should determine the appropriate 
precautions or guidelines that should be instituted for participants with tattoos, body piercings, or 
other body art.
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.
7.8
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 for the maximum treatment duration specified in 
protocol (see Section 7.1.1). Study treatment will be provided via an 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 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 (and non-investigational product at the 
discretion of the investigator) for any of the following reasons:
•
Participant’s request to stop study treatment. Participants who request to discontinue study 
treatment will remain in the study and must continue to be followed for protocol specified 
follow-up procedures. The only exception to this is when a participant specifically withdraws 
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consent for any further contact with him/her or persons previously authorized by participant to 
provide this information
•
Any clinical adverse event (AE), laboratory abnormality or intercurrent illness which, in the 
opinion of the investigator, indicates that continued participation in the study is not in the best 
interest of the participant
•
Termination of the study by Bristol-Myers Squibb (BMS)
•
Loss of ability to freely provide consent through imprisonment or involuntarily incarceration 
for treatment of either a psychiatric or physical (eg, infectious disease) illness
•
Additional protocol specific criteria for discontinuation (Section 8.1.1) 
Refer to the Schedule of Activities for data to be collected at the time of treatment discontinuation 
and follow-up and for any further evaluations that can be completed.
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. 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
Nivolumab Dose Discontinuation 
Nivolumab treatment should be permanently discontinued for the following:
•
Any Grade 2 drug-related uveitis, eye pain or blurred vision that does not respond to topical 
therapy and does not improve to Grade 1 severity within the re-treatment period OR requires 
systemic treatment
•
Any Grade 3 non-skin, drug-related adverse event lasting > 7 days or recurs, with the following 
exceptions for laboratory abnormalities, drug-related uveitis, pneumonitis, bronchospasm, 
neurologic toxicity, hypersensitivity reactions, infusion reactions, and endocrinopathies:
−
Grade 3 drug-related uveitis, pneumonitis, bronchospasm, neurologic toxicity, 
hypersensitivity reaction, or infusion reaction of any duration requires discontinuation
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−
Grade 3 drug-related endocrinopathies, adequately controlled with only physiologic 
hormone replacement do not require discontinuation. Adrenal insufficiency requires 
discontinuation regardless of control with hormone replacement. 
−
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 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:
−
Grade 4 neutropenia ≤7 days
−
Grade 4 lymphopenia or leukopenia or asymptomatic amylase or lipase
−
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
−
Grade 4 drug-related endocrinopathy adverse events, such as, 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 > 10 weeks from the previous dose requires 
discontinuation, with the following exceptions:
−
Dosing delays to allow for prolonged steroid tapers to manage drug-related adverse events 
are allowed. 
−
Dosing delays lasting > 10 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 > 10 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.
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8.1.2
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 and/or total bilirubin abnormalities, dosing may 
resume when laboratory values return to baseline and management with corticosteroids, if 
needed, is complete.
•
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.
8.1.3
Post Study Treatment Study Follow-up
BMS may request that survival data be collected on all treated participants outside of the protocol 
defined window (Schedule of Activities). 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.
Participants who discontinue study treatment may continue to be followed.
8.2
Discontinuation from the Study
Participants who request to discontinue study treatment will remain in the study and must continue 
to be followed for protocol specified follow-up procedures. The only exception to this is when a 
participant specifically withdraws consent for any further contact with him/her or persons 
previously authorized by participant to provide this information. 
•
Participants should notify the investigator of the decision to withdraw consent from future 
follow-up in writing, whenever possible.
•
The withdrawal of consent should be explained in detail in the medical records by the 
investigator, as to whether the withdrawal is from further treatment with study treatment only 
or also from study procedures and/or post treatment study follow-up, and entered on the 
appropriate CRF page.
•
In the event that vital status (whether the participant is alive or dead) is being measured, 
publicly available information should be used to determine vital status only as appropriately 
directed in accordance with local law.
•
If the participant withdraws consent for disclosure of future information, the sponsor may 
retain and continue to use any data collected before such a withdrawal of consent.
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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 assignment. 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 laboratory tests should be performed as clinically 
indicated or to comply with local regulations. Laboratory toxicities (eg, suspected drug induced 
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liver enzyme evaluations) will be monitored during the follow-up phase via on site/local labs until 
all study drug related toxicities resolve, return to baseline, or are deemed irreversible. 
If a participant shows pulmonary-related signs (hypoxia, fever) or symptoms (eg. dyspnea, cough, 
fever) consistent with possible pulmonary adverse events, the participant should be immediately 
evaluated to rule out pulmonary toxicity, according to the suspected pulmonary toxicity 
management algorithm in the BMS-936558 (nivolumab) Investigator Brochure and Appendix 4. 
Some of the assessments referred to in this protocol 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
Study evaluations will take place in accordance with the Schedule of Activities (Section 2), 
according to RECIST 1.1 criteria. 25 High resolution CT with oral/intravenous contrast or 
contrast-enhanced MRI is 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 start of study treatment. Brain MRI 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 RECIST 1.1 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 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 12 weeks, or sooner if clinically indicated.
9.1.1
Imaging Assessment for the Study
Radiographic tumor assessments will be conducted at Week 8 (± 7 days) and every 8 weeks 
(± 7 days) up to 2 years or until disease progression (or until discontinuation of study therapy in 
patients receiving nivolumab beyond progression), lost to follow-up, or withdrawal of study 
consent. Participants who discontinue earlier than 2 years or completed 2 years of treatment but 
achieve SD/PR/CR at the end of Follow-up Visit 2 will have imaging scans every 3 months (12 
weeks ± 7 days) until documented radiographic disease progression or up to a maximum duration 
of 5 years after first dose. Tumor assessments for all participants should continue as per protocol 
even if dosing is interrupted. Tumor measurements should be made by the same investigator or 
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radiologist for each assessment whenever possible. Assessment of partial assessment response 
(PR) and complete response (CR) must be confirmed at least 4 weeks following initial assessment. 
Changes in tumor measurements and tumor responses to guide ongoing study treatment decisions 
will be assessed by the investigator using RECIST 1.1 (see Appendix 3 for details of RECIST 1.1). 
Central imaging assessments are not planned for this study; however, copies of all scans will be 
stored for possible future central analysis, if determined to be necessary by BMS. At the Sponsor’s 
discretion, scans may be collected centrally to be reviewed by independent radiologists.
9.2
Adverse Events
The definitions of an AE or serious adverse event (SAE) can be found in Appendix 7.
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 7.
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 until [the 
follow-up contact], at the timepoints specified in the Schedule of Activities (Section 1). Nonserious 
AE information should also be collected from the start of a placebo lead-in period or other 
observational period intended to establish a baseline status for the participants.
Sections 5.6.1 and 5.6.2 in the Investigator Brochure (IB) represent the Reference Safety 
Information to determine expectedness of serious adverse events for expedited reporting. 
Following the participant’s written consent to participate in the study, all SAEs, whether related 
or not related to study drug, must be collected, including those thought to be associated with 
protocol-specified procedures.
All SAEs must be collected that occur during the screening period and within 100 days of 
discontinuation of dosing. If applicable, SAEs must be collected that relate to any later 
protocol-specified procedure (eg, a follow-up skin biopsy).
The investigator must report any SAE that occurs after these time periods and that is believed to 
be related to study drug or protocol-specified procedure.
•
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 7. 
•
The investigator will submit any updated SAE data to the sponsor within 24 hours of this being 
available.
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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 7.
9.2.1.1
Adverse Events of Special Interest 
Definition of immune-mediated adverse events (IMAEs) 
Immune-mediated AEs are specific events (that include pneumonitis, diarrhea/colitis, hepatitis, 
nephritis/renal 
dysfunction, 
rash, 
and 
endocrine 
[adrenal 
insufficiency, 
hypothyroidism/thyroiditis, hyperthyroidism, diabetes mellitus, and hypophysitis]) for which 
participants received immunosuppressive medication for treatment of the event, with the exception 
of endocrine events (hypothyroidism/thyroiditis, hyperthyroidism, hypophysitis, diabetes mellitus, 
adrenal insufficiency), which are included regardless of treatment since these events are often 
managed without immunosuppression. 
Immune-mediated AEs are specific events (or groups of PTs describing specific events) that 
include pneumonitis, diarrhea/colitis, hepatitis, nephritis/renal dysfunction, rash, endocrine 
(adrenal insufficiency, hypothyroidism/thyroiditis, hyperthyroidism, diabetes mellitus, and 
hypophysitis), and other specific events, considered as potential immune-mediated events by 
investigator, that meet the definition summarized below: 
•
those occurring within 100 days of the last dose 
•
regardless of causality
•
with no clear alternate etiology based on investigator assessment, or with an immune-mediated 
component 
•
treated 
with 
immune-modulating 
medication 
(Of 
note, 
adrenal 
insufficiency, 
hypothyroidism/thyroiditis, hyperthyroidism, diabetes mellitus, and hypophysitis are 
considered IMAEs regardless of immune-modulating medication use, since endocrine drug 
reactions are often managed without immune-modulating medication).
Table 9.2.1.1-1 below provides a summary of the IMAEs category and their respective preferred 
terms.
Table 9.2.1.1-1:
Preferred Terms Included in Analysis of IMAEs to Support 
Warnings and Precautions
IMAE Category
PTs included under IMAE Category
Pneumonitis
Pneumonitis, interstitial lung disease
Diarrhea/Colitis
Diarrhea, colitis, enterocolitis
Hepatitis
Hepatotoxicity, hepatitis, hepatitis acute, autoimmune hepatitis, AST 
increased, ALT increased, bilirubin increased, ALP increased
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Table 9.2.1.1-1:
Preferred Terms Included in Analysis of IMAEs to Support 
Warnings and Precautions
IMAE Category
PTs included under IMAE Category
Adrenal insufficiency
Adrenal insufficiency
Hypothyroidism/Thyroiditis
Hypothyroidism, thyroiditis
Thyroiditis acute (collapsed with thyroiditis for frequency), Autoimmune 
thyroiditis (collapsed with thyroiditis for frequency)
Hyperthyroidism
Hyperthyroidism
Hypophysitis
Hypophysitis
Diabetes mellitus
Diabetes mellitus, diabetic ketoacidosis
Nephritis and renal dysfunction
Nephritis, nephritis allergic, tubulointerstitial nephritis, acute renal failure, 
renal failure, increased creatinine
Rash
Rash, rash maculopapular
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 participant. (In order to prevent reporting bias, participants should 
not be questioned regarding the specific occurrence of one or more AEs.)
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.
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 7).
•
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 7.
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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.
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 7.
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.
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.
•
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
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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 7 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
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).
9.4
Safety
Planned time points for all safety assessments are listed in the Schedule of Activities. Some of the 
assessments referred to in this protocol 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.”
9.4.1
Clinical Safety Laboratory Assessments
Investigators must document their review of each laboratory safety report.
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Please refer to the Schedule of Activities in Section 2 for details regarding required laboratory 
tests. 
9.4.2
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. 
 
 
 
 
 
 
 
 
 
 
 
 
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Pharmacodynamics
Not applicable. 
9.7
Pharmacogenomics
Not applicable.
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9.9
Health Economics OR Medical Resource Utilization and Health 
Economics
Health Economics/Medical Resource Utilization and Health Economics parameters will not be 
evaluated in this study.
10.
STATISTICAL CONSIDERATIONS
10.1
Sample Size Determination 
Approximately 200 participants will be enrolled in order to treat up to 120 participants. This 
number of treated participants was chosen to provide descriptive analysis to estimate incidence 
rate of high-grade (Grades 3-4 or Grade 5), drug-related, select AEs and rate of immune-mediated 
AEs in all treated participants with nivolumab alternate dosing schedule. Overall, the safety profile 
of nivolumab monotherapy is manageable and generally consistent across completed and ongoing 
clinical trials with no MTD reached at any dose tested up to 10 mg/kg. Most AEs were low-grade 
(Grade 1 to 2) with relatively few related high-grade (Grades 3 to 4) AEs. Rates of high-grade 
(Grades 3-4 or Grade 5), drug-related, select AEs and rate of immune-mediated AEs by category 
observed in 2L NSCLC CheckMate 063, 017 and 057 were low and <7%. Nivolumab monotherapy 
has been extensively studied in multiple tumor types, including melanoma, NSCLC, RCC, cHL, 
Head and Neck, and UC with body weight normalized dosing (mg/kg). PPK modelling predicted 
median and 95th percentile of exposures are maintained below those in 10 mg/kg every 2 weeks,26
which was established as a safe and well-tolerable dose across multiple tumor types. There was no 
clinical meaningful relationship between nivolumab exposure or body weight and frequency or 
severity of AEs. Therefore, a 480 mg Q4W is expected to be safe and tolerable in those patients.
Table 10.1-1 shows the 95% Confidence Intervals for different AE rates for a sample size of 120 
participants. 
Table 10.1-1:
95% Confidence Intervals for different AE rates for a sample size of 
120
Number of participants with AE (%)
Exact 95% CI around proportion
0/120 (0%)
0%-3.0%
1/120 (0.8%)
0.8%-4.6%
2/120 (1.7%)
0.2%-5.9%
3/120 (2.5%)
0.5%-7.1%
4/120 (3.3%)
0.9%-8.3%
5/120 (4.2%)
1.4%-9.5%
6/120 (5.0%)
1.9%-10.6%
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With a sample size of 120, the chance of observing at least one participant with the event is greater 
than 80% for true probabilities of events higher than 1.3%.
•
If true probability of event is 1%, the chance of observing at least 1 participant with event 
among 120 treated participants is 70%.
•
If true probability of event is 2%, the chance of observing at least 1 participant with event 
among 120 treated participants is 91%.
Precision of secondary endpoint ORR, when sample size is 120, is provided in Table 10.1-2. If 24 
responders are observed among the 120 treated participants (ORR =20%), the 2-sided exact 95% 
CI will be (13.2%, 28.3%). It is assumed that response rate would be similar to ORR observed in 
2L NSCLC CheckMate017 and 057. With a target ORR = 19 %, this study has approximately 90% 
of power to exclude a 9% ORR (the null hypothesis) with a 0.05 two-sided significance level. The 
threshold response rate set at 9.0% is based on the response rate of docetaxel reported by Hanna 
et al27. as well as Japanese phase 2 ONO-4538-05 and 06 study. 
Table 10.1-2:
Precision of Secondary Endpoint of ORR
Number of responders (%)
Exact 95% CI around ORR
10/120 (8.3%)
7.1-24.7
11/120 (9.2)
8.1-26.4
18/120 (15%)
9.1%-22.7%
19/120 (15.8%)
9.8%-23.6%
20/120 (16.7%) 
10.5%-24.6%
21/120 (17.5%)
11.2%-25.5%
22/120 (18.3%)
11.9%-26.4%
23/120 (19.2%)
12.6%-27.4%
24/120 (20.0%)
13.2%- 28.3%
10.2
Populations for Analyses
For purposes of analysis, the following populations are defined:
Population
Description
Enrolled Participants: 
All participants who signed an informed consent form and were 
registered into the IVRS. 
Treated Participants: 
All participants who received at least 1 dose of nivolumab. 
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10.3
Statistical Analyses
The statistical analysis plan will be developed and finalized before database lock and will describe 
the selection of participants to be included in the analyses, and procedures for accounting for 
missing, unused, and spurious data. Below is a summary of planned statistical analyses of the 
primary and secondary endpoints.
10.3.1
Efficacy Analyses
Endpoint
Statistical Analysis Methods
Primary
NA
Secondary
•
The PFS/OS curve will be estimated using the Kaplan-Meier (KM) 
product-limit method. Two-sided 95% confidence intervals for median 
PFS/OS will be computed by Klein and Moeschberger method. PFS/OS 
rates at 6, 12, 18, 24, 36, 48, and 60 months will be estimated using KM 
estimates on the PFS/OS curve. Minimum follow-up must be longer 
than or equal to the time point to generate the rates. Associated 
two sided 95% CIs will be calculated using the Greenwood’s formula. 
The status of participants who are censored in the PFS/OS 
Kaplan Meier analysis will be tabulated.
•
BOR will be summarized by response category. Objective Response 
Rate (ORR) and 95% exact CI will be calculated using Clopper-Pearson 
method. Duration of response will be estimated using KM product-limit 
method for participants who achieve confirmed PR or CR Two-sided 
95% confidence intervals for median DOR will be computed by Klein 
and Moeschberger method.
10.3.2
Safety Analyses
Endpoint
Statistical Analysis Methods
Primary
• Incidence of high-grade (worst CTC Grade 3, 4 or 5), drug-related, select 
AEs by category (subcategory for endocrine events). The select AE consist 
of a list of preferred terms grouped by specific category (eg, pulmonary 
events, gastrointestinal events categories) and by subcategory (eg, thyroid 
disorders, diabetes, pituitary, adrenal disorders subcategories). These 
categories and subcategories are defined by the Sponsor, and the list that is 
most current at the time of analysis will be used. Also changes may be made 
to this list with each new version of MedDRA. Drug-related AEs are those 
events with relationship to study drug “Related,” as recorded on the CRF. 
If the relationship to study drug is missing, the AE will be considered as 
drug-related.
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Endpoint
Statistical Analysis Methods
•
Select AEs will be summarized for each category/subcategory using a 
30-day safety window and repeated using the 100-day safety window 
(sensitivity analysis) (refer to core safety SAP).
•
Overall summary of Grades 3 to 5 drug-related, select AEs by worst CTC 
grade presented by Category or Subcategory / PT.
•
Overall summary of drug-related select AEs by worst CTC grade presented 
by Category or Subcategory / PT (any grade, Grades 3-4, Grade 5).
•
Overall summary of any select AEs by worst CTC grade presented by 
Category or Subcategory/PT (any grade, Grades 3-4, Grade 5).
•
Overall summary of any serious select AEs by worst CTC grade presented 
by Category or Subcategory /PT (any grade, Grades 3-4, Grade 5).
•
Overall summary of drug-related serious select AEs by worst CTC grade 
presented by Category or Subcategory /PT (any grade, Grades 3-4, Grade 
5).
•
Overall summary of any select AEs leading to discontinuation by worst 
CTC grade presented by Category or Subcategory /PT (any grade, Grades
3-4, Grade 5).
•
Overall summary of drug-related, select AEs leading to discontinuation by 
worst CTC Grade presented by Category or Subcategory /PT (any grade, 
Grades 3-4, Grade 5).
•
Summary of frequency of unique select AEs
Time-to onset of Grades 3 to 5 drug-related, select AE (for participants who 
experienced at least 1
select AE) will be summarized for each 
category/subcategory of select AEs. Time to onset of select AE for a specific 
category was defined as the time between the day of the first dose of study 
treatment and the onset date of the earliest select AE in this category.
Time to resolution of Grade 3 to 5 drug-related select AE will be summarized 
separately for each category/subcategory. Time-to resolution analyses are 
restricted to treated participants who experienced the specific events. The 
following summary statistics will be reported: percentage of participants who 
experienced the specific events, percentage of participants with resolution of 
the longest select AE, median time-to resolution along with 95% CI (derived 
from Kaplan-Meier estimation) and ranges.
•
Incidence of immune-mediated AEs by Category. Immune-mediated AEs
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 (eg, pneumonitis, 
diarrhea/colitis, hepatitis, adrenal insufficiency, hypothyroidism, rash). 
IMAEs can include events with an alternate etiology which were 
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exacerbated by the induction of autoimmunity. Information supporting the 
assessment will be collected on the participant’s case report form.
IMAEs will be summarized for each category/subcategory using a 100-day 
safety window and repeated using the 30-day safety window (sensitivity 
analysis) (refer to core safety SAP).
•
Summary of Immune-Mediated Adverse Events by Worst CTC Grade (Any 
Grade, Grades 3-4, Grade 5).
•
Summary of Serious immune-mediated AEs Leading to Discontinuation by 
Worst CTC Grade, by Category.
•
Summary of Immune-Mediated AEs Leading to Discontinuation by Worst 
CTC Grade, by Category.
•
Summary of Any Immune-Mediated AEs Leading to Dose Delay or 
Reduction by Worst CTC Grade, by category.
•
Time-to onset of IMAE (for participants who experienced at least 1 IMAE) 
will be summarized for each category/subcategory of IMAEs. 
•
Time to resolution of IMAEs will be summarized separately for each 
category/subcategory, for participants who experienced at least 
1 immune-mediated AE.
Select AEs and IMAEs analyses will include AEs with an onset date and time 
on or after the date and time of the first dose of study treatment (or with an 
onset date on or after the day of first dose of study treatment if time is not 
collected or is missing). For participants who are off study treatment, AEs will 
be included if an event occurred within a safety window of 30/100 days after 
the last dose of study treatment. No “subtracting rule” will be applied when an 
AE occurs both pre-treatment and post-treatment with the same preferred term 
and grade.
Secondary
Not Applicable
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10.3.5
Interim Analyses 
Interim analyses may be performed. 
10.3.6
Final Analyses 
The final analysis will be performed when all participants have completed the study treatment.
Data cuts for publication purposes earlier than all participants completing the study are possible.
The Statistical Analysis Plan will further describe the planned analyses.
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11.
REFERENCES
1
Jemal A, Bray F, Center MM. et al. Global Cancer Statistics CA Cancer J Clin 2011;61:69–
90.
2
Surveillance, Epidemiology, and End Results (SEER) Program (www.seer.cancer.gov) 
Research Data (1973-2011), National Cancer Institute, DCCPS, Surveillance Research 
Program, Surveillance Systems Branch, released April 2014, based on the November 2013 
submission. Non-Small Cell Cancer of the Lung and Bronchus (Invasive). 5-Year Relative and 
Period Survival by Race, Sex, Diagnosis Year, Age and Stage at Diagnosis.
3
Scagliotti GV, Parikh P, Von Pawel J, et al. Phase III study comparing cisplatin plus 
gemcitabine with cisplatin plus pemetrexed in chemotherapy-naive patients with advanced 
stage non-small cell lung cancer. J Clin Oncol 2008; 26: 3543-51.
4
Paz-Ares LG, De Marinis F, Dediu M, et al. PARAMOUNT: Final overall survival results of 
the phase III study of maintenance pemetrexed versus placebo immediately after induction 
treatment with pemetrexed plus cisplatin for advanced nonsquamous non-small cell lung 
cancer. J Clin Oncol 2013.
5
Shaw AT, Varghese AM, Solomon FJ, et al. Pemetrexed-based chemotherapy in patients with 
advanced, ALK-positive non-small cell lung cancer. Annals of Oncology 2013; 24: 59-66.
6
Borghaei H, Paz-Ares L, Horn L, et al. Nivolumab versus Docetaxel in Advanced 
Nonsquamous Non-small Cell Lung Cancer. N Engl J Med 2015;373:1627-39.
7
Pardoll D. Does the immune system see tumors as foreign or self? Annu Rev Immunol. 
2003;21:807-39.
8
Zitvogel L, Tesniere A, Kroemer G. Cancer despite immunosurveillance: immunoselection 
and immunosubversion. Nat Rev Immunol. 2006;6:715-27.
9
Dunn GP, Bruce AT, Ikeda H, et al. Cancer immunoediting: from immunosurveillance to 
tumor escape. Nat Immunol. 2002;3:991-8.
10 Greenwald RJ, Freeman GH, Sharpe AH. The B7 family revisited. Annu Rev Immunol. 
2004;23:515-48.
11 Nivolumab Investigator Brochure. Version 15. Bristol-Myers Squibb: Princeton (NJ). June 26, 
2016. Document Control No.: 930038243
12 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.
13 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.
14 Keir M E, Butte M J, Freeman G J, Sharpe A H. PD-1 and Its Ligands in Tolerance and 
Immunity. Annu. Rev. Immunol. 2008. 26:677–704.
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15 Freeman GJ, Long AJ, Iwai Y, et al. Engagement of the PD-1 immunoinhibitory receptor by a 
novel B7 family member leads to negative regulation of lymphocyte activation. J Exp Med. 
2000; 192: 1027-34.
16 Latchman Y, Wood CR, Chernova T, et al. PD-L2 is a second ligand for PD-1 and inhibits T 
cell activation. Nat Immunol. 2001; 2: 261-8.
17 Carter LL, Fouser LA, Jussif J, et al. PD-1: PD-L1 inhibitory pathway affects both CD4+ 
andCD8+ T cells and is overcome by IL-1. Eur J Immunol. 2002; 32: 634-43.  
18 Barber DL, wherry EJ, Masopust D et al. Restoring function in exhausted CD8 T cells during 
chronic viral infection. Nature. 2006; 439: 682-7.
19 Dong H, chen L. B7-H1 pathway and its role in the evasion of tumor immunity. J Mol Med. 
2003; 81: 281-7.
20 Konishi J, Yamazaki K, Azuma M, et al. B7-H1 expression on non-small cell lung cancer cells 
and its relationship with tumor-infiltrating lymphocytes and their PD-1 expression. Clin 
Cancer Res. 2004; 10: 5094-10.
21 Thompson RH, Gillett MD, Cheville JC, et al. Costimulatory B7-H1 in renal cell carcinoma 
participants; indicator of tumor aggressiveness and potential therapeutic target. Proc Natl Acad 
Sci USA. 2004; 101: 17174-9.
22 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.
23 Hamanishi J, Mandai M, Iwasaki M, et al. Programmed cell death 1 ligand 1 and 
tumorinfiltrating CD8+ T lymphocytes are prognostic factors of human ovarian cancer. PNAS. 
2007; 104: 3360-65.
24 Pardoll D M, The blockade of immune checkpoints in cancer immunotherapy. Nature 2012; 
12: 252-64.
25 Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid 
tumours: Revised RECIST guideline (version 1.1). Eur J Cancer. (2009); 45:228-247.
26 CA209003. Data on File.
27 Hanna N, Shepherd FA, Fossella FV, Pereira JR, Marinis F, Pawel J, et al. Randomized phase 
III trial of pemetrexed versus docetaxel in patients with non-small-cell lung cancer previously 
treated with chemotherapy. J ClinOncol. 2004;22(9):1589-97.
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12.
APPENDICES
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APPENDIX 1
ABBREVIATIONS AND TRADEMARKS
Term
Definition
AE
adverse event
ALT
alanine aminotransferase
AST
aspartate aminotransferase
BMS
Bristol-Myers Squibb
BP
blood pressure
BUN
blood urea nitrogen
Ca++
calcium
CBC
complete blood count
CFR
Code of Federal Regulations 
CI
confidence interval
CNS
Central nervous system
CRF
Case Report Form, paper or electronic
CR
Complete response
C1W1D1
Cycle 1 Week 1 Day 1 
DMC
Data monitoring committee
DOR
Duration of response
ECG
electrocardiogram
eCRF
Electronic Case Report Form
EDC
Electronic Data Capture
FDA
Food and Drug Administration
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Term
Definition
FSH
follicle stimulating hormone
GCP
Good Clinical Practice
HBsAg
hepatitis B surface antigen
HCV
hepatitis C virus
HIV
Human Immunodeficiency Virus
HR
heart rate
ICH
International Conference on Harmonisation 
IEC
Independent Ethics Committee
IMAE
Immune-mediated adverse event
IMP
investigational medicinal products
IND
Investigational New Drug Exemption
I-O
Immuno-oncology 
IRB
Institutional Review Board
IRT
Interactive Response Technology
IV
intravenous
K+
potassium
kg
kilogram
LDH
lactate dehydrogenase
mg
milligram
min
minute
mL
milliliter
MTD
maximum tolerated dose
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Term
Definition
N
number of subjects or observations
N/A
not applicable
NSCLC
Non-small cell lung cancer
ORR
Overall response rate 
PD
Progressive diseases 
PFS
Progression-free survival
PR
Partial response 
SAE
serious adverse event
SOP
Standard Operating Procedures
ULN
Upper limit of normal
WBC
white blood cell
WOCBP
women of childbearing potential
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APPENDIX 2
PERFORMANCE STATUS SCALES
STATUS
SCALES
STATUS
KARNOFSKY
ZUBROD-ECOG-
WHO
Normal, no complaints
100
0
Normal activity
Able to carry on normal activities Minor 
signs or symptoms of disease
90
0
Symptoms, but fully 
ambulatory
Normal activity with effort
80
1
Cares for self. Unable to carry on normal 
activity or to do active work
70
1
Symptomatic, but in 
bed < 50% of the day.
Requires occasional assistance, but able to 
care for most of his needs
60
2
Requires considerable assistance and 
frequent medical care
50
2
Needs to be in bed 
> 50% of the day, but 
not bedridden
Disabled. Requires special care and 
assistance
40
3
Severely disabled. Hospitalization 
indicated though death non imminent
30
3
Unable to get out of 
bed
Very sick. Hospitalization necessary. 
Active supportive treatment necessary
20
4
Moribund
10
4
Dead
0
5
Dead
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APPENDIX 3
RECIST 1.1 GUIDELINES
1.
EVALUATION OF LESIONS
At baseline, tumor lesions/lymph nodes will be categorized measurable or non-measurable as 
follows:
1.1
Measurable
Tumor lesions: Must be accurately measured in at least one dimension (longest diameter in the 
plane of measurement is to be recorded) with a minimum size of:
1. 10 mm by CT scan (CT scan slice thickness no greater than 5 mm)
2. 10 mm caliper measurement by clinical exam (lesions which cannot be accurately measured 
with calipers should be recorded as non-measurable)
3. 20 mm by chest x-ray
Malignant lymph nodes: To be considered pathologically enlarged and measurable, a lymph node 
must be ≥15 mm in short axis when assessed by CT scan (CT scan slice thickness recommended 
to be no greater than 5 mm).
Lymph nodes merit special mention since they are normal anatomical structures which may be 
visible by imaging even if not involved by tumor. Pathological nodes which are defined as 
measurable and may be identified as target lesions must meet the criterion of a short axis of 
≥15 mm by CT scan. Only the short axis of these nodes will contribute to the baseline sum. The 
short axis of the node is the diameter normally used by radiologists to judge if a node is involved 
by solid tumor. Nodal size is normally reported as two dimensions in the plane in which the image 
is obtained (for CT scan this is almost always the axial plane; for MRI the plane of acquisition 
may be axial, saggital or coronal). The smaller of these measures is the short axis. For example, 
an abdominal node which is reported as being 20 mm x 30 mm has a short axis of 20 mm and 
qualifies as a malignant, measurable node. In this example, 20 mm should be recorded as the node 
measurement. All other pathological nodes (those with short axis ≥10 mm but < 15 mm) should 
be considered non-target lesions. Nodes that have a short axis < 10 mm are considered 
non-pathological and should not be recorded or followed.
1.2
Non-Measurable
All other lesions are considered non-measurable, including small lesions (longest diameter 
< 10mm or pathological lymph nodes with ≥10 to < 15 mm short axis) as well as truly 
non-measurable lesions. Lesions considered truly non-measurable include: leptomeningeal 
disease, ascites, pleural or pericardial effusion, inflammatory breast disease, lymphangitic 
involvement of skin or lung, abdominal masses/abdominal organomegaly identified by physical 
exam that is not measurable by reproducible imaging techniques.
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2.
BASELINE DOCUMENTATION OF ‘TARGET’ AND ‘NON-TARGET’ 
LESIONS
When more than one measurable lesion is present at baseline all lesions up to a maximum of five 
lesions total (and a maximum of two lesions per organ) representative of all involved organs should 
be identified as target lesions and will be recorded and measured at baseline (this means in 
instances where patients have only one or two organ sites involved a maximum of two and four 
lesions respectively will be recorded).
Target lesions should be selected on the basis of their size (lesions with the longest diameter), be 
representative of all involved organs, but in addition should be those that lend themselves to 
reproducible repeated measurements. It may be the case that, on occasion, the largest lesion does 
not lend itself to reproducible measurement in which circumstance the next largest lesion which 
can be measured reproducibly should be selected.
A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target 
lesions will be calculated and reported as the baseline sum diameters. If lymph nodes are to be 
included in the sum, then as noted above, only the short axis is added into the sum. The baseline 
sum diameters will be used as reference to further characterize any objective tumor regression in 
the measurable dimension of the disease.
All other lesions (or sites of disease) including pathological lymph nodes should be identified as 
non-target lesions and should also be recorded at baseline. Measurements are not required and 
these lesions should be followed as ‘present’, ‘absent’, or in rare cases ‘unequivocal progression’ 
(more details to follow). In addition, it is possible to record multiple nontarget lesions involving 
the same organ as a single item on the case record form (eg, ‘multiple enlarged pelvic lymph nodes’ 
or ‘multiple liver metastases’).
3.
RESPONSE CRITERIA
3.1
Evaluation of Target Lesions
Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes 
(whether target or non-target) must have reduction in short axis to < 10 mm.
Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, taking 
as reference the baseline sum diameters.
Progressive Disease (PD): At least a 20% increase in the sum of diameters of target lesions, taking 
as reference the smallest sum on study (this includes the baseline sum if that is the 
smallest on study). In addition to the relative increase of 20%, the sum must also 
demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or 
more new lesions is also considered progression).
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest sum diameters while on study.
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3.1.1
Special Notes on the Assessment of Target Lesions
3.1.1.1
Lymph nodes
Lymph nodes identified as target lesions should always have the actual short axis measurement 
recorded (measured in the same anatomical plane as the baseline examination), even if the nodes 
regress to below 10 mm on study. This means that when lymph nodes are included as target lesions, 
the ‘sum’ of lesions may not be zero even if complete response criteria are met, since a normal 
lymph node is defined as having a short axis of < 10 mm. Case report forms or other data collection 
methods may therefore be designed to have target nodal lesions recorded in a separate section 
where, in order to qualify for CR, each node must achieve a short axis < 10 mm. For PR, SD and 
PD, the actual short axis measurement of the nodes is to be included in the sum of target lesions.
3.1.1.2
Target lesions that become ‘too small to measure’
While on study, all lesions (nodal and non-nodal) recorded at baseline should have their actual 
measurements recorded at each subsequent evaluation, even when very small (eg, 2 mm). 
However, sometimes lesions or lymph nodes which are recorded as target lesions at baseline 
become so faint on CT scan that the radiologist may not feel comfortable assigning an exact 
measure and may report them as being ‘too small to measure’. When this occurs it is important 
that a value be recorded on the case report form. If it is the opinion of the radiologist that the lesion 
has likely disappeared, the measurement should be recorded as 0 mm. If the lesion is believed to 
be present and is faintly seen but too small to measure, a default value of 5 mm should be assigned 
(Note: It is less likely that this rule will be used for lymph nodes since they usually have a definable 
size when normal and are frequently surrounded by fat such as in the retroperitoneum; however, 
if a lymph node is believed to be present and is faintly seen but too small to measure, a default 
value of 5 mm should be assigned in this circumstance as well). This default value is derived from 
the 5 mm CT slice thickness (but should not be changed with varying CT slice thickness). The 
measurement of these lesions is potentially non-reproducible, therefore providing this default 
value will prevent false responses or progressions based upon measurement error. To reiterate, 
however, if the radiologist is able to provide an actual measure, that should be recorded, even if it 
is below 5 mm.
3.1.1.3
Lesions that split or coalesce on treatment
When non-nodal lesions ‘fragment’, the longest diameters of the fragmented portions should be 
added together to calculate the target lesion sum. Similarly, as lesions coalesce, a plane between 
them may be maintained that would aid in obtaining maximal diameter measurements of each 
individual lesion. If the lesions have truly coalesced such that they are no longer separable, the 
vector of the longest diameter in this instance should be the maximal longest diameter for the 
‘coalesced lesion’.
3.2
Evaluation of Non-Target Lesions
This section provides the definitions of the criteria used to determine the tumor response for the 
group of non-target lesions. While some non-target lesions may actually be measurable, they need 
not be measured and instead should be assessed only qualitatively at the time points specified in 
the protocol.
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•
Complete Response (CR): Disappearance of all non-target lesions and normalization of tumor 
marker level. All lymph nodes must be non-pathological in size (< 10mm short axis). 
•
Non-CR/Non-PD: Persistence of one or more non-target lesion(s) and/or maintenance of 
tumor marker level above the normal limits.
•
Progressive Disease (PD): Unequivocal progression (see comments below) of existing non-
target lesions. (Note: the appearance of one or more new lesions is also considered 
progression).
3.2.1
Special Notes on Assessment of Progression of Non-Target Disease
The concept of progression of non-target disease requires additional explanation as follows:
3.2.1.1
When the patient also has measurable disease
In this setting, to achieve ‘unequivocal progression’ on the basis of the non-target disease, there 
must be an overall level of substantial worsening in non-target disease such that, even in presence 
of SD or PR in target disease, the overall tumor burden has increased sufficiently to merit 
discontinuation of therapy (see examples in Appendix 2 and further details below). A modest 
‘increase’ in the size of one or more non-target lesions is usually not sufficient to qualify for 
unequivocal progression status. The designation of overall progression solely on the basis of 
change in non-target disease in the face of SD or PR of target disease will therefore be extremely 
rare.
3.2.1.2
When the patient has only non-measurable disease
This circumstance arises in some trials when it is not a criterion of study entry to have measurable 
disease. The same general concepts apply here as noted above, however, in this instance there is 
no measurable disease assessment to factor into the interpretation of an increase in non-measurable 
disease burden. Because worsening in non-target disease cannot be easily quantified (by definition: 
if all lesions are truly non-measurable) a useful test that can be applied when assessing patients for 
unequivocal progression is to consider if the increase in overall disease burden based on the change 
in non-measurable disease is comparable in magnitude to the increase that would be required to 
declare PD for measurable disease: ie, an increase in tumor burden representing an additional 73%
increase in ‘volume’ (which is equivalent to a 20% increase diameter in a measurable lesion). 
Examples include an increase in a pleural effusion from ‘trace’ to ‘large’, an increase in 
lymphangitic disease from localized to widespread, or may be described in protocols as ‘sufficient 
to require a change in therapy’. If ‘unequivocal progression’ is seen, the patient should be 
considered to have had overall PD at that point. While it would be ideal to have objective criteria 
to apply to non-measurable disease, the very nature of that disease makes it impossible to do so; 
therefore the increase must be substantial.
3.2.2
New Lesions
The appearance of new malignant lesions denotes disease progression; therefore, some comments 
on detection of new lesions are important. There are no specific criteria for the identification of 
new radiographic lesions; however, the finding of a new lesion should be unequivocal: ie, not 
attributable to differences in scanning technique, change in imaging modality or findings thought 
to represent something other than tumor (for example, some ‘new’ bone lesions may be simply 
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healing or flare of pre-existing lesions). This is particularly important when the patient’s baseline 
lesions show partial or complete response. For example, necrosis of a liver lesion may be reported 
on a CT scan report as a ‘new’ cystic lesion, which it is not.
A lesion identified on a follow-up study in an anatomical location that was not scanned at baseline 
is considered a new lesion and will indicate disease progression. An example of this is the patient 
who has visceral disease at baseline and while on study has a CT or MRI brain ordered which 
reveals metastases. The patient’s brain metastases are considered to be evidence of PD even if 
he/she did not have brain imaging at baseline.
If a new lesion is equivocal, for example because of its small size, continued therapy and follow-up 
evaluation will clarify if it represents truly new disease. If repeat scans confirm there is definitely 
a new lesion, then progression should be declared using the date of the initial scan. While FDG-
PET response assessments need additional study, it is sometimes reasonable to incorporate the use 
of FDG-PET scanning to complement CT scanning in assessment of progression (particularly 
possible ‘new’ disease). New lesions on the basis of FDG-PET imaging can be identified according 
to the following algorithm:
1. Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of PD based 
on a new lesion.
2. No FDG-PET at baseline and a positive FDG-PET at follow-up: If the positive FDG-PET at 
follow-up corresponds to a new site of disease confirmed by CT, this is PD. If the positive 
FDG-PET at follow-up is not confirmed as a new site of disease on CT, additional follow-up 
CT scans are needed to determine if there is truly progression occurring at that site (if so, the 
date of PD will be the date of the initial abnormal FDG-PET scan). If the positive FDG-PET 
at follow-up corresponds to a pre-existing site of disease on CT that is not progressing on the 
basis of the anatomic images, this is not PD.
3.3
Response Assessment
3.3.1
Evaluation of Best Overall Response
The best overall response is the best response recorded from the start of the study treatment until 
the end of treatment taking into account any requirement for confirmation. The patient’s best 
overall response assignment will depend on the findings of both target and non-target disease and 
will also take into consideration the appearance of new lesions. Furthermore, depending on the 
nature of the study and the protocol requirements, it may also require confirmatory measurement.
3.3.2
Time Point Response
It is assumed that at each protocol specified time point, a response assessment occurs. Table 3.3.2-
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 3.3.2-2 is to be used. 
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Table 3.3.2-1:
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
CR
Not evaluated
No
PR
PR
Non-PD or not all 
evaluated
No
PR
SD
Non-PD or not all 
evaluated
No
SD
Not all evaluated
Non-PD
No
NE
PD
Any
Yes or No
PD
Any
PD
Yes or No
PD
Any
Any
Yes
PD
CR = complete response, PR = partial response, SD = stable disease, PD = progressive disease and NE = inevaluable
Table 3.3.2-2:
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.
3.3.3
Best Overall Response 
Best response determination of complete or partial response requires confirmation: Complete or 
partial responses may be claimed only if the criteria for each are met at a subsequent time point of 
≥4 weeks later. In this circumstance, the best overall response can be interpreted as in Table 3.3.3-
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 
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overstate progression should it be based on increase in size of the nodes. As noted earlier, this 
means that patients with CR may not have a total sum of ‘zero’ on the case report form (CRF).
Table 3.3.3-1:
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.
3.3.4
Confirmation Scans
Verification of Response: To be assigned a status of CR or PR, changes in tumor measurements 
must be confirmed by consecutive repeat assessments that should be performed no less than 
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 
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initial scan. If repeat scans do not confirm PD, then the subject is considered to not have 
progressive disease.
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APPENDIX 4
MANAGEMENT ALGORITHIMS
These general guidelines constitute guidance to the Investigator and may be supplemented by 
discussions with the Medical Monitor representing the Sponsor. The guidance applies to all 
immuno-oncology agents and regimens. 
A general principle is that differential diagnoses should be diligently evaluated according to 
standard medical practice. Non-inflammatory etiologies should be considered and appropriately 
treated. 
Corticosteroids are a primary therapy for immuno-oncology drug-related adverse events. The oral 
equivalent of the recommended IV doses may be considered for ambulatory patients with low-
grade toxicity. The lower bioavailability of oral corticosteroids should be taken into account when 
switching to the equivalent dose of oral corticosteroids. 
Consultation with a medical or surgical specialist, especially prior to an invasive diagnostic or 
therapeutic procedure, is recommended. 
The frequency and severity of the related adverse events covered by these algorithms will depend 
on the immuno-oncology agent or regimen being used.
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APPENDIX 5
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 
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Progestogen-only hormonal contraception associated with inhibition of ovulationb 
−
oral 
−
injectable 
Highly Effective Methods That Are User Independent
•
Implantable progestogen-only hormonal contraception associated with inhibition of 
ovulation b
•
Intrauterine device (IUD)c
•
Intrauterine hormone-releasing system (IUS)c
•
Bilateral tubal occlusion
•
Vasectomized partner 
A vasectomized partner is a highly effective contraception method provided that the partner 
is the sole male sexual partner of the WOCBP and the absence of sperm has been confirmed. 
If not, an additional highly effective method of contraception should be used. 
•
Sexual abstinence
Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study drug. The 
reliability of sexual abstinence needs to be evaluated in relation to the duration of the study 
and the preferred and usual lifestyle of the participant.
•
It is not necessary to use any other method of contraception when complete abstinence is 
elected. 
•
WOCBP participants who choose complete abstinence must continue to have pregnancy 
tests, as specified in Section 2. 
•
Acceptable alternate methods of highly effective contraception must be discussed in the 
event that the WOCBP participants chooses to forego complete abstinence 
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
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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
•
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 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 treatment.
•
Refrain from donating sperm for the duration of the study treatment and until 7 months after 
the end of treatment.
COLLECTION OF PREGNANCY INFORMATION
Guidance for collection of Pregnancy Information and outcome of pregnancy on the Pregnancy 
Surveillance Form is provided in Section 9.2.5 and the Appendix for Adverse Events and Serious 
Adverse Events Definitions and procedures for Evaluating, Follow-up and Reporting
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APPENDIX 6
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 CRF 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 the Sponsor or designee immediately. A 
potential serious breach is defined as a Quality Issue (eg, protocol deviation, etc) that is likely to 
affect to a significant degree 1 or more of the following: (1) the physical safety or mental integrity 
of 1 or more subjects/participants; (2) the scientific value of the trial (eg, reliability and robustness 
of generated data). Items (1) or (2) can be associated with either GCP Regulation(s) or Trial 
protocol(s).
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 (eg, 
advertisements), and any other written information to be provided to subjects/participants. 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/participants and any updates. 
The investigator, Sponsor or designee should provide the IRB/IEC with reports, updates and other 
information (eg, expedited safety reports, amendments, and administrative letters) according to 
regulatory requirements or institution procedures.
COMPLIANCE WITH THE PROTOCOL AND PROTOCOL REVISIONS
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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/participants. 
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/participants 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/participants 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/participants 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/participants, 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 (ie, Global or Local) sample
informed consent form which will include all elements required by ICH, GCP and applicable
regulatory requirements. The sample informed consent form will adhere to the ethical principles 
that have their origin in the Declaration of Helsinki.
Investigators must:
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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/participants, 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/participants must be protected, 
respecting the privacy and confidentiality rules applicable to regulatory requirements, the 
subjects'/participants’ signed ICF and, in the US, the subjects’/participants’ signed HIPAA 
Authorization.
The consent form must also include a statement that BMS and regulatory authorities have direct 
access to participant records. 
Subjects/participants unable to give their written consent (e.g., stroke or subjects/participants with 
or severe dementia) may only be enrolled in the study with the consent of a legally acceptable 
representative. The participant must also be informed about the nature of the study to the extent 
compatible with his or her understanding, and should this participant become capable, he or she 
should personally sign and date the consent form as soon as possible. The explicit wish of a 
participant who is unable to give his or her written consent, but who is capable of forming an 
opinion and assessing information to refuse participation in, or to be withdrawn from, the clinical 
study at any time should be considered by the investigator.
The rights, safety, and well-being of the study subjects/participants are the most important 
considerations and should prevail over interests of science and society.
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SOURCE DOCUMENTS
The Investigator is responsible for ensuring that the source data are accurate, legible, 
contemporaneous, original and attributable, whether the data are hand-written on paper or entered 
electronically. If source data are created (first entered), modified, maintained, archived, retrieved, 
or transmitted electronically via computerized systems (and/or any other kind of electronic 
devices) as part of regulated clinical trial activities, such systems must be compliant with all 
applicable laws and regulations governing use of electronic records and/or electronic signatures. 
Such systems may include, but are not limited to, electronic medical/health records (EMRs/EHRs), 
adverse event tracking/reporting, protocol required assessments, and/or drug accountability 
records).
When paper records from such systems are used in place of electronic format to perform regulated 
activities, such paper records should be certified copies. A certified copy consists of a copy of 
original information that has been verified, as indicated by a dated signature, as an exact copy 
having all of the same attributes and information as the original. 
STUDY TREATMENT RECORDS
Records for study treatments (whether supplied by BMS, its vendors, or the site) must substantiate 
study treatment integrity and traceability from receipt, preparation, administration, and through 
destruction or return. Records must be made available for review at the request of BMS/designee 
or a Health Authority.
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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/biocomparability, 
if applicable 
•
dates and initials of person responsible for 
Investigational Product 
dispensing/accountability, as per the Delegation 
of Authority Form.
Sourced by site, and not supplied by 
BMS or its vendors (examples include IP 
sourced 
from 
the 
sites 
stock or 
commercial supply, or a specialty 
pharmacy)
The investigator or designee accepts responsibility 
for documenting traceability and study drug integrity 
in accordance with requirements applicable under 
law and the SOPs/standards of the sourcing 
pharmacy. 
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 
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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/participants 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 
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.
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If the investigator withdraws from the study (e.g., relocation, retirement), the records shall be 
transferred to a mutually agreed upon designee (e.g., another investigator, study site, IRB). Notice 
of such transfer will be given in writing to BMS or designee. 
RETURN OF STUDY TREATMENT
For this study, study treatments (those supplied by BMS, a vendor or sourced by the investigator) 
such as partially used study treatment containers, vials and syringes may be destroyed on site. 
If..
Then
Study treatments supplied by BMS (including 
its vendors
Any unused study treatments supplied by BMS 
can only be destroyed after being inspected and 
reconciled by the responsible Study Monitor 
unless study treatments containers must be 
immediately destroyed as required for safety,
or to meet local regulations (e.g., cytotoxics or 
biologics).
If study treatments will be returned, the return 
will be arranged by the responsible Study 
Monitor.
Study treatments sourced by site, not supplied 
by BMS (or its vendors) (examples include 
study treatments sourced from the sites stock 
or 
commercial 
supply, 
or 
a 
specialty 
pharmacy)
It 
is 
the 
investigator’s 
or 
designee’s 
responsibility to dispose of all containers 
according to the institutional guidelines and 
procedures.
It is the investigator’s or designee’s responsibility to arrange for disposal, provided that procedures 
for proper disposal have been established according to applicable federal, state, local, and 
institutional guidelines and procedures, and provided that appropriate records of disposal are kept. 
The following minimal standards must be met:
•
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.
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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 
A Signatory Investigator must be selected to sign the clinical study report. 
For each CSR related to this protocol, the following criteria will be used to select the signatory 
investigator:
•
External Principal Investigator designated at protocol development
•
National Coordinating Investigator 
•
Study Steering Committee chair or their designee
•
Participant recruitment (e.g., among the top quartile of enrollers)
•
Involvement in trial design
•
Regional representation (e.g., among top quartile of enrollers from a specified region or 
country)
•
Other criteria (as determined by the study team)
SCIENTIFIC PUBLICATIONS
The data collected during this study are confidential and proprietary to Sponsor or designee. Any 
publications or abstracts arising from this study must adhere to the publication requirements set 
forth in the clinical trial agreement (CTA) governing [Study site or Investigator] participation in 
the study. These requirements include, but are not limited to, submitting proposed publications to 
Sponsor or designee at the earliest practicable time prior to submission or presentation and 
otherwise within the time period set forth in the CTAg.
Scientific Publications (such as abstracts, congress podium presentations and posters, and 
manuscripts) of the study results will be a collaborative effort between the study Sponsor and the 
external authors. No public presentation or publication of any interim results may be made by 
any principal investigator, sub-investigator, or any other member of the study staff without the 
prior written consent of the Sponsor.
Authorship of publications at BMS is aligned with the criteria of the International Committee of 
Medical Journal Editors (ICMJE, www.icmje.org). Authorship selection is based upon 
significant contributions to the study (ie, ICMJE criterion #1). Authors must meet all 4 ICMJE 
criteria for authorship:
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1) Substantial intellectual contribution to the conception or design of the work; or the acquisition 
of data (ie, evaluable subjects with quality data), analysis, or interpretation of data for the work 
(eg, problem solving, advice, evaluation, insights and conclusion); AND
2) Drafting the work or revising it critically for important intellectual content; AND
3) Final approval of the version to be published; AND
4) Agreement to be accountable for all aspects of the work in ensuring that questions related to 
the accuracy or integrity of any part of the work are appropriately investigated and resolved.
Those who make the most significant contributions, as defined above, will be considered by 
BMS for authorship of the primary publication. Sub-investigators will generally not be 
considered in the primary publication. Geographic representation will also be considered.
Authors will be listed by order of significant contributions (highest to lowest), with the exception 
of the last author. Authors in first and last position have provided the most significant 
contributions to the work.
For secondary analyses and related publications, author list and author order may vary from 
primary to reflect additional contributions.
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APPENDIX 7
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.
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.
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)
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Requires inpatient hospitalization or causes prolongation of existing hospitalization (see NOTE 
below)
NOTE: 
The following hospitalizations are not considered SAEs in BMS clinical studies: 
o
a visit to the emergency room or other hospital department < 24 hours, that does 
not result in admission (unless considered an important medical or life-
threatening event)
o
elective surgery, planned prior to signing consent
o
admissions as per protocol for a planned medical/surgical procedure
o
routine health assessment requiring admission for baseline/trending of health 
status (e.g., routine colonoscopy)
o
medical/surgical admission other than to remedy ill health and planned prior to 
entry into the study. Appropriate documentation is required in these cases
o
admission encountered for another life circumstance that carries no bearing on 
health status and requires no medical/surgical intervention (e.g., lack of housing, 
economic inadequacy, caregiver respite, family circumstances, administrative 
reason)
o
admission for administration of anticancer therapy in the absence of any other 
SAEs (applies to oncology protocols)
Results in persistent or significant disability/incapacity
Is a congenital anomaly/birth defect
is an important medical event (defined as a medical event(s) that may not be immediately life-
threatening or result in death or hospitalization but, based upon appropriate medical and 
scientific judgment, may jeopardize the participant or may require intervention [e.g., medical, 
surgical] to prevent one of the other serious outcomes listed in the definition above.) Examples 
of such events include, but are not limited to, intensive treatment in an emergency room or at 
home for allergic bronchospasm; blood dyscrasias or convulsions that do not result in 
hospitalization.) Potential drug induced liver injury (DILI) is also considered an important 
medical event. (See Section 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).
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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.
All SAEs must be followed to resolution or stabilization.
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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.
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 enrollment.
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APPENDIX 8
REVISED PROTOCOL SUMMARY OF CHANGE HISTORY
Overall Rationale for the Revised Protocol 01, 26-Jan-2018
The CA209907 protocol is being revised to increase the number of participants on the study.
Summary of key changes for Revised Protocol 01
Section Number & Title
Description of Change
Brief Rationale
Synopsis Number or 
Participants
Synopsis Sample Size 
Determination 
Figure 5.1-1 Study Design 
Schematic 
Section 5.2 Number of 
Participants
Section 10.1 Sample Size 
Determination
The number of treated 
participants increased to 
120 participants. 
Sample 
size 
expanded 
to 
provide additional data 
Table 2.-1  Laboratory rest
Added Follicle stimulating 
hormone (FSH)-only 
required to confirm 
menopause in women < 
age 55
Align 
FSH 
Testing 
with 
Women 
of 
Childbearing 
Potential in Appendix
Synopsis, Table 2: 95% 
Confidence Intervals for 
different AE rates for a sample 
size of 120 and text
Table 10.1-1 Confidence 
Intervals for different AE rates 
for a sample size of 70 and text
Table 10.1-2 Precision of 
Secondary Endpoint of ORR
Section 10.3.5 Interim 
Analysis
Statistical analyses were 
updated.
Change 
in 
number 
of 
participants 
requires 
new 
confidence 
intervals 
and 
probabilities.
Interim 
analysis 
may 
be 
performed.
6.2 Exclusion Criteria, 
3) Prior/Concomitant Therapy
4) Physical and Laboratory 
Test Findings
Exclude/prohibit botanical 
preparations within 4 weeks 
prior to first treatment.
Botanical 
preparations
are 
excluded to minimize risks of 
any interactions with study 
drugs.
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Summary of key changes for Revised Protocol 01
Section Number & Title
Description of Change
Brief Rationale
Serum creatinine 
parameters changed 
Serum creatinine parameters 
updated for safety at program 
level.
Section 7.7.1 Prohibited and/or 
Restricted Treatments
Exclude/prohibit botanical 
preparations
Botanical 
preparations
are 
excluded to minimize risks of 
any interactions with study 
drugs.
Section 7.8 Treatment After 
the End of the Study
Added language for the 
maximum 
treatment 
duration 
specified 
in 
protocol
Consistent 
with 
maximum 
treatment duration throughout 
protocol
Section 8.1.1 Nivolumab Dose 
Discontinuation 
Neurologic toxicity added 
and adrenal insufficiency/ 
ACTH deficiency updated
Additional criteria complies 
with program level standards 
for drug safety.
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