A Randomized, Multicenter, Double Blind, Phase III Study of Adjuvant Nivolumab or Placebo in Subjects With Resected Esophageal, or Gastroesophageal Junction Cancer
Phase: PHASE3
Conditions: Advanced Cancer
Sponsor: Bristol-Myers Squibb

Official Title of Study: 
A Randomized, Multicenter, Double Blind, Phase III Study of Adjuvant Nivolumab or Placebo in 
Subjects with Resected Esophageal, or Gastroesophageal Junction Cancer 
 
 
NCT Number: NCT02743494 
Document Date (Date in which document was last revised): April 26, 2024 
 
 
 

Page:
1
Protocol Number:
CA209577
IND Number:
126406
EU Trial Number
2023-509360-24
Date:
06-Jan-2016
Revised Date:
26-Apr-2024
CLINICAL PROTOCOL CA209577
A Randomized, Multicenter, Double Blind, Phase III Study of Adjuvant Nivolumab or Placebo 
in Subjects with Resected Esophageal, or Gastroesophageal Junction Cancer
(CheckMate 577: CHECKpoint pathway and nivoluMab clinical Trial Evaluation 577)
Protocol Amendment: 04
Study Director/Medical Monitor
250 Water Street, Cambridge, MA 02141
Telephone (office): 
Fax: 
24-hr Emergency Telephone Number
USA:
International: 
Bristol-Myers Squibb Research and Development
Route 206 & Province Line Road
Lawrenceville, NJ 08543
Avenue de Finlande 4
B-1420 Braine-l’Alleud, Belgium
Uxbridge Business Park
Sanderson Road, Uxbridge, Middlesex, UB8 1DH, United Kingdom
This document is the confidential and proprietary information of Bristol-Myers Squibb 
Company and its global affiliates (BMS). By reviewing this document, you agree to keep it 
confidential and to use and disclose it solely for the purpose of assessing whether your 
organization will participate in and/or the performance of the proposed BMS sponsored 
study. Any permitted disclosures will be made only on a confidential "need to know" basis
within your organization or to your independent ethics committee(s). Any other use, copying, 
disclosure or dissemination of this information is strictly prohibited unless expressly 
authorized in writing by BMS. Any supplemental information (eg, amendments) that may 
be added to this document is also confidential and proprietary to BMS and must be kept in 
confidence in the same manner as the contents of this document. Any person who receives 
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this document without due authorization from BMS is requested to return it to BMS or 
promptly destroy it. All other rights reserved. References to BMS in this protocol may apply 
to partners to which BMS has transferred obligations, eg, a Contract Research Organization 
(CRO).
© 2024 Bristol-Myers Squibb Company
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DOCUMENT HISTORY
Document
Date of Issue
Summary of Change
Protocol 
Amendment 04
26-Apr-2024
Added the option to conduct a time-driven analysis
 
 
 
Revised 
Protocol 03
06-Jun-2019

Added exclusion criteria, on-study, and post-study requirements regarding 
live/attenuated vaccines.

Updated language regarding hepatitis B or C virus exclusion criteria.

Updated language for WOCBP in Section 3.3.3 and Appendix.

Moved OS from co-primary endpoint to secondary endpoint.

Added PFS2 to exploratory endpoint and follow-up procedures.

Added language regarding monitoring for infusion-related reactions.

Added language regarding dose interruptions, delays, and discontinuation.

Added myocarditis to Grade 3 non-skin drug-related adverse events (AEs).

Removed AE assessment from survival follow-up visits.

Clarified language regarding diagnosis of recurrence.

Added option for review of reports 
 

Replaced
original sample-size determinations based on co-primary 
endpoints.

 


Added new section to update sample size and power estimates based on new 
assumptions. 

Updated to provide new triggers and timing for the interim and final 
analyses.
 
 
 

Added two separate sections to address each the DFS and OS analyses.

Made multiple updates to bring protocol in line with current program 
standards.
Administrative 
Letter 03
01-Aug-2017
Medical Monitor information updated
Revised 
Protocol 02
04-May-2017
Incorporates Amendment 06 and Administrative Letter 02
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Protocol Amendment: 04
Date: 26-Apr-2024
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Document
Date of Issue
Summary of Change
Amendment 
06
04-May-2017
The main purpose of the amendment was to modify the inclusion criteria to 
increase the time between complete resection and randomization from 4-14 
weeks to 4-16 weeks.
Other changes incorporated included:

Revised the term 'PD-L1 expression,' 'PD-L1 expression level,' and 'PD-L1 
evaluable status' to 'PD-L1 status' to account for the inclusion of patients 
where the PD-L1 results are indeterminate or non-evaluable.  Updated the 
stratifications to account for the inclusion of patients with a PD-L1 result of 
indeterminate or non-evaluable.

Revised the estimated enrollment and study duration, time to achieve
 
 

Revised the maximum dose delay window to 42 days during Cycles 1-8 and 
70 days during Cycles 9-17

Revised the study design/schematic to remove the reference to 'distant' 
recurrence

Revised the screening window from 28 days to 49 days

Revised the study drug dosing window.  For Cycles 1-8, subjects may have 
study drug administered up to 2 days before or 3 days after the scheduled 
dosing date.  For Cycles 9-17, subjects may be dosed within a +/- 3 day 
window.

Clarified that the biomarker assessments during the Follow-Up Phase 
(Table 5.1-3) only need to be collected upon the first recurrence of disease

 

Clarified that if the biomarker samples are collected at the scheduled time, 
but subsequently the dose of study drug is delayed, additional biomarker 
samples are not required to be collected

Revised the Flow Chart/Time and Events Schedule to resolve minor 
inconsistencies and to provide clarifications

Fixed typos and resolved minor inconsistencies
Administrative 
Letter 02
30-Nov-2016
To correct a formatting issue with the indenting of the bullets in protocol 
Section 4.5.2 (Dose Delay Criteria).
Revised 
Protocol 01
24-Aug-2016
Incorporates Amendment 05 and Administrative Letter 01
Amendment 
05
24-Aug-2016
The main purpose the amendment was to:

Modify the nivolumab Dose Delay Criteria (Section 4.5.2), Criteria to 
Resume Treatment (Section 4.5.4), and Discontinuation of Subjects from 
Treatment (Section 4.5.5) criteria to align with the US Package Insert and 
EU Summary of Product Characteristics
Other changes incorporated included:

Change the BMS Medical Monitor

Revised the study schematic

Clarify that subjects will receive their randomized treatment (nivolumab or 
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Document
Date of Issue
Summary of Change
placebo) for the duration of the On-Treatment Period

Changed the term BMS and BMS Medical Monitor to Sponsor or designee

Clarified that 
 

Increased the time from complete resection to randomization to 4-14 weeks

Specified the order of priority of the imaging modalities for this trial

Specified that adverse events will be documented for a minimum of 100 
days after last dose of study drug

Specified that during the Follow-Up phase 
 

Revised certain Inclusion/Exclusion criterion

Updated the duration of contraception use for WOCBP and males subjects 
with female partners that are WOCBP

Removed the methods of contraception from protocol Section 3.3

Removed reference to unblinded site staff and an unblinded site monitor

Added information regarding resuming dosing following resolution of an 
AE or immunosuppression tapering

Increased the number of tumor slides from the surgically resected specimen 
from 

Specified that  slides would be required for the optional tumor samples

Added albumin to the list of analytes required at the Screening Visit

Allowed for Total T3/T4 to be reported by the lab if free T3/T4 are not 
available based on site capabilities

Updated the On-Treatment Procedural Outline notes to reflect that 
assessments should be performed prior to dosing at the required Cycles

Removed reference to the plasma samples in the On-Treatment Procedural 
Outline table

Clarified that urinalysis is required at the Follow-Up visits if clinically 
indicated

Removed PK and immunogenicity sample collections at Follow-Up Visit 1 
and 2

Specified the collection timepoints for the Outcomes Research Assessments 
during the On-Treatment Period

Added language that allows for additional pregnancy testing to be 
performed during the Follow-Up Period

Separated the Safety Assessment section of the protocol into sub-sections 
based on the study phase

Included information regarding pulmonary adverse events and treatment

Added language regarding the planned analysis for the Tumor Samples and 
Peripheral Blood Marker

Added information regarding immune-mediated adverse events

Added information regarding AE and SUSAR reporting

Added information that a female partner of a male subject must sign an 
informed consent form to disclose information regarding a pregnancy

Updated terminology used for the statistical censoring scheme
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Date: 26-Apr-2024
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Document
Date of Issue
Summary of Change

Updated the abbreviations list

Revised the Appendix 2 (Safety Management Algorithms) 

Added Appendix 3 (Women of Childbearing Potential and Methods of 
Contraception) 

Other minor changes incorporated into this amendment include changes in 
document names, study materials that will be provided to sites, removal of 
duplicate statements, revisions to section numbering, and formatting 
changes
Administrative 
Letter 01
10-Feb-2016

Fixed the protocol title

Removed the reference to neck as an anatomical imaging area for the 
CT/MRI scan 

Updated a section number  
Original 
Protocol
06-Jan-2016
Not applicable
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OVERALL RATIONALE FOR REVISED PROTOCOL 04
The rationale for the change to the overall survival (OS) final analysis (FA) trigger includes factors 
observed during the conduct of the trial. The actual OS event accrual in the study has been much 
slower than projected. Initial projections for the OS FA estimated 
 
Blinded 
OS event tracking commenced in 2021 after the first planned interim analysis was completed. 
While Bristol-Myers Squibb (BMS) remains blinded to the number of OS events by treatment arm,
the overall accrual of events has slowed significantly year over year, since tracking began. 
 
 
The treatment landscape has changed markedly since the study was designed. Patients who 
experience recurrence after adjuvant therapy have increased treatment options and can receive 
subsequent therapy with immune checkpoint inhibitors (ICI) or a combination of immune 
checkpoint inhibitors with chemotherapy. A portion of patients may also be cured with treatment.
Increased treatment options may reduce disease mortality, therefore impacting the OS event rate.
Protocol Amendment 04 adds the option to conduct a time-driven analysis. 
 
 
SUMMARY OF KEY CHANGES FOR REVISED PROTOCOL 04
Section Number & 
Title
Description of Change
Brief Rationale
Title Page
Updated European Union (EU) 
Trial Number.
Updated Medical Monitor 
address.
Administrative update.
Synopsis
Statistical 
Considerations
Added the option to conduct 
overall survival (OS) final 
analysis (FA)
 
Refer to the overall rationale for 
revised protocol. 
Section 2.1: Good 
Clinical Practice
Section 6.1.1: Serious 
Adverse Event 
Collection and 
Reporting
Replaced Directive 2001/20/EC 
with European Regulation 
536/2014.
To update the legal framework of 
the trial after transition to EU-CTR.
Section 8.1.4: Timing 
of the DFS and OS 
Interim and Final 
Analyses
Section 8.1.5:
Potential Adjustment 
Added the option to conduct OS 
FA 
 
Refer to the overall rationale for 
revised protocol. 
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SUMMARY OF KEY CHANGES FOR REVISED PROTOCOL 04
Section Number & 
Title
Description of Change
Brief Rationale
of Analysis Timing for 
DFS and OS
Throughout
Minor typographical and 
grammatical errors have been 
corrected.
For clarity and flow.
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SYNOPSIS
Clinical Protocol CA209577
Protocol Title: A Randomized, Multicenter, Double Blind, Phase III Study of Adjuvant 
Nivolumab or Placebo in Subjects with Resected Esophageal, or Gastroesophageal Junction 
Cancer
(CheckMate 577: CHECKpoint pathway and nivoluMab clinical Trial Evaluation 577)
Investigational Product(s), Dose and Mode of Administration, Duration of Treatment with 
Investigational Product(s):  
Subject will be randomized to nivolumab (BMS-936558) or placebo monotherapy.  Subjects 
randomized to nivolumab will receive 240 mg nivolumab administered as an IV infusion over 30 
minutes every 2 weeks for 16 weeks (8 doses) followed by 480 mg nivolumab administered as an 
IV infusion over 30 minutes every 4 weeks beginning at Week 17 (2 weeks after the 8th dose). 
Subjects randomized to placebo will receive placebo administered as an IV infusion over 
30 minutes every 2 weeks for 16 weeks (8 doses) followed by placebo as an IV infusion over 30 
minutes every 4 weeks beginning at Week 17 (2 weeks after the 8th dose).
Treatment will continue until disease recurrence, unacceptable toxicity, or subject withdrawal of 
consent with a maximum of 1-year total duration of study medication.
Study Phase:  Phase 3
Research Hypothesis: 
In subjects with resected esophageal (EC) and gastroesophageal junction (GEJ) cancer, the 
administration of nivolumab will improve overall survival (OS), Disease-free survival (DFS) or 
both compared with placebo. 
Objectives: 
Primary objectives: 

To compare DFS of nivolumab versus placebo in subjects with resected EC or GEJ cancer. 
Secondary objectives: 

To compare OS of nivolumab versus placebo in subjects with resected EC or GEJ cancer. 

To evaluate 1, 2, and 3 year survival rates of nivolumab versus placebo in subjects with 
resected EC or GEJ cancer.
Exploratory objectives:

To assess the overall safety and tolerability of nivolumab versus placebo in subjects with 
resected EC or GEJ cancer.
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
To evaluate the distant metastasis free survival (DMFS) in subject with resected EC or GEJ 
cancer.

To evaluate whether PD-L1 status is a predictive biomarker for DFS and OS in subjects with 
resected EC or GEJ cancer.

To evaluate PD-L1 status prior to CRT and at the time of surgery in subjects with resected EC 
or GEJ cancer

To explore potential biomarkers associated with clinical efficacy (DFS, and OS) and/or 
incidence of adverse events of nivolumab by analyzing biomarker measures within the tumor 
microenvironment and periphery 
 in comparison to 
clinical outcomes.

 
 

To characterize the pharmacokinetics and explore exposure-response relationships with 
respect to safety and efficacy

To characterize the immunogenicity of nivolumab. 

To assess the subject’s overall health status using the 3-level version of the EQ-5D (EQ-5D-
3L) index and visual analog scale

To assess the subject’s cancer-related quality of life using the Functional Assessment of Cancer 
Therapy-Esophageal (FACT-E) questionnaire and selected components, including the 
Esophageal Cancer Subscale (ECS) and 7-item version of the FACT-General (FACT-G7) 

To assess progression-free survival after the next line of the subsequent therapy (PFS2) as 
assessed by investigators.
Study Design:  
This is a phase 3, randomized, double-blind, placebo controlled study of adjuvant nivolumab in 
subjects with resected esophageal cancer (EC), or gastroesophageal junction (GEJ) cancer who 
have received chemoradiotherapy (CRT) followed by surgery.
Nivolumab 
240 mg IV q2w X 16wks
→480mg q4wks 
Placebo 
IV q2W X16wks
→q4wks 
Treatment until  
recurrence, toxicity, or 
consent withdrawal, or 
maximum of 1-year 
treatment duration 
R
R0 resection
Residual 
disease:
ypT1 or 
Greater
ypN1 or 
Greater
ECOG PS 0–1
2:1; N= 760
Stage II/III 
EC/GEJ
Neoadjuvant
CRT→ Surgery
F/U 
Visits
Survival 
F/U 
Visits
Treatment
Follow-Up
Screening
Prior to
Screening
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After CRT followed by surgery, subjects will sign the informed consent form. Subjects whose 
tumors do not achieve pathological complete response (non-pCR) will be randomized in a blinded 
fashion 2:1 ratio to two arms between nivolumab (BMS-936558) or placebo monotherapy. 
Subjects randomized to nivolumab will receive 240 mg nivolumab administered as an IV infusion 
over 30 minutes every 2 weeks for 16 weeks (8 doses) followed by 480 mg nivolumab 
administered as an IV infusion over 30 minutes every 4 weeks beginning at Week 17 (2 weeks 
after the 8th dose). Subjects randomized to placebo will receive placebo administered as an IV 
infusion over 30 minutes every 2 weeks for 16 weeks (8 doses) followed by placebo as an IV 
infusion over 30 minutes every 4 weeks beginning at Week 17 (2 weeks after the 8th dose).   
The treatment will be given until disease recurrence, unacceptable toxicity, or subject withdrawal 
of consent with a maximum of 1-year total duration of study medication.
Stratification factors: 
1) PD-L1 status (1% vs. < 1% or indeterminate or non-evaluable)
2) Pathologic lymph node status (positive ypN1 vs. negative ypN0)
3) Histology (squamous vs. adenocarcinoma)
Study Population: Subjects must meet all eligibility criteria specified in Section 3.3 of the 
protocol, including the following:
Key Inclusion Criteria

All subjects must have Stage II or Stage III (per AJCC 7th edition) carcinoma of the esophagus 
or gastroesophageal junction and have histologically confirmed predominant adenocarcinoma 
or squamous cell carcinoma esophageal or gastroesophageal junction cancer at the time of 
initial diagnosis.

Subjects must complete pre-operative chemoradiotherapy followed by surgery prior to 
randomization. Platinum based chemotherapy should be used. Chemotherapy and radiation 
regimens can be followed as local standards of care per NCCN or ESMO guidelines.

Subject must have complete resection (R0), have been surgically rendered free of disease with 
negative margins on resected specimens
 
 Subject must have residual pathologic 
disease, ie, non-pathologic complete response (non-pCR) of their EC or GEJ, with at least 
ypN1 or ypT1 listed in the pathology report of resected specimens. For any cases of uncertainty 
(eg, ypNx), it is recommended that the Medical Monitor or designee be consulted prior to 
randomization. The pathology reports of detectable lesion(s) confirming malignancy must be 
reviewed, dated, and signed by the investigator prior to randomization.

Complete resection must be performed in a window of 4-16 weeks prior to randomization.

ECOG performance status score of 0 or 1.

All subjects must have disease-free status documented by a complete physical examination 
and imaging studies within 4 weeks prior to randomization. Imaging studies must include 
CT/MRI scan of chest and abdomen.
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
Tumor tissue from the resected site of disease must be provided for biomarker analyses. In 
order to be randomized, a subject must have a PD-L1 status classification (1%, < 1% or 
indeterminate or non-evaluable) as determined by the central lab. If insufficient tumor tissue 
content is provided for analysis, acquisition of additional archived tumor tissue (block and /or 
slides) for the biomarker analysis is required.
Key exclusion criteria

Subjects with cervical esophageal carcinoma. Location of tumor as it relates to eligibility can 
be discussed with BMS medical monitor. 

Subjects who do not receive concurrent CRT prior to surgery. Subjects who only receive 
chemotherapy or only radiation prior to surgery are not eligible. 

Subjects with Stage IV resectable disease.

Subjects with an active, known or suspected autoimmune disease. Subjects 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.

Subjects with a condition requiring systemic treatment with either corticosteroids (> 10 mg 
daily prednisone or equivalent) or other immunosuppressive medications within 14 days of 
randomization. Inhaled or topical steroids, and adrenal replacement steroid > 10 mg daily 
prednisone equivalent, are permitted in the absence of active autoimmune disease.
Study Drug:
Includes both Investigational [Medicinal] Products (IP/IMP) and Non-
investigational [Medicinal] Products (Non-IP/Non-IMP) as listed:
Study Drug for BMS-936558
Medication 
Potency 
IP/Non-IP 
Nivolumab 
10 mg/ml
IP
placebo
-
IP
Study Assessments: 
Disease-free survival (DFS) is the primary endpoint of this study. Subjects will be assessed for 
recurrence (until distant recurrence) by CT or MRI as follows:

Baseline assessment should be performed 4 weeks prior to the randomization.

Subjects on treatment will be evaluated for recurrence every 12 weeks 7 days

Subjects who discontinue treatment for reasons other than distant recurrence will continue to 
have surveillance assessments (until distant recurrence) every 12 weeks 7 days during the 
first year after randomization, every 12 weeks 14 days during the second year, after that 
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follow local standard in the range of 6-12 months between year 3 and year 5 with the last 
assessment at year 5.
OS will be followed continuously while subjects are on the study drug 
 
Statistical Considerations:  
Sample Size: The sample size determination takes into consideration the comparison of the 
primary endpoint of DFS and the first secondary endpoint of OS between the 2 treatment arms. 
The study will require approximately 760 subjects to be randomized at a 2:1 ratio to nivolumab 
and placebo 
 
 
 
Overall survival will be tested following the overall hierarchical testing procedure upon 
demonstration of superiority in DFS at either interim or final analyses for all randomized subjects.
With the sample size of 760, it is required to observe 
 
 
 
 
 
Endpoints:  
Primary endpoints: DFS is the primary endpoint of this study.
Disease-Free Survival is time between randomization date and first date of recurrence or death, 
whichever occurs first. Recurrence is defined as the appearance of one or more new lesions, which 
can be local, regional, or distant in location from the primary resected site (by imaging or pathology 
whichever comes first). All deaths without prior recurrence will be included as DFS event -
regardless of cause or of how long it has been since the last known disease evaluation. For subjects 
who remain alive and without recurrence, DFS will be censored on the date of last evaluable 
disease assessment.
Secondary endpoint: Overall survival and overall survival rates are secondary endpoints.
Overall Survival is time between the date of randomization and the date of death. For subjects 
without documentation of death, OS will be censored on the last date the subject was known to be 
alive. 
The overall survival rate at 1, 2, and 3 years is defined as the probability that a subject is alive at 
1, 2, and 3 years, respectively, following randomization.
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Analyses: DFS will be compared between treatment arms using 
 
 
 
 
 
 
 
Overall survival will be 
 
 
 
 
 
 
 
 
Survival rate analysis will be carried out only for those time points which are mature enough by 
the time of the given database-lock. 
 
 
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TABLE OF CONTENTS 
 
 
TITLE PAGE ................................................................................................................ 
 
DOCUMENT HISTORY .............................................................................................. 
 
OVERALL RATIONALE FOR REVISED PROTOCOL 04 ...................................... 
 
SUMMARY OF KEY CHANGES FOR REVISED PROTOCOL 04 ......................... 
 
SYNOPSIS .................................................................................................................... 
 
TABLE OF CONTENTS .............................................................................................. 
 
1 INTRODUCTION AND STUDY RATIONALE ..................................................... 
 
1.1 Study Rationale ................................................................................................. 
 
1.2 Research Hypothesis ......................................................................................... 
 
1.3 Objectives(s) ..................................................................................................... 
 
1.3.1 Primary Objective .................................................................................... 
 
1.3.2 Secondary Objectives ............................................................................... 
 
1.3.3 Exploratory Objectives ............................................................................ 
 
1.4 Product Development Background ................................................................... 
 
1.4.1 Nivolumab Mechanism of Action ............................................................. 
 
1.4.2 Gastric, Gastroesophageal Junction and Esophageal Cancer Background
..................................................................................................................... 
 
1.4.3 Local and Locoregional Esophageal, and Gastroesophageal Junction 
Cancer Background .................................................................................... 
 
1.4.4 Rationale for the Blockage of PD-1/PD-L1 in Gastric and Esophageal 
Cancer ......................................................................................................... 
 
1.4.5 Previous Studies of Nivolumab in Esophageal and Gastric Cancer ....... 
 
1.4.6 Summary of Nivolumab Monotherapy Safety .......................................... 
 
1.4.7 Rationale for CA209577 Study Design .................................................... 
 
1.4.7.1 Rationale for DFS Being the Single Primary Endpoint and OS 
Being the First Secondary Endpoint to Be Tested in a Hierarchical Way
............................................................................................................... 
 
1.4.7.2 Rationale for Flat Dosing of Nivolumab Monotherapy .................. 
 
1.4.7.3 Rationale for 30 minutes Infusion Times ........................................ 
 
1.4.7.4 Rationale for Placebo as the Comparator and Blinding ................ 
 
1.4.7.5 Rationale for Treating for 1 Year Total Duration .......................... 
 
1.4.7.6 Rationale for Evaluation of PD-L1 Expression as a Predictive 
Biomarker of Efficacy ........................................................................... 
 
1.4.7.7 Rationale for the Stratification Factors .......................................... 
 
1.5 Overall Risk/Benefit Assessment ..................................................................... 
 
2 ETHICAL CONSIDERATIONS ............................................................................... 
 
2.1 Good Clinical Practice ...................................................................................... 
 
2.2 Institutional Review Board/Independent Ethics Committee ............................. 
 
2.3 Informed Consent.............................................................................................. 
 
3 INVESTIGATIONAL PLAN .................................................................................... 
 
3.1 Study Design and Duration ............................................................................... 
 
3.2 Post Study Access to Therapy ........................................................................... 
 
3.3 Study Population ............................................................................................... 
 
3.3.1 Inclusion Criteria ..................................................................................... 
 
1
3
7
7
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3.3.2 Exclusion Criteria .................................................................................... 
 
3.3.2.1 Target Disease Exceptions .............................................................. 
 
3.3.2.2 Medical History and Concurrent Diseases ..................................... 
 
3.3.2.3 Physical and Laboratory Test Findings .......................................... 
 
3.3.2.4 Allergies and Adverse Drug Reaction ............................................. 
 
3.3.2.5 Other Exclusion Criteria................................................................. 
 
3.3.3 Women of Childbearing Potential ........................................................... 
 
3.4 Concomitant Treatments ................................................................................... 
 
3.4.1 Prohibited and/or Restricted Treatments................................................. 
 
3.4.2 Permitted Therapy ................................................................................... 
 
3.5 Discontinuation of Subjects following any Treatment with Study Drug .......... 
 
3.6 Post Study Drug, Study Follow-up ................................................................... 
 
3.6.1 Withdrawal of Consent ............................................................................ 
 
3.6.2 Lost to Follow-Up .................................................................................... 
 
4 STUDY DRUG .......................................................................................................... 
 
4.1 Investigational Product ..................................................................................... 
 
4.2 Non-investigational Product ............................................................................. 
 
4.3 Storage and Dispensing..................................................................................... 
 
4.4 Method of Assigning Subject Identification ..................................................... 
 
4.5 Selection and Timing of Dose for Each Subject ............................................... 
 
4.5.1 Antiemetic Premedications ...................................................................... 
 
4.5.2 Dose Delay Criteria ................................................................................. 
 
4.5.2.1 Adverse Event Management Algorithms for Immuno-Oncology 
Agents .................................................................................................... 
 
4.5.3 Dose Modifications .................................................................................. 
 
4.5.4 Criteria to Resume Treatment .................................................................. 
 
4.5.5 Discontinuation of Subjects from Treatment: .......................................... 
 
4.5.6 Treatment of Nivolumab-Related Infusion Reactions .............................. 
 
4.6 Blinding/Unblinding ......................................................................................... 
 
4.7 Treatment Compliance ...................................................................................... 
 
4.8 Destruction of Study Drug ................................................................................ 
 
4.9 Return of Study Drug ........................................................................................ 
 
5 STUDY ASSESSMENTS AND PROCEDURES ..................................................... 
 
5.1 Flow Chart/Time and Events Schedule ............................................................. 
 
5.1.1 Retesting During Screening or Lead-in Period ....................................... 
 
5.2 Study Materials ................................................................................................. 
 
5.3 Safety Assessments ........................................................................................... 
 
5.3.1 Screening Safety Assessments .................................................................. 
 
5.3.2 On-Treatment Safety Assessments ........................................................... 
 
5.3.3 Follow-Up Safety Assessments ................................................................ 
 
5.3.4 Imaging Assessment for the Study............................................................ 
 
5.4 Efficacy Assessments ........................................................................................ 
 
5.4.1 Definitions of Recurrence ........................................................................ 
 
5.4.2 Methods of Measurement ......................................................................... 
 
5.4.3 Date of Recurrence .................................................................................. 
 
5.5 Pharmacokinetic Assessments .......................................................................... 
 
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5.6 Biomarker Assessments .................................................................................... 
 
5.6.1 Tumor Samples......................................................................................... 
 
5.6.1.1 In situ Hybridization EBV RNA (EBER) of FFPE Sections ............ 
 
5.6.1.2 Microsatellite Instability Testing .................................................... 
 
5.6.1.3 HER2 ............................................................................................... 
 
5.6.1.4 Characterization of Tumor Infiltrating Lymphocytes (TILs) and 
Tumor Antigens ..................................................................................... 
 
5.6.1.5 Characterization of T Cell Repertoire ............................................ 
 
5.6.1.6 Gene Expression Profiling .............................................................. 
 
5.6.1.7 Tumor Genotyping, Mutational Analysis, and Tumor Antigen 
Profiling ................................................................................................ 
 
5.6.2 Peripheral Blood Markers ....................................................................... 
 
5.6.2.1 Soluble Biomarkers ......................................................................... 
 
5.6.2.2 Immunophenotyping ........................................................................ 
 
5.6.2.3 T Cell Repertoire Analysis .............................................................. 
 
5.6.2.4 Whole Blood for Germline DNA ..................................................... 
 
5.6.2.5 Peripheral Blood Mononuclear Cells (PBMCs) ............................. 
 
5.7 Outcomes Research Assessments ..................................................................... 
 
5.8 Other Assessments ............................................................................................ 
 
5.8.1 Immunogenicity Assessments ................................................................... 
 
6 ADVERSE EVENTS ................................................................................................. 
 
6.1 Serious Adverse Events .................................................................................... 
 
6.1.1 Serious Adverse Event Collection and Reporting .................................... 
 
6.2 Nonserious Adverse Events .............................................................................. 
 
6.2.1 Nonserious Adverse Event Collection and Reporting .............................. 
 
6.3 Laboratory Test Result Abnormalities .............................................................. 
 
6.4 Pregnancy .......................................................................................................... 
 
6.5 Overdose ........................................................................................................... 
 
6.6 Potential Drug Induced Liver Injury (DILI) ..................................................... 
 
6.7 Other Safety Considerations ............................................................................. 
 
7 DATA MONITORING COMMITTEE AND OTHER EXTERNAL COMMITTEES
................................................................................................................................. 
 
8 STATISTICAL CONSIDERATIONS....................................................................... 
 
8.1 Sample Size Determination ............................................................................... 
 
8.1.1 Assumptions of the Control Arm .............................................................. 
 
8.1.2 Assumptions of the Treatment Effect ........................................................ 
 
8.1.3 Sample Size and Power ............................................................................ 
 
8.1.4 Timing of the DFS and OS Interim and Final Analyses .......................... 
 
8.1.5 Potential Adjustment of Analysis Timing for DFS and OS ...................... 
 
8.2 Populations for Analyses .................................................................................. 
 
8.3 Endpoints .......................................................................................................... 
 
8.3.1 Primary Endpoint..................................................................................... 
 
8.3.2 Secondary Endpoint(s) ............................................................................. 
 
8.3.2.1 Overall Survival .............................................................................. 
 
8.3.2.2 Overall Survival Rate ...................................................................... 
 
8.3.3 Exploratory Endpoint(s) .......................................................................... 
 
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8.4 Analyses ............................................................................................................ 
 
8.4.1 Demographics and Baseline Characteristics........................................... 
 
8.4.2 Efficacy Analyses ..................................................................................... 
 
8.4.2.1 Protection of Type-I Error .............................................................. 
 
8.4.2.2 Primary Efficacy Endpoint ............................................................. 
 
8.4.2.3 Secondary Efficacy Endpoints ........................................................ 
 
8.4.2.4 Exploratory Efficacy Endpoints ...................................................... 
 
8.4.3 Safety Analyses......................................................................................... 
 
8.4.4 Pharmacokinetic Analyses ....................................................................... 
 
8.4.5 Biomarker Analyses ................................................................................. 
 
8.4.6 Outcomes Research Analyses .................................................................. 
 
8.4.7 Other Analyses ......................................................................................... 
 
8.5 Interim Analyses ............................................................................................... 
 
8.5.1 DFS Analyses ........................................................................................... 
 
8.5.2 OS Analyses ............................................................................................. 
 
9 STUDY MANAGEMENT ........................................................................................ 
 
9.1 Compliance ....................................................................................................... 
 
9.1.1 Compliance with the Protocol and Protocol Revisions ........................... 
 
9.1.2 Monitoring ............................................................................................... 
 
9.1.2.1 Source Documentation .................................................................... 
 
9.1.3 Investigational Site Training.................................................................... 
 
9.2 Records ............................................................................................................. 
 
9.2.1 Records Retention .................................................................................... 
 
9.2.2 Study Drug Records ................................................................................. 
 
9.2.3 Case Report Forms .................................................................................. 
 
9.3 Clinical Study Report and Publications ............................................................ 
 
10 GLOSSARY OF TERMS ........................................................................................ 
 
11 LIST OF ABBREVIATIONS .................................................................................. 
 
12 REFERENCES ........................................................................................................ 
 
APPENDIX 1 ECOG PERFORMANCE STATUS ..................................................... 
 
APPENDIX 2 MANAGEMENT ALGORITHMS ....................................................... 
 
APPENDIX 3 WOMEN OF CHILDBEARING POTENTIAL DEFINITIONS AND 
METHODS OF CONTRACEPTION ..................................................................... 
 
APPENDIX 4 COUNTRY SPECIFIC REQUIREMENTS ......................................... 
 
APPENDIX 5 PROTOCOL AMENDMENT SUMMARY OF CHANGE HISTORY
................................................................................................................................. 
 
 
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1
INTRODUCTION AND STUDY RATIONALE
1.1
Study Rationale
CA209577 is a phase 3, randomized, double-blind, placebo controlled study of adjuvant nivolumab 
in subjects with resected esophageal cancer (EC), or gastroesophageal junction (GEJ) cancer who 
have received chemoradiotherapy (CRT) followed by surgery. Over the last 30 years in Western 
Europe, North America and Australia there has been a dramatic shift in the histological subtypes 
of EC from squamous cell to adenocarcinoma.1,2 This has been attributed to a decline in smoking 
and an increase in adenocarcinoma risk factors including obesity, gastro-esophageal reflux disease 
(GERD) and Barrett’s esophagus. Adenocarcinoma of the lower esophagus or gastroesophageal 
junction has increased dramatically amongst both men and women in the last 3 decades and its 
incidence is increasing faster than any other solid tumor in the Western world.3 CRT followed by 
surgery (trimodality therapy) is now considered as a standard of care for the local and locoregional 
EC and GEJ cancers in the US and EU, and also a treatment option in Asia including Japan.4,5,6
However, only 25-30% of subjects whose tumors have a pathological complete response (pCR) 
and those subjects have been shown to have a survival benefit with a 50% of 5 year survival 
rate.7,8,9,10,11 The remaining 70-75% of subjects whose tumors did not achieve pathological 
complete response (non-pCR) have a significantly worse survival with a 37% of 5 year survival 
rate, and much worse for lymph node positive subjects where the median survival is only 9 months 
and 5 year survival is 17%.11 There is no established standard of care in the adjuvant setting in 
subjects who have received CRT followed by surgery and no clinical trials have been performed 
in this patient population for many years. Thus there is a significant medical need for novel
treatment strategies in both EC and GEJ cancers which represents a major health care problem and 
whose prevalence is increasing rapidly.
Immunotherapeutic approaches recently have demonstrated clinical efficacy in several advanced 
cancer types, including melanoma, non-small cell lung cancer (NSCLC), and renal cell carcinoma 
(RCC).12,13,14,15 In addition to advanced cancers, immunotherapy has also recently demonstrated 
a clinical benefit in adjuvant setting. Ipilimumab, a fully human monoclonal antibody that blocks 
CTLA-4 to augment anti-tumor immune responses, provided a clinically and statistically 
significant improvement in recurrence free survival (RFS) compared to placebo in stage III 
melanoma, and was recently approved by FDA.16
The preliminary data from Nivolumab monotherapy in heavily pre-treated GC (Gastric Cancer), 
GEJ and adenocarcinoma esophageal cancer (AEC) patients showed durable anti-tumor activity 
with 12 % objective response rate (ORR), and the duration of response (DCR) was 7 months.17 In 
addition, in the squamous esophageal cancer (SEC) patients, nivolumab also showed durable anti-
tumor activity with 17.2% ORR.18 These results are promising for the advanced GC and EC 
patients where there is a paucity of treatment options and, in fact, demonstrate more activity than 
ramucirumab which has recently been approved for 2L or 3L treatment in advanced GC or GEJ 
cancer.19
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BMS-936558
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An immunotherapy approach is plausible in the adjuvant setting in EC or GEJ cancer, considering 
the lack of effective treatment options, clinical activity in the adjuvant setting in melanoma as well 
as several advanced solid tumors, and the promising preliminary results with PD-1/PD-L1 
blockade in the advanced GC and EC patients. 
1.2
Research Hypothesis 
In subjects with resected esophageal and gastroesophageal junction cancer, the administration of 
nivolumab will improve overall survival (OS), Disease-free survival (DFS) or both compared with 
placebo.
1.3
Objectives(s)
1.3.1
Primary Objective

To compare disease-free survival (DFS) of nivolumab versus placebo in subjects with resected 
EC or GEJ cancer. 
1.3.2
Secondary Objectives

To compare overall survival (OS) of nivolumab versus placebo in subjects with resected EC
or GEJ cancer.

To evaluate 1, 2, and 3 year survival rates of nivolumab versus placebo in subjects with 
resected EC or GEJ cancer.
1.3.3
Exploratory Objectives

To assess the overall safety and tolerability of nivolumab versus placebo in subjects with 
resected EC or GEJ cancer.

To evaluate the distant metastasis free survival (DMFS) in subject with resected EC or GEJ 
cancer.

To evaluate whether PD-L1 status is a predictive biomarker for DFS and OS in subjects with 
resected EC or GEJ cancer.

To evaluate PD-L1 status prior to CRT and at the time of surgery in subjects with resected EC 
or GEJ cancer.

To explore potential biomarkers associated with clinical efficacy (DFS, and OS) and/or 
incidence of adverse events of nivolumab by analyzing biomarker measures within the tumor 
microenvironment and periphery 
 in comparison to 
clinical outcomes.

 
 

To characterize the pharmacokinetics (PK) and explore exposure-response relationships with 
respect to safety and efficacy.

To characterize the immunogenicity of nivolumab.
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
To assess the subject’s overall health status using the 3-level version of the EQ-5D 
(EQ-5D-3L) index and visual analog scale.

To assess the subject’s cancer-related quality of life using the Functional Assessment of Cancer 
Therapy-Esophageal (FACT-E) questionnaire and selected components, including the 
Esophageal Cancer Subscale (ECS) and 7-item version of the FACT-General (FACT-G7).

To assess progression-free survival after the next line of the subsequent therapy (PFS2) as 
assessed by investigators.
1.4
Product Development Background
1.4.1
Nivolumab Mechanism of Action
Immunotherapeutic approaches recently have demonstrated clinical efficacy in several cancer
types, including melanoma, NSCLC, and RCC.20,21,22,23.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. Nivolumab has demonstrated activity in several tumor 
types, including melanoma, renal cell cancer (RCC), and NSCLC.24 Nivolumab (Opdivo) is 
approved in multiple countries including the US for treatment of previously treated, unresectable 
or metastatic melanoma and previously treated, metastatic squamous NSCLC, and non-squamous 
NSCLC and RCC.25
1.4.2
Gastric, Gastroesophageal Junction and Esophageal Cancer 
Background 
Esophageal cancer causes over 400,000 deaths worldwide each year.3 The principle histologic 
types of esophageal cancer are esophageal squamous cell carcinoma (ESC) and esophageal 
adenocarcinoma (EAC). The relative frequency of histologic subtypes differs greatly by 
geographical location. Over the last 30 years in Western Europe, North America and Australia 
there has been a dramatic shift in the histological subtypes from squamous cell to adenocarcinoma, 
mainly located in the distal esophagus.1 This has been attributed to a decline in smoking and an 
increase in adenocarcinoma risk factors including obesity, gastro-esophageal reflux disease 
(GERD) and possibly with falling incidence of helicobacter pylori infection and an increase in the 
incidence of Barrett’s esophagus.3 In contrast to the Western population, in Asia, squamous cell 
carcinoma predominates. ESC is mainly located in the upper or middle esophagus; smoking and 
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BMS-936558
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alcohol intake are considered the main contribution factors however other lifestyle choices such 
as methods of food preparation have been implicated.26 GEJ tumors which are predominantly 
adenocarcinoma type were treated historically either like EC or GC depending on the design of 
prior studies.7,27,28,29,30 The classification of GEJ has however changed from GC to EC in the 
United States and Europe and the NCCN esophageal guidelines now place GEJ with EC instead 
of GC.4 In Asia, however, physicians treat GEJ like GC.6
1.4.3
Local and Locoregional Esophageal, and Gastroesophageal Junction 
Cancer Background 
Approximately 50% of esophageal cancers will be locally or locoregionally advanced at diagnosis 
and thus amenable to potentially curative locoregional therapy. Five-year survival rates for all 
patients with EC have shown modest improvements over the past 35 years from 5% in 1975 to 
approximately 20% for patients diagnosed in 2004.3 Five year survival rates for loco-regionally 
advanced disease treated with surgery alone has been consistently poor ranging from 6% to 26% 
in published series.10,31,32
The high incidence of recurrence, both local and distant, after ostensibly curative surgery has 
provided the impetus for many studies of multimodality therapy incorporating radiation and/or 
chemotherapy primarily in the neoadjuvant setting aimed at reducing the overall risk of relapse 
and death. The appropriate management of locally advanced disease has been contentious for a 
number of years and no standard of care has been clearly defined that has been accepted 
worldwide. For patients with adenocarcinoma there is clinical trial data supporting the various 
approaches of induction concurrent chemo-radiation (CRT), chemotherapy, peri-operative 
chemotherapy, or resection following by adjuvant CRT or chemotherapy. Recent data suggests 
that preoperative CRT is superior to surgery alone and this approach is now regarded as standard 
of care in the United States and Europe countries.7
Peri-operative chemotherapy
Multiple studies have evaluated the role of neo-adjuvant chemotherapy prior to definitive surgery 
for esophageal cancer.33,34,35 Cisplatin-based combinations result in 50% or greater regression of 
tumor, in half of patients however a pathological complete response (pCR) occurs in only 2-6% of 
all patients.33,34,35 A large US Intergroup study and several other smaller studies conducted in 
Europe showed no survival benefit to preoperative chemotherapy followed by surgery when 
compared with surgery alone.36 Conflicting data arose from the MRC – OEO2 study conducted in 
the United Kingdom which reported a 5 year survival advantage of 6% for neoadjuvant 
chemotherapy when compared with surgery alone.34 Similarly a Japanese study comparing 
preoperative chemotherapy with postoperative chemotherapy in patients with ESC suggested a 
survival advantage for preoperative therapy of 12% at 5 years.37 Of note this study did not have a 
surgery only control arm. 
Several phase III studies of peri-operative chemotherapy primarily looking at gastric cancer have 
enrolled subpopulations of lower esophageal or GEJ adenocarcinoma patients. The MAGIC study 
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BMS-936558
nivolumab
conducted in the United Kingdom included 26% of patients with lower esophageal or GEJ 
adenocarcinoma.27 This study demonstrated a 13% improvement in 5 year survival for patients 
who received multiagent ECF (epirubicin, cisplatin, fluorouracil) chemotherapy for 3 cycles 
preoperatively followed by a further 3 cycles postoperatively. Subgroup analyses suggested that 
the trend for improved survival was preserved in the group of patients with lower esophageal or 
GEJ tumors. A French study by Ychou et al randomized 224 adenocarcinoma patients 
(72% esophageal or GEJ tumors) to 2 or 3 cycles of preoperative cisplatin/5-flourouracil followed 
by 3 or 4 cycles of postoperative therapy, of note only 50% of patients who received at least one 
cycle of preoperative chemotherapy actually received postoperative therapy.35 Despite closing 
early due to poor recruitment this study showed a significant survival advantage at 5 years of 14% 
in favor of the chemotherapy group over surgery alone. In 2011 a meta-analysis of preoperative 
chemotherapy suggested a hazard ratio (HR) for all-cause mortality of 0.87 (95% confidence 
interval [CI] 0.79 – 0.96) in favor of chemotherapy compared with surgery alone which translated 
to a 2 year absolute survival advantage of 5%.38 Analysis by histology suggested a significant 
benefit to neoadjuvant chemotherapy for adenocarcinoma, HR 0.83 (0.71 – 0.95; p = 0.01), 
however the benefit for squamous tumors did not reach significance, HR 0.92 (0.81 – 1.04; p = 
0.18). At present some consider peri-operative chemotherapy in tumors of the GEJ that are 
classified as Siewert stage 3 and where a gastric origin is favored. Neoadjuvant chemoradiation is 
however the treatment of choice in patients with operable esophageal or gastroesophageal junction 
carcinomas. 
Preoperative chemo-radiotherapy
Many trials have been conducted to address the potential benefit of preoperative concurrent 
chemo-radiation using either surgery alone or preoperative radiation followed by surgery as a 
control arm. In general, these trials report a pCR in 25% to 30% of patients with associated
long-term survival for this subset.10,39,40.Approximately two thirds of patients are down-staged 
after preoperative CRT. Median survival rates with trimodality therapy (chemo-radiation followed 
by surgery) in recent studies exceed 2 years, and 3-year and 5-year survival rates are in the 30% 
to 40% range in US and European studies. These outcomes compare favorably with historic series 
of surgery alone which demonstrated 5-year survival rates of 15% to 20%. The first randomized 
study to show a survival advantage for trimodality therapy was published in 1996, however it was 
criticized for non-uniform staging of patients and the poor survival rate of the surgery only control 
patients.41 Nevertheless this study encouraged the adoption of trimodality therapy as a standard of 
care in the United States. 
Several other studies published during the 2000’s failed to support a survival advantage for the 
trimodality approach.9,42,43 Many of these studies were flawed, including utilizing suboptimal 
chemotherapy and radiation schedules, being statistically underpowered or adopting lower 
radiation dosing. Importantly these studies did suggest that achieving pCR was prognostically 
important after preoperative therapy with a significant improvement in overall survival for those 
achieving pCR.44
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BMS-936558
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The Dutch CROSS study, published in 2012, has confirmed the benefits of tri-modality treatment 
in esophageal cancer.7 This large, well conducted study examined weekly, low dose, radio-
sensitizing carboplatin (AUC 2)/paclitaxel (50 mg/m2) chemotherapy for 5 weeks concurrent with 
a standard radiation schedule followed by surgery compared with surgery alone. The majority of 
patients had adenocarcinoma (74.7%) with 24% having tumors of the GEJ. Multimodality 
treatment was well tolerated with over 90% of patients receiving all scheduled chemotherapy and 
radiation. R0 resections were significantly more frequent after preoperative therapy (92% vs. 69% 
for surgery alone, p < 0.001), lymph node positivity at resection was markedly reduced by 
preoperative therapy (31% vs. 75%, p < 0.001 for surgery alone) and there was no increase in 
postoperative morbidity or mortality. In the CROSS study with long-term follow-up, median 
overall survival was more than doubled for patients who received multimodality therapy (49.4 
months vs. 24 months for surgery alone, p = 0.011) and the benefit of multimodality therapy 
appeared to be preserved across tumor histological subtypes and all other stratified variables. 
Interestingly in this study while there was a higher rate of pCR with preoperative therapy for 
squamous (49%) compared with adenocarcinomas (23%) this translated into better outcomes for 
patients with squamous histology with 81.6 months compared with adenocarcinoma type with 43.2 
months.45 The survival in patients with pCR after neoadjuvant CRT followed by surgery is much 
better than non-PCR patients some reported even doubled survival outcome across the histological 
types.11,46 There is concern however that the chemotherapy used in the CROSS regimen is using 
radiation sensitizing doses of chemotherapy rather than full systemic doses. Adjuvant 
chemotherapy has been proposed after trimodality therapy but widespread consensus is that 
additional chemotherapy may not add significant benefits.47
Post-operative therapy
Postoperative chemotherapy and CRT have also been investigated. .CRT demonstrated a survival 
benefit of 36 months compared to 27 months seen with surgery alone in resectable adenocarcinoma 
GC and GEJ patients who did not receive neoadjuvant chemotherapy in the INT-0116 study.48
However, the regimen (bolus fluorouracil and leucovorin before and after chemoradiation with the 
same combination) used in INT-0116 study is associated high rates of Grade 3 or 4 hematologic 
and gastrointestinal (GI) toxicities and is therefore no longer widely used. Recently, alternative 
postoperative CRT regimens have been investigated, but those did not improve survival compared 
to 0116 study.49
Postoperative chemotherapy in GC is the standard of care in Asia supported by the ACTS-GC and 
CLASSIC studies. These two large trials demonstrated improved survival compared to surgery 
with 5 year survival rates of 71.7% vs. 61.1% and 78% vs. 69%, respectively.50,51
The survival of local and locoregional GEJ cancer patients in Asia is much higher than the US and 
Europe, where 5 year survival has not exceeded 50% across preoperative, perioperative and 
post-operative approaches.7,27,28 Differences in biology, screening and diagnosis, and surgical 
techniques are some of the factors thought to contribute to the survival differences between Asia 
and the US and Europe. 
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BMS-936558
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As described before, treatment of local and locoregional GEJ tumors include preoperative, 
perioperative and post-operative approaches. Despite these improvements compared to surgery 
alone, there still exists a substantial unmet medical need in the US and Europe.7,27,28 Recent data 
suggests that the survival of preoperative CRT is numerically better than other approaches, and 
this approach is now regarded as standard of care in the US and Europe.7 For patients who 
complete preoperative CRT but do not have pCR of their tumors, no accepted adjuvant therapy 
exists and mOS is less than 2 years.52 This population continues to have a high unmet medical 
need.
1.4.4
Rationale for the Blockage of PD-1/PD-L1 in Gastric and Esophageal 
Cancer
PD-1 is a 55 kD type I transmembrane protein primarily expressed on activated T cells, B cells, 
myeloid cells, and antigen-presenting cells (APCs).53 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.54,55,56,57
PD-L1 or PD-L2 expressing tumors have been reported in around 40% of patients in GC and EC 
respectively. PD-L1 expression was associated with depth of muscle invasion, tumor size, and 
lymph node metastasis. The overall survival of patients with PD-L1 or PD-L2–positive tumors 
was significantly worse than those with of PD-L1 non expressing tumors.58,59 Thus, blockage of 
PD-1/PD-L1/PD-L2 might improve the survival of this population.
Pembrolizumab, a PD-1 inhibitor, reported anti-tumor activity in both advanced GC and EC tumor 
types who had PD-L1 expressing tumors recently. PD-L1 expression tumor (cut off 1%) was 
reported in 40% of GC patients as well as EC patients which is consistent with previous reports. 
The ORR in patients with PD-L1 expressing tumors was around 33% (13/39) and 30.4% (7/23) in 
GC and EC, respectively.60,61
1.4.5
Previous Studies of Nivolumab in Esophageal and Gastric Cancer
Nivolumab monotherapy was investigated in subjects with advanced GC including EAC and GEJ 
cancer in a phase 1/2 study CA209032. A total of 59 subjects received nivolumab 3 mg/kg every 
2 weeks, approximately 70% of the subjects were GEJ and AEC. The preliminary data showed a 
durable anti-tumor activity with ORR 12%, and the duration of response was 7 months. The 
response was confirmed in both PD-L1 expressing and non-expressing tumors.17 Thus, this study 
will not limit to subjects with PD-L1 expressing tumor only, but stratify by PD-L1 status. 
Preliminary data from an ongoing phase 2 study in subjects with heavily pre-treated ESC, also 
suggested a durable antitumor activity in nivolumab monotherapy with ORR 17.2%.18
These internal and external promising data of PD-1 inhibitors support us to investigate nivolumab 
in the EC as well as GEJ. A clinical benefit has been demonstrated in adjuvant setting in melanoma 
and research efforts are ongoing in other tumors. It is hoped that a similar OS benefit can be seen 
in the adjuvant setting in the EC/GEJ post trimodality therapy in patients who have failed to 
achieve a complete pathological response.
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1.4.6
Summary of Nivolumab Monotherapy Safety
In clinical trials, Nivolumab has demonstrated an acceptable benefit-risk across multiple tumor 
types, including advanced melanoma, RCC, NSCLC, and liver cancer.
Overall, the safety profile of nivolumab monotherapy as well as combination therapy is 
manageable and generally consistent across completed and ongoing clinical trials with no MTD 
reached at any dose tested up to 10 mg/kg. There was no pattern in the incidence, severity, or 
causality of AEs to nivolumab dose level. Most AEs were low-grade (Grade 1 to 2) with relatively 
few related high-grade (Grade 3 to 4) AEs. Most high-grade events were manageable with the use 
of corticosteroids or hormone replacement therapy (endocrinopathies) as instructed in the 
management algorithms provided in nivolumab investigator brochure.
A total of 39 and 306 subjects with selected recurrent or treatment-refractory malignancies have 
been treated in a completed Phase 1 single-dose study (CA209001) and an ongoing Phase 1 
multidose study (CA209003), respectively. As the safety profile from CA209003 to date is 
consistent with that observed for CA209001, only data from the larger and more recent study, 
CA209003, is presented below.
In CA209003 (n=306, including 129 subjects with NSCLC), as of the 05-Mar-2013 data base lock, 
drug related AEs of any grade occurred in 75% of subjects. The most frequent drug-related AEs 
occurring in > 5% of subjects included fatigue (28%), rash (15%), diarrhea (13%), pruritus (11%), 
nausea (9%), decreased appetite (9%), hemoglobin decreased (6%) and pyrexia (6%). The majority 
of events were low grade, with grade 3/4 drug-related AEs observed in 17% of patients. The most 
common Grade 3/4 drug-related AEs occurring in > 1% of subjects were fatigue (2%), pneumonitis 
(1%), diarrhea (1%), abdominal pain (1%), hypophosphatemia (1%), and lymphopenia (1%). 
Drug-related serious AEs (SAEs) occurred in 14% of patients; 8% were of Grade 3/4 including 
pneumonitis (1%) and diarrhea (1%). The spectrum, frequency, and severity of drug-related AEs 
were generally similar across the dose levels tested. A review of the safety data by tumor type 
(RCC, NSCLC, mCRPC, CRC, and melanoma) also did not show any clinically meaningful 
differences in the proportion of subjects with AEs noted across tumor type.
Select adverse events with potential immune-related causality, previously termed “immune related 
adverse events” or “adverse events of special interest” were also analyzed taking into account 
multiple events, with rates adjusted for treatment duration. Most events occurred within the first 
6 months of therapy; cumulative or novel toxicities were not observed with prolonged drug 
exposure. Nineteen of 306 patients (6%) experienced grade 3-4 treatment related select adverse 
events. Fifty-two of 230 patients (23%) with drug-related adverse events required management 
with systemic glucocorticoids and/or other immunosuppressive agents. Twenty-one of 52 (40%) 
resumed nivolumab therapy after toxicity resolved, while others discontinued therapy.
Although tumor progression was the most common cause of mortality, there were 3 drug-related 
deaths associated with grade 3-4 pneumonitis. Pneumonitis (any grade) occurred in 12 of 
306 patients (4%), and grade 3-4 pneumonitis occurred in 4 patients (1%), with clinical 
presentations ranging from asymptomatic radiographic abnormalities to progressive, diffuse 
pulmonary infiltrates associated with cough, fever, and/or dyspnea. No clear relationship between 
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the occurrence of pneumonitis and tumor type, dose level, or treatment duration was noted. In 9 of 
12 patients, pneumonitis was reversible with treatment discontinuation and/or immunusuppression 
(glucocorticoids, infliximab, mycophenolate). There were no pneumonitis associated deaths 
between November 2011 and March 2013, the point of data analysis, while 79 patients continued 
to receive nivolumab during this time (median 29 weeks, range 2-69 weeks).
In CA209032 study, Nivolumab monotherapy has been administrated to subjects with heavily
pre-treated advanced GC, GEJ and EAC. As of Nov 2015, 59 subjects received nivolumab 3 mg/kg 
every 2 weeks. Nivolumab related AEs of any grade occurred in 70% of subjects (41/59), most of 
them were grade 1 and 2. Grade 3 - 4 drug related AEs were observed in 17% of subjects (10/59), 
and no grade 5 drug related events. The safety profile in patients with advanced GC including GEJ 
and EAC is considered tolerable and manageable similar with other tumor types.17
Additional details on the safety profile of nivolumab, including results from other clinical studies, 
are also available in the nivolumab IB.
1.4.7
Rationale for CA209577 Study Design
1.4.7.1
Rationale for DFS Being the Single Primary Endpoint and OS Being the 
First Secondary Endpoint to Be Tested in a Hierarchical Way
Disease-free survival is considered a meaningful measurement of clinical benefit in the adjuvant 
setting:

Disease-free survival
directly measures disease recurrence
that is confirmed by 
imaging/cytology/pathology. Disease-free survival can be used to evaluate whether adjuvant 
immunotherapy after complete resection prevents or delays recurrence in subjects who have 
not obtained a pathological complete response following trimodal therapy.62

Disease-free survival is not impacted by effects introduced by subsequent therapies. Though 
OS is considered a golden standard endpoint in oncology studies, it does reflect a combined 
treatment effect of the adjuvant setting and therapies administrated in subsequent lines. 
 
 
Disease-free survival is expected to have a strong correlation with OS in this study population: 

In the adjuvant treatment of gastric cancer, DFS has been demonstrated to be an acceptable
surrogate for OS in meta-analyses comparing adjuvant chemotherapy versus surgery alone in
curatively resected gastric cancer.63 In this publication, the author concluded that the analysis
showed both very tight individual-level association between DFS and OS and very high trial-
level association between the effects of adjuvant chemotherapy on DFS and the treatment 
effects on OS. Though CA209577 studies adjuvant nivolumab administrated in subjects with
resected esophageal or gastroesophageal junction cancer, the similar correlation as seen in 
gastric cancer between DFS and OS is also expected in this study.

 
 
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1.4.7.2
Rationale for Flat Dosing of Nivolumab Monotherapy
The nivolumab dose of 240 mg every 2 weeks (Q2W) was selected based on clinical data and 
modeling and simulation approaches using population PK (PPK) and exposure-response analyses 
of data from studies in multiple tumor types (melanoma, non-small-cell lung cancer [NSCLC], and 
renal cell carcinoma [RCC]) where body weight normalized dosing (mg/kg) has been used.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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At 4 months after initiation of treatment, subjects will be switched from nivolumab 240 mg every 
2 weeks to nivolumab 480 mg every 4 weeks (Q4W), which provides a more convenient dosing 
regimen for subjects. 
 
 
 
 
 
 
 
 
 
 
1.4.7.3
Rationale for 30 minutes Infusion Times 
Long infusion times place a burden on patients and treatment centers. Establishing that nivolumab 
can be safely administered using shorter infusion times of 30 minutes duration in subjects will 
diminish the burden provided no change in safety profile. Previous clinical studies show that 
nivolumab has been administered safely over 60 minutes at doses ranging up to 10 mg/kg over 
long treatment duration. In Study CA209010, (a Phase 2, randomized, double blinded, 
dose-ranging study of nivolumab in subjects with advanced/metastatic clear cell RCC) a dose 
association was observed for infusion site reactions and hypersensitivity reactions (1.7% at 
0.3 mg/kg, 3.7% at 2 mg/kg and 18.5% at 10 mg/kg). All the events were Grade 1 - 2 and were 
manageable. An infusion duration of 30 minutes for 240 mg or 480 mg nivolumab (60% of the 
dose provided at 10 mg/kg) is not expected to present any safety concerns compared to the prior 
experience at 10 mg/kg nivolumab dose infused over a 60-minute duration. Overall, infusion 
reactions including high-grade hypersensitivity reactions have been uncommon across nivolumab 
clinical studies. A change in safety profile is not anticipated with 30-minute infusion of nivolumab.
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1.4.7.4
Rationale for Placebo as the Comparator and Blinding 
There are no standards of treatment for patients with EC and GEJ who received CRT followed by 
surgery and achieved complete resection (R0). Perioperative chemotherapy and post-operative 
(adjuvant) CRT or chemotherapy attempted to improve the survival, however, a meta-analysis 
found no relevant differences for postoperative morbidity/mortality compared to surgery alone.66
But poor compliances of post-operative chemotherapy were reported with only 20-40% of planned 
doses due to the higher toxicity.27,67,68,69 At the present time, the standard of care is for patients to 
go on surveillance imaging after trimodality therapy. Taken together, placebo is considered to be 
acceptable comparator for this population.
The subjects will be randomized into a 2:1 ratio of nivolumab to placebo, this will allow more 
subjects access to the active drug. The study will be double-blinded in order to minimize the bias 
arising from placebo, which might affect treatment duration between the arms and have an impact 
on the primary endpoint of disease-free survival. In addition, blinding will reduce bias in reporting,
classification, and management of adverse events. 
1.4.7.5
Rationale for Treating for 1 Year Total Duration
The optimal treatment duration for patients in the adjuvant setting for EC, GEJ and GC is not 
known. S1 monotherapy for one year treatment in the adjuvant setting is a standard treatment 
practice for GC in Japan based on the data from ACTS-GC. This regimen was very tolerable with 
22.8% grade 3 or 4 AEs.29 Capecitabine in combination with oxaliplatin for 6 months is also a 
SOC in GC adjuvant setting in Asia. However, this combination regimen has a toxicity concern 
with 56% Grade 3 or 4 AEs, which prevents physicians from selecting the combination regimen 
as the first choice in the adjuvant setting.51
Throughout the nivolumab development program, most protocols have dosed until progression, 
unacceptable toxicity, or withdrawal of consent. In the absence of dose-limiting toxicity, the 
treatment duration for many prior Nivolumab trials was usually not restricted.
Based on the data from S1 monotherapy for 1 year treatment, which provides promising survival 
benefit and tolerated safety profile in GC including GEJ, and the well tolerated safety profile of 
Nivolumab monotherapy, one year treatment duration is considered a reasonable duration of drug 
administration.
1.4.7.6
Rationale for Evaluation of PD-L1 Expression as a Predictive Biomarker 
of Efficacy
PD-L1 is expressed by many tumor types and its expression has been noted to correlate with
decreased immune system function and worse clinical prognosis. It is hypothesized that PD-L1
expression within the tumor microenvironment, either on tumor cells, macrophages or
lymphocytes is a means of evading immune system detection and destruction. Still others postulate 
that PD-L1 expression on tumor cells is a surrogate for interferon-gamma release from neighboring 
activated T cells and thus portends a good prognosis for immunotherapy agents, and in particular, 
agents targeting the PD-1/PD-L1 axis. 
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In the study CA209057 nivolumab versus docetaxel in previously treated non-squamous NSCLC, 
nivolumab demonstrated superior OS (HR=0.73; 96% CI: 0.59-0.89; P = 0.00155) and improved
ORR (19.2% vs 12.4%; P = 0.0235). In subjects with PD-L1 expressing tumors, Nivolumab 
significantly improved ORR vs docetaxel (P=0.0246), with ORR as high as 36%, OS 
approximately doubled with nivolumab vs docetaxel across the PD-L1 expression continuum (The 
detail HRs at different PD-L1 cut off refer Table 1.4.7.6-1). In contrast, no difference in OS was 
seen between nivolumab and docetaxel when PD-L1 was not expressed in the tumor.70
Table 1.4.7.6-1:
PD-L1 Quantifiable patients
PD-L1 expression
Nivolumab, n
(N = 231)
Docetaxel n
(N = 224)
OS HR
(95% CI)
< 1%
108
101
0.9 (0.66, 1.24)
1%
123
123
0.59 (0.43, 0.81)
< 5%
136
138
1.01 (0.76, 1.33)
5%
95
86
0.43 (0.3, 0.63)
< 10%
145
145
1.00 (0.76, 1.31)
10%
86
79
0.4 (0.27, 0.59)
Approximately 40% of EC and GC patients reported have PD-L1 expressing tumors, which are 
associated with depth of muscle invasion, tumor size, lymph node metastasis and poor 
survival.58,59.Recently, Pembrolizumab has demonstrated to have significant anti-tumor activity in
PD-L1 expressing upper GI tumors (cut off with 30% ORR in the heavily pre-treated 
metastatic EC and GC in phase 1/2 studies.60,61 In the nivolumab CA209032 study, the ORR of 
Nivolumab monotherapy seems better in subjects with PD-L1 expressing tumors (1% cut off) with 
27% than subjects with PD-L1 non expressing tumors with 12%.17 As the signal of anti-tumor 
activity also found in PD-L1 non-expressing tumors, stratifying PD-L1 status will help understand 
whether PD-L1 expression will be a potential predictive biomarker for DFS and OS or not. Patients 
will not be selected for inclusion based on PD-L1 status. 
1.4.7.7
Rationale for the Stratification Factors
The stratification factors in this study are PD-L1 status (1% vs. < 1% or indeterminate or non-
evaluable), pathological lymph node (positive ypN1 vs. negative ypN0) and histology 
(adenocarcinoma vs. squamous). 
The rational of PD-L1 status as the stratification factor described in previous Section 1.4.7.6. 
AJCC stage II and III are the initial clinical diagnostic stages to determine eligibility however the 
subjects will be randomized after CRT and surgery in this study. Patient outcome might correlate 
with the initial diagnosis stage, but the best correlation with survival is associated with surgical 
pathology staging. Pathological lymph node positive status is reported to result in worse survival 
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in patients with gastroesophageal cancer after trimodality therapy.7,11 Thus, the pathological 
lymph status is a better stratification factor at randomization than the initial diagnostic AJCC stage.
Squamous histology showed a higher pCR rate and survival compared to adenocarcinoma in the 
CROSS study.7 The HR of mOS for patients with squamous cell type was 0.48 (mOS 81.6 months 
vs. 21.1 months in CRT/surgery vs. surgery alone), however, the HR for patients with 
adenocarcinomas was 0.73 (mOS 43·2 months vs. 27·1 months in CRT/surgery vs. surgery alone). 
The higher pCR rate might contribute to improved survival in squamous histology compared to 
adenocarcinomas (49% vs. 23%). On the other hand, a meta-analysis of 12 randomized studies 
comparing neoadjuvant CRT versus surgery alone (n = 1854), shows the survival benefits for 
neoadjuvant CRT were similar in both subgroups: squamous-cell carcinoma (HR 0.80, 95% CI 
0.68–0.93; p = 0.004) and adenocarcinoma (0.75, 95% CI 0.59–0.95; p = 0.02).71 Patients with 
non-pCR tumors (the target population for this study) were reported to have a worse survival 
compared to the population achieving a pCR tumors across both histologic subtypes.11,46 However, 
there are no reports to compare directly the survival or DFS between squamous and 
adenocarcinoma types in tumors with non-pCR. Therefore, the potential risk of unbalance in the 
two treatment arms by the different survival outcome of the two histology types might be mitigated 
by stratifying for histology.
1.5
Overall Risk/Benefit Assessment
Patients with EC including GEJ whose tumor did not achieve pCR after CRT followed surgery 
have a significant unmet medical need. Approximately 70-75% of patients have non-PCR tumors 
after neoadjuvant CRT at the time of surgery. This population has a significantly worse survival 
with a 37% 5 year survival rate, and even worse for lymph node positive patients where the median 
survival is only 9 months and 5 year survival is 17%.11 There is no established standard of care in 
the adjuvant setting in patients who have received trimodality therapy for esophageal cancer and 
no clinical trials have been performed in this patient population for many years.
Nivolumab monotherapy has demonstrated clinical activity across several tumor types, including 
Melanoma, NSCLC, RCC as well as advanced/metastatic GC and EC. Nivolumab has been 
approved for sever tumor types in multi countries and region including the US, EU and Japan.
The overall safety experience with nivolumab, as a monotherapy or in combination with other
therapeutics, is based on experience in approximately 8,600 subjects treated to date. The AE profile 
has been consistent across multiple tumor types including GC and EC, with no maximum tolerated 
dose reached at any nivolumab monotherapy dose up to 10 mg/kg.Treatment related AEs have 
included pulmonary toxicity, renal toxicity (including acute renal failure), endocrine
abnormalities, GI toxicity, dermatologic toxicity (including rash), and hepatotoxicity. In most 
cases, these AEs have been managed successfully with supportive care and, in more severe cases, 
a combination of dose delay, permanent discontinuation, and/or initiation of systemic 
corticosteroids.
The robust clinical activity demonstrated by nivolumab in several tumor types including 
advanced/metastatic EC and GC, the manageable safety profile, and the lack of standard of care 
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for subjects with EC including GEJ whose tumors with non-pCR after CRT following surgery
supports the further development of nivolumab in this population.
2
ETHICAL CONSIDERATIONS
2.1
Good Clinical Practice
This study will be conducted in accordance with Good Clinical Practice (GCP), as defined by the 
International Conference on Harmonisation (ICH) and in accordance with the ethical principles 
underlying European Regulation 536/2014 and the United States Code of Federal Regulations, 
Title 21, Part 50 (21CFR50).
The study will be conducted in compliance with the protocol. The protocol and any amendments 
and the subject informed consent will receive Institutional Review Board/Independent Ethics 
Committee (IRB/IEC) approval/favorable opinion prior to initiation of the study.
All potential serious breaches must be reported to BMS immediately. A serious breach is a breach 
of the conditions and principles of GCP in connection with the study or the protocol, which is 
likely to affect, to a significant degree, the safety or physical or mental integrity of the subjects of 
the study or the scientific value of the study.
Personnel involved in conducting this study will be qualified by education, training, and 
experience to perform their respective tasks.
This study will not use the services of study personnel where sanctions have been invoked or where 
there has been scientific misconduct or fraud (eg, loss of medical licensure, debarment). 
2.2
Institutional Review Board/Independent Ethics Committee 
Before study initiation, the investigator must have written and dated approval/favorable opinion 
from the IRB/IEC for the protocol, consent form, subject recruitment materials 
(eg, advertisements), and any other written information to be provided to subjects. The investigator 
or BMS should also provide the IRB/IEC with a copy of the Investigator Brochure or product 
labeling information to be provided to subjects and any updates. 
The investigator, 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.
2.3
Informed Consent
Investigators must ensure that subjects are clearly and fully informed about the purpose, potential 
risks, and other critical issues regarding clinical studies in which they volunteer to participate. 
In situations where consent cannot be given to subjects, their legally acceptable representatives (as 
per country guidelines) are clearly and fully informed about the purpose, potential risks, and other 
critical issues regarding clinical studies in which the subject volunteers to participate. 
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 
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regulatory requirements. The sample informed consent form will adhere to the ethical principles 
that have their origin in the Declaration of Helsinki.
Investigators must:

Provide a copy of the consent form and written information about the study in the language in 
which the subject is most proficient prior to clinical study participation. The language must be 
non-technical and easily understood. 

Allow time necessary for subject or subject's legally acceptable representative to inquire about 
the details of the study.

Obtain an informed consent signed and personally dated by the subject or the subject's legally 
acceptable representative and by the person who conducted the informed consent discussion. 

Obtain the IRB/IEC’s written approval/favorable opinion of the written informed consent form 
and any other information to be provided to the subjects, prior to the beginning of the study, 
and after any revisions are completed for new information.

If informed consent is initially given by a subject’s legally acceptable representative or legal 
guardian, and the subject subsequently becomes capable of making and communicating his or 
her informed consent during the study, consent must additionally be obtained from the subject.

Revise the informed consent whenever important new information becomes available that is 
relevant to the subject's consent. The investigator, or a person designated by the investigator, 
should fully inform the subject or the subject's legally acceptable representative or legal 
guardian, of all pertinent aspects of the study and of any new information relevant to the 
subject's willingness to continue participation in the study. This communication should be 
documented. 
The confidentiality of records that could identify subjects must be protected, respecting the privacy 
and confidentiality rules applicable to regulatory requirements, the subjects' signed ICF and, in the 
US, the subjects’ signed HIPAA Authorization.
The consent form must also include a statement that BMS and regulatory authorities have direct 
access to subject records. 
Subjects unable to give their written consent (eg, stroke or subjects with or severe dementia) may 
only be enrolled in the study with the consent of a legally acceptable representative. The subject 
must also be informed about the nature of the study to the extent compatible with his or her 
understanding, and should this subject become capable, he or she should personally sign and date 
the consent form as soon as possible. The explicit wish of a subject who is unable to give his or 
her written consent, but who is capable of forming an opinion and assessing information to refuse 
participation in, or to be withdrawn from, the clinical study at any time should be considered by 
the investigator.
The rights, safety, and well-being of the study subjects are the most important considerations and 
should prevail over interests of science and society.
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3
INVESTIGATIONAL PLAN
3.1
Study Design and Duration
The study design schematic is presented in Figure 3.1-1.
Figure 3.1-1:
Study Design Schematic
This is a phase 3, randomized, double-blind, placebo controlled study of adjuvant nivolumab in 
subjects with resected esophageal cancer (EC), or gastroesophageal junction (GEJ) cancer who 
have received chemoradiotherapy (CRT) followed by surgery.
After CRT followed by surgery, subjects will sign the informed consent form (ICF). 
Approximately 760 subjects whose tumors do not achieve pathological complete response 
(non-pCR) will be randomized in a blinded fashion in a 2:1 ratio to two arms between nivolumab 
(BMS-936558) or placebo monotherapy. Subjects randomized to nivolumab will receive 240 mg 
nivolumab administered as an IV infusion over 30 minutes every 2 weeks for 16 weeks (8 doses) 
followed by 480 mg nivolumab administered as an IV infusion over 30 minutes every 4 weeks 
beginning at Week 17 (2 weeks after the 8th dose). Subjects randomized to placebo will receive 
placebo administered as an IV infusion over 30 minutes every 2 weeks for 16 weeks (8 doses) 
followed by placebo as an IV infusion over 30 minutes every 4 weeks beginning at Week 17 
(2 weeks after the 8th dose). The treatment will be given until disease recurrence, unacceptable 
toxicity, or subject withdrawal of consent with a maximum of 1-year total duration of study 
medication.
Randomization stratification factors: 
1. PD-L1 status (1% vs. < 1% or indeterminate or non-evaluable)
2. Pathologic lymph node status (positive ypN1vs. negative ypN0)
3. Histology (squamous vs. adenocarcinoma). 
This study will consist of three phases: screening, treatment, and follow-up.
Nivolumab 
240 mg IV q2w X 16wks
→480mg q4wks 
Placebo 
IV q2W X16wks
→q4wks 
Treatment until  
recurrence, toxicity, or 
consent withdrawal, or 
maximum of 1-year 
treatment duration 
R
R0 resection
Residual 
disease:
ypT1 or 
Greater
ypN1 or 
Greater
ECOG PS 0–1
2:1; N= 760
Stage II/III 
EC/GEJ
Neoadjuvant
CRT→ Surgery
F/U 
Visits
Survival 
F/U 
Visits
Treatment
Follow-Up
Screening
Prior to
Screening
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For a complete list of study required procedures, please refer to Section 5. 
Screening phase: 

Begins by establishing the subject’s initial eligibility and signing of the ICF. Subject must 
receive pre-operative CRT followed by curative surgery. 

Subjects must have been surgically rendered free of disease with negative margins on resected 
specimens 
 
 
 
 
 

The pathology reports of detectable lesion(s) confirming malignancy must be reviewed, dated, 
and signed by the investigator prior to randomization

Subjects must have PD -L1 IHC testing, with results, performed by the central lab during the 
Screening period. 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 randomization. The resected tumor tissue sample must be obtained 
 
to randomization but after completion of CRT treatment, and there can have 
been no systemic therapy (eg, adjuvant) given after the sample was obtained. 
 
 
 Additional details regarding these 
requirements can be found in the lab manual.

Archive tumor tissues at pre-neoadjuvant chemoradiotherapy (ie, the initial diagnosis biopsy) 
for PD-L1 status biomarker analysis is optional. Additionally details regarding these 
requirements can be found in the lab manual.

All subjects must have disease-free status documented by a complete physical examination 
and imaging studies within 4 weeks prior to randomization. Imaging studies must include 
CT/MRI scan of chest and abdomen.
Treatment phase:

Following confirmation of the subject’s eligibility, the randomization entry to the IWRS can 
be made. The subject is randomly assigned in a 2:1 ratio to the nivolumab or to the placebo 
arm.

Administration of nivolumab or placebo is to begin within 3 calendar days of randomization 
as an IV infusion over 30 minutes at 240 mg every 2 weeks for 16 weeks (8 doses) followed 
by nivolumab 480 mg as a 30 minute infusion every 4 weeks beginning at Week 17 (2 weeks 
after the 8th dose).

Adverse event assessments should be documented at each clinic visit and WOCBP must have 
a pregnancy test every 4 weeks 1 week, see the details in Table 5.1-2

Treated subjects will be evaluated for recurrence every 12 weeks 1 week, see the details in 
Table 5.1-2. 
 
 

Pharmacokinetic and immunogenicity sampling will be collected 
 
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
The Outcomes Research Assessments and Health Care Resource Utilization data will be 
completed prior to the first dose and as described in Table 5.1-2 and Table 5.1-3, and in 
Section 5.7.

This phase ends when the subject is discontinued early from study therapy (ie, disease 
recurrence, unacceptable toxicity, or subject withdrawal of consent) or at a maximum of 1 year 
of treatment. 
Follow up phase: 

Begins after 1 year of treatment or when the decision is made to discontinue a subject from 
study therapy.

After completion of the first two follow -up visits (FU 1 at day 30 days 1 week and FU 2 at 
84 days 1 week from FU1), 
 
See the details in Table 5.1-3

Subjects who discontinue treatment for reasons other than distant recurrence will continue to 
have surveillance assessments (until distant recurrence) every 12 weeks 1 week during the 
first year after randomization, every 12 weeks 2 week during the second year, after that 
follow local standard in the range of 6-12 months between year 3 and year 5 with the last 
assessment at year 5. See the details in Table 5.1-3

All adverse events will be documented for a minimum of 100 days after the last dose of study 
drug Subjects will be followed for drug-related toxicities until these toxicities resolve, return 
to baseline or are deemed irreversible. See the details in Table 5.1-3

The Outcomes Research Assessments, Health Care Resource Utilization data collection, and 
biomarker sampling will continue as detailed in Table 5.1-3
 
  
3.2
Post Study Access to Therapy
At the end of the study, BMS will not continue to provide BMS supplied study drug to 
subjects/investigators unless BMS chooses to extend the study. The investigator should ensure that 
the subject receives appropriate standard of care to treat the condition under study.
3.3
Study Population
For entry into the study, the following criteria MUST be met.
3.3.1
Inclusion Criteria
1. Signed Written Informed Consent
a) Subjects must have signed and dated an IRB/IEC approved written informed consent form 
in accordance with regulatory and institutional guidelines. This must be obtained before 
the performance of any protocol related procedures that are not part of normal subject care
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b) Subjects must be willing and able to comply with scheduled visits, treatment schedule, 
laboratory tests, tumor biopsies, and other requirements of the study.
2. Target Population
a) All subjects must have Stage II or Stage III (per AJCC 7th edition) carcinoma of the 
esophagus or gastroesophageal junction and have histologically confirmed predominant 
adenocarcinoma or squamous cell carcinoma esophageal or gastroesophageal junction 
cancer at the time of initial diagnosis.
b) Subjects must complete pre-operative (neoadjuvant) chemoradiotherapy followed by 
surgery prior to randomization. Platinum based chemotherapy should be used. 
Chemotherapy and radiation regimens can be followed as local standards of care per NCCN 
or ESMO guidelines.
c) Subject must have complete resection (R0), have been surgically rendered free of disease 
with negative margins on resected specimens 
 
 
d) Subject must have residual pathologic disease, ie, non-pathologic complete response 
(non-pCR) of their EC or GEJ, with at least ypN1 or ypT1 listed in the pathology report of 
the resected specimens. For any cases of uncertainty (eg, ypNx), it is recommended that 
the Medical Monitor or designee be consulted prior to randomization. The pathology 
reports of detectable lesion(s) confirming malignancy must be reviewed, dated, and signed 
by the investigator prior to randomization.
e) Complete resection must be performed in a window 4-14 weeks prior to randomization.
Inclusion Criteria 2e is no longer applicable per Protocol Amendment 06. Refer to 
Inclusion Criteria 2l
f)
Surgery requiring local/epidural anesthesia must be completed at least 72 hours before 
study drug administration.
g) ECOG performance status score of 0 or 1.
h) All subjects must have disease-free status documented by a complete physical examination 
and imaging studies within 4 weeks prior to randomization. Imaging studies must include 
CT/MRI scan of chest and abdomen. 
i)
Tumor tissue from the resected site of disease must be provided for biomarker analyses. In 
order to be randomized, a subject must have a PD-L1 status classification (1%, < 1% or 
indeterminate or non-evaluable) as determined by the central lab. If insufficient tumor 
tissue content is provided for analysis, acquisition of additional archived tumor tissue 
(block and /or slides) for the biomarker analysis is required.
j)
All baseline laboratory requirements will be assessed and should be obtained within 
14 days prior to randomization. Screening laboratory values must meet the following 
criteria (Using CTCAE v4.) 
i)
WBCs 
2000/L
ii) Neutrophils 
1500/L
iii) Platelets 
100 x 10³/L
iv) Hemoglobin 
9.0 g/dL
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v) Creatinine: Serum creatinine 1.5 x upper limit of normal (ULN) or creatinine 
clearance > 50 mL/minute (using Cockcroft/Gault formula)
Female CrCl = (140- age in years) x weight in kg x 0.85
                               72 x serum creatinine in mg/ dL
Male CrCl = (140- age in years) x weight in kg x 1.00
                             72 x serum creatinine in mg/ dL
vi) AST 
3 x ULN 
vii)ALT 
3 x ULN
viii) Total Bilirubin 1.5 x ULN (except subjects with Gilbert Syndrome who must 
have total bilirubin < 3.0 x ULN)
k) Subject Re-enrollment: This study permits the re-enrollment of a subject that has 
discontinued the study as a pre-treatment failure (ie, subject has not been randomized). If 
re-enrolled, the subject must be re-consented.
l)
Complete resection must be performed in a window 4-16 weeks prior to randomization
3. Age and Reproductive Status
a) Males and Females, 18 years of age 
b) Women of childbearing potential (WOCBP) must have a negative serum or urine 
pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 24 hours 
prior to the start of study drug.
c) Women must not be breastfeeding
d) Women of childbearing potential (WOCBP) must agree to follow instructions for 
method(s) of contraception for a period of 30 days (duration of ovulary cycle) plus the time 
required for the investigational drug to undergo approximately five half-lives. WOCBP
receiving nivolumab should use an adequate method to avoid pregnancy for 5 months 
(30 days plus the time required for nivolumab to undergo approximately five half-lives) 
after the last dose of investigational product. 
e) Males who are sexually active with WOCBP must agree to follow instructions for 
method(s) of contraception for a period of 90 days (duration of sperm turnover) plus the 
time required for the investigational drug to undergo approximately five half-lives. Males 
receiving nivolumab who are sexually active with WOCBP must continue contraception 
for 7 months (90 days plus the time required for nivolumab to undergo approximately five 
half-lives) after the last dose of investigational drug.) In addition, male subjects must be 
willing to refrain from sperm donation during this time. 
f)
Azoospermic males are exempt from contraceptive requirements. WOCBP who are 
continuously not heterosexually active are also exempt from contraceptive requirements, 
and still must undergo pregnancy testing as described in this section.
Investigators shall counsel WOCBP, and male subjects who are sexually active with WOCBP, on 
the importance of pregnancy prevention and the implications of an unexpected pregnancy. 
Investigators shall advise WOCBP and male subjects who are sexually active with WOCBP on the 
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use of highly effective methods of contraception. Highly effective methods of contraception 
(see Appendix 3) have a failure rate of < 1% when used consistently and correctly.
At a minimum, subjects must agree to the use one highly effective method of contraception. See 
Appendix 3 for details on highly effective methods of contraception.
3.3.2
Exclusion Criteria
3.3.2.1
Target Disease Exceptions
a) Subjects with cervical esophageal carcinoma. Location of tumor as it relates to eligibility 
can be discussed with BMS medical monitor. 
b) Subjects who do not receive concurrent CRT prior to surgery. Subjects who only receive 
chemotherapy or only radiation prior to surgery are not eligible. 
c) Subjects with Stage IV resectable disease
3.3.2.2
Medical History and Concurrent Diseases
a) Treatment directed against the resected GEJ and esophageal cancer (eg, chemotherapy, 
targeted agents, radiation, or biologic therapy) that is administered after the complete 
resection.
b) Subjects with previous malignancies are excluded unless a complete remission was 
achieved at least 5 years prior to study entry and no additional therapy is required or 
anticipated to be required during the study period (exceptions include but are not limited 
to, non-melanoma skin cancers; in situ bladder cancer, or in situ colon cancers; in situ 
cervical cancers/dysplasia; or breast carcinoma in situ) - Exclusion Criteria 3.3.2.2b is 
no longer applicable per Protocol Amendment 05
c) Subjects with active, known, or suspected autoimmune disease. Subjects 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. 
d) Subjects with a condition requiring systemic treatment with either corticosteroids (> 10 mg 
daily prednisone or equivalent) or other immunosuppressive medications within 14 days 
of study drug administration. Inhaled or topical steroids, and adrenal replacement steroids 
>10 mg daily prednisone equivalent, are permitted in the absence of active autoimmune 
disease.
e) Subjects with interstitial lung disease that is symptomatic or may interfere with the 
detection or management of suspected drug-related pulmonary toxicity. 
f)
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) All toxicities attributed to prior anti-cancer therapy other than nephropathy, neuropathy, 
hearing loss, alopecia and fatigue must have resolved to Grade 1 (NCI CTCAE version 4) 
or baseline before administration of study drug. Subjects with toxicities attributed to prior 
anti-cancer therapy which are not expected to resolve and result in long lasting sequelae , 
such as peripheral neuropathy after platinum based therapy, are permitted to enroll. 
Peripheral neuropathy must have resolved to Grade 2 (NCI CTCAE version 4).
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h) Any serious or uncontrolled medical disorder or active infection that, in the opinion of the 
investigator, may increase the risk associated with study participation, study drug 
administration, or would impair the ability of the subject to receive protocol therapy.
i)
Known history of positive test for human immunodeficiency virus (HIV) or known 
acquired immunodeficiency syndrome (AIDS). NOTE: Testing for HIV must be performed 
at sites where mandated by local regulation
j)
Prior malignancy active within the previous 3 years except for locally curable cancers that 
have been apparently cured, such as basal or squamous cell skin cancer, superficial bladder 
cancer, or carcinoma in situ of the prostate, cervix, or breast.
k) Subjects who have received a live/attenuated vaccine within 30 days of the first treatment.
3.3.2.3
Physical and Laboratory Test Findings
a) Any positive test result for hepatitis B virus or hepatitis C virus indicating presence of 
virus, e.g. Hepatitis B surface antigen (HBsAg, Australia antigen) positive, or Hepatitis C 
antibody (anti-HCV) positive (except if HCV-RNA negative)..
3.3.2.4
Allergies and Adverse Drug Reaction
a) History of allergy or hypersensitivity to study drug components.
b) History of severe hypersensitivity reaction to any monoclonal antibody.
3.3.2.5
Other Exclusion Criteria
a) Prisoners or subjects who are involuntarily incarcerated
b) Subjects who are compulsorily detained for treatment of either a psychiatric or physical 
(eg, infectious disease) illness
Eligibility criteria for this study have been carefully considered to ensure the safety of the study 
subjects and that the results of the study can be used. It is imperative that subjects fully meet all 
eligibility criteria.
3.3.3
Women of Childbearing Potential
Women of childbearing potential (WOCBP) is defined as any female who has experienced 
menarche and who has not undergone surgical sterilization (hysterectomy, bilateral salpingectomy,
or bilateral oophorectomy) and is not postmenopausal. A postmenopause 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.
*Females treated with hormone replacement therapy, (HRT) are likely to have artificially 
suppressed FSH levels and may require a washout period in order to obtain a physiologic 
FSH level. The duration of the washout period is a function of the type of HRT used. The duration 
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of the washout period below are suggested guidelines and the investigators should use their 
judgment in checking serum FSH levels. 

1 week minimum for vaginal hormonal products (rings, creams, gels)

4 week minimum for transdermal products

8 week minimum for oral products
Other parenteral products may require washout periods as long as 6 months. If the serum FSH level 
is > 40 mIU/ml at any time during the washout period, the woman can be considered 
postmenopausal.
3.4
Concomitant Treatments
3.4.1
Prohibited and/or Restricted Treatments
The following medications are prohibited during the treatment and follow-up phases (before 
recurrence) of the study (unless utilized to treat a drug-related adverse event):

Immunosuppressive agents

Immunosuppressive doses of systemic corticosteroids (except as stated in Section 3.4.2)

Any concurrent anti-neoplastic therapy (including, but not limited to chemotherapy, hormonal 
therapy, immunotherapy, radiation therapy, or standard or investigational agents for treatment 
of esophageal or GEJ cancer.

Any live/attenuated vaccine (eg varicella, zoster, yellow fever, rotavirus, oral polio and 
measles, mumps, rubella [MMR]) during treatment and until 100 days post the last dose.
3.4.2
Permitted Therapy
Subjects are permitted the use of topical, ocular, intra-articular, intranasal and inhalational 
corticosteroids (with minimal systemic absorption). Adrenal replacement doses of systemic 
corticosteroids are permitted even if > 10 mg daily prednisone (or equivalent). A brief course (less 
than 3 weeks) of corticosteroids for prophylaxis (eg, for contrast dye allergy) or for treatment of 
non-autoimmune conditions (eg, delayed-type hypersensitivity reaction caused by a contact 
allergen) is permitted.
3.5
Discontinuation of Subjects following any Treatment with Study Drug 
Subjects MUST discontinue investigational product (and non-investigational product at the 
discretion of the investigator) for any of the following reasons:

Subject’s request to stop study treatment

Recurrence (local, regional or distant)

Any clinical adverse event (AE), laboratory abnormality or intercurrent illness which, in the 
opinion of the investigator, indicates that continued participation in the study is not in the best 
interest of the subject

Termination of the study by Bristol-Myers Squibb (BMS)
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
Loss of ability to freely provide consent through imprisonment or involuntarily incarceration 
for treatment of either a psychiatric or physical (eg, infectious disease) illness

Unblinding a subject for any reason (emergency or non-emergency)

Additional protocol specified reasons for discontinuation (see Section 4.5.5)
This is a survival study; therefore subjects discontinuing study treatment will remain on study for 
documentation of progression and death.
In the case of pregnancy, the investigator must immediately notify the Sponsor or designee of this 
event. In most cases, the blinded study drug will be permanently discontinued. If the investigator 
determines a possible favorable benefit/risk ratio that warrants continuation of blinded study 
drug(s), a discussion between the investigator and the Sponsor or designee must occur. 
All subjects who discontinue study drug should comply with protocol specified follow-up 
procedures as outlined in Section 5. The only exception to this requirement is when a subject 
withdraws consent for all study procedures including post-treatment study follow-up or loses the 
ability to consent freely (ie, is imprisoned or involuntarily incarcerated for the treatment of either 
a psychiatric or physical illness).
If study drug is discontinued prior to the subject’s completion of the study, the reason for the 
discontinuation must be documented in the subject’s medical records and entered on the 
appropriate case report form (CRF) page.
Subjects must be followed for safety for at least 100 days after the last dose of study therapy. 
Follow-up (FU1) occurs approximately 30 days (+/- 7 days) after last dose or coinciding with the 
date of discontinuation (+/- 7 days) if the date of discontinuation is greater than 35 days after the 
last dose. Follow up visit #2 (FU2) occurs approximately 84 days (+/- 7 days) after FU1. These 
follow-up visits #1 and #2 should occur in person. 
 
 
  
3.6
Post Study Drug, Study Follow-up
In this study, DFS is the primary endpoint. Post study follow-up is of critical importance and is 
essential to preserving subject safety and the integrity of the study. Subjects who discontinue study 
drug must continue to be followed for collection of recurrence (till distant recurrence) and/or 
survival follow-up data as required and in line with Section 5 until death or the conclusion of the 
study. The importance of follow up should be clearly communicated to study subjects.
BMS may request that survival data be collected on all randomized subjects outside of the protocol 
defined window (per Table 5.1-3). At the time of this request, each subject will be contacted to 
determine their survival status unless the subject has withdrawn consent for all contact.
3.6.1
Withdrawal of Consent
Subjects who request to discontinue study drug will remain in the study and must continue to be 
followed for protocol specified follow-up procedures. The only exception to this is when a subject 
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specifically withdraws consent for any further contact with him/her or persons previously 
authorized by subject to provide this information. Subjects should notify the investigator of the 
decision to withdraw consent from future follow-up in writing, whenever possible. The 
withdrawal of consent should be explained in detail in the medical records by the investigator, as 
to whether the withdrawal is from further treatment with study drug only or also from study 
procedures and/or post treatment study follow-up, and entered on the appropriate CRF page. In the 
event that vital status (whether the subject is alive or dead) is being measured, publicly available 
information should be used to determine vital status only as appropriately directed in accordance 
with local law.
3.6.2
Lost to Follow-Up
All reasonable efforts must be made to locate subjects to determine and report their ongoing status. 
This includes follow-up with persons authorized by the subject as noted above. Lost to follow-up 
is defined by the inability to reach the subject after a minimum of three documented phone calls, 
faxes, or emails as well as lack of response by subject to one registered mail letter. All attempts 
should be documented in the subject’s medical records. If it is determined that the subject has died, 
the site will use permissible local methods to obtain the date and cause of death.
If investigator’s use of third-party representative to assist in the follow-up portion of the study has 
been included in the subject’s informed consent, then the investigator may use a Sponsor-retained 
third-party representative to assist site staff with obtaining subject’s contact information or other 
public vital status data necessary to complete the follow-up portion of the study. The site staff and 
representative will consult publicly available sources, such as public health registries and 
databases, in order to obtain updated contact information. If after all attempts, the subject remains 
lost to follow-up, then the last known alive date as determined by the investigator should be 
reported and documented in the subject’s medical records.
4
STUDY DRUG
Study drug includes both Investigational [Medicinal] Product (IP/IMP) and Non-investigational 
[Medicinal] Product (Non-IP/Non-IMP) and can consist of the following:
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Table 4-1:
Study Drugs for CA209577
Product Description / 
Class and Dosage Form
Potency
IP/Non-IMP
Blinded or Open 
Label
Packaging/ Appearance
Storage Conditions
(per label)
Nivolumab
(BMS-936558-01)
Solution for Injection
100 mg (10 mg/mL)
IMP
Blinded
10 mL Vial/Clear to 
opalescent colorless to 
pale yellow liquid. May 
contain particles
2 to 8C. Protect from 
light and freezing
Placebo
N/A
IMP
Blinded
10 mL Vial/Clear to 
opalescent colorless to 
pale yellow liquid. May 
contain particles
2 to 8C. Protect from 
light and freezing
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4.1
Investigational Product
An investigational product, also known as investigational medicinal product in some regions, is 
defined a pharmaceutical form of an active substance or placebo being tested or used as a reference 
in a clinical study, including products already with a marketing authorization but used or 
assembled (formulated or packaged) differently than the authorized form, or used for an 
unauthorized indication, or when used to gain further information about the authorized form.
The investigational product should be stored in a secure area according to local regulations. It is 
the responsibility of the investigator to ensure that investigational product is only dispensed to 
study subjects. The investigational product must be dispensed only from official study sites by 
authorized personnel according to local regulations. 
In this protocol, investigational products are: nivolumab and placebo for nivolumab.
4.2
Non-investigational Product
Other medications used as support or escape medication for preventative, diagnostic, or therapeutic 
reasons, as components of the standard of care for a given diagnosis, may be considered as non-
investigational products. 
In this protocol, non-investigational product(s) is/are: medications used to treat nivolumab 
infusion-related reactions (eg, steroids, anti-emetics); these non-investigational products should be 
sourced by the investigator sites if available and permitted by local regulations.
4.3
Storage and Dispensing
The product storage manager should ensure that the study drug is stored in accordance with the 
environmental conditions (temperature, light, and humidity) as determined by BMS. If concerns 
regarding the quality or appearance of the study drug arise, the study drug should not be dispensed 
and contact BMS immediately. Investigational product documentation (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).
Storage facilities for controlled substances must be securely locked and substantially constructed, 
with restricted access to prevent theft or diversion, as applicable by local regulations.
Infusion-related supplies (eg, IV bags, in-line filters, diluents) will not be supplied by the sponsor 
and should be purchased locally if permitted by local regulations.
For study drug, please refer to the current version of the Investigator Brochures and/or drug 
preparation manual for complete storage, handling, dispensing, and infusion information. For 
diluents, please refer to the package insert, summary of product characteristics, or equivalent 
documentation.
Study drug is to be administered as an approximately 30-minute IV infusion. At the end of the 
infusion, flush the line with a sufficient quantity of normal saline or dextrose solution in an 
identical fashion as nivolumab in order to maintain the blind.
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4.4
Method of Assigning Subject Identification
After the subject’s initial eligibility is established and informed consent has been obtained, the 
subject must be enrolled into the study by entering information into IWRS to obtain the subject 
number. Every subject that signs the informed consent form must be assigned a subject number in 
IWRS. Specific instructions for using IWRS will be provided to the investigational site in a 
separate document. The investigator or designee will register the subject for enrollment by 
following the enrollment procedures established by BMS. The following information is required 
for enrollment:

Date that informed consent was obtained

Date of birth

Gender at birth
Once enrolled in IWRS, enrolled subjects that have met all eligibility criteria (the required tumor 
tissue received and result obtained by the central laboratory and the pathology report approved by 
the investigator) will be ready to be randomized through the IWRS. The following information is 
required for subject randomization:

Subject number

Date of birth

PD-L1 status (Note that the result of PD-L1 expression 1%, or PD-L1 expression < 1% or 
indeterminate or non-evaluable is entered by the central laboratory vendor into IWRS and both 
the site and the BMS study team remain blinded to the result)

Pathologic evidence of disease in lymph nodes (ypN0 vs. ypN1)

Histology (Squamous vs. adenocarcinoma)
Subjects meeting all eligibility criteria will be randomized in a 2:1 ratio to Arm A nivolumab or 
Arm B placebo stratified by the following factors:

PD-L1 status (1% vs. < 1% or indeterminate or non-evaluable) 

Pathologic evidence of disease in lymph nodes (ypN0 vs. ypN1)

Histology (Squamous cell type vs. adenocarcinoma)
The exact procedures for using the IWRS will be detailed in the IWRS manual.
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4.5
Selection and Timing of Dose for Each Subject
Table 4.5-1:
Nivolumab (or placebo) dosing
Drug
Dose
Frequency of 
administration
Route of 
administration
Duration
Nivolumab
(or placebo)
240 mg (or placebo)
[Cycles 1-8]
Every 2 weeks, for 
8 doses
Intravenous (IV) 
infusion
Until recurrence or 
discontinuation 
from study for a 
maximum of 1 year
480 mg (or placebo)
[Cycles 9-17]
Every 4 weeks 
starting at Cycle 9
Subjects will receive treatment with nivolumab (BMS-936558) or placebo monotherapy. Subjects 
randomized to nivolumab will receive 240 mg nivolumab administered as an IV infusion over 
30 minutes every 2 weeks for 16 weeks (8 doses) followed by 480 mg nivolumab administered as 
an IV infusion over 30 minutes every 4 weeks beginning at Week 17 (2 weeks after the 8th dose). 
Subjects randomized to placebo will receive placebo administered as an IV infusion over 
30 minutes every 2 weeks for 16 weeks (8 doses) followed by placebo as an IV infusion over 
30 minutes every 4 weeks beginning at Week 17 (2 weeks after the 8th dose). Treatment will be 
given until disease recurrence, unacceptable toxicity, or subject withdrawal of consent with a 
maximum of 1-year total duration of study medication.
First dose must be administered within 3 calendar days following randomization. There are no 
pre-medications recommended on the first cycle. If an acute infusion reaction is noted, subjects 
should be managed according to Section 4.5.6. At the end of the infusion, flush the line with a 
sufficient quantity of diluent. Refer to drug preparation manual for more detail.
Dosing modifications:
There will be no dose modifications allowed for the management of toxicities of individual 
subjects. Subjects should be carefully monitored for infusion reactions during nivolumab 
administration. If an acute infusion reaction is noted, subjects should be managed according to 
Section 4.5.6.
Doses of nivolumab may be interrupted, delayed, or discontinued depending on how well the 
subject tolerates the treatment. Dosing visits are not skipped, only delayed.
Dosing window:
For Cycles 1-8, subjects may have study drug administered up to 2 days before or 3 days after the 
scheduled dosing date. Subjects may be dosed no less than 12 days from the previous dose. For 
Cycles 9-17, subjects may be dosed within a +/- 3 day window. A maximum delay of 6 weeks (42 
days) between doses of nivolumab (or placebo) during Cycles 1-8 or a maximum delay of 10 weeks 
(70 days) between doses of nivolumab (or placebo) during Cycles 9-17 are allowed.
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4.5.1
Antiemetic Premedications
Antiemetic premedications should not be routinely administered prior to dosing of drugs. See 
Section 4.5.6 for premedication recommendations following a nivolumab related infusion reaction.
4.5.2
Dose Delay Criteria
Dose delay criteria apply for all drug-related adverse events. Treatment delays up to 6 weeks 
(42 days) from the last dose of nivolumab (or placebo) during Cycles 1-8 or up to 10 weeks (70 
days) from the last dose of nivolumab (or placebo) during Cycles 9-17 are allowed.
Nivolumab (or placebo) administration should be delayed for the following:

Any Grade 2 non-skin, drug-related adverse event, with the following exceptions:

Grade 2 drug-related fatigue does not require a treatment delay

Grade 2 drug-related creatinine, AST, ALT or Total Bilirubin abnormalities

Any Grade 3 skin, drug-related adverse event

Any Grade 3 drug-related laboratory abnormality (excluding AST, ALT or Total Bilirubin), 
with the following exceptions for lymphopenia, and asymptomatic amylase or lipase:

Grade 3 lymphopenia does not require dose delay

Any Grade 3 drug-related amylase or lipase abnormalities that is not associated with 
symptoms or clinical manifestations of pancreatitis do not require a dose delay. 

Any adverse event, laboratory abnormality, or intercurrent illness which, in the judgment of 
the investigator, warrants delaying the dose of study medication.
Subjects who require delay of nivolumab should be re-evaluated weekly or more frequently if 
clinically indicated and resume nivolumab dosing when re-treatment criteria are met.
Note: per BMS standards, the term “interruption” is reserved for interruption of the actual IV 
infusion during administration. The terms omission and interruption should not be used 
synonymously when completing the CRF forms.
4.5.2.1
Adverse Event Management Algorithms for Immuno-Oncology Agents
Immuno-oncology (I-O) agents are associated with adverse events that can differ in severity and 
duration than adverse events caused by other therapeutic classes. Nivolumab is considered 
immuno-oncology agent in this protocol. Early recognition and management of adverse events 
associated with immuno-oncology agents may mitigate severe toxicity. Management algorithms 
have been developed to assist investigators in assessing and managing the following groups of 
adverse events:

Gastrointestinal

Renal

Pulmonary

Hepatic

Endocrinopathies
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
Skin

Neurological
In order to standardize the management of adverse events for all subjects, treatment management 
algorithms recommended for utilization in this study are from the current IB and included in the 
Appendix 2 of this protocol. Adverse event treatment management algorithms included in the 
current IB might be considered for individual cases.
For subjects expected to require more than 4 weeks of corticosteroids or other immunosuppressants 
to manage an adverse event, consider recommendations provided in the current IB.
4.5.3
Dose Modifications
Dose reductions for the management of toxicities of individual subjects or dose escalations are not 
permitted. All dose modifications rules apply to both arms given the blinded nature of this study
4.5.4
Criteria to Resume Treatment
All criteria to resume treatment apply to both arms given the blinded nature of this study. Subjects 
may resume treatment with study drug when the treatment-related AE(s) resolve to Grade 1 or 
baseline value, with the following exceptions:

Subjects may resume treatment in the presence of Grade 2 fatigue

Subjects who have not experienced a Grade 3 drug-related skin AE may resume treatment in 
the presence of Grade 2 skin toxicity

For subjects with Grade 2 AST, ALT, or TBILI elevations, dosing may resume when 
laboratory values return to baseline and management with corticosteroids, if needed, is 
complete

Subjects with combined Grade 2 AST/ALT AND
total bilirubin values meeting 
discontinuation parameters (Section 4.5.5) should have treatment permanently discontinued

Drug-related pulmonary toxicity, diarrhea, or colitis, must have resolved to baseline before 
treatment is resumed. Subjects with persistent Grade 1 pneumonitis after completion of a 
steroid taper over at least 1 month may be eligible for retreatment if discussed with and 
approved by the BMS Medical Monitor

Grade 2 or 3 drug-related endocrinopathies adequately controlled with only physiologic 
hormone replacement may resume treatment after consultation with the BMS Medical 
Monitor, except for Grade 3 adrenal insufficiency which requires permanent discontinuation 
as described in Section 4.5.5
If the criteria to resume treatment are met, the subject should restart treatment at the next scheduled 
time point per protocol.
However, if the treatment is withheld past the window period of the next scheduled time point per 
protocol to ensure adequate recovery from the adverse event or tapering of immunosuppression, 
the dosing should start as soon as possible once it is safe to do so (ie, no need to wait until the 
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subsequent scheduled time point to resume dosing). If treatment is delayed > 6 weeks (42 days) 
from the last dose of nivolumab (or placebo) during Cycles 1-8 or > 10 weeks (70 days) from the 
last dose of nivolumab (or placebo) during Cycles 9-17, the subject must be permanently 
discontinued from study therapy, except as specified in Section 4.5.5. 
4.5.5
Discontinuation of Subjects from Treatment:
All discontinuation criteria for nivolumab also apply for the placebo, given the blinded nature of 
this study.
Treatment should be permanently discontinued for the following:

Any Grade 2 drug-related uveitis, eye pain, or blurred vision that does not respond to topical 
therapy and does not improve to Grade 1 severity within the re-treatment period OR requires 
systemic treatment 

Any Grade 3 non-skin, drug-related adverse event lasting > 7 days, with the following 
exceptions for drug-related laboratory abnormalities, uveitis, pneumonitis, bronchospasm, 
hypersensitivity reactions, infusion reactions, and endocrinopathies:

Grade 3 drug-related uveitis, pneumonitis, bronchospasm, myocarditis, hypersensitivity 
reaction, or infusion reaction of any duration requires discontinuation

Grade 3 drug-related endocrinopathies adequately controlled with only physiologic
hormone replacement do not require discontinuation, except for Grade 3 adrenal 
insufficiency which requires permanent discontinuation as described in Section 4.5.5

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 drug-related AST or ALT > 3 x ULN and total bilirubin > 2 x ULN

Any drug-related Grade 4 endocrinopathy and Grade 3 adrenal insufficiency requires 
discontinuation

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

Isolated Grade 4 amylase or lipase abnormalities that are not associated with symptoms or 
clinical manifestations of pancreatitis. 

Isolated Grade 4 electrolyte imbalances/abnormalities that are not associated with clinical 
squeal and are corrected with supplementation/appropriate management within 72 hours of 
their onset

Dosing that is withheld > 6 weeks (42 days) from the last dose of nivolumab (or placebo) 
during Cycles 1-8 or > 10 weeks (70 days) from the last dose of nivolumab (or placebo) during 
Cycles 9-17, with the following exceptions:
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
Dosing delays to allow for prolonged steroid tapers to manage drug-related adverse events 
are allowed. 

Dosing delays lasting > 6 weeks or > 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 subject with a dosing delay lasting > 6 weeks (42 days) from 
the last dose of nivolumab (or placebo) during Cycles 1-8 or > 10 weeks (70 days) from the last 
dose of nivolumab (or placebo) during Cycles 9-17, 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 under current illness which, in the judgment of 
the Investigator, presents a substantial clinical risk to the subject with continued nivolumab 
dosing.
Post treatment study follow-up is critically important and is essential to preserving subject safety 
and the integrity of the study. Subjects who discontinue study treatment will continue to be 
followed for collection of tumor surveillance assessments, safety, QoL questionnaires and 
biomarker sampling as per protocol. 
4.5.6
Treatment of Nivolumab-Related Infusion Reactions
Since nivolumab contains only human immunoglobulin protein sequences, it is unlikely to be 
immunogenic and induce infusion or hypersensitivity reactions. However, if such a reaction were 
to occur, it might manifest with fever, chills, rigors, headache, rash, pruritus, arthalgias, 
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) guidelines.
Treatment recommendations are provided below and may be modified based on local treatment 
standards and guidelines, as appropriate:
For Grade 1 symptoms: (Mild reaction; infusion interruption not indicated; intervention not 
indicated)

Remain at bedside and monitor subject until recovery from symptoms. The following 
prophylactic premedications are recommended for future infusions: diphenhydramine 50 mg 
(or equivalent) and/or paracetamol 325 to 1000 mg (acetaminophen) at least 30 minutes before 
additional nivolumab administrations.
For Grade 2 symptoms: (Moderate reaction requires therapy or infusion interruption but responds 
promptly to symptomatic treatment [eg, antihistamines, non-steroidal anti-inflammatory drugs, 
narcotics, corticosteroids, bronchodilators, IV fluids]; prophylactic medications indicated for 
24 hours).
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
Stop the nivolumab infusion, begin an IV infusion of normal saline, and treat the subject with 
diphenhydramine 50 mg IV (or equivalent) and/or paracetamol 325 to 1000 mg 
(acetaminophen); remain at bedside and monitor subject until resolution of symptoms. 
Corticosteroid or bronchodilator therapy may also be administered as appropriate. If the 
infusion is interrupted, then restart the infusion at 50% of the original infusion rate when 
symptoms resolve; if no further complications ensue after 30 minutes, the rate may be 
increased to 100% of the original infusion rate. Monitor subject closely. If symptoms recur 
then no further nivolumab will be administered at that visit. Administer diphenhydramine 
50 mg IV, and remain at bedside and monitor the subject until resolution of symptoms. The 
amount of study drug infused must be recorded on the electronic case report form (eCRF).

For future infusions, the following prophylactic premedications are recommended:
diphenhydramine 50 mg (or equivalent) and/or paracetamol 325 to 1000 mg (acetaminophen) 
should be administered at least 30 minutes before additional nivolumab administrations. If 
necessary, corticosteroids (recommended dose: up to 25 mg of IV hydrocortisone or 
equivalent) may be used.
For Grade 3 or Grade 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 subject as follows. Recommend bronchodilators, epinephrine 0.2 to 1 mg of a 1:1,000 
solution for subcutaneous administration or 0.1 to 0.25 mg of a 1:10,000 solution injected 
slowly for IV administration, and/or diphenhydramine 50 mg IV with methylprednisolone 
100 mg IV (or equivalent), as needed. Subject should be monitored until the investigator is 
comfortable that the symptoms will not recur. Nivolumab will be permanently discontinued. 
Investigators should follow their institutional guidelines for the treatment of anaphylaxis. 
Remain at bedside and monitor subject until recovery from symptoms.
In the case of late-occurring hypersensitivity symptoms (eg, appearance of a localized or 
generalized pruritus within 1 week after treatment), symptomatic treatment may be given (eg, oral 
antihistamine, or corticosteroids).
4.6
Blinding/Unblinding
The Sponsor, subjects, investigator and site staff will be blinded to the study therapy administered. 
Blinding of treatment assignment is critical to the integrity of this clinical study. However, in the 
event of a medical emergency or pregnancy in an individual subject in which knowledge of the 
investigational product is critical to the subject's management, the blind for that subject may be 
broken by the investigator. The subject’s safety takes priority over any other considerations in 
determining if a treatment assignment should be unblinded.
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Before breaking the blind of an individual subject's treatment, the investigator should determine 
that the unblinded information is necessary, ie, that it will alter the subject's immediate 
management. In many cases, particularly when the emergency is clearly not related to the 
investigational product, the problem may be properly managed by assuming that the subject is 
receiving active product. It is highly desirable that the decision to unblind treatment assignment 
be discussed with the Medical Monitor, but the investigator always has ultimate authority for the 
decision to unblind. The Principal Investigator should only call in for emergency unblinding 
AFTER the decision to discontinue the subject has been made.
For this study, the method of unblinding for emergency purposes is through the IWRS. For 
information on how to unblind for emergency, please consult the IWRS manual.
In cases of accidental unblinding, contact the Medical Monitor and ensure every attempt is made 
to preserve the blind. Any request to unblind a subject for non-emergency purposes should be 
discussed with the Medical Monitor.
In addition, designated staff of Bristol-Myers Squibb Research & Development may be unblinded 
prior to database lock to facilitate the bioanalytical analysis of pharmacokinetic samples and 
immunogenicity. A bioanalytical scientist in the Bioanalytical Sciences department of Bristol-
Myers Squibb Research & Development (or a designee in the external central bioanalytical 
laboratory) will be unblinded to the randomized treatment assignments in order to minimize 
unnecessary bioanalytical analysis of samples.
To further minimize bias, the sponsor central study team and the investigative clinical site staff are 
blinded to results from PD-L1 analysis.
4.7
Treatment Compliance
Treatment compliance will be monitored by drug accountability as well as the subject’s medical 
record and eCRF.
4.8
Destruction of Study Drug
For this study, study drugs (those supplied by BMS or sourced by the investigator) such as partially 
used study drug containers, vials and syringes may be destroyed on site. 
Any unused study drugs can only be destroyed after being inspected and reconciled by the 
responsible Study Monitor unless study drug containers must be immediately destroyed as required 
for safety, or to meet local regulations (eg, cytotoxics or biologics). 
On-site destruction is allowed provided the following minimal standards are met:

On-site disposal practices must not expose humans to risks from the drug.

On-site disposal practices and procedures are in agreement with applicable laws and 
regulations, including any special requirements for controlled or hazardous substances.

Written procedures for on-site disposal are available and followed. The procedures must be 
filed with the site’s SOPs and a copy provided to BMS upon request.

Records are maintained that allow for traceability of each container, including the date 
disposed of, quantity disposed, and identification of the person disposing the containers. The 
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method of disposal, ie, incinerator, licensed sanitary landfill, or licensed waste disposal vendor 
must be documented.

Accountability and disposal records are complete, up-to-date, and available for the Monitor to 
review throughout the clinical trial period.
If conditions for destruction cannot be met the responsible Study Monitor will make arrangements 
for return of study drug.
It is the investigator’s responsibility to arrange for disposal of all empty containers, provided that 
procedures for proper disposal have been established according to applicable federal, state, local, 
and institutional guidelines and procedures, and provided that appropriate records of disposal are 
kept.
4.9
Return of Study Drug
If study drug will not be destroyed upon completion or termination of the study, all unused and/or 
partially used study drug that was supplied by BMS must be returned to BMS. The return of study 
drug will be arranged by the responsible Study Monitor. 
It is the investigator’s responsibility to arrange for disposal of all empty containers, provided that 
procedures for proper disposal have been established according to applicable federal, state, local, 
and institutional guidelines and procedures, and provided that appropriate records of disposal are 
kept. 
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5
STUDY ASSESSMENTS AND PROCEDURES
5.1
Flow Chart/Time and Events Schedule 
Table 5.1-1:
Screening Procedural Outline (CA209577)
Procedure
Screening Visit
(Day - 49 till Day - 1 
prior to Randomization)
Notes
Eligibility Assessments
Informed Consent
X
Inclusion/Exclusion Criteria
X
All inclusion/exclusion criteria should be assessed during screening and confirmed 
prior to randomization.
Medical History
X
Review of pathology report
X
The pathology report must be reviewed, signed and dated by the investigator prior 
to randomization.
Tumor Tissue Samples
X
Sufficient tumor tissue from the resected site of the disease (either a formalin-fixed, 
paraffin-embedded [FFPE] tissue block or
 
) must be available 
 to randomization, and sent to a central laboratory for 
biomarker analysis. PD-L1 status will be assessed prior to randomization.
Archive tumor tissues at pre-neoadjuvant chemoradiotherapy (ie, the initial 
diagnosis biopsy) for PD-L1 status biomarker analysis is optional. If this optional 
sample is provided, please send either a formalin-fixed, paraffin embedded [FFPE] 
tissue block or  slides. 
 
 
Safety Assessments
Physical Examination
X
Within 14 days prior to randomization
Physical Measurements
X
Include Height and Weight
Within 14 days prior to randomization
Vital Signs 
X
Including BP, HR, temperature, Obtain vital signs at the screening visit and within 
72 hours prior to first dose
Performance Status (ECOG)
X
Within 14 days prior to randomization
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Table 5.1-1:
Screening Procedural Outline (CA209577)
Procedure
Screening Visit
(Day - 49 till Day - 1 
prior to Randomization)
Notes
Assessment of Signs and Symptoms
X
Within 14 days prior to randomization
Serious Adverse Event (SAE) Assessment
X
After informed consent is signed.
Concomitant Medication Collection
X
Within 14 days prior to first dose
Electrocardiogram (ECG)
X
Within 14 days prior to randomization
Laboratory Tests
X
On site/local complete blood count (CBC) w/differential, Chemistry panel 
including: LDH, AST, ALT, ALP, T-Bil, blood urea nitrogen (BUN) or serum urea 
level, creatinine, Na, K, Cl, total protein, glucose, albumin, amylase, lipase within 
14 days prior to randomization.
Urinalysis as clinically indicated within 14 days prior to randomization.
Endocrine panel (TSH, Free T4, Free T3. Total T3/T4 are acceptable if free T3/T4 
are not available), Hep B/C (HBV sAG, HCV antibody or HCV RNA), HIV (when 
required by local regulations), within 28 days prior to randomization.
Pregnancy Test (WOCBP only)
X
Serum or urine to be done at screening visit and repeated within 24 hours of first 
dose of study therapy
Efficacy assessment
Baseline Tumor Imaging Assessment
X
See Section 5.4
After complete resection and within 28 days prior to randomization. 
Disease-free status should be documented. 
IWRS
IWRS entry
X
IWRS entries must be made as follows:
For subject number assignment at the time informed consent is obtained
Prior to dosing for study drug vial assignment (call should be made within 3 days 
prior to dosing)
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Table 5.1-2:
On-Treatment Procedural Outline (CA209577)
Procedure
Cycle 1 
Day 1 
(C1D1) 
Each cycle on Day 1
(up to 2 days prior to 
dosing, unless indicated 
otherwise in the Notes)
Notes
Each cycle duration is 2 weeks until 8 doses of nivo/placebo are 
complete. Remaining subsequent cycles are 4 weeks in duration
Treatment is until recurrence or discontinuation from study for 
maximum treatment duration of 1 year
Safety Assessments
Targeted Physical Examination
X
X
To be performed within 72 hours prior to dosing
Vital Signs 
X
X
Including BP, HR, temperature, Obtain vital signs within 72 hours prior to 
first dose.
Weight and ECOG Performance Status
X
X
Within 72 hours prior to dosing
See Appendix 1 for ECOG Performance Status scale
Adverse Events Assessment
Continuously
Assessed using NCI CTCAE v. 4.0.
Review of concomitant medications
X
X
Laboratory Tests
X
X
Within 72 hours prior to each dose. 
Include CBC w/differential, LFT’s, BUN or serum urea level, creatinine, 
Na, K, Cl, LDH, Glucose, amylase, lipase, TSH (with reflexive Free T4 
and Free T3. Total T3/T4 are acceptable if free T3/T4 are not available.)a
Note: Laboratory tests do not need to be repeated if performed within 
14 days prior to first dose
Pregnancy Test (WOCBP only)
X
See Note
Serum or urine within 24 hours prior to the initial administration of study 
drug, then every 4 weeks (1 week) regardless of dosing schedule
PK and Immunogenicity Assessments
PK samples
Immunogenicity blood sample
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Table 5.1-2:
On-Treatment Procedural Outline (CA209577)
Procedure
Cycle 1 
Day 1 
(C1D1) 
Each cycle on Day 1
(up to 2 days prior to 
dosing, unless indicated 
otherwise in the Notes)
Notes
Each cycle duration is 2 weeks until 8 doses of nivo/placebo are 
complete. Remaining subsequent cycles are 4 weeks in duration
Treatment is until recurrence or discontinuation from study for 
maximum treatment duration of 1 year
Efficacy Assessments
Tumor Imaging Assessment
See Section 5.4. Every 12 weeks (7 days) from first dose of study treatment through 12 months or distant 
recurrence whichever comes first
Exploratory Biomarker Assessments
Outcomes Research Assessments
FACT-E
X
See Note
Assessed following drug vial assignment and preferably prior to 
procedures at Cycles 1, 3, 5, 7, 9, 10, 11, 12, 13, 14, 15, 16, and 17 
(2 days).
EQ-5D
X
See Note
Health Care Resource Utilization
X
See Note
Study Drug
IWRS Drug Vial Assignment
X
X
Vials may be assigned up to 3 days prior to first dose date
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Table 5.1-2:
On-Treatment Procedural Outline (CA209577)
Procedure
Cycle 1 
Day 1 
(C1D1) 
Each cycle on Day 1
(up to 2 days prior to 
dosing, unless indicated 
otherwise in the Notes)
Notes
Each cycle duration is 2 weeks until 8 doses of nivo/placebo are 
complete. Remaining subsequent cycles are 4 weeks in duration
Treatment is until recurrence or discontinuation from study for 
maximum treatment duration of 1 year
Dispense Study Treatment (Active drug 
or placebo - blinded)
X
X
First dose to be administered within 3 calendar days of randomization, 
then every 2 weeks for 8 doses and every 4 weeks beginning at week 17 
(2 weeks after the 8th dose). See Section 4.5. 
For Cycles 1-8, subjects may have study drug administered up to 2 days 
before or 3 days after the scheduled dosing date. Subjects may be dosed no 
less than 12 days from the previous dose. For Cycles 9-17, subjects may 
be dosed within a +/- 3 day window.  
a TSH, Free T3, Free T4 (Total T3/T4 are acceptable if free T3/T4 are not available) should be performed prior to dosing at Cycles 1, 4, 7, 10, 12, 14, and 16
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Table 5.1-3:
Follow-Up Procedural Outline (CA209-577)
Procedure
Follow-up, Visits 1 and 2a
FU1: 30 days (7 days)
FU 2: 84 days (7 days)
Survival Follow-Up 
Visitsb
 from FU2 
(14 days)
Notes
Safety Assessments
Targeted Physical Examination
X
Adverse Events Assessment
X
Assessed using NCI CTCAE v. 4.0. 
See Sections 6.1.1 and 6.2.1.
Review of Subsequent Cancer Therapy
X
X
Review of Concomitant Medications
X
Laboratory Tests
X
Include CBC w/differential, LFT’s, BUN or serum urea level, 
creatinine, Na, K, Cl, LDH, Glucose, amylase, lipase, TSH 
(with reflexive Free T4 and Free T3. Total T3/T4 are 
acceptable if free T3/T4 are not available.)
Urinalysis as clinically indicated
To be done at FU1. To be repeated at FU2 if study related 
toxicity persists.
Pregnancy Test (WOCBP only)
X
Serum or urine pregnancy testing is only required at FU1 and 
FU2, unless increased frequency and duration is required per 
local regulations.
Efficacy Assessments
Tumor Imaging Assessment
Every 12 weeks (7 days) 12 months
Every 12 weeks (14 days) > 12 months through 
24 months
After that follow local standard in the range 
6-12 months between year 3 and year 5 with the last
assessment at year 5. 
Until distant recurrence. All time points are relative 
to the first dose of study treatment
See Section 5.4.
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Table 5.1-3:
Follow-Up Procedural Outline (CA209-577)
Procedure
Follow-up, Visits 1 and 2a
FU1: 30 days (7 days)
FU 2: 84 days (7 days)
Survival Follow-Up 
Visitsb
 
from FU2 
(14 days)
Notes
Outcomes Research Assessments
EQ-5D
X
X
Prior to any assessments at FU1 and 2. 
 
(14 days) after FU2, 
 
 up to 2 years from last dose
FACT-E
X
Prior to any assessments at FU1 and 2. 
ECS
X
 (14 days) after FU2, 
 
 up to 2 years from last dose.
FACT-G7
X
Health Care Resource Utilization
X
Exploratory Biomarker Assessments
Subject Status
Survival Status
X
X
 (14 days) or more frequently as needed after 
FU2, 
 
 to include subsequent anticancer therapy.
Progression-free survival after the next 
line of subsequent therapy (PFS2)
X
X
Following first progression, subjects will continue to be 
followed during the safety and survival follow-up visits. 
Timing of second progression per investigator’s assessments 
will be documented.
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a Follow-up visit 1 (FU1) = 30 days (7 days) from the last dose, Follow-up visit 2 (FU2) = 84 days (7 days) from follow-up visit 1. These follow-up visits 
should occur in person.
b
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5.1.1
Retesting During Screening or Lead-in Period
Retesting of laboratory parameters and/or other assessments within any single Screening or 
Lead-in period will be permitted (in addition to any parameters that require a confirmatory value).
Any new result will override the previous result (ie, the most current result prior to Randomization) 
and is the value by which study inclusion will be assessed, as it represents the subject’s most 
current, clinical state.
Laboratory parameters and/or assessments that are included in Table 5.1-1, Screening Procedural 
Outline may be repeated in an effort to find all possible well-qualified subjects. Consultation with 
the Medical Monitor may be needed to identify whether repeat testing of any particular parameter 
is clinically relevant.
5.2
Study Materials

NCI CTCAE Version 4.0

Nivolumab Investigator Brochure

Pharmacy Binder

Laboratory Manuals for collection and handling of blood samples (including biomarker and 
immunogenicity samples) and tissue specimens

Site manual for operation of IWRS, 

Manual for entry of local laboratory data

Pregnancy Surveillance Forms

Subject Questionnaires: FACT-E (ECS, FACT-G7), EQ-5D

AJCC Cancer Staging Manual for Esophageal Cancers

NCCN Guidelines for Esophageal and Esophagogastric Junction Cancers

ESMO Clinical Practice Guidelines for Oesophageal Cancer

Image Acquisition Guideline

Imaging Site Operations Manual
5.3
Safety Assessments
5.3.1
Screening Safety Assessments
At baseline, a medical history will be obtained to capture relevant underlying conditions. The 
baseline examinations should include weight, height, ECOG performance status, BP, HR, 
temperature, electrocardiogram (as noted in Table 5.1-1). A pathology report to determine the 
subject’s current disease status must be reviewed, signed and dated by the investigator prior to 
randomization. Baseline signs and symptoms are those that are assessed within 14 days prior to 
first dose of study drug. Concomitant medications including steroid doses will be collected within 
14 days prior to first dose of study drug through the study treatment period. 
Baseline local laboratory assessments that should be done within 14 days prior to randomization 
include: CBC with differential, Chemistry panel including: LDH, AST, ALT, ALP, T-Bil, blood 
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urea nitrogen (BUN) or serum urea level, creatinine, Na, K, Cl, total protein, glucose, albumin, 
amylase, lipase, and urinalysis (as clinically indicated).  
Laboratory assessments that should be done within 28 days prior to randomization include: 
endocrine panel (TSH, Free T4, Free T3; Total T3/T4 are acceptable if free T3/T4 are not 
available), Hepatitis B and C (HBV sAG, HCV antibody or HCV RNA), HIV (when required by 
local regulations (see Table 5.1-1). 
Pregnancy testing for WOCBP should be done at screening, within 24 hours prior to first dose.
Serious AEs are to be collected as soon as the informed consent form is signed.
5.3.2
On-Treatment Safety Assessments
Subjects will be evaluated for safety if they have received any study drug. Adverse event 
assessments will be continuous during the treatment phase. Adverse events and laboratory values 
will be graded according to the NCI-CTCAE version 4.
The start and stop time of the study therapy infusions and any interruptions or infusion rate 
reductions should be documented.
On study local laboratory assessments should be done within 72 hours prior to dosing (laboratory 
tests should not be repeated if performed within 14 days prior to the first dose) to include; CBC 
w/differential, LFTs (ALT, AST, total bilirubin, alkaline phosphatase), BUN or serum urea level, 
creatinine, Na, K, Cl, LDH, glucose, amylase, and lipase prior to each dose. TSH with reflexive 
Free T4, Free T3 (Total T3/T4 are acceptable if free T3/T4 are not available), can be performed at 
Cycles 1, 4, 7, 10, 12, 14, and 16 (Table 5.1-2). Additional measures including non-study required 
laboratory tests should be performed as clinically indicated or to comply with local regulations. 
Laboratory toxicities (eg, suspected drug induced liver enzyme elevations) 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. 
Pregnancy testing for WOCBP should be done every 4 weeks relative to dosing on Day 1 of 
Cycle 1 regardless of dosing schedule.
On-treatment targeted physical examination, weight, ECOG performance status, BP, HR, 
temperature (Table 5.1-2) should be performed within 72 hours prior to dosing. If there are any 
new or worsening clinically significant changes since the last exam, report changes on the 
appropriate non-serious or serious adverse events page. 
If a subject shows pulmonary-related signs (hypoxia, fever) or symptoms (eg, dyspnea, cough, 
fever) consistent with possible pulmonary adverse events, the subject should be immediately 
evaluated to rule out pulmonary toxicity, according to the suspected pulmonary toxicity 
management algorithm in the BMS-936558 (nivolumab) Investigator Brochure 
Some of the previously referred to assessments 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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5.3.3
Follow-Up Safety Assessments
Adverse events will be assessed, concomitant medication, and subsequent cancer therapy will be 
reviewed as described in Table 5.1-3. A physical examination will be performed at follow-up visits 
FU1 and FU2. Laboratory and pregnancy tests will be performed as described in Table 5.1-3.
5.3.4
Imaging Assessment for the Study
Any incidental findings of potential clinical relevance that are not directly associated with the 
objectives of the protocol should be evaluated and handled by the Study Investigator as per 
standard medical/clinical judgment.
5.4
Efficacy Assessments
Study evaluations will take place in accordance with the flow charts in Section 5.1. 
Baseline assessments of the chest and abdomen should be performed within 28 days prior to 
randomization utilizing CT or MRI. Subsequent assessments should include chest and abdomen 
and any clinically indicated sites. Subjects will be evaluated for disease recurrence every 12 weeks 
from the date of first treatment (+/- 7 days) for the first 12 months, then every 12 weeks 
(+/- 14 days) between months 12 and 24, and then according to local standards with a minimum 
of one scan every 6-12 months between years 3-5.  
Disease assessment with contrast-enhanced computed tomography (CT) scans acquired on 
dedicated CT equipment is preferred for this study. Should a subject have contraindication for CT 
intravenous contrast, a non-contrast CT of the chest and a contrast-enhanced MRI of the abdomen, 
should be obtained. A contrast-enhanced MRI of the chest is also acceptable instead of a non-
contrast CT of the chest. The same imaging method as was used at baseline.
 
Refer to CA209577 imaging Site Operations Manual and/or Image Acquisition Guidelines for 
more specific details.
5.4.1
Definitions of Recurrence 
Recurrence is defined as the appearance of one or more new lesions, which can be local, regional, 
or distant in location from the primary resected site (confirmed by imaging or cytology/pathology). 
Local or regional recurrence: Any anastomotic recurrence or/and occurring either in the 
mediastinum or upper abdomen at the site of previous esophageal resection and nodal clearance or 
in the cervical area where no lymphadenectomy had been performed. 
Distant metastasis: Any recurrence occurring in distant organs, pleura and peritoneum. If both 
loco-regional recurrence and distant metastases occurred, the case was considered as distant 
metastases.
Diagnosis of recurrence should be unequivocal. If a new lesion is equivocal, for example because 
of its small size or ambiguous etiology, the suspected lesion should be confirmed with cytology or 
histopathology. If biopsy is not possible, the subject should continue therapy, and a follow-up 
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imaging evaluation (in no less than 4 weeks) should be performed. If repeat scans or 
cytology/histology confirm recurrence, then recurrence should be declared using the date of the 
initial scan. For clinically clear recurrence case, the diagnosis can be done by imaging only. 
Criteria used to determine CT lymph node metastases were a lymph node diameter at least 1 cm
in short axis. The appearance of new malignant lesions denotes disease recurrence. 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. 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 recurrence, unless found to be secondary or 
concurrent malignancy which is non-esophageal or non-gastro-esophageal junction-originated 
malignancy. An example of this is the subject who has CT or MRI brain scan ordered in the on 
treatment phase which reveals metastases. The subject’s brain metastases are considered to be 
evidence of recurrence even if he/she did not have brain imaging at baseline.
5.4.2
Methods of Measurement

CT and MRI are an essential part of the work-up to establish recurrence. Conventional CT with 
IV contrast and MRI gadolinium should be performed with contiguous cuts of 10 mm or less 
slice thickness. Spiral CT should be performed using a 3- or 5-mm contiguous reconstruction 
algorithm; this specification applies to the tumors of the chest, abdomen and other clinically 
relevant sites. In each institute the same technique for CT/MRI should be used to characterize 
each new lesion.

For subjects allergic to contrast media, they may have a CT performed without contrast or 
MRI after consulted with site radiologist.

PET alone will not be considered for the disease assessment. Complementary CT and/or MRI 
or biopsy must be performed in such cases.

Cytology and/or histology are mandatory to confirm recurrence in solitary or in doubtful 
lesions, cutaneous, subcutaneous or lymph node lesions. Histological or cytological evidence 
of recurrence should be attempted in all cases except for brain metastases when safe and 
clinically feasible. An example when obtaining a biopsy to confirm recurrence may not be safe 
and clinically feasible is brain metastases.

Clinically detected new lesions:

Superficial cutaneous lesions: the neoplastic nature must be confirmed by 
cytology/histology.

Deep subcutaneous lesions and lymph node lesions should be documented by ultrasound 
and histological/cytological evidence should be attempted. In absence of pathology report, 
lesion recurrence will be documented with a CT scan/MRI.

Tumor markers or auto-antibodies alone cannot be used to assess recurrence.

 
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5.4.3
Date of Recurrence
The first date when recurrence was observed is taken into account regardless the method of 
assessment. Therefore recurrence will be declared for any lesion when:

Only imaging was performed and recurrence confirmed

Only pathology was done and malignancy confirmed (in solitary or in doubtful lesions, any 
new lesions in esophagus and or stomach, lymph node or distant metastasis)

Both pathology and imaging were done and recurrence/malignancy confirmed. In this case, the 
date of whichever examination comes first is considered the date of recurrence.

The first recurrence was noted, and any additional recurrence found within 1 month was 
considered to have occurred simultaneously, the first confirmed recurrence is considered the 
date of recurrence. 
5.5
Pharmacokinetic Assessments
Samples for pharmacokinetic and immunogenicity assessment will be collected for subjects 
assigned to both arms 
 
 
 
 
 
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Further details of sample collection, processing, and shipment will be provided in the laboratory 
procedures manual.
5.6
Biomarker Assessments
Samples for biomarker assessment will be collected for subjects assigned 
 
 
 
 
 
 
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5.6.1
Tumor Samples
Tumor specimens will be obtained from consenting subjects prior to treatment to characterize 
immune cell populations and expression of selected tumor markers. Tumor tissue (block or slides) 
must be available for submission prior to randomization.
5.6.1.1
In situ Hybridization EBV RNA (EBER) of FFPE Sections
 
 
 
5.6.1.2
Microsatellite Instability Testing
A MSI-H (Microsatellite Instability-High) in tumors refers to changes in 2 or more of the 
5 National Cancer Institute-recommended panels of microsatellite markers in tumor tissue 
compared to a reference whole blood sample (baseline SNP collection). 
 
 
 
 
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MSI testing will only be performed centrally if the test was not performed locally by the site.
5.6.1.3
HER2
HER2 status, as determined by FISH or IHC and measured locally by the site should be provided 
if known. In cases in which HER2 is unknown, central testing of tumor tissue may be performed 
using these platforms.
5.6.1.4
Characterization of Tumor Infiltrating Lymphocytes (TILs) and Tumor 
Antigens
Immunohistochemistry (IHC) will be used to assess the number and composition of immune 
infiltrates in order to define the immune cell subsets present within formalin-fixed, 
paraffin-embedded (FFPE) tumor tissue before and after exposure to therapy. 
 
 
5.6.1.5
Characterization of T Cell Repertoire
DNA sequencing may be performed on pre-and post-treatment tumor tissue to assess the 
composition of the T cell repertoire. 
 
5.6.1.6
Gene Expression Profiling
Tumor tissue 
 
 
5.6.1.7
Tumor Genotyping, Mutational Analysis, and Tumor Antigen Profiling
RNA and DNA from tumor samples will be analyzed 
 
 
 
 
 
 
 
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5.6.2
Peripheral Blood Markers
A variety of factors that may impact the immunomodulatory properties and efficacy of nivolumab 
will be investigated in peripheral blood specimens 
 
 
 
5.6.2.1
Soluble Biomarkers
Soluble factors, 
 
will be characterized and quantified by immunoassays in serum. 
 
 
 
 
 
5.6.2.2
Immunophenotyping
The proportion of specific lymphocyte subsets and expression levels of T cell co-stimulatory 
markers in peripheral blood mononuclear cell (PBMC) preparations will be quantified by flow 
cytometry. 
 
 
5.6.2.3
T Cell Repertoire Analysis
 
 
 
 
 
 
5.6.2.4
Whole Blood for Germline DNA
Whole blood will be collected from all subjects prior to treatment to 
 
 
 
 
5.6.2.5
Peripheral Blood Mononuclear Cells (PBMCs)
Peripheral blood samples will be taken 
 
 
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5.7
Outcomes Research Assessments
Subjects will be asked to complete the EQ-5D-3L and FACT-E before any clinical activities are 
performed during on-study clinic visits and at follow up visits 1 and 2. At designated visits during 
the survival follow up phase, subjects will be asked to complete the EQ-5D-3L, ECS, and 
FACT-G7. The questionnaires will be provided in the subject’s preferred language, when 
available, and may be administered by telephone during the survival follow-up phase. A 
standardized script will be used to facilitate telephone administration of the EQ-5D. Similar scripts 
do not exist for the ECS or FACT-G7, though subjects will be provided with hard copies of these 
questionnaires to take home and use as visual aids during telephone interviews. 
Subjects’ reports of general health status will be measured using the EQ-5D. The EQ-5D is a 
standardized instrument used to measure self-reports of health status and functioning. The 
instrument’s descriptive system consists of 5 dimensions:  mobility, self-care, usual activities, 
pain/discomfort, and anxiety/depression. Each dimension has 3 levels, reflecting "no health 
problems," "moderate health problems," and "extreme health problems." A dimension for which 
there are no problems is said to be at level 1, while a dimension for which there are extreme 
problems is said to be at level 3. Thus, the vectors 11111 and 33333 represent the best health state 
and the worst health state, respectively, described by the EQ-5D. Altogether, the instrument 
describes 35 = 243 health states. Empirically derived weights can be applied to an individual’s 
responses to the EQ-5D descriptive system to generate an index measuring the value to society of 
his or her current health. Such preference-weighting systems have been developed for Japan, UK, 
US, Spain, Germany, and numerous other populations. In addition, the EQ-5D includes a visual 
analog scale that allows respondents to rate their own current health on a 101-point scale ranging 
from “best imaginable” to “worst imaginable” health.
The FACT-E questionnaire and selected components, including the FACT-G7 and ECS, will be 
used to assess the effects of underlying disease and its treatment on health-related quality of life 
(HRQL). As a generic cancer-related core, the FACT-E includes the 27-item FACT-General 
(FACT-G) to assess symptoms and treatment-related effects impacting physical well-being (PWB; 
seven items), social/family well-being (SWB; seven items), emotional well-being (EWB; six 
items), and functional well-being (FWB; seven items). Seven of these items comprise the 
FACT-G7, an abbreviated version of the FACT-G that provides a rapid assessment of general 
HRQL in cancer patients. In addition, the FACT-E includes a 17-item disease-specific ECS that 
assesses concerns related to swallowing, vocalization, breathing, dry mouth, eating, disrupted 
sleep due to coughing, stomach pain, and weight loss. Each FACT-E item is rated on a five-point 
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scale ranging from 0 (not at all) to 4 (very much). Scores for the PWB, FWB, SWB, and EWB 
subscales can be combined to produce a FACT-G total score, which provides an overall indicant 
of generic HRQL, while the FACT-G and ECS scores can be combined to produce a total score 
for the FACT-E, which provides a composite measure of general and targeted HRQL. Higher 
scores indicate better HRQL. The full FACT-E will be administered to subjects during the 
on-treatment phase and at follow up visits 1 and 2. To minimize subject response and 
administrative burden, only the FACT-G7 and ECS will be administered during the survival phase 
after FU2 for up to 2 years after the last dose.
In addition to the aforementioned subject-reported outcomes, health care resource utilization data 
will be collected for all randomized subjects using an internal case report form developed for use 
in previous trials. The form, which is completed by study staff, records information about hospital 
admissions, including number of days spent in various wards and discharge diagnosis, as well as 
non-protocol specified visits related to study therapy, including date of visit, reason for visit, and 
type of visit. The health care resource utilization data will be used to support subsequent economic 
evaluations.
5.8
Other Assessments 
5.8.1
Immunogenicity Assessments
Blood samples for immunogenicity analysis will be collected according to the schedule given in 
 Only samples collected from subjects receiving nivolumab will be evaluated for 
development of Anti-Drug Antibody (ADA) by a validated electrochemiluminescent (ECL) 
immunoassay.
Samples may also be analyzed for neutralizing antibodies and PK samples may be used for ADA 
analysis in the event of insufficient volume, to complete immunogenicity assessment, or to follow 
up on suspected immunogenicity-related AEs.
Further details of sample collection, processing, and shipment will be provided in the laboratory 
procedures manual.
6
ADVERSE EVENTS
An Adverse Event (AE) is defined as any new untoward medical occurrence or worsening of a 
preexisting medical condition in a clinical investigation subject administered study drug and that 
does not necessarily have a causal relationship with this treatment. An AE can therefore be any 
unfavorable and unintended sign (such as an abnormal laboratory finding), symptom, or disease 
temporally associated with the use of study drug, whether or not considered related to the study 
drug.
The causal relationship to study drug is determined by a physician and should be used to assess all 
adverse events (AE). The causal relationship can be one of the following:
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Related: There is a reasonable causal relationship between study drug administration and 
the AE.
Not related: There is not a reasonable causal relationship between study drug 
administration and the AE. 
The term "reasonable causal relationship" means there is evidence to suggest a causal relationship. 
Adverse events can be spontaneously reported or elicited during open-ended questioning, 
examination, or evaluation of a subject. (In order to prevent reporting bias, subjects should not be 
questioned regarding the specific occurrence of one or more AEs.)
6.1
Serious Adverse Events
A Serious Adverse Event (SAE) is any untoward medical occurrence that at any dose: 

results in death

is life-threatening (defined as an event in which the subject was at risk of death at the time of 
the event; it does not refer to an event which hypothetically might have caused death if it were 
more severe)

requires inpatient hospitalization or causes prolongation of existing hospitalization (see NOTE
below)

results in persistent or significant disability/incapacity

is a congenital anomaly/birth defect 

is an important medical event (defined as a medical event(s) that may not be immediately life-
threatening or result in death or hospitalization but, based upon appropriate medical and 
scientific judgment, may jeopardize the subject or may require intervention [eg, medical, 
surgical] to prevent one of the other serious outcomes listed in the definition above.) Examples 
of such events include, but are not limited to, intensive treatment in an emergency room or at 
home for allergic bronchospasm; blood dyscrasias or convulsions that do not result in 
hospitalization.) Potential drug induced liver injury (DILI) is also considered an important 
medical event. (See Section 6.6 for the definition of potential DILI.)
Suspected transmission of an infectious agent (eg, pathogenic or nonpathogenic) via the study drug 
is an SAE. 
Although pregnancy, overdose, cancer, and potential drug induced liver injury (DILI) are not 
always serious by regulatory definition, these events must be handled as SAEs. (See Section 6.1.1
for reporting pregnancies).
Any component of a study endpoint that is considered related to study therapy (eg, death is an 
endpoint, if death occurred due to anaphylaxis, anaphylaxis must be reported) should be reported 
as SAE (see Section 6.1.1 for reporting details).
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NOTE: 
The following hospitalizations are not considered SAEs in BMS clinical studies: 

a visit to the emergency room or other hospital department < 24 hours, that does not result 
in admission (unless considered an important medical or life-threatening event)

elective surgery, planned prior to signing consent

admissions as per protocol for a planned medical/surgical procedure

routine health assessment requiring admission for baseline/trending of health status (eg, 
routine colonoscopy)

medical/surgical admission other than to remedy ill health and planned prior to entry into 
the study. Appropriate documentation is required in these cases

admission encountered for another life circumstance that carries no bearing on health status 
and requires no medical/surgical intervention (eg, lack of housing, economic inadequacy, 
caregiver respite, family circumstances, administrative reason).

Admission for administration of anticancer therapy in the absence of any other SAEs 
6.1.1
Serious Adverse Event Collection and Reporting
Sections 5.6.1-1 and 5.6.1-2 in the Investigator Brochure (IB) represent the Reference Safety 
Information to determine expectedness of serious adverse events for expedited reporting. 
Following the subject’s written consent to participate in the study, all SAEs, whether related or not 
related to study drug, must be collected, including those thought to be associated with protocol-
specified procedures. All SAEs must be collected that occur during the screening period and within 
100 days of discontinuation of dosing. 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. 
An SAE report must be completed for any event where doubt exists regarding its seriousness. 
If the investigator believes that an SAE is not related to study drug, but is potentially related to the
conditions of the study (such as withdrawal of previous therapy or a complication of a study 
procedure), the relationship must be specified in the narrative section of the SAE Report Form.
SAEs, whether related or not related to study drug, and pregnancies must be reported to Sponsor 
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. 
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.
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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.
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.
BMS will be reporting adverse events to regulatory authorities and ethics committees according to 
local applicable laws including European Regulation 536/2014 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.
6.2
Nonserious Adverse Events
A nonserious adverse event is an AE not classified as serious.
6.2.1
Nonserious Adverse Event Collection and Reporting
The collection of nonserious AE information should begin at initiation of study drug. Nonserious 
AE information should also be collected from the start of a placebo lead-in period or other 
observational period intended to establish a baseline status for the subjects. 
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. Nonserious AEs should be followed to resolution or stabilization, or reported 
as SAEs if they become serious (see Section 6.1.1). Follow-up is also required for nonserious AEs 
that cause interruption or discontinuation of study drug and for those present at the end of study 
treatment as appropriate. All identified nonserious AEs must be recorded and described on the 
nonserious AE page of the CRF (paper or electronic). 
Completion of supplemental CRFs may be requested for AEs and/or laboratory abnormalities that 
are reported/identified during the course of the study.
Every adverse event must be assessed by the investigator with regard to whether it is considered 
immune-mediated. Immune-mediated adverse events (IMAEs) are AEs consistent with an 
immune-mediated mechanism or immune-mediated component for which non-inflammatory 
etiologies (eg, infection or tumor progression) have been ruled out. IMAEs can include events with 
an alternate etiology that were exacerbated by the induction of autoimmunity. Information 
supporting the assessment will be collected on the subject’s case report form.
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6.3
Laboratory Test Result Abnormalities
The following laboratory test result abnormalities should be captured on the nonserious AE CRF 
page or SAE Report Form (paper or electronic) as appropriate:

Any laboratory test result that is clinically significant or meets the definition of an SAE 

Any laboratory test result abnormality that required the subject to have study drug discontinued 
or interrupted

Any laboratory test result abnormality that required the subject to receive specific corrective 
therapy.
It is expected that wherever possible, the clinical rather than laboratory term would be used by the 
reporting investigator (eg, anemia versus low hemoglobin value).
6.4
Pregnancy
If, following initiation of the study drug, it is subsequently discovered that a study subject is 
pregnant or may have been pregnant at the time of study exposure, including during at least 5 half 
lives after product administration, the investigator must immediately notify the Sponsor or 
designee of this event and complete and forward a Pregnancy Surveillance Form to BMS Designee 
within 24 hours of awareness of the event and in accordance with SAE reporting procedures 
described in Section 6.1.1.
In most cases, the study drug will be permanently discontinued in an appropriate manner (eg, dose 
tapering if necessary for subject safety).
In the rare event that the benefit of continuing study drug is thought to outweigh the risk, after 
consultation with BMS, the pregnant subject may continue study drug after a thorough discussion 
of benefits and risk with the subject 
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 subject should be reported to 
Sponsor or designee. In order for BMS to collect any pregnancy surveillance information from the 
female partner, the female partner must sign an informed consent form for disclosure of the 
information. Information on this pregnancy will be collected on the Pregnancy Surveillance Form.
6.5
Overdose
All occurrences of overdose must be reported as SAEs (see Section 6.1.1 for reporting details).
6.6
Potential Drug Induced Liver Injury (DILI)
Wherever possible, timely confirmation of initial liver-related laboratory abnormalities should 
occur prior to the reporting of a potential DILI event. All occurrences of potential DILIs, meeting 
the defined criteria, must be reported as SAEs (see Section 6.1.1 for reporting details).
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Potential drug induced liver injury is defined as: 
1. AT (ALT or AST) elevation > 3 times upper limit of normal (ULN)
AND
2. Total bilirubin > 2 times ULN, without initial findings of cholestasis (elevated serum alkaline 
phosphatase),
AND
3. No other immediately apparent possible causes of AT elevation and hyperbilirubinemia, 
including, but not limited to, viral hepatitis, pre-existing chronic or acute liver disease, or the 
administration of other drug(s) known to be hepatotoxic.
6.7
Other Safety Considerations
Any significant worsening noted during interim or final physical examinations, electrocardiogram, 
x-ray filming, any other potential safety assessment required or not required by protocol should 
also be recorded as a nonserious or serious AE, as appropriate, and reported accordingly. 
7
DATA MONITORING COMMITTEE AND OTHER EXTERNAL 
COMMITTEES
A Data Monitoring Committee (DMC) will be established to provide oversight of safety and 
efficacy considerations in protocol CA209577. Additionally, the DMC will provide advice to the 
sponsor regarding actions the committee deems necessary for the continuing protection of subjects 
enrolled in the study. The DMC will be charged with assessing such actions in light of an 
acceptable benefit/risk profile for nivolumab. The DMC will act in an advisory capacity to BMS 
and will monitor subject safety and evaluate the available efficacy data for the study. The oncology 
therapeutic area of BMS has primary responsibility for design and conduct of the study. 
When required, adjudicated events will be submitted to the DMC and Health Authorities for review 
on a specified timeframe in accordance with the adjudication documentation.
8
STATISTICAL CONSIDERATIONS
8.1
Sample Size Determination
The sample size determination takes into consideration the comparison of the primary endpoint of 
DFS and the first secondary endpoint of OS between the 2 treatment arms.
8.1.1
Assumptions of the Control Arm
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8.1.2
Assumptions of the Treatment Effect
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8.1.3
Sample Size and Power
According to 
 
 
 
 
Overall survival will be tested following the overall hierarchical testing procedure64 upon 
demonstration of superiority in DFS at either interim or final analyses for all randomized subjects.
With the sample size 
 
 
 
 
8.1.4
Timing of the DFS and OS Interim and Final Analyses
Timing of the Interim and Final DFS Analyses
 
 
 
 
 
 
 
Timing of the Interim and Final OS Analyses
Based on the current design, the first interim OS analysis is planned at the time of the DFS interim 
analysis, and the second interim OS analysis is planned at the time of the DFS final analysis. 
 
 
 
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 final OS analyses will be derived based on 
the exact number of deaths observed 
 
 
8.1.5
Potential Adjustment of Analysis Timing for DFS and OS
As discussed in the Section 8.1.1, there was no historical trial with the exact same population 
studied in this trial. 
 
 
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8.2
Populations for Analyses

All Enrolled Subjects: All subjects who signed an informed consent form and were registered 
into the IWRS.

All Randomized Subjects: All subjects who were randomized to any treatment arm in the study. 
This is the primary dataset for analyses of study conduct, study population, and efficacy. 

All Treated Subjects: All randomized subjects who received at least one dose of nivolumab or 
placebo during the study. This is the primary dataset for analyses of exposure and safety.

PK Subjects: Subjects with available serum time-concentration data from randomized subjects 
dosed with nivolumab.

Outcome Research subjects: randomized subjects who have an assessment at 
screening/baseline and at least 1 follow-up assessment

Immunogenicity subjects: nivolumab treated subjects who have an assessment at 
screening/baseline and at least 1 follow-up assessment
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
Biomarker subjects: All randomized subjects with available biomarker data (PD-L1 status and 
other assays).
8.3
Endpoints
8.3.1
Primary Endpoint
Disease-free survival is the primary endpoint of this study. Disease-free survival is the time 
between randomization date and first date of recurrence or death, whichever occurs first. 
Recurrence is defined as the appearance of one or more new lesions, which can be local, regional, 
or distant in location from the primary resected site (by imaging or pathology). DFS will be 
programmatically determined based on the disease recurrence date provided by the investigator. 
All deaths without prior recurrence will be included as DFS event - regardless of cause or of how 
long it has been since the last known disease evaluation. For subjects who remain alive and without 
recurrence, DFS will be censored on the date of last evaluable disease assessment.
Detailed censoring rules for the primary definition of DFS are presented in Table 8.3.1-1. 
(Sensitivity analyses of DFS will be described in the Statistical Analysis Plan [SAP]).
Table 8.3.1-1:
Censoring Scheme Used in the Primary Definition of DFS
Situation 
Date of Event or Censoring 
Outcome
Recurrencea,c
Date of first recurrence 
Event
Deathb,c without recurrence 
Date of death 
Event
No baseline disease assessment 
Date of randomization 
Censored
No on-study disease assessments 
and no death 
Date of randomization 
Censored
No recurrence and no death 
Date of last evaluable disease 
assessment 
Censored
New anticancer therapy, tumor-
directed radiotherapy, or tumor-
directed surgery received without 
recurrence reported prior to or on 
the same day of disease assessment
Date of last evaluable disease 
assessment prior to or on the same 
date of initiation of subsequent 
therapy
Censored
Second non-esophageal and non-
GEJ primary cancer reported prior 
to or on the same day of disease 
assessment
Date of last evaluable disease 
assessment prior to or on the same 
date of diagnosis of second non-
esophageal and non-GEJ primary 
cancer
Censored
a recurrence = appearance of one or more new lesions, which can be local, regional, or distant in location from the 
primary resected site
b All deaths will be included as DFS event - regardless of cause or of how long it has been since the last known 
disease evaluation.
c Without receiving preceding new anticancer therapy, tumor-directed radiotherapy, or tumor-directed surgery
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8.3.2
Secondary Endpoint(s)
8.3.2.1
Overall Survival
Overall survival is the time between the date of randomization and the date of death. For subjects 
without documentation of death, OS will be censored to the last date the subject was known to be 
alive.
8.3.2.2
Overall Survival Rate
The overall survival rate at 1, 2, and 3 years is defined as the probability that a subject is alive at 
1, 2, and 3 years, respectively, following randomization.
8.3.3
Exploratory Endpoint(s) 

Safety and tolerability objective will be measured by the incidence of adverse events (AEs), 
serious adverse events (SAEs), deaths, and laboratory abnormalities.

DMFS is defined as the time between the date of randomization and the date of first distant 
recurrence or date of death (whatever the cause), whichever occurs first. For subjects who 
remain alive and distant recurrence-free, DMFS will be censored on the date of last disease 
assessment.

The objective to evaluate PD-L1 status as a predictive biomarker will be measured by the 
primary endpoint of DFS and the secondary endpoint of OS based on PD-L1 status level.

The objective to evaluate PD-L1 status prior to CRT and at the time of surgery will be 
measured by the mean change in PD-L1 status level and by the proportion of PD-L1 positive 
and negative subjects.

Pharmacokinetics will be measured using serum concentration-time data.

PFS2 is defined as the time from randomization to the date of investigator-defined documented 
objective disease progression on the subsequent next-line therapy or start of second subsequent 
next-line therapy or death due to any cause, whichever comes first. Details for censoring will 
be provided in the SAP.
Assessments for other exploratory endpoints including biomarker analysis, immunogenicity, and 
outcomes research are discussed in Sections 5.6 and 5.8, respectively. Corresponding endpoints 
will be detailed in the SAP(s). 
8.4
Analyses
8.4.1
Demographics and Baseline Characteristics
Demographic and baseline characteristics will be summarized by treatment arm as randomized 
using descriptive statistics for all randomized subjects.
8.4.2
Efficacy Analyses
8.4.2.1
Protection of Type-I Error
For the analysis purposes of primary endpoint of DFS and the first secondary endpoint of OS, the 
overall hierarchical approach64 will be used 
 
 
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The details will be provided in the statistical analysis plan (SAP).
8.4.2.2
Primary Efficacy Endpoint
DFS will be compared between treatment arms 
 
 
 
 
 
8.4.2.3
Secondary Efficacy Endpoints
Overall survival will be
 
 
 
 
 
Survival rate analysis will be carried out only for those time points which are mature enough by 
the time of the given database-lock. 
 
 
No formal statistical comparison between the 2 arms will be performed on the 
survival rate.
8.4.2.4
Exploratory Efficacy Endpoints
The HR for DMFS and PFS2
 via a Cox 
model with treatment arm as the only covariate in the model. 
 
 
 
 
8.4.3
Safety Analyses
Safety analyses will be performed in all treated subjects. Descriptive statistics of safety will be 
presented using NCI CTCAE version 4.0 by treatment group. All on-study AEs, treatment-related 
AEs, SAEs, and treatment-related SAEs will be tabulated using worst grade per NCI CTCAE v 
4.0 criteria by system organ class and preferred term. On-study lab parameters including 
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hematology, chemistry, liver function, and renal function will be summarized using worst grade 
NCI CTCAE v 4.0 criteria.
8.4.4
Pharmacokinetic Analyses
The concentration vs. time data obtained in this study may be combined with data from other 
studies in the clinical development program to develop population PK models. These models may 
be used to evaluate the effects of intrinsic and extrinsic covariates on the PK of nivolumab and to 
determine measures of individual exposure (such as steady state peak, trough and time averaged 
concentration). Model determined exposures may be used for exposure response analyses of 
selected efficacy and safety endpoints. If the analyses are conducted, the results of population PK 
and exposure response analyses will be reported separately.
8.4.5
Biomarker Analyses
To evaluate PD-L1 status as a predictive biomarker, a Cox proportional hazards model will be 
used to test the interaction between PD-L1 status (positive vs negative) and treatment arm for the 
OS and DFS endpoints. Additionally, OS and DFS will be analyzed within each PD-L1 expression 
subgroup (positive and negative) including log-rank tests and HRs with corresponding CIs. OS 
and DFS curves and medians will be estimated using KM methodology. These analyses will be 
descriptive and not adjusted for multiplicity.
Methodology for further exploratory biomarker analyses will be described in the SAP.
8.4.6
Outcomes Research Analyses
The analysis of EQ-5D and FACT-E (including FACT-G, FACT-G7, and ECS) data will be 
performed in all randomized subjects who have an assessment at baseline (Day 1, assessment prior 
to administration of drug on day of first dose) and at least 1 subsequent assessment while on 
treatment. Questionnaire completion rate, defined as the proportion of questionnaires actually 
received out of the expected number, will be calculated and summarized at each assessment point.  

EQ-5D data will be described by treatment group as randomized in the following ways:

EQ-5D index scores will be summarized at each assessment time point using descriptive 
statistics (ie, N, mean with SD and 95% CI, median, first and third quartiles, minimum, 
maximum). The UK scoring algorithm will be applied as a reference case.

EQ-VAS scores will be summarized at each assessment time point using descriptive statistics 
(ie, N, mean with SD and 95% CI, median, first and third quartiles, minimum, maximum).

The proportion (N) of subjects reporting no, moderate, or extreme problems will be presented 
for each of the 5 EQ-5D dimensions at each assessment time point. Subjects with missing data 
will be excluded from the analysis.

A by-subject listing of the level of problems in each dimension, corresponding EQ-5D health 
state (ie, 5-digit vector), EQ-5D index score, and EQ-VAS score will be provided.
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From the beginning of the on-treatment phase through follow-up visit 2, data for the FACT-E will 
be described by assigned treatment group in the following ways:

ECS, FACT-G7, FACT-G, and FACT-E total scores will be summarized at each assessment 
time point using descriptive statistics (ie, N, mean with SD and 95% CI, median, first and third 
quartiles, minimum, maximum).  

Changes from baseline in ECS, FACT-G7, FACT-G, FACT-E total scores will be summarized 
at each post-baseline assessment time point using descriptive statistics (ie, N, mean with SD 
and 95% CI, median, first and third quartiles, minimum, maximum).  
During the survival follow-up phase, data for the ECS and FACT-G7 will be described by assigned 
treatment group in the following ways:

ECS and FACT-G7 scores will be summarized at each assessment time point using descriptive 
statistics (ie, N, mean with SD and 95% CI, median, first and third quartiles, minimum, 
maximum).  

Changes from baseline in ECS and FACT-G7 scores will be summarized at each post-baseline 
assessment time point using descriptive statistics (ie, N, mean with SD and 95% CI, median, 
first and third quartiles, minimum, maximum).  
8.4.7
Other Analyses 
Immunogenicity may be reported for ADA positive status (such as persistent positive, only last 
sample positive, other positive, baseline positive) and ADA negative status, relative to baseline. 
In addition, presence of neutralizing antibodies may be reported, if applicable. Effect of 
immunogenicity on safety, efficacy, biomarkers and PK may be explored. Additional details will 
be described in the SAP.
8.5
Interim Analyses
8.5.1
DFS Analyses
 
 
 
 
 
 
 
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8.5.2
OS Analyses
Two OS interim analyses are planned. The first interim OS analysis is planned at the time of the 
DFS interim analysis, and the second interim OS analysis is planned at the time of the DFS final 
analysis. Details of the 2 OS interim analyses are specified in Section 8.1.4. 
 
 
 
9
STUDY MANAGEMENT
9.1
Compliance
9.1.1
Compliance with the Protocol and Protocol Revisions
The study shall be conducted as described in this approved protocol. All revisions to the protocol 
must be discussed with, and be prepared by, BMS. The investigator should not implement any 
deviation or change to the protocol without prior review and documented approval/favorable 
opinion from the IRB/IEC of an amendment, except where necessary to eliminate an immediate 
hazard(s) to study subjects. 
If a deviation or change to a protocol is implemented to eliminate an immediate hazard(s) prior to 
obtaining IRB/IEC approval/favorable opinion, as soon as possible the deviation or change will be 
submitted to:

IRB/IEC for review and approval/favorable opinion

BMS

Regulatory Authority(ies), if required by local regulations
Documentation of approval signed by the chairperson or designee of the IRB(s)/IEC(s) must be 
sent to BMS.
If an amendment substantially alters the study design or increases the potential risk to the subject: 
(1) the consent form must be revised and submitted to the IRB(s)/IEC(s) for review and 
approval/favorable opinion; (2) the revised form must be used to obtain consent from subjects 
currently enrolled in the study if they are affected by the amendment; and (3) the new form must 
be used to obtain consent from new subjects prior to enrollment.
If the revision is done via an administrative letter, investigators must inform their IRB(s)/IEC(s).
9.1.2
Monitoring
BMS representatives will review data centrally to identify potential issues to determine a schedule 
of on-site visits for targeted review of study records. 
Representatives of BMS must be allowed to visit all study site locations periodically to assess the 
data quality and study integrity. On site they will review study records and directly compare them 
with source documents, discuss the conduct of the study with the investigator, and verify that the 
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facilities remain acceptable. Certain CRF pages and/or electronic files may serve as the source 
documents.  
In addition, the study may be evaluated by BMS internal auditors and government inspectors who 
must be allowed access to CRFs, source documents, other study files, and study facilities. BMS 
audit reports will be kept confidential.
The investigator must notify BMS promptly of any inspections scheduled by regulatory authorities, 
and promptly forward copies of inspection reports to BMS. 
9.1.2.1
Source Documentation
The Investigator is responsible for ensuring that the source data are accurate, legible, 
contemporaneous, original and attributable, whether the data are hand-written on paper or entered 
electronically. If source data are created (first entered), modified, maintained, archived, retrieved, 
or transmitted electronically via computerized systems (and/or any other kind of electronic 
devices) as part of regulated clinical trial activities, such systems must be compliant with all 
applicable laws and regulations governing use of electronic records and/or electronic signatures. 
Such systems may include, but are not limited to, electronic medical/health records (EMRs/EHRs), 
adverse event tracking/reporting, protocol required assessments, and/or drug accountability 
records).
When paper records from such systems are used in place of electronic format to perform regulated 
activities, such paper records should be certified copies. A certified copy consists of a copy of 
original information that has been verified, as indicated by a dated signature, as an exact copy 
having all of the same attributes and information as the original. 
9.1.3
Investigational Site Training
Bristol-Myers Squibb will provide quality investigational staff training prior to study initiation. 
Training topics will include but are not limited to: GCP, AE reporting, study details and procedure, 
electronic CRFs, study documentation, informed consent, and enrollment of WOCBP.
9.2
Records
9.2.1
Records Retention
The investigator must retain all study records and source documents for the maximum period 
required by applicable regulations and guidelines, or institution procedures, or for the period 
specified by BMS, whichever is longer. The investigator must contact BMS prior to destroying 
any records associated with the study.
BMS will notify the investigator when the study records are no longer needed.
If the investigator withdraws from the study (eg, relocation, retirement), the records shall be 
transferred to a mutually agreed upon designee (eg, another investigator, IRB). Notice of such 
transfer will be given in writing to BMS.
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9.2.2
Study Drug Records 
It is the responsibility of the investigator to ensure that a current disposition record of study drug 
(inventoried and dispensed) is maintained at the study site to include investigational product. 
Records or logs must comply with applicable regulations and guidelines and should include:

amount received and placed in storage area

amount currently in storage area

label identification number or batch number 

amount dispensed to and returned by each subject, including unique subject identifiers

amount transferred to another area/site for dispensing or storage

nonstudy disposition (eg, lost, wasted) 

amount destroyed at study site, if applicable

amount returned to BMS

retain samples for bioavailability/bioequivalence, if applicable 

dates and initials of person responsible for Investigational Product dispensing/accountability, 
as per the Delegation of Authority Form.
BMS will provide forms to facilitate inventory control if the investigational site does not have an 
established system that meets these requirements.
9.2.3
Case Report Forms
An investigator is required to prepare and maintain adequate and accurate case histories designed 
to record all observations and other data pertinent to the investigation on each individual treated 
or entered as a control in the investigation. Data that are derived from source documents and 
reported on the CRF must be consistent with the source documents or the discrepancies must be 
explained. Additional clinical information may be collected and analyzed in an effort to enhance 
understanding of product safety. CRFs may be requested for AEs and/or laboratory abnormalities 
that are reported or identified during the course of the study.
For sites using the BMS electronic data capture tool, electronic CRFs will be prepared for all data 
collection fields except for fields specific to SAEs and pregnancy, which will be reported on the 
paper or electronic SAE form and Pregnancy Surveillance form, respectively. 
The confidentiality of records that could identify subjects must be protected, respecting the privacy 
and confidentiality rules in accordance with the applicable regulatory requirement(s).
The investigator will maintain a signature sheet to document signatures and initials of all persons 
authorized to make entries and/or corrections on CRFs. 
The completed CRF, including any paper or electronic SAE/pregnancy CRFs, must be promptly 
reviewed, signed, and dated by the investigator or qualified physician who is a subinvestigator and 
who is delegated this task on the Delegation of Authority Form. For electronic CRFs, review and 
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approval/signature is completed electronically through the BMS electronic data capture tool. The 
investigator must retain a copy of the CRFs including records of the changes and corrections.
Each individual electronically signing electronic CRFs must meet BMS training requirements and 
must only access the BMS electronic data capture tool using the unique user account provided by 
BMS. User accounts are not to be shared or reassigned to other individuals.
9.3
Clinical Study Report and Publications
A Signatory Investigator must be selected to sign the clinical study report. 
For this protocol, the Signatory Investigator will be selected as appropriate based on the following 
criteria:
1) External Principal Investigator designated at protocol development
2) National Coordinating Investigator 
3) Subject recruitment (eg, among the top quartile of enrollers)
4) Involvement in trial design
5) Regional representation (eg, among top quartile of enrollers from a specified region or country)
6) Other criteria (as determined by the study team)
The data collected during this study are confidential and proprietary to BMS. Any publications or 
abstracts arising from this study must adhere to the publication requirements set forth in the clinical 
trial agreement (CTA) governing participation in the study. These requirements include, but are 
not limited to, submitting proposed publications to BMS at the earliest practicable time prior to 
submission or presentation and otherwise within the time period set forth in the CTA.
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GLOSSARY OF TERMS
Term
Definition
Complete Abstinence
If one form of contraception is required, Complete 
Abstinence is defined as complete avoidance of heterosexual 
intercourse and is an acceptable form of contraception for all 
study drugs. Female subjects must continue to have 
pregnancy tests. Acceptable alternate methods of highly 
effective contraception must be discussed in the event that 
the subject chooses to forego complete abstinence.
If two forms of contraception is required, Complete 
abstinence is defined as complete avoidance of heterosexual 
intercourse and is an acceptable form of contraception for all 
study drugs. Subjects who choose complete abstinence are 
not required to use a second method of contraception, but 
female subjects must continue to have pregnancy tests. 
Acceptable alternate methods of highly effective 
contraception must be discussed in the event that the subject 
chooses to forego complete abstinence.
Expanded definition Complete abstinence as defined as 
complete avoidance of heterosexual intercourse is an 
acceptable form of contraception for all study drugs. This 
also means that abstinence is the preferred and usual lifestyle 
of the patient. This does not mean periodic abstinence 
(eg, calendar, ovulation, symptothermal, profession of 
abstinence for entry into a clinical trial, post-ovulation 
methods) and withdrawal, which are not acceptable methods 
of contraception. Subjects who choose complete abstinence 
are not required to use a second method of contraception, but 
female subjects must continue to have pregnancy tests. 
Acceptable alternate methods of highly effective 
contraception must be discussed in the event that the subject 
chooses to forego complete abstinence
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LIST OF ABBREVIATIONS
Term
Definition
AE
adverse event
AEC
Adenocarcinoma Esophageal cancer
ALT
alanine aminotransferase
ANC
absolute neutrophil count
ANOVA
analysis of variance
AST
aspartate aminotransferase
AT
Aminotransaminases
AUC
area under the concentration-time curve
AUC(INF)
area under the concentration-time curve from time zero extrapolated to
infinite time
AUC(0-T)
area under the concentration-time curve from time zero to the time of 
the last quantifiable concentration
AUC(TAU)
area under the concentration-time curve in one dosing interval
A-V
Atrioventricular
-HCG
beta-human chorionic gonadotrophin
BID, bid
bis in die, twice daily
BMI
body mass index
BMS
Bristol-Myers Squibb
BP
blood pressure
BUN
blood urea nitrogen
C
Celsius
C12
concentration at 12 hours
C24
concentration at 24 hours
Ca++
Calcium
Cavg
average concentration
CBC
complete blood count
CFR
Code of Federal Regulations 
CI
confidence interval
C1-
Chloride
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Term
Definition
CLcr
creatinine clearance
cm
Centimeter
Cmax, CMAX
maximum observed concentration
Cmin, CMIN
trough observed concentration
CNS
Central nervous system
CRC
Clinical Research Center
CRF
Case Report Form, paper or electronic
CRT
Chemoradiotherapy
Ct
Expected concentration at a certain time, usually at the end of an 
expected future dosing interval (eg, concentration at 24 hours, 
concentration at 12 hours, etc.)
Ctau
Concentration in a dosing interval (eg, concentration at 24 hours, 
concentration at 12 hours, etc.)
CTCAE
Common Terminology Criteria for Adverse Events
Ctrough
Trough observed plasma concentration
CV
coefficient of variation
CYP
cytochrome p-450
D/C
Discontinue
dL
Deciliter
DFS
Disease Free Survival
DMFS
distant metastasis free survival
EC
Esophageal Cancer
ECG
Electrocardiogram
eCRF
Electronic Case Report Form
ECOG
Eastern Cooperative Oncology Group
ECS
Esophageal Cancer Subscale
EDC
Electronic Data Capture
EEG
electroencephalogram
eg
exempli gratia (for example)
EQ-5D-3L
EuroQol questionnaire comprising 5 dimensions, with each dimension
having 3 levels
FACT-E
Functional Assessment of Cancer Therapy-Esophageal
FACT-G7
7-item version of FACT-General
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Term
Definition
FDA
Food and Drug Administration
FFPE
formalin-fixed, paraffin-embedded
FSH
follicle stimulating hormone
g
Gram
GC
Gastric Cancer
GCP
Good Clinical Practice
G criteria
adjusted R2 value of terminal elimination phase
GEJ
GastroEsophageal Junction 
GGT
gamma-glutamyl transferase
GFR
glomerular filtration rate
h
Hour
HBsAg
hepatitis B surface antigen
HBV
hepatitis B virus
HCV
hepatitis C virus
HCO3-
Bicarbonate
HIV
Human Immunodeficiency Virus
HR
heart rate or hazard ratio
HRT
hormone replacement therapy
ICD
International Classification of Diseases
ICH
International Conference on Harmonisation 
ie
id est (that is)
IEC
Independent Ethics Committee
IMP
investigational medicinal products
IND
Investigational New Drug Exemption
IRB
Institutional Review Board
IV
Intravenous
IWRS
Interactive Web Response System
K
slope of the terminal phase of the log concentration-time curve
K+
Potassium
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Term
Definition
kg
Kilogram

Kaplan-Meier
z
terminal disposition rate constant
L
Liter
LDH
lactate dehydrogenase
mg
Milligram
Mg++
Magnesium
min
Minute
mL
Milliliter
mmHg
millimeters of mercury
MSI
Microsatellite Instability
MSI-H
Microsatellite Instability - High
MSI-L
Microsatellite Instability - Low
MSI-S
Microsatellite Instability - Stable
MTD
maximum tolerated dose
g
Microgram
N
number of subjects or observations
Na+
Sodium
N/A
not applicable
ng
Nanogram
NIMP
non-investigational medicinal products 
NSAID
nonsteroidal anti-inflammatory drug
NSCLC
Non-Small Cell Lung Cancer
OS
Overall Survival
pCR
pathological complete response
PCR
polymerase chain reaction
PBMC
peripheral blood mononuclear cell
PD
pharmacodynamics
PD-1/PD-L1/PD-L2
programmed cell death protein 1/programmed cell death ligand 1 or 2
PFS2
Progression-free survival after the next line of the subsequent therapy
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Term
Definition
PK
pharmacokinetics
QC
quality control
QD, qd
quaque die, once daily
R0
complete resection
R2
coefficient of determination
RBC
red blood cell
RCC
Renal Cell Cancer
SAE
serious adverse event
SD
standard deviation
SNP
single nucleotide polymorphism
SOP
Standard Operating Procedures
Subj
Subject
SUSAR
Suspected, Unexpected Serious Adverse Reaction
TAO
Trial Access Online, the BMS implementation of an EDC capability
T-HALF
Half life
Tmax, TMAX
time of maximum observed concentration
TR_Cmax
Cmax treatment ratio
TSH
thyroid stimulating hormone
ULN
upper limit of normal
WBC
white blood cell
WHO
World Health Organization
WOCBP
women of childbearing potential
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12
REFERENCES
1
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of increasing adiposity on Barrett’s esophagus Am J Gastroenterol. 2008 Feb;103(2):292-300
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GLOBOCAB 2012: Estimated Cancer Incidence, Mortality and prevalence Worldwide in 2012 
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4
NCCN guideline for Esophageal and Esophagogastric junction cancers, Version 3. 2015; 
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Stahl M, Mariette C, Haustermans K, et al. Oesophageal Cancer: ESMO Clinical Practice 
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Japan society of Clinical Oncology. Clincial practice guideline for esophageal cancer 2012.
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P.van Hagen, Hulshof, van Lanschot et al. Preoperative Chemoradiotherapy for Esophageal 
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Van Meerten E, Muller K, Tilanus HW, et al. Neoadjuvant concurrent chemoradiation with 
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Bosset JF, Gignoux M, Triboulet JP, et al. Chemoradiotherapy followed by surgery compared 
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10 Walsh TN, Noonan N, Hollywood D et al. A comparison of multimodal therapy and surgery 
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11 Reynolds JV, Muldoon C, Hollywood D, et al. Long-term Outcomes Following Neoadjuvant 
Chemoradiotherapy for Esophageal Cancer. Ann Surg 2007;245: 707–716
12 “CheckMate 025: a randomised, open-label, phase III study of nivolumab (NIVO) versus 
everolimus (EVE) in advanced renal cell carcinoma (RCC)”. ESMO 2015, LBA 3. 
13
Brahmer J, Reckamp KL, Baas P, et al. Nivolumab versus Docetaxel in Advanced Squamous-
Cell Non–Small-Cell Lung Cancer. N Engl J Med 2015; 373:123-135
14 Borghaei H, Paz-Ares L,  Horn L, et al. Nivolumab versus Docetaxel in Advanced 
Nonsquamous Non–Small-Cell Lung Cancer. NEJM 2015 September 27.
15 Mellman I, Coukos G & Dranoff G. Cancer immunotherapy comes of age. Nature 2011 Dec 
22;29 4 8 0:480-89.
16 Alexander M M Eggermont, Vanna Chiarion-Sileni, Jean-Jacques Grob, et al. Adjuvant 
ipilimumab versus placebo after complete resection of high-risk stage III melanoma (EORTC 
18071): a randomised, double-blind, phase 3 trialOncol 2015; 16: 522–30
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17 Dung T. Le,Johanna Bendell,  Emiliano Calvo et al. Safety and Activity of Nivolumab 
Monotherapy in Advanced and Metastatic (A/M) Gastric Gastroesophageal Junction Cancer 
(GC/GEC): Results From the CheckMate-032 Study. ASCO GI 2016
18 T Ura, K Muro, H Hara et al. Phase 2 study of nivolumab (anti-PD-1; Ono-4538) in patients 
with esophageal cancer: preliminary report. ESMO 2015, P236.
19 Fuchs CS, Tomasek J, Yong CJ et al. Ramucirumab monotherapy for previously treated 
advanced gastric or gastro-oesophageal junction adenocarcinoma (REGARD): an 
international, randomized, multicentre, placebo-controlled, phase 3 trial. Lancet 2014; 383: 
31–39
20 “CheckMate 025: a randomised, open-label, phase III study of nivolumab (NIVO) versus 
everolimus (EVE) in advanced renal cell carcinoma (RCC)”. ESMO 2015, LBA 3. 
21 Brahmer J, Reckamp KL, Baas P, et al. Nivolumab versus Docetaxel in Advanced Squamous-
Cell Non–Small-Cell Lung Cancer. N Engl J Med 2015; 373:123-135
22 Borghaei H, Paz-Ares L,  Horn L, et al. Nivolumab versus Docetaxel in Advanced 
Nonsquamous Non–Small-Cell Lung Cancer. NEJM 2015 September 27.
23 Mellman I, Coukos G & Dranoff G. Cancer immunotherapy comes of age. Nature 2011 Dec 
22;29 4 8 0:480-89.
24 Brahmer JR, Drake CG, Wollner I, et al. Phase I Study of Single-Agent Anti–Programmed 
Death-1 
(MDX-1106) 
in 
Refractory 
Solid 
Tumors: 
Safety, 
Clinical 
Activity, 
Pharmacodynamics, and Immunologic Correlates. J Clin Oncol 2010; 28:3167-3175.
25 Opdivo Prescribing Information, 2015.
26 Ozawa S, et al: Comprehensive registry of esophageal cancer in Japan, 2002. Esophagus. 2010; 
7(1): 7-22.
27 Cunningham D, Allum WH, Stenning SP et al Perioperative chemotherapy versus surgery 
alone for resectable gastroesophageal cancer N Engl J Med. 2006 Jul 6;355(1):11-20
28 Macdonald J, Smalley S, Enedetti Jet al. Chemoradiotherapy after surgery compared with 
surgery alone for adenocarcinoma of the stomach or gastroesophageal junction. N Engl J Med 
2001;345:725-30
29 Sakuramoto S, Sasako M, Yamaguchi T, et al. Adjuvant chemotherapy for gastric cancer with 
S-1, an oral fluoropyrimidine. N Engl J Med. 2007;357(18):1810-20.(Erratum in 
2008;358(18):1977.)
30 Bang YJ, Kim YW, Yang HK et al. Adjuvant capecitabine and oxaliplatin for gastric cancer 
after D2 gastrectomy (CLASSIC): a phase 3 open-label, randomised controlled trial. Lancet. 
2012;379(9813):315-21
31 Boonstra JJ, Kok TC, Wijnhoven BP et al Chemotherapy followed by surgery versus surgery 
alone in patients with resectable oesophageal squamous cell carcinoma: long-term results of a 
randomized controlled trial BMC Cancer. 2011 May 19;11:181
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32 Kelsen DP, Ginsberg R, Pajak TF et al Chemotherapy followed by surgery compared with 
surgery alone for localized esophageal cancer N Engl J Med 1998 Dec 31;339(27):1979-1984
33 Ancona E, Ruol A, Santi S et al Only pathologic complete response to neoadjuvant 
chemotherapy improves significantly the long term survival of patients with resectable 
esophageal squamous cell carcinoma: final report of a randomized, controlled trial of 
preoperative chemotherapy versus surgery alone Cancer. 2001; 91(11):2161-74. 
34 Allum WH, Stenning SP, Bancewicz J et al Long-term results of a randomized trial of surgery 
with or without preoperative chemotherapy in esophageal cancer J Clin Oncol. 2009 Oct 
20;27(30):5062-67. 
35 Ychou M, Boige V, Pignon JP et al Perioperative chemotherapy compared with surgery alone 
for resectable gastroesophageal adenocarcinoma: an FNCLCC and FNCD multicenter phase 
III trial J Clin Oncol. 2011 May 1;29(13):1715-21
36 Schuhmacher C, Gretschel S, Lordick F et al Neoadjuvant chemotherapy compared with 
surgery alone for locally advanced cancer of the stomach and cardia: European Organisation 
for Research and Treatment of Cancer randomized trial 40954 J Clin Oncol. 2010 Dec 
10;28(35):5210-8
37 Ando N, Kato H, Igaki H et al A randomized trial comparing postoperative adjuvant 
chemotherapy with cisplatin and 5-flourouracil versus preoperative chemotherapy for 
localized advanced squamous cell carcinoma of the thoracic esophagus (JCOG9907) Ann Surg 
Oncol 2012 Jan;19(1):68-74
38 Sjoquist KM, Burmeister BH, Smithers BM et al Survival after neoadjuvant chemotherapy or 
chemoradiotherapy for resectable oesophageal carcinoma: an updated meta-analysis Lancet 
Oncol. 2011 Jul; 12(7):681-92
39 Bosset JF, Gignoux M, Triboulet JP, et al. Chemoradiotherapy followed by surgery compared 
with surgery alone in squamous-cell cancer of the esophagus. N Engl J Med 1997; 337:161-
167
40 Urba SG, Orringer MB, Turrisi A et al Randomized trial of preoperative chemoradiation versus 
surgery alone in patients with locoregional esophageal carcinoma J Clin Oncol. Jan 
15;19(2):305-13
41 Ordu AD, Nieder C, Geinitz H et al. Association between radiation dose and pathological 
complete response after preoperative radiochemotherapy in esophageal squamous cell cancer. 
Anticancer Res. 2014 Dec;34(12):7255-61.
42 Burmeister BH, Smithers BM, Gebski V et al Surgery alone versus chemoradiotherapy 
followed by surgery for resectable cancer of the esophagus: a randomized controlled phase III 
trial Lancet Oncol. 2005 Sep;6(9):659-68
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43 C. S. Fuchs, J. E. Tepper, D. Niedzwiecki, D et al. Postoperative adjuvant chemoradiation for 
gastric or gastroesophageal junction (GEJ) adenocarcinoma using epirubicin, cisplatin, and 
infusional (CI) 5-FU (ECF) before and after CI 5-FU and radiotherapy (CRT) compared with 
bolus 5-FU/LV before and after CRT: Intergroup trial CALGB 80101. J Clin Oncol 29: 2011 
(suppl; abstr 4003)
44 Urba SG, Orringer MB, Turrisi A et al Randomized trial of preoperative chemoradiation versus 
surgery alone in patients with locoregional esophageal carcinoma. J Clin Oncol. 2001 Jan 
15;19(2):305-13.
 
 
46 Ordu AD, Nieder C, Geinitz H et al. Association between radiation dose and pathological 
complete response after preoperative radiochemotherapy in esophageal squamous cell cancer. 
Anticancer Res. 2014 Dec;34(12):7255-61.
47 Ulrich Ronellenfitsch, Matthias Schwarzbach, Ralf Hofheinz et al. Preoperative 
chemo(radio)therapy versus primary surgery for gastroesophageal adenocarcinoma: 
Systematic review with meta-analysis combining individual patient and aggregate data. 
European Journal of Cancer (2013) 49, 3149– 3158
48 Macdonald J, Smalley S, Enedetti Jet al. Chemoradiotherapy after surgery compared with 
surgery alone for adenocarcinoma of the stomach or gastroesophageal junction. N Engl J Med
2001;345:725-30.
49 C. S. Fuchs, J. E. Tepper, D. Niedzwiecki, D et al. Postoperative adjuvant chemoradiation for 
gastric or gastroesophageal junction (GEJ) adenocarcinoma using epirubicin, cisplatin, and 
infusional (CI) 5-FU (ECF) before and after CI 5-FU and radiotherapy (CRT) compared with 
bolus 5-FU/LV before and after CRT: Intergroup trial CALGB 80101. J Clin Oncol 29: 2011 
(suppl; abstr 4003)
50 Sakuramoto S, Sasako M, Yamaguchi T, et al. Adjuvant chemotherapy for gastric cancer with 
S-1, an oral fluoropyrimidine. N Engl J Med. 2007;357(18):1810-20.(Erratum in 
2008;358(18):1977.)
51 Bang YJ, Kim YW, Yang HK et al. Adjuvant capecitabine and oxaliplatin for gastric cancer 
after D2 gastrectomy (CLASSIC): a phase 3 open-label, randomised controlled trial. Lancet. 
2012;379(9813):315-21
52 Jae Y. Kim, Rebecca A. Nelson, Joseph Kim et al. How well does pathologic stage predict 
survival for esophageal adenocarcinoma after neoadjuvant therapy? J Thorac Dis 
2015;7(4):734-739
53 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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54 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.
55 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.
56 Carter LL, Fouser LA, Jussif J, et al. PD-1: PD-L1 inhibitory pathway affects both CD4+ and 
CD8+ T cells and is overcome by IL-1. Eur J Immunol. 2002;32:634-43.
57 Barber DL, Wherry EJ, Masopust D et al. Restoring function in exhausted CD8 T cells during 
chronic viral infection. Nature 2006;439:682-7.
58 Wu C, Zhu Y, Jiang J et al. Immunohistochemical localization of programmed death-1 ligand-
1 (PD-L1) in gastric carcinoma and its clinical significance. Acta Histochem. 2006;108(1):19-
24
59 Ohigashi Y, Sho M, Yamada Y et al. Clinical significance of programmed death-1 ligand-1 
and programmed death-1 ligand-2 expression in human esophageal cancer. Clin Cancer Res. 
2005;11(8):2947-53.
60 Bang YJ, et al. Relationship between PD-L1 expression and clinical outcomes in patients with 
advanced gastric cancer treated with the anti-PD-1 monoclonal antibody pembrolizumab (MK-
3475) in KEYNOTE-012.ASCO 2015, abstract 4001
61 T Doi et al. Pembrolizumab (MK-3475) for patients (pts) with advanced esophageal 
carcinoma: Preliminary results from KEYNOTE-028. ASCO 2015 Abstract 4010
62 Abate E, DeMeeste S, Zehetner J, et al. Recurrence after Esophagectomy forAdenocarcinoma: 
Defining Optimal Follow-Up Intervals and Testing. J Am Coll Surg 2010;210:428–435.
63 Oba K, Paoletti X, Alberts S, et al. Disease-free survival as a surrogate for overall survival in 
adjuvant trials of gastric cancer: a meta-analysis. J Natl Cancer Inst 2013;105:1600-1607.
64 Glimm E, Maurer W, Bretz F. Hierarchical testing of multiple endpoints in group‐ sequential 
trials. Stat Med 2010;29:219-228.
 
 
66 Ulrich 
Ronellenfitsch, 
Matthias 
Schwarzbach, 
Ralf 
Hofheinz 
et 
al.Preoperative 
chemo(radio)therapy versus primary surgery
for gastroesophageal adenocarcinoma: 
Systematic review with
meta-analysis combining individual patient and aggregate 
data.European Journal of Cancer (2013) 49, 3149– 3158 
67 Kelsen DP, Winter KA, Gunderson LL, et al. Long-term results of RTOG trial 8911 (USA 
Intergroup 113): a random assignment trial comparison of chemotherapy followed by surgery 
compared with surgery alone for esophageal cancer. J Clin Oncol 2007;25:3719–25.
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68 Ychou M, Boige V, Pignon JP et al. Perioperative Chemotherapy Compared With Surgery 
Alone for Resectable Gastroesophageal Adenocarcinoma: An FNCLCC and FFCD 
Multicenter Phase III Trial. J Clin Oncol 29:1715-1721.
69 Ychou M, Boige V, Pignon JP et al. Perioperative Chemotherapy Compared With Surgery 
Alone for Resectable Gastroesophageal Adenocarcinoma: An FNCLCC and FFCD 
Multicenter Phase III Trial. J Clin Oncol 29:1715-1721.
70 Paz-Ares L, Horn L, Borghaei H, et al. J Clin Oncol 33, 2015 (suppl; abstrLBA109).
71 Katrin M Sjoquist, Bryan H Burmeister, B Mark Smithers etc. Survival after neoadjuvant 
chemotherapy or chemoradiotherapy for resectable oesophageal carcinoma: an updated meta-
analysis Lancet Oncol 2011; 12: 681–92
 
 
 
 
 
 
 
 
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APPENDIX 1
ECOG PERFORMANCE STATUS 
ECOG PERFORMANCE STATUSa
0
Fully active, able to carry on all pre-disease performance without restriction
1
Restricted in physically strenuous activity but ambulatory and able to carry out work of a 
light or sedentary nature, eg, light house work, office work
2
Ambulatory and capable of all selfcare but unable to carry out any work activities. Up and 
about more than 50% of waking hours
3
Capable of only limited selfcare, confined to bed or chair more than 50% of waking hours
4
Completely disabled. Cannot carry on any selfcare. Totally confined to bed or chair
5
Dead
a Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, and Carbone PP. Toxicity and Response 
Criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol 1982; 5: 649-655.
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APPENDIX 2
MANAGEMENT ALGORITHMS 
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 3
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.*
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 hormone-releasing system (IUS)c

Intrauterine device (IUD)c

Bilateral tubal occlusion

Vasectomized partner
A vasectomized partner is a highly effective contraception method provided that the partner 
is the sole male sexual partner of the WOCBP and the absence of sperm has been confirmed. 
If not, an additional highly effective method of contraception should be used. 

Sexual abstinence
Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study drug. The 
reliability of sexual abstinence needs to be evaluated in relation to the duration of the study 
and the preferred and usual lifestyle of the participant.

It is not necessary to use any other method of contraception when complete abstinence is 
elected. 

WOCBP participants who choose complete abstinence must continue to have pregnancy 
tests, as specified in Section 2. 

Acceptable alternate methods of highly effective contraception must be discussed in the 
event that the WOCBP participants chooses to forego complete abstinence 
NOTES: 
a Typical use failure rates may differ from those when used consistently and correctly. Use should be consistent 
with local regulations regarding the use of contraceptive methods for participants participating in clinical 
studies. 
b Hormonal contraception may be susceptible to interaction with the study drug, which may reduce the efficacy 
of the contraceptive method.  Hormonal contraception is permissible only when there is sufficient evidence 
that the IMP and other study medications will not alter hormonal exposures such that contraception would be 
ineffective or result in increased exposures that could be potentially hazardous.  In this case, alternative 
methods of contraception should be utilized. 
c Intrauterine devices and intrauterine hormone releasing systems are acceptable methods of contraception in the 
absence of definitive drug interaction studies when hormone exposures from intrauterine devices do not alter
contraception effectiveness
Unacceptable Methods of Contraception*

Male or female condom with or without spermicide.  Male and female condoms cannot be 
used simultaneously
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
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)
* Local laws and regulations may require use of alternative and/or additional 
contraception methods.
CONTRACEPTION GUIDANCE FOR MALE PARTICIPANTS WITH PARTNER(S) OF 
CHILD BEARING POTENTIAL.
Male participants with female partners of childbearing potential are eligible to participate if they 
agree to the following during the treatment and until the end of relevant systemic exposure.

Inform any and all partner(s) of their participation in a clinical drug study and the need to 
comply with contraception instructions as directed by the investigator.

Male participants are required to use a condom for study duration and until end of relevant 
systemic exposure defined as 7 months after the end of study treatment.

Female partners of males participating in the study to consider use of effective methods of 
contraception until the end of relevant systemic exposure, defined as 7 months after the end 
of treatment in the male participant.

Male participants with a pregnant or breastfeeding partner must agree to remain abstinent 
from penile vaginal intercourse or use a male condom during each episode of penile 
penetration during the treatment and until 7 months after the end of study treatment. 

Refrain from donating sperm for the duration of the study treatment and until 7 months after 
the end of study treatment.
COLLECTION OF PREGNANCY INFORMATION
Guidance for collection of Pregnancy Information and outcome of pregnancy on the Pregnancy 
Surveillance Form is provided in Section 6.4 and the Appendix for Adverse Events and Serious 
Adverse Events Definitions and procedures for Evaluating, Follow-up and Reporting
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APPENDIX 4
COUNTRY SPECIFIC REQUIREMENTS
Argentina, Czech Republic, France, Germany, Italy, Spain, and Any Other Countries 
Where Exclusion of HIV Positive Participants Is Locally Mandated
Country-specific language
Section 5 Flow
Chart/Time and Events
Schedule, Table 5.1-1: 
Screening Procedural 
Outline (CA209577), 
Safety Assessments,
LaboratoryTests
Add “HIV” to the list of laboratory tests
Section 3.3.2 Exclusion
Criteria, 3.3.2.2 Medical History, 
Exclusion criterion i
“Known history of testing positive for human
immunodeficiency virus (HIV) or known acquired
immunodeficiency syndrome (AIDS)”to be replaced with
“Positive test for HIV”.
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APPENDIX 5
PROTOCOL AMENDMENT SUMMARY OF CHANGE HISTORY
OVERALL RATIONALE FOR REVISED PROTOCOL 03
The rationale for study design changes include factors observed during the conduct of the trial. 
The actual enrollment in the study has been much slower than initial projections. The enrollment 
period was re-estimated to be 26 months (versus 15 months in the original protocol) in the 
Revised Protocol 02 (04-May-2017). More recently it was re-projected to approximately
 
When evaluating the impact of the slow enrollment to the study design and conduct, published 
external data related to the study population were examined and the impact on study assumptions 
in the control arm were evaluated. The data from the chemoradiotherapy followed by surgery 
(CRT + S) arm in the CROSS trial with long-term follow up (CROSS LT) was considered the 
most relevant data to the study population. In consultation with external clinical experts and 
using data from the CROSS LT trial, it was concluded that the median disease-free survival 
(DFS) and overall survival (OS) in the placebo arm should be much longer than the original 
assumption.
 
 Therefore, changes in the study design were needed in 
order to ensure that the study is adequately powered.
Given the above considerations and the rationale in Section 1.4.7.1 of Revised Protocol 03, the 
following major changes were made:
1) DFS has become the single primary endpoint in the study and OS changed from a co-primary 
endpoint to the first secondary endpoint to be tested hierarchically.
2) Progression-free survival after the next line of subsequent therapy (PFS2) has been added as 
an exploratory endpoint to the study per recent EMA guidance. PFS2 has recently been 
proposed as a surrogate for OS, particularly for trials evaluating maintenance therapy.
 were held prior to this protocol 
revision. Revisions apply to future subjects enrolled in the study, and where applicable, to all 
subjects currently enrolled.
SUMMARY OF KEY CHANGES FOR REVISED PROTOCOL 03
Section Number & 
Title
Description of Change
Brief Rationale
Synopsis
1.3.1, Primary 
Objectives;
1.3.2, Secondary 
Objectives
Moved overall survival (OS) 
from co-primary objective to 
secondary objective.
See overall rational for the 
revised protocol above.
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SUMMARY OF KEY CHANGES FOR REVISED PROTOCOL 03
Section Number & 
Title
Description of Change
Brief Rationale
Synopsis
1.3.3, Exploratory 
Objectives
Added progression-free survival 
after the next line of subsequent 
therapy (PFS2) as an exploratory 
objective.
See overall rational for the 
revised protocol above.
1.4.3, Local and 
Locoregional 
Esophageal, and 
Gastroesophageal 
Junction Cancer 
Background 
Added direct reference to the 
CROSS study long-term follow-
up.
See overall rational for the 
revised protocol above.
1.4.7.1, Rationale for 
DFS Being Single 
Primary Endpoint and 
OS Being First 
Secondary Endpoint to 
Be Tested in a 
Hierarchical Way
Replaced entire section with 
robust rationale supporting 
disease-free survival (DFS) as 
single primary and OS as first 
secondary endpoints.
See overall rational for the 
revised protocol above.
3.1, Study Design and 
Duration
Changed accrual from 
 
 and removed sentence 
for total expected duration of 
study.
See overall rational for the 
revised protocol above.
3.3.2.2, Medical 
History and 
Concurrent Disease;
3.4.1, Prohibited 
and/or Restricted 
Treatments
Added exclusion criteria, on-
study, and post-study 
requirements regarding 
live/attenuated vaccines.
To bring in line with current 
program standards.
The use of vaccines in the study 
has been guided according to the 
program-wide recommendation.
3.3.2.3, Physical and 
Laboratory Test 
Findings
Updated language for clarity 
regarding hepatitis B or C virus 
exclusion criteria.
To bring in line with current 
program standards.
3.3.3, Women of 
Childbearing Potential
Updated to be consistent with 
updated appendix.
To bring in line with current 
program standards.
3.6, Post Study Drug, 
Study Follow-up
Removed OS from being 
included as a co-primary 
endpoint.
To reflect the design change.
4.5, Selection and 
Timing of Dose for 
Each Subject
Added language regarding 
monitoring for infusion-related 
reactions.
To bring in line with current 
program standards.
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SUMMARY OF KEY CHANGES FOR REVISED PROTOCOL 03
Section Number & 
Title
Description of Change
Brief Rationale
Added language regarding dose 
interruptions, delays, and 
discontinuation.
4.5.5, Discontinuation 
of Subjects from 
Treatment:
Added myocarditis to Grade 3
non-skin drug-related adverse 
events (AEs).
To bring in line with current 
program standards.
Table 5.1-3: Follow-
up Procedural Outline
Removed AE assessment from 
survival follow-up visits.
Correction to assessment table, 
marked in error previously.
Table 5.1-3: Follow-
up Procedural Outline
Removed specific instructions 
from exploratory biomarkers 
assessments in favor of cross-
referencing the full sampling 
schedule.
Editorial change.
Table 5.1-3: Follow-
up Procedural Outline
Added x to show that survival
status will be collected at follow-
up visits 1 and 2.
Added PFS2 assessments at 
follow-up visits 1 and 2 and 
survival follow-up visits.
Correction to assessment table
To ensure adequate assessments 
in order to evaluate PFS2.
5.4.1, Definitions of 
recurrence
Clarified language regarding 
diagnosis of recurrence.
To bring in line with current 
standards.
5.4.2, Methods of 
Measurement
5.7, Outcomes 
Research Assessments
Clarified that questionnaires will 
be provided in the subject’s 
preferred language when 
available.
To bring in line with current 
program language
6.2.1, Nonserious 
Adverse Event 
Collection and 
Added clarifying language 
regarding immune-mediated 
adverse events.
To bring in line with current 
program standards.
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SUMMARY OF KEY CHANGES FOR REVISED PROTOCOL 03
Section Number & 
Title
Description of Change
Brief Rationale
Reporting
8.1, Sample Size 
Determination
Replaced the original sample-
size determinations based on co-
primary endpoints.
See overall rational for the 
revised protocol above.
8.1.1, Assumptions of 
Control Arm
8.1.2, Assumptions of 
the Treatment Effect
Synopsis
8.1.3, Sample Size and 
Power
Added new section to update 
sample size and power estimates 
based on new assumptions 
provided in Sections 8.1.1 and 
8.1.2.
Synopsis was revised to reflect 
the information in these new 
sections.
To reflect the updated sample size 
and power based on new 
assumptions.
8.1.4, Timing of the 
DFS and OS Interim 
and Final Analyses
Updated entire section to provide 
new triggers and timing for the 
interim and final analyses.
8.1.5, Potential 
Adjustment of 
Analysis Timing for 
DFS and OS
Added new section to explain 
how timing of DFS/OS analyses 
will be adjusted to maintain a 
strong control of type I error.
To add flexibility in the trigger of 
the DFS/OS analyses should the 
blinded pooled data suggests 
variability of the DFS/OS rates in 
the control arm. The Statistical 
Analysis Plan will document such 
change.
Synopsis
8.3, Endpoints;
8.3.1, Primary 
Removed OS from being a co-
primary endpoint; removed 
headings for Sections 8.3.1.1 and 
See overall rational for the 
revised protocol above.
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SUMMARY OF KEY CHANGES FOR REVISED PROTOCOL 03
Section Number & 
Title
Description of Change
Brief Rationale
Endpoints
8.3.1.2.
Synopsis was revised to reflect 
the information in these new 
sections.
Synopsis
8.3.2.1, Overall 
Survival;
8.3.2.2, Overall 
Survival Rate
Added new section to define OS 
and added new section heading 
to distinguish OS rate.
Synopsis was revised to reflect 
the information in these new 
sections.
To be consistent with changes in
primary and secondary endpoints.
Synopsis
8.3.3, Exploratory 
Endpoint(s)
Updated PD-L1 status bullet to 
distinguish DFS as primary and 
OS as secondary endpoints.
Added bullet defining PFS2 as 
exploratory endpoint.
Synopsis was revised to reflect 
the information in these new 
sections.
To be consistent with changes in 
primary and secondary endpoints.
8.4.2.1, Protection of 
Type-I Error
Moved discussion of addressing 
family-wise error rate across 
DFS and OS analyses at interim 
and final analyses to a new 
section.
To reflect the design change.
8.4.2.2, Primary 
Efficacy Endpoint
Moved error-rate discussion to 
new section and removed 
mention of OS as a primary 
endpoint.
To reflect the design change.
8.4.2.3, Secondary 
Efficacy Endpoint
Added language describing OS 
analyses as secondary endpoint.
To be consistent with changes in 
secondary endpoints.
8.4.2.4, Exploratory 
Efficacy Endpoint
Added PFS2 to exploratory 
endpoint analyses.
To be consistent with changes in 
endpoints.
8.5, Interim Analyses;
8.5.1, DFS Analyses;
8.5.2, OS Analyses
Removed text under Interim 
Analyses and added two separate 
sections to address each of the 
DFS and OS analyses.
To be consistent with Section 
8.1.4. 
12, References
References have been added and 
Updated to bring in line with all 
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SUMMARY OF KEY CHANGES FOR REVISED PROTOCOL 03
Section Number & 
Title
Description of Change
Brief Rationale
deleted.
new text revisions.
Appendix 2, 
Management 
Algorithms
Updated to reflect current IB.
Updated to bring in line with 
current program standards.
Appendix 3, Women 
of Childbearing 
Potential Definition
Updated to reflect current 
version of appendix.
Updated to bring in line with 
current program standards.
Appendix 4, County 
Specific Requirements
Added
Updated to bring in line with 
current program standards.
Global
Typographical and grammatical, 
errors have been corrected.
Minor, therefore have not be 
summarized.
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