Clinical trial NCT03143153
Conditions: Various Advanced Cancer
Sponsor: Bristol-Myers Squibb
Start date: 2017-06-29; Completion date: 2025-01-13
Enrollment: 970 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The main purpose of this study is to compare how long subjects with esophageal cancer live overall or live without disease progression after receiving nivolumab and ipilimumab or nivolumab combined with fluorouracil plus cisplatin versus fluorouracil plus cisplatin

Detailed description:

Arms: arm 1: None arm 2: None arm 3: None
Interventions: intervention 1: Nivolumab intervention 2: Ipilimumab intervention 3: Cisplatin intervention 4: Fluorouracil
Intervention descriptions: intervention 1: Specified dose on specified days intervention 2: Specified dose on specified days intervention 3: Specified dose on specified days intervention 4: Specified dose on specified days

Protocol documents:
Prot_000.pdf: 
Official Title of Study: 
A Randomized Phase 3 Study of Nivolumab plus Ipilimumab or Nivolumab Combined with 
Fluorouracil plus Cisplatin versus Fluorouracil plus Cisplatin in Subjects with Unresectable 
Advanced, Recurrent or Metastatic Previously Untreated Esophageal Squamous Cell Carcinoma 
 
 
NCT Number: NCT03143153 
Document Date (Date in which document was last revised): October 29, 2020 


Page: 1
Protocol Number: CA209648
IND Number: 126,406
Ex-US Non-IND
EUDRACT Number 2016-001514-20
Date: 01-Jun-2016
Revised Date: 29-Oct-2020
Clinical Protocol CA209648
A Randomized Phase 3 Study of Nivolumab plus Ipilimumab or Nivolumab Combined with 
Fluorouracil plus Cisplatin versus Fluorouracil plus Cisplatin in Subjects with Unresectable 
Advanced, Recurrent or Metastatic Previously Untreated Esophageal Squamous Cell Carcinoma
(CheckMate 648: CHECKpoint pathway and nivoluMab clinical Trial Evaluation 648)
Revised Protocol Number: 05
Medical Monitor
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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 
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be added to this document is also confidential and proprietary to BMS and must be kept in 
confidence in the same manner as the contents of this document. Any person who receives 
this  document  without  due  authorization  from  BMS  
is  requested  to  return  
it  to  BMS  or 
promptly destroy it. All other rights reserved. References to BMS in this protocol may apply 
to partners to which BMS has transferred obligations, eg, a Contract Research Organization 
(CRO).
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DOCUMENT HISTORY
Document 
Date of Issue
Summary of Change
Revised 
Protocol 05
29-Oct-2020
This revised protocol allows for the final PFS analysis to be triggered 
when 136 PFS events per BICR are observed among the PD-L1 
expressing subjects in the chemotherapy arm or when at least 12 months 
minimum follow up is reached, if the target number of PFS events is 
unlikely to be reached.
Revised 
Protocol 04
12-Sep-2018
This revised protocol restricts study entry to participants of previous 
nivolumab clinical studies where overall survival was listed as a primary 
or co-primary endpoint. Live /attenuated vaccines were prohibited and 
the inclusion criterion related to the assessment of renal function was 
expanded to allow the consideration of measured creatinine clearance. 
Cisplatin infusion times longer than 120 minutes were allowed if deemed 
necessary by investigator per local standard of care/local label.
PFS2/TSST was added as an exploratory endpoint. The section on 
biomarker assessments was revised. Program updates were added and 
internal inconsistencies were corrected.
Revised 
Protocol 03
02-Feb-2018
This revised protocol removed the procedures for the reinitiation of 
nivolumab ±ipilimumab treatment after disease progression for up to 1 
additional year.  In addition, it added clarification to the treatment 
beyond progression procedures to limit treatment to a maximum duration 
of 24 months.
Revised 
Protocol 02
25-Oct-2017
To align the protocol with the latest SmPC, simplify procedures, and 
provide clarifications in the protocol. 
Revised 
Protocol 01
21-Dec-2016
Incorporates Amendment(s) 02
Amendment 02 
21-Dec-2016
Expansion of the esophageal cohort into a 3-arm randomized Phase 3 
study in first line squamous esophageal cancer. The study now includes a 
nivolumab plus chemotherapy arm (fluorouracil and cisplatin) and a 
chemotherapy alone arm in addition to the existing nivolumab and 
ipilimumab arm. The gastric cohort was removed.
Administrative 
Letter 01
30-Mar-2017
To correct typographical errors to Study Drug Table in Synopsis, and 
Table 4.5.1.1-1 and Table 5.1-2, and Section 4.5.1.1.  
Original 
Protocol
01-Jun-2016
Not applicable
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OVERALL RATIONALE FOR THE REVISED PROTOCOL 05
Per  protocol, the  planned  
interim  analysis  
(PFS  
final  analysis and  OS  
interim  analysis)  will  be 
triggered  when  136  PFS  events  per  blinded  
independent  central  
reviewer  
(BICR)  are  observed 
among subjects expressing at least 1% tumor PD-L1 in the chemotherapy arm (Arm C). PFS event 
tracking  
is  conducted  by  an  
independent  external  statistical  group  
(Axio,  
Inc),  which  supports 
statistical  analyses  and  generates  reports  for  review  by  an  independent  Data  Monitoring 
Committee. BMS remains blinded to the number of PFS events in arm A and arm B. Event tracking 
commenced  in  July  2020.  PFS  events  are  observed  
to  be  
tracking at  a  much  slower  rate  
than 
projected  per protocol.  This  is  largely  due  to  censoring  due  
to  start  of  subsequent  
therapy  or 
withdrawal of consent prior to progression, the extent of which was unforeseen when this protocol 
was developed. 
This protocol amendment adds another trigger for the interim analysis (Final PFS/Interim OS) in 
the event that the target number of PFS events is not reached. The revised protocol allows for the 
final PFS analysis to be triggered when 136 PFS events are observed among the PD-L1 expressing 
subjects in the chemotherapy arm, or when at least 12 months minimum follow up (defined as the 
time from the date of the last patient was randomized to the clinical cutoff date) is reached. In the 
eventuality that the target number of PFS events is not reached, the 12 months minimum follow-
up ensures adequate follow-up for PFS in this patient population.
As per original design, OS IA will be conducted at the same time as PFS final analysis (FA) and 
the alpha allocation will be calculated per the specified method (see section 7.5 of SAP).
SUMMARY OF KEY CHANGES FOR REVISED PROTOCOL 05
Section Number & Title 
Description of Change 
Brief Rationale
Synopsis,Section 8.1: Sample Size 
Determination
Amended trigger for the IA
Added provision for triggering the 
planned IA when at least 12 months 
minimum follow-up is reached, in the 
eventuality that the planned 136 PFS 
events per BICR among the PD L1 
expressing subjects in the 
chemotherapy are unlikely to be 
reached.
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SYNOPSIS
Clinical Protocol CA209648
Protocol  Title: A  Randomized  Phase  3  Study  of  Nivolumab  plus  Ipilimumab  or  Nivolumab  Combined  with 
Fluorouracil plus Cisplatin versus Fluorouracil plus Cisplatin in Subjects with Unresectable Advanced, Recurrent or 
Metastatic Previously Untreated Esophageal Squamous Cell Carcinoma
Investigational  Product(s),  Dose  and  Mode  of  Administration,  Duration  of  Treatment  with  Investigational 
Product(s):
• Nivolumab + Ipilimumab: Nivolumab 3 mg/kg as a 30-minute infusion every 2 weeks and ipilimumab 1 mg/kg 
as a 30-minute infusion every 6 weeks (Arm A) or 
• Nivolumab  +  Chemotherapy:  Nivolumab  240  mg  as  a  30-minute  
infusion every 2 weeks (i.e. on Day1 and 
Day 15),  
fluorouracil  800 mg/m²/day as  an IV  continuous  
infusion  on  Day 1  
through  Day 5  (for  5  days),  and 
cisplatin 80 mg/m² as a 30- to 120-minute infusion* on day 1 of 4-week cycle(Arm B) or 
• Chemotherapy: fluorouracil 800 mg/m²/day as an IV continuous infusion on Day 1 through Day 5 (for 5 days), 
and cisplatin 80 mg/m²/day as a 30- to 120-minute infusion* on day 1 of 4-week cycle (Arm C).
*Subjects are allowed to receive treatment with cisplatin 80 mg/m² as an IV infusion over a period of longer than 120 
min if it is in accordance with local standard of care/local label.
Treatment with nivolumab or nivolumab with ipilimumab (arms A and B) will be given for up to 24 months in the 
absence of disease progression or unacceptable toxicity
. Chemotherapy (Arms B, and C) will be given as per the study 
dosing schedule until disease progression, unacceptable toxicityor other reasons specified in the protocol.
Study Phase:Phase 3
Research Hypothesis:
• The administration of nivolumab plus ipilimumab will improve overall survival (OS) compared with fluorouracil 
and  cisplatin  combination in  subjects  with  unresectable  advanced,  
recurrent  or  metastatic ESCC  with  PD-L1 
expression ≥1%. 
• The  administration  of  nivolumab  combined  with  fluorouracil  plus  cisplatin  will  
improve  OS  compared  with 
fluorouracil and cisplatin combination alone in subjects with unresectable advanced, recurrent or metastatic ESCC 
with PD-L1 expression ≥1%.
• The administration of nivolumab plus ipilimumab will improve progression free survival (PFS) as assessed by a 
blinded independent central review committee (BICR) compared with fluorouracil and cisplatin combination in 
subjects with unresectable advanced, recurrent or metastatic ESCC with PD-L1 expression ≥1%. 
• The administration of nivolumab combined with fluorouracil plus cisplatin will improve PFS as assessed by a 
BICR  compared  with  fluorouracil  and  cisplatin  combination  alone in  subjects  with  unresectable  advanced, 
recurrent or metastatic ESCC with PD-L1 expression ≥1%.
Objectives: 
Primary Objectives
• To compare the OS of nivolumab plus ipilimumab (Arm A) to fluorouracil plus cisplatin chemotherapy (Arm C) 
in subjects with PD-L1 expression ≥1%.
• To compare the OS of nivolumab combined with fluorouracil plus cisplatin (Arm B) to fluorouracil plus cisplatin 
chemotherapy (Arm C) in subjects with PD-L1 expression ≥1%.
• To compare the PFS of nivolumab plus ipilimumab (Arm A) to fluorouracil and cisplatin combination (Arm C) 
as assessed by a BICR in subjects with PD-L1 expression ≥1%.
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• To compare the PFS of nivolumab combined with fluorouracil plus cisplatin (Arm B) to fluorouracil and cisplatin 
combination (Arm C) as assessed by a BICR in subjects with PD-L1 expression ≥1%.
Secondary Objectives 
• To  compare  
the  OS  of  nivolumab  plus  
ipilimumab  
(Arm  A)  and  nivolumab  combined  with  fluorouracil  plus 
cisplatin (Arm B) to fluorouracil and cisplatin combination (Arm C) in all randomized subjects.
• To  compare  
the  PFS  of  nivolumab  plus  
ipilimumab  
(Arm A)  and nivolumab  combined  with  
fluorouracil plus 
cisplatin (Arm B) to fluorouracil and cisplatin combination (Arm C) as assessed by a BICR in all randomized 
subjects.
• To compare the objective response rate (ORR) of nivolumab plus ipilimumab (Arm A) and nivolumab combined 
with fluorouracil plus cisplatin (Arm B) to fluorouracil and cisplatin combination (Arm C) as assessed by a BICR
in subjects with PD-L1 expression ≥1%.
• To compare the ORR of nivolumab plus ipilimumab (Arm A) and nivolumab combined with fluorouracil plus 
cisplatin (Arm B) to fluorouracil and cisplatin combination (Arm C) as assessed by a BICR in all randomized 
subjects.
Exploratory Objectives 
Exploratory objectives are listed in Section 1.3.3 of the protocol
Study  Design: This  
is  a  
randomized  Phase  3  study  of  nivolumab  plus ipilimumab  or  nivolumab  combined  with 
fluorouracil plus cisplatin compared with fluorouracil in combination with cisplatin in adult (≥18 years) male and 
female subjects with unresectable, advanced, recurrent or metastatic, previously untreated ESCC. The total number of 
subjects to be randomized is approximately 939 subjects.
After signing the informed consent form, and upon confirmation of the subject’s eligibility, subjects with unresectable,
advanced,  recurrent  or  metastatic  ESCC  will  be  randomized  in  a 1:1:1  ratio  
to  one  of  the  following  open-label 
treatments (Arms A, B and C):
• Arm  A:  Subjects  will  
receive  
treatment  with  nivolumab  3  mg/kg as  a  30-minute  
infusion  every  2  weeks  and 
ipilimumab 1 mg/kg as a 30-minute infusion every 6 weeks.
• Arm B: Subjects will receive treatment with nivolumab 240 mg as a 30-minute infusion on Day 1 and Day 15, 
fluorouracil 800 mg/m²/day as an IV continuous infusion from Day 1 through Day 5 (for 5 days), and cisplatin 
80 mg/m² as a 30- to 120-minute infusion* on day 1 of each 4-week cycle.
• Arm C: Subjects will receive treatment with fluorouracil 800 mg/m²/day as an IV continuous infusion on Day 1 
through Day 5 (for 5 days), and cisplatin 80 mg/m² as a 30- to 120-minute infusion* on day 1 of each 4-week 
cycle.
*Subjects are allowed to receive treatment with cisplatin 80 mg/m² as an IV infusion over a period of longer than 120 
min if it is in accordance with local standard of care/local label.
Stratification factors:
1.  PD-L1 status (≥1% vs < 1% [including indeterminate])*
2.  Region (East Asia (Japan, Korea, Taiwan) vs Rest of Asia vs Rest of world)
3.  Eastern Cooperative Oncology Group (ECOG) performance status (0 vs 1).
4.  Number of organs with metastases (≤1 vs. ≥2)
*The proportions of subjects with or without PD-L1 tumor expression will be monitored and reassessed as needed to 
ensure that the sample size of randomized subjects with PD-L1 tumor expression ≥1% is adequate for analysis (ie, 
approximately 50% of all comers).
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Study Population: Subjects must meet all eligibility criteria specified in Section 3.3 of the protocol. The key inclusion 
and exclusion criteria are as follows.
Key Inclusion Criteria:
a) Subjects  must  have  histologically  confirmed  squamous  cell  carcinoma  or  adenosquamous  cell  carcinoma 
(predominant squamous differentiation) of esophagus (per AJCC 7th edition, see Appendix 4). 
b) Subjects  must  have  unresectable advanced,  recurrent  or  metastatic  ESCC  (per AJCC  7th  edition, see 
Appendix 4).
c) Subjects must not be amenable to curative approaches such as definitive chemoradiation and/or surgery
d) No prior systemic anticancer therapy given as primary therapy for advanced or metastatic disease.
i .Prior  adjuvant,  neoadjuvant,  or  definitive,  chemotherapy/radiotherapy/chemoradiotherapy for  ESCC is 
permitted  
if  given as  part  of  curative  
intent regimen  and  completed before  enrollment. A  
recurrence-free 
period  is  required  for  24  weeks  after  completion  of  neoadjuvant  or  adjuvant  chemotherapies,  or  after 
completion of multimodal therapies (chemotherapies and chemoradiotherapies) for locally advanced diseases 
e) ECOG Performance Status of 0 or 1, see Appendix 3
f) Subjects must have at least one measurable lesion by CT or MRI per RECIST 1.1 criteria; radiographic tumor 
assessment must be performed within 28 days prior to randomization. 
g) Tumor tissue must be provided for biomarker analyses. Either 1 formalin fixed paraffin embedded (FFPE) 
tumor tissue block or 15 unstained tumor tissue slides, with an associated pathology report if available, must 
be submitted for biomarker evaluation prior to study drug administration. The tumor tissue sample may
 be 
fresh or archival if obtained within 6 months prior to randomization, and there can have been no systemic 
therapy
 (eg, adjuvant) given after the sample was obtained. Tissue must be a core needle biopsy
, excisional 
or incisional biopsy. Fine needle biopsies or drainage of pleural effusions with cytospins are not considered 
adequate for biomarker review and randomization. Biopsies of  bone lesions that do not have a soft tissue 
component or decalcified bone tumor samples are also not acceptable. 
h) In order to be randomized, a subject must have an evaluable PD-L1 expression classification ≥ 1% or < 1%, 
or indeterminate) as determined by the central lab.
a. Subjects with non-evaluable results will not be allowed to be randomized.
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Key Exclusion Criteria:
a) Subjects must have recovered from the effects of major surgery or significant traumatic injury at least 14 days 
before randomization. 
b) Prior malignancy requiring active treatment 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.
c) Subjects  with  active,  known,  or  suspected  autoimmune  disease.  Subjects  with  Type I  diabetes  mellitus, 
residual hypothyroidism due to autoimmune thyroiditis only requiring hormone replacement, skin disorders 
(such as vitiligo, psoriasis, or alopecia) not requiring systemic treatment are permitted to enroll. For any cases 
of  uncertainty,  it  
is  recommended  that  a  BMS  medical  monitor  be  consulted  prior  
to  signing  informed 
consent.
d) Subjects with a condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone 
equivalent) or other immunosuppressive medications within 14 days of start of study treatment. Inhaled or 
topical steroids, and adrenal replacement steroid doses > 10 mg daily prednisone equivalent, are permitted in 
the absence of active autoimmune disease.
e) 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.
Study Drug: includes both Investigational [Medicinal] Products (IP/IMP) and Non-investigational [Medicinal] 
Products (Non-IP/Non-IMP) as listed:
Study Drug for CA209648
Medication 
Potency 
IP/Non-IP 
Nivolumab
10 mg/mL
IP
Ipilimumab
5 mg/mL
IP
Fluorouracil
1 g/vial (50 mg/ mL)
IP
Cisplatin
100 mg (1 mg/mL)
IP
Study Assessments: Subjects will be assessed for response by CT or MRI. Radiologic assessments will be performed 
at baseline (within 28 days prior to randomization), then every 6 weeks (± 7 days) up to and including Week 48, and 
then every 12 weeks (± 7 days) thereafter, regardless of treatment schedule, until disease progression (unless treatment 
beyond  progression  is  permitted)  or  the  subject  discontinues  the  study,  whichever  comes  first.  Subjects  who 
discontinue study drug for reasons other than PD and who continue in the follow-up phase of the study will continue 
to have tumor assessments as indicated above. All radiologic images from the study  will be submitted to a central 
imaging core lab for analysis by a BICR. The BICR will review tumor images in all randomized subjects to determine 
RECIST 1.1 response for the analyses of PFS and ORR.
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Statistical Considerations:
Sample size: The sample size is based on the primary objectives, ie, on the comparisons of the PFS/OS distributions 
of subjects with PD-L1 expressing tumors between those who were randomized to receive nivolumab plus ipilimumab 
vs those randomized to receive chemotherapy, and between those who were randomized to receive nivolumab plus 
chemotherapy vs those randomized to receive chemotherapy. 
Sample  size  calculations  assume  that  the  prevalence  of  subjects  with  PD-L1  tumor  expression  level ≥1%  is 
approximately 50%. (During enrollment, the proportion of subjects with or without PD-L1 tumor expression will be 
monitored, and may be re-assessed in case it does not reflect study assumptions.)
Piecewise mixture cure rate model was used for the design setup, assuming for both experimental arms the same OS 
distributions and the same PFS distributions. As a result, for each of the nivolumab plus ipilimumab vs chemotherapy 
and nivolumab plus chemotherapy vs chemotherapy comparisons:
• 250 PFS events in approximately 313 subjects with PD-L1 expressing tumors will provide approximately 90% 
power to detect an average HR of 0.62 with a Type I error of 1.5% (two-sided)
• 250 OS events in approximately 313 subjects with PD-L1 expressing tumors will provide approximately 90% 
power to detect an average HR of 0.6 with a Type I error of 1% (two-sided).
To have approximately 313 randomized subjects with PD-L1 expressing tumors for each comparison, approximately 
470 subjects with PD-L1 expressing tumors need to be randomized in a 1:1:1 ratio in the 3 arms. Which therefore 
translates to a total of approximately 939 subjects (with any PD-L1 result) to be randomized in a 1:1:1 ratio to the 
nivolumab plus ipilimumab or nivolumab plus chemotherapy or chemotherapy arms. Assuming a piecewise constant 
accrual rate, it is estimated that these 939 subjects will be accrued within 29 months.
Although for the comparison of both experimental arms with the control arm, the same treatment effect is assumed, 
observed treatment effects may vary. Therefore, the events of interest (OS, PFS) observed in the chemotherapy arm 
onlywill be used for determining the timing of the interim and final efficacy analyses. Final PFS analysis is planned 
when 136 PFS events per BICR are observed among the PD-L1 expressing subjects in the chemotherapy arm. This is 
expected to be reached after approximately 33 months. If the planned number of PFS events is unlikely to be reached 
for any unforeseen reasons, the final PFS analysis may occur when at least 12 months minimum follow-up (defined 
as the time  
from the date  when  
the  
last  patient  was randomized to the  clinical  cutoff  date)  
is reached.  Should  
this 
scenario occur, corresponding to PFS events of 110 and 121, the power would be 80% and 85%, respectively (details 
of this scenario are discussed in Appendix 7 of the SAP). Final OS analysis is planned when 140 events are observed 
among the PD-L1 expressing subjects in the chemotherapy arm. This is expected to be reached after approximately 
49 months. 
Simulations were conducted in R-v3.1.3.
Endpoints:
Primary Endpoint
Overall  survival  
(OS)  
in  subjects  with  PD-L1  expressing  
tumors.  OS  
is  defined  as  
the  
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. 
Progression-free Survival (PFS) (as assessed by BICR) in subjects with PD-L1 expressing tumors. PFS is defined as 
the time from randomization to the date of the first documented PD per BICR or death due to any cause. Subjects who 
die without a reported prior PD per BICR (and die without start of subsequent therapy) will be considered to have 
progressed on the date of death. Subjects who did not have documented PD per BICR per RECIST1.1 criteria and 
who did not die, will be censored at the date of the last evaluable tumor assessment on or prior to initiation of the 
subsequent anti-cancer therapy
. Subjects who did not have any on-study tumor assessments and did not die (or died 
after initiation of the subsequent anti-cancer therapy) will be censored at the randomization date. Subjects who started 
any subsequent anti-cancer therapy without a prior reported PD per BICR will be censored at the last tumor assessment 
on or prior to initiation of the subsequent anti-cancer therapy. 
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Secondary Endpoints
Overall  survival  
(OS)  
in  All Randomized  subjects.  OS  
is  defined  
the  same  way  as  
for  
the  primary  endpoint  
(for 
subjects with PD-L1 expressing tumors). 
Progression-free Survival (PFS) (as assessed by BICR) in All Randomized subjects. PFS is defined the same way as 
for the primary endpoint (for subjects with PD-L1 expressing tumors). 
Objective  Response  Rate  (ORR)  (as  assessed  by  BICR)  in  subjects  with  PD-L1  expressing  tumors  and  All 
Randomized subjects. It is defined as the number of subjects with a best overall response (BOR) of CR or PR divided 
by the number of randomized subjects in the population for each treatment group. BOR is defined as the best response 
designation  as  determined  by  BICR,  recorded  between  the  date  of  randomization  and  the  date  of  objectively 
documented  progression  
(per  RECIST  1.1  as  determined  by  BICR)  or  
the  date  of  subsequent  anti-cancer  
therapy 
(including  
tumor-directed  
radiotherapy  and  
tumor-directed  surgery),  whichever  occurs first.  For  subjects  without 
documented progression or subsequent anti-cancer therapy, all available response designations will contribute to the 
BOR determination.
Analyses:
Primary Endpoint
Progression free survival in subjects with PD-L1 expressing tumors will be compared 
• between nivolumab plus ipilimumab vs chemotherapy using a two-sided log rank test and an endpoint-specific
(i.e. initially allocated) significance level of 1.5%; and
• between nivolumab plus chemotherapy vs chemotherapy using a two-sided log rank test and an endpoint-specific
significance level of 1.5%. 
Overall survival in subjects with PD-L1 expressing tumors will be compared 
• between nivolumab plus ipilimumab vs chemotherapy using a two-sided log rank test and an endpoint-specific
overall significance level of 1% defined for the groups sequential testing procedure; 
• between nivolumab plus chemotherapy vs chemotherapy using a two-sided log rank test and an endpoint-specific
overall significance level of 1% defined for the groups sequential testing procedure. 
All tests will be stratified by region (East Asia [Japan, Korea, Taiwan] vs Rest of Asia vs RoW), ECOG status (0 vs 1), 
and number of organs with metastases (≤1 vs ≥2) as recorded in the IRT. Endpoint-specific significance levels are 
split based on the conservative Bonferroni method and may be updated through graphical approach where the family-
wise error rate will be protected in the strong sense. Rules for updating endpoint-specific significance levels following 
the Bonferroni-based graphical approach by Maurer and Bretz (2013) will be detailed in the statistical analysis plan 
(SAP).
For each comparison, the HR with its associated two-sided 100*(1 - adjusted α)% confidence intervals (CI) will be 
estimated via a stratified Cox model with treatment arm as the only covariate in the model. Both PFS and OS for each 
treatment arm will be estimated and plotted using the Kaplan-Meier (KM) product-limit method. Median survival time 
along with 95% CI will be constructed based on a log-log transformed CI for the survival function.
Secondary Endpoints
Time-to-event endpoints (OS and PFS as assessed by BICR in all randomized subjects) will be estimated and plotted 
using  the  KM  product-limit  method  for  each  treatment  arm.  Median  survival  time  along  with  95%  CI  will  be 
constructed based on a log-log transformed CI for the survival function. The HR with its associated two-sided 95% 
CI will be estimated via a stratified Cox model with treatment arm as the only covariate in the model. 
Overall Survival and PFS in all randomized subjects will be tested only if significance level is passed on them. Rules 
for passing on significance levels will be defined together with the graphical approach in the SAP. Comparisons will 
use a two-sided log rank test, stratified by the same stratification factors as the primary endpoint and by PD-L1 status 
(≥1% vs < 1% [including indeterminate]) as recorded in IRT. 
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Clinical Protocol
CA209648
BMS-936558
nivolumab
ORR  as assessed  by  BICR  and  by  
investigator  
in  subjects  with  PD-L1  expressing  
tumors  and in  all  
randomized 
subjects will be computed in each treatment group along with the exact 95% CI using Clopper-Pearson method. An 
estimate of the difference in ORRs, and corresponding 95% CI will be calculated using Cochran-Mantel-Haenszel 
(CMH)  methodology  and  adjusted  by  the  randomization  stratification  factors.  The  stratified  odds  ratios 
(Mantel-Haenszel estimator) between the treatments will be provided along with the 95% CI. 
ORR as assessed by BICR in subjects with PD-L1 expressing tumors and in all randomized subjects will be tested 
only if significance level is passed on them. Rules for passing on significance levels will be defined together with the 
graphical approach in the SAP. Comparisons will use a two-sided CMH test.
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1.1.1 Disease Background 
................................................................................ 
1.1.1.1 Unresectable Advanced, Recurrent or Metastatic Esophageal 
Cancer
 ...................................................................................................
 
1.1.1.2 The First Line Treatment in ESCC 
................................................. 
1.1.2 Rationale for the Blockade of PD-1/PD-L1 in ESCC 
.............................. 
1.1.3 Previous Studies of Nivolumab in Esophageal Cancer 
........................... 
1.1.4 Rationale for Nivolumab plus Ipilimumab in First-line ESCC Subjects . 
1.1.5 Rationale for Nivolumab plus Fluorouracil and Cisplatin Combination in 
First-line ESCC Subjects 
............................................................................ 
1.1.5.1 Rationale for Fluorouracil (800 mg/m2/day on Days 1 - 5) plus 
Cisplatin (80 mg/m2 on Day 1) Every 4 Weeks Regimen as First-line 
Standard Chemotherapy 
....................................................................... 
1.1.6 Rationale for Dose Selection of Nivolumab in Combination with 
Ipilimumab (Arm A) and Chemotherapy (Arm B) in First-line ESCC 
Subjects
 .......................................................................................................
 
1.1.7 Rationale for Shorter Infusion Times for Nivolumab and Ipilimumab 
.... 
1.1.8 Rationale for Including Subjects with PD-L1 and Non PD-L1 Expressing 
Tumors and Stratification by PD-L1 Expression 
........................................ 
1.1.9 Rationale for Two-Year Duration of Treatment 
...................................... 
1.3.1 Primary Objectives 
.................................................................................. 
1.3.2 Secondary Objectives 
............................................................................... 
1.3.3 Exploratory Objectives 
............................................................................ 
1.4.1 Mechanism of Action 
................................................................................ 
1.4.1.1 Nivolumab Mechanism of Action 
.................................................... 
1.4.1.2 Ipilimumab Mechanism of Action 
................................................... 
1.4.1.3 Nivolumab-plus-Ipilimumab Mechanism of Action 
........................ 
1.4.2 Summary of Clinical Pharmacology 
........................................................ 
1.4.2.1 Nivolumab 
....................................................................................... 
1.4.2.2 Ipilimumab 
...................................................................................... 
1.4.3 Safety Summary 
........................................................................................ 
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3.1.1 Screening Phase 
....................................................................................... 
3.1.2 Treatment Phase 
...................................................................................... 
3.1.2.1 Nivolumab plus Ipilimumab (Arm A) 
.............................................. 
3.1.2.2 Nivolumab Combined with Fluorouracil plus Cisplatin (Arm B) 
... 
3.1.2.3 Fluorouracil and Cisplatin Combination (Arm C) 
......................... 
3.1.3 Follow-up Phase 
...................................................................................... 
3.3.1 Inclusion Criteria 
..................................................................................... 
3.3.2 Exclusion Criteria 
.................................................................................... 
3.3.3 Women of Childbearing Potential ........................................................... 
3.4.1 Prohibited and/or Restricted Treatments................................................. 
3.4.2 Other Restrictions and Precautions 
......................................................... 
3.4.3 Permitted Therapy ................................................................................... 
3.6.1 Withdrawal of Consent ............................................................................ 
3.6.2 Lost to Follow-Up 
.................................................................................... 
4.5.1 Dosing 
...................................................................................................... 
4.5.1.1 Nivolumab plus Ipilimumab Dosing (Arm A) 
................................. 
4.5.1.2 Nivolumab Combined with Fluorouracil plus Cisplatin Dosing 
(Arm B).................................................................................................. 
4.5.1.3 Fluorouracil plus Cisplatin Dosing (Arm C) 
.................................. 
4.5.2 Dose Delay Criteria 
................................................................................. 
4.5.2.1 Dose Delay Criteria for Nivolumab and/or Ipilimumab (Arms A and 
B)
 ...........................................................................................................
 
4.5.2.2 Dose Delay Criteria for Fluorouracil and Cisplatin Combination 
(Arm C) 
................................................................................................. 
4.5.2.3 Dose Delay Criteria for Nivolumab Combined with Fluorouracil 
plus Cisplatin Platinum in Arm B 
......................................................... 
4.5.3 Dose Reductions....................................................................................... 
4.5.3.1 Dose Reductions for Nivolumab or Ipilimumab 
............................. 
4.5.3.2 Dose Reductions for Fluorouracil and Cisplatin combination....... 
4.5.4 Criteria to Resume Dosing....................................................................... 
4.5.4.1 Criteria to Resume Nivolumab or Ipilimumab (Arms A and B) 
...... 
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4.5.4.2 Criteria to Resume Fluorouracil and Cisplatin Combination (Arm 
C)........................................................................................................... 
4.5.4.3 Criteria to Resume Nivolumab Combined with Fluorouracil and 
Cisplatin (Arm B) 
.................................................................................. 
4.5.5 Treatment Discontinuation Criteria ........................................................ 
4.5.5.1 Nivolumab and/or Ipilimumab Treatment Discontinuation (Arms A 
and B) 
.................................................................................................... 
4.5.5.2 Fluorouracil and Cisplatin Dose Discontinuation (Arms B and C)
............................................................................................................... 
4.5.6 Treatment Beyond Disease Progression 
.................................................. 
4.5.7 Management Algorithms for Immuno-oncology Agents 
.......................... 
4.5.8 Treatment of Nivolumab or Ipilimumab Related Infusion Reactions 
...... 
5.1.1 Retesting During Screening 
..................................................................... 
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............................................................ 
5.6.1 Tumor Samples......................................................................................... 
5.6.1.1 Tumor Sample Collection Details 
................................................... 
5.6.1.2 Characterization of Tumor Infiltrating Lymphocytes (TILs) and 
Tumor Antigens 
..................................................................................... 
5.6.1.3 Characterization of T cell Repertoire 
............................................. 
5.6.1.4 Gene Expression Profiling 
.............................................................. 
5.6.1.5 Tumor Genotyping, Mutational Analysis, and Tumor Antigen 
Profiling
 ................................................................................................
 
5.6.1.6 Microsatellite instability status 
....................................................... 
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 Plasma for circulating tumor DNA 
................................................. 
5.6.2.6 Stool for microbiome....................................................................... 
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6.1.1 Serious Adverse Event Collection and Reporting 
.................................... 
6.2.1 Nonserious Adverse Event Collection and Reporting 
.............................. 
6.7.1 Adverse Events of Interest 
........................................................................ 
8.3.1 Primary Endpoint..................................................................................... 
8.3.2 Secondary Endpoint(s) 
............................................................................. 
8.3.3 Exploratory Endpoint(s) 
.......................................................................... 
8.4.1 Demographics and Baseline Characteristics........................................... 
8.4.2 Efficacy Analyses 
..................................................................................... 
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 
......................................................................................... 
9.1.1 Compliance with the Protocol and Protocol Revisions 
........................... 
9.1.2 Monitoring 
............................................................................................... 
9.1.2.1 Source Documentation 
.................................................................... 
9.2.1 Records Retention 
.................................................................................... 
9.2.2 Study Drug Records 
................................................................................. 
9.2.3 Case Report Forms 
.................................................................................. 
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CA209648
BMS-936558
nivolumab
1 
INTRODUCTION AND STUDY RATIONALE
Esophageal cancer (EC) is a worldwide health problem. EC is the 8th most common cancer and 
the 6th leading cause of cancer death worldwide.
1The 5-year survival for patients with esophageal 
cancer improved only modestly over the last 50 years to 17% during the period 1996 to 2003.
2,3
The majority of EC patients require palliative treatment at some point in the course of their disease. 
Cytotoxic  chemotherapy  can  provide  symptom  palliation,  
improve  quality  of  
life,  and prolong 
survival  in  patients  with  advanced  EC. In  
the  current  EC  standard  
treatments,  platinum-based 
combination  chemotherapy  regimens  provide  higher  response  rates  than  do  single  agents. 
However, this translates into only modestly longer duration of disease control and survival and the 
therapeutic efficacy of platinum-based chemotherapy has reached a plateau. Therefore, new, more 
effective therapies are urgently needed.
Cancer immunotherapy such as a checkpoint inhibitor has recently demonstrated clinical activities 
and  survival  benefits  as  a  monotherapy  and  in  combination  with other  immunotherapies  or 
conventional  chemotherapies  in  multiple cancer types.  Nivolumab  (Opdivo®) monotherapy  or 
nivolumab  combined  with  ipilimumab  (Yervoy®)  has  been  approved  in  multiple  countries 
including the US for treatment of metastatic melanoma, non-small cell lung cancer (NSCLC), and 
advanced renal cell carcinoma (RCC). Nivolumab combined with platinum-doublet chemotherapy 
is under investigation in a Phase 3 NSCLC trial. 
CA209648 is a randomized, global Phase 3 study of nivolumab plus ipilimumab or nivolumab in 
combination with fluorouracil plus cisplatin versus fluorouracil and cisplatin chemotherapy as first 
line-therapy  in  unresectable, advanced,  recurrent  or  metastatic esophageal  squamous  cell 
carcinoma  (ESCC).  This  study  will  determine  if  nivolumab  plus ipilimumab  and  nivolumab 
combined with fluorouracil plus cisplatin improve overall survival (OS) and/or progression free 
survival  (PFS) over fluorouracil  and  cisplatin  standard  of  care  chemotherapy  in  subjects  with 
ESCC whose tumors express PD-L1. Additional objectives include further characterization of the 
efficacy,  adverse event  profile, pharmacokinetics,  patient  reported  outcomes  and  potential 
predictive biomarkers of nivolumab in combination with ipilimumab or nivolumab in combination 
with fluorouracil and cisplatin in subjects with ESCC.
1.1 
Study Rationale
1.1.1 
Disease Background
1.1.1.1 
Unresectable Advanced, Recurrent or Metastatic Esophageal Cancer
Although  the principal histologic  types  of  esophageal  cancer  are ESCC  and  esophageal 
adenocarcinoma  (EAC),  ESCC  is  the  predominant  histologic  type  of  esophageal cancer 
worldwide. 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 carcinoma to adenocarcinoma.4This has been 
attributed to a decline in smoking and an increase in adenocarcinoma risk factors including obesity, 
GERD and Barrett’s esophagus. In contrast, the incidence of ESCC is increasing in Asian countries 
probably due to increased tobacco and alcohol consumption.5
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nivolumab
Approximately  50%  of  esophageal  cancers  will  be  localized  or  loco-regionally  advanced  at 
diagnosis and thus amenable to potentially curative loco-regional 
treatment. However, the majority 
of patients with esophageal cancer will require palliative treatment at some point in the course of 
their disease. Unresectable advanced, recurrent or metastatic ECis  not a curable condition, and 
thus  requires  
treatment with  systemic  cytotoxic  chemotherapy for palliation  of  symptoms  and 
prolongation  of  survival. Five-year  survival  rates  for all  patients  with  esophageal  cancer have 
shown modest improvements over the past 35 years from 5% in 1975 to approximately 20% for 
patients diagnosed in 2004.6The prognosis of patients with metastatic EC is poor with a 5-year 
survival rate of 4%.
7
Because of the histological and anatomical distribution, the majority of clinical trials conducted 
since the mid-1990s have included gastric, esophageal, and GEJ cancer, regardless of histology.8,9
However, squamous cell carcinoma (SCC) and adenocarcinoma are now being considered separate 
diseases  as  differences  in  genomic  alternations  in  biologic  pathways  between  SCC  and 
adenocarcinoma  are  beginning  to  be  elucidated.10,11Worldwide  platinum-based  combination 
chemotherapy is the most commonly used regimen to treat recurrent or metastatic EC. However, 
adding  another  cytotoxic  agent  
to  platinum  has  not  dramatically  
improved  clinical  activity  and 
survival  over  
the  past  few  decades.  Therefore,  more  effective  new  
therapies  using  a histology 
specific approach are urgently required.
1.1.1.2 
The First Line Treatment in ESCC
Despite a large number of randomized trials, there is no consensus as to the best regimen for initial 
chemotherapy of advanced esophageal cancer and notably there is almost complete lack of recent 
randomized  control  trial  data  in this  disease  setting  for  ESCC. The  majority  of  clinical  trials 
conducted since the  mid-1990s  
in gastric, esophageal, and GEJ cancer, regardless of  histology;
current  NCCN guidelines,12ESMO  guidelines,13and  Japan  Esophageal  Cancer  guidelines
recommend  platinum-based  chemotherapy  regimens  as  first  line  treatment  in  unresectable 
advanced, recurrent or metastatic ESCC and EAC.
In  general,  combination  chemotherapy  regimens  provide  higher  response  rates  
than  do  single 
agents,  and  
two-drug  cytotoxic  regimens  are  preferred  because  of  lower  
toxicity  compared  
to 
three-drug cytotoxic regimens.
12The combination of cisplatin and 5-fluorouracil (5-FU) is one of 
the most commonly used regimens due to its activity and well-established toxicity profile and has 
been  approved  worldwide  by  health  authorities  for  the  first  line  treatment  of  ESCC.  Yet  the 
response rates with this combination are still not regarded as sufficient (15% - 45%) and median 
survival is less than 10.4 months.14,15,16,17
Oxaliplatin based  regimens  are  also  commonly  used  mainly  in  
the US  and  EU. Oxaliplatin  is 
considered less toxic compared to cisplatin, therefore oxaliplatin regimens tend to be used in older 
patients  or  those with  poor  performance  status.  However,  oxaliplatin  is  not  approved  for 
esophageal cancer treatment  
in some Asian countries  
including Japan. In randomized trials, the 
ECF (epirubicin, cisplatin, 5-FU) and DCF (docetaxel, cisplatin, 5-FU) combinations  have also 
evolved as potential first-line treatment options in medically fit patients. Largely based upon the 
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nivolumab
results of the REAL2 trial, epirubicin, oxaliplatin, and capecitabine (EOX) could also be used as
first-line regimen for patients who are able to tolerate combination chemotherapy. 
The outcome for patients with unresectable advanced, recurrent or metastatic esophageal cancer 
has  not  improved  over  a couple  of  decades  as  the  therapeutic  efficacy  of  platinum-based 
chemotherapy has reached a plateau. Thus, there is a high unmetmedical need for more effective 
new therapies in first line EC patients.
1.1.2 
Rationale for the Blockade of PD-1/PD-L1 in ESCC
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).18Binding of PD-1 to PD-L1 and PD-L2 has 
been  shown  
to  down-regulate  T-cell  activation  
in  both  murine  and  human  systems,  
leading  
to
suppression of immune surveillance and permission of neoplastic growth.
19,20,21,22
PD-L1  or PD-L2  expressing  
tumor  was  
reported in  44 - 54% of  ESCC  patients.23,24It  has also
been demonstrated that PD-L1 expression is associated with worse OS outcomes hence supporting 
the rationale that PD-L1 blockade might improve survival in ESCC.
24
Anti PD-L1 inhibitors have been investigated in EC treatment demonstrating anti-tumor activity.
In KEYNOTE-028, pembrolizumab monotherapy demonstrated promising antitumor activity and 
manageable safety profile  
in  heavily treated EC patients with PD-L1≥1% (N = 23). The ORR 
was  30.4%,  and  the  stable  disease  rate  was  13.0%  with a  median duration  of  response  of 
40.0 weeks. Six-month and 12-month PFS rates were 30.4% and 21.7%, respectively. The ORR 
in ESCC (N = 17) was 29.4%.
25
ONO-4538-07  demonstrated that  nivolumab  monotherapy  
in  Japanese patients with ESCC was 
effective in a patient population refractory or intolerant to standard treatments (median number of
prior regimens was 3). The ORR by Central Review was 17.2% and the responses were durable. 
Nivolumab  had  a  tolerable  safety  profile  in  pre-treated  ESCC patients  and  there  were  no 
treatment-related deaths.
26
These promising data support further investigation of the use of immunotherapy in the treatment 
of ESCC.
1.1.3 
Previous Studies of Nivolumab in Esophageal Cancer
ONO-4538-07, a Phase 2, multi-center, open-label, single-arm study of nivolumab monotherapy 
3 mg/kg IV every 2 weeks (Q2W) was conducted in subjects with esophageal cancer refractory or 
intolerant to standard therapies. The primary endpoint was ORR (immune-related response criteria
(IRRC) assessed  according  
to  
response  evaluation  criteria  
in  solid  
tumors  RECIST  1.1).  Other 
secondary endpoints were ORR (investigator’s assessment), OS, PFS, DCR, time to progression 
(TTP),  
time  
to  
response  (TTR),  best  overall  response  (BOR),  
immune-related  ORR  (ir-ORR), 
ir-PFS, ir-DCR, duration of response (DOR), percent change from baseline in the sum of tumor 
diameters, and response of the primary esophageal lesion. The data included in this document is 
as of 17-May-2015; OS data as of 17-Nov-2015. This trial is being conducted at investigational 
sites in Japan. 
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BMS-936558
nivolumab
A total of 65 subjects were enrolled and treated with nivolumab monotherapy. The  median age 
was  62 years and  around  70%  of  
the  subjects  had  3  or  more  prior  
treatment  
regimens  such  as 
fluoropyrimidine, platinum, and taxanes (docetaxel or paclitaxel). Histological tumor type in all 
the subjects was squamous cell carcinoma. 54% of patients (21/37) expressed PD-L1 above the 
expression level of 1%. 
Preliminary safety data demonstrated that the majority of subjects (84.6%) experienced an AE but 
most were Grade 1/2. Grade 3/4 AEs/SAEs occurred in 19% of patients and included: diarrhea, 
dysphagia,  
fatigue,  
liver  function  abnormal,  
lung  
infection,  pneumonia  and  decreased  appetite. 
The  most  frequent  drug-related  SAEs  were  lung  infection  (3.1%),  dehydration  (3.1%)  and 
interstitial  lung  disease  (3.1%).  Most  of  the  AEs  were  manageable  and  there  were  no 
treatment-related  deaths  reported during  the  study. Additional  details  are  provided  in  the 
investigator brochure.
Preliminary  data of  clinical activity  are  summarized  
inTable  1.1.3-1. Nivolumab demonstrates 
single-agent  activity  in  subjects  with  esophageal  cancer  (N = 64).  Ten subjects had  a  partial 
response,  1 had  a  complete  response,  and  16 had  stable  disease  under  central  review 
(Table 1.1.3-1). The ORR by central review was 17.2% and the mDORwas durable. The  mOS
was  10.78 months  
(95% CI:  7.39,  13.34)  and themedian  PFSwas  1.51months (95%  CI:1.41, 
2.83) in 64 evaluable subjects.
23
Table 1.1.3-1: 
Summary of Clinical Activity - ONO-4538-07
BOR/ORR
Investigator
Central Review
Response
N
% (95% CI)
N
% (95% CI)
Complete Response (CR)
2
3.1 (0.9, 10.7) 
1
1.6 (0.3, 8.3)
Partial Response (PR)
12 
18.8 (11.1, 30.0) 
10  
15.6 (8.7, 26.4)
Stable Disease (SD)
20 
31.3 (21.2, 43.4) 
16 
25.0 (16.0, 36.8)
Progressive Disease (PD)
29
45.3
29
45.3
NE
1
1.6
8
12.5
ORR (CR+PR)
14
21.9 (13.5, 33.4) 
11 
17.2 (9.9, 28.2)
Source: Preliminary data from Study ONO-4538-07, as of 17-May-2015.
1.1.4 
Rationale for Nivolumab plus Ipilimumab in First-line ESCC Subjects
The  combination  of  nivolumab  and  ipilimumab  was  evaluated  in  CA209004  (MDX1106-04), 
a Phase 1b multiple ascending dose study in subjects with treatment-naive and previously treated
advanced  melanoma. Results showed promising activity with  higher, but tolerable toxicity than
ipilimumab alone.
27Based on these data, CA209069, a Phase 2 study, compared the combination
to  ipilimumab  alone  in  treatment-naïve  patients  with advanced melanoma: nivolumab 
1 mg/kg + ipilimumab 3 mg/kg every 3 weeks x4 followed by nivolumab 3 mg/kg every 2 weeks 
versus ipilimumab 3 mg/kg every 3 weeks x 4.28
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BMS-936558
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In  patients  with  BRAF  wild  type  tumors,  
the  ORR  was 61%  (44/72),  including  22%  (16/72) 
complete responses (CR) in the group treated with the combination, compared to 11% (4/37) with 
0 CRs in those treated with ipilimumab alone. The median PFS was not reached in the combination 
versus 4.4  months  
for  
ipilimumab alone (HR = 0.4). It should  be  noted that in the combination 
group,  
the  ORR  was  independent  of  PD-L1 expression.  In  
this group,  ORR  was  58%  among 
patients with PD-L1 expressing tumors and 55% among those with PD-L1 non-expressing tumors. 
In contrast, in the ipilimumab alone group, the ORR was numerically higher among patients with 
PD-L1  expressing  
tumors  
(18%)  compared  
to those  with  PD-L1  non- expressing  
tumors  
(4%). 
Grade  3 - 4  
treatment-related  AEs  were  
reported in  54%  of  patients  
receiving  
the  combination 
compared to 24% for ipilimumab alone.
Based on the initial data in melanoma, and the activity observed with nivolumab and ipilimumab
in lung cancer, the nivolumab plus ipilimumab combination has been also evaluated as first-line
therapy in patients with advanced NSCLC. In CA209012, early combination cohorts evaluated the 
2 dosing  schedules  that  were  studied  in the  CA209004  Study in  melanoma.  However,  these 
regimens  
resulted  
in  significant toxicity,  with  39% of  patients  discontinuing  
treatment  due to  a 
treatment-related adverse event. Thus, additional combination cohorts were initiated (nivolumab 
1 mg/kg plus ipilimumab 1 mg/kg every 3 weeks for four cycles, nivolumab 1 mg/kg every 2 weeks 
plus ipilimumab 1 mg/kg every 6 weeks, and nivolumab 3 mg/kg every 2 weeks plus ipilimumab 
1 mg/kg every 12 weeks or 6 weeks), using lower doses of both nivolumab and ipilimumab, or the 
approved dose of nivolumab with less frequent dosing of ipilimumab. These regimens were better 
tolerated, although clinical activity was suboptimal when nivolumab was given at the lower dose 
(1 mg/kg). Therefore the regimens which were considered potentially suitable for further clinical 
development were nivolumab 3 mg/kg every 2 weeks plus ipilimumab 1 mg/kg given either every 
12 weeks or every 6 weeks. Each study arm included 15 - 18 % squamous cell carcinoma patients 
and the safety data are not dissimilar to what has been observed in the nivolumab monotherapy 
cohort (Arm F in CA209012). (SeeTable 1.1.4-1).
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Table 1.1.4-1: 
Treatment-related Adverse Events from Selected Cohorts in
CA209012 (1L NSCLC)
Arma
No. 
Subjects/ 
Arm
Follow-up 
time 
(Median, 
months)
No. 
Subjects 
still On-
treatment
No. 
Subjects 
with Drug-
related AEs
No. Subjects 
with Grade 
3 - 4 Drug-
related AEs
No. Subjects d/c due 
to Drug-related AEs 
(All Grades)
Pb
38
12.8 
9 (24%) 
31 (82%) 
14 (37%)
4 (11%)
Qb
39
11.8 
7 (18%) 
28 (72%) 
13 (33%)
5 (13%)
Fc
52
14.2 
5 (10%) 
37 (71%) 
10 (19%)
5 (10%)
a P: nivolumab 3 mg/kg every 2 weeks plus ipilimumab every 12 weeks; Q: nivolumab 3 mg/kg every 2 weeks plus 
ipilimumab 1 mg/kg every 6 weeks; F: nivolumab 3 mg/kg every 2 weeks.
b Based on March 2015 database lock
c Based on Jan 2016 database lock
A numerically  highest response rate was observed with the arm of nivolumab  3  mg/kg Q2W  + 
ipilimumab 1 mg/kg  Q12W (Table  1.1.4-2). It  would  be  expected  that  the  ipilimumab  every 
6-week schedule would be more active in the absence of safety issues, which were not observed
in CA209012. However as these cohorts have small numbers of subjects it is difficult to draw any 
firm  conclusions.29Currently  the  combination  of  nivolumab  3  mg/kg  Q2W  plus  ipilimumab 
1 mg/kg  Q6W  combination  regimen  in  being  further  evaluated  in  the  Phase  3  CA209227  in 
previously untreated advanced NSCLC as the Q6W ipilimumab schedule was chosen to avoid any 
potential loss of efficacy with less frequent dosing.
Table 1.1.4-2: 
Efficacy of First-line Treatment of Nivolumab/Ipilimumab 
Combination in NSCLC
Nivo 3 Q2W + Ipi 1
Q12W (n = 38)
Nivo 3 Q2W+ Ipi 1
Q6W (n = 39)
Confirmed ORR, % (95% CI)
47% (31 - 64)
(38% [23 - 55])
PFS rate at 24 wks (95% CI)
68% (50 - 80)
47% (31 - 62))
mPFS, mos (95% CI)
8.1 (5·6 - 13·6)
3.9 (2·6 - 13·2)
1 year overall survival
NC
69% (52 - 81)
Median length of follow-up, months
12.8
11.8
Based on Ja2016 database lock.
NC = Not calculated (when more than 25% of patients were censored)
Given  the  similarity  of  the  patient  profiles  in  CA209012  with  ESCC  (the  CA209012  study 
population included 15 - 18% squamous cell carcinoma patients), nivolumab at a dose of 3 mg/kg
every 2 weeks plus ipilimumab 1 mg/kg every 6 weeks (ie, a dose and frequency of ipilimumab
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that improves tolerability to the combination with nivolumab) will be evaluated in first-line ESCC
subjects.
1.1.5 
Rationale for Nivolumab plus Fluorouracil and Cisplatin Combination in 
First-line ESCC Subjects
Cancer therapeutics  such  as  chemotherapy  may  modulate tumor/immune-system  
interactions  
in
favor of the immune system. Chemotherapy can result in tumor cell death with a resultant increase 
in tumor antigen delivery to antigen-presenting cells. Tumor cell death may also lead to a reduction 
in soluble and membrane-bound factors inhibiting tumor-infiltrating T-cells. Chemotherapy may 
also disrupt immune system regulatory networks by decreasing numbers of T-regulatory cells.
Nivolumab added to chemotherapy has been evaluated in several cohorts of chemotherapy-naive
subjects with advanced NSCLC (squamous 29% and  non-squamous 71%)  
in Study CA209012. 
Nivolumab  10  mg/kg  was  combined  with gemcitabine  +  cisplatin  and  pemetrexed  +  cisplatin. 
Nivolumab 10 mg/kg, and 5 mg/kg, was combined with paclitaxel and carboplatin.
The safety profile of nivolumab plus platinum-doublet chemotherapy reflects additive toxicities of 
the individual agents, which were manageable using established safety guidelines (Appendix 1). 
95% of patients (53 of 56 patients) and 45% of patients (25 of 56 patients) experienced any grade 
and Grade 3 or 4 treatment-related AEs, respectively.30The most commonly reported (≥30% of 
patients) treatment-related AEs of any grade were fatigue, nausea, decreased appetite, and alopecia 
and the most common (≥5% of patients) treatment-related Grade 3 or 4 AEs were pneumonitis, 
fatigue, and acute renal failure. Treatment-related AEs led to discontinuation of all study therapy 
in 21% of patients (12 of 56 patients). The frequency of most immune-related AEs was higher than 
what  has  been observed  in  nivolumab monotherapy.  However,  these  treatment-related  AEs, 
including pneumonitis, were effectively managed and did not lead to any deaths.
The observed response rates of nivolumab and chemotherapy (Table 1.1.5-1) were similar to that
of platinum-doublet chemotherapy alone, though the duration of responses is longer. The median
duration of response across all the nivolumab + chemotherapy cohorts was 27.3 weeks. The 1-year 
survival rate for all cohorts combined is 71%.
Table 1.1.5-1: 
Efficacy of First-Line Treatment Nivolumab + Chemotherapy in 
NSCLC 
Nivo/Gem/Cis
(n = 12)
Nivo/Pem/Cis
(n = 15)
Nivo/Pac/Carbo
(n = 29)
Nivo/Chemo
(n = 56)
ORR, n (%)
4 (33%)
7 (47%)
13 (45%)
24 (43%)
Median DOR 
(wks)
45
24.4
27.3
27.3
PFS rate at 24 wks
51%
71%
43%
52%
Median PFS (wks)
24.7
29.7
21.4
24.7
OS rate at 12 mos
50%
87%
72%
71%
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Table 1.1.5-1: 
Efficacy of First-Line Treatment Nivolumab + Chemotherapy in 
NSCLC 
Nivo/Gem/Cis
(n = 12)
Nivo/Pem/Cis
(n = 15)
Nivo/Pac/Carbo
(n = 29)
Nivo/Chemo
(n = 56)
OS rate at 18 mos
33%
60%
62%
55%
Median OS (wks)
50.5
83.4
89.6
83.4
Platinum-based doublet chemotherapy is considered standard of care treatment in first-line ESCC 
as  well as  for  NSCLC.  The  combination  of  5-FU + and  cisplatin  is  
the  most  commonly  used 
regimen in the first-line ESCC patients due to its activity and well-established toxicity profile. 
Since platinum-doublet  chemotherapy  +  nivolumab  combination  regimens  were  tested  in  1L 
NSCLC  patients  (in  a  patient  population  which  included  29%  squamous  histology)  and 
demonstrated encouraging clinical activity with acceptable safety profile, the combination of 5-FU 
and  cisplatin  
(a  globally accepted  standard  
therapy  
in first-line  ESCC)  plus  nivolumab  will  be 
evaluated in this trial.
1.1.5.1 
Rationale for Fluorouracil (800 mg/m2/day on Days 1 - 5) plus Cisplatin 
(80 mg/m
2on Day 1) Every 4 Weeks Regimen as First-line Standard 
Chemotherapy
As described  
in Section 1.1.1.2, over the past two decades, the combination of  
fluorouracil and 
cisplatin  (FP)  has  been  commonly  used  as  a  standard  1L  chemotherapy  in  patients  with  both
metastatic and  
localized esophageal cancer. The  FP regimen which  
is currently used  
in clinical 
practice  varies  among  countries.  Current  NCCN  guidelines12 recommends  fluorouracil 
(750 - 1000 mg/m² on Days 1 - 4) plus cisplatin (75 - 100 mg/m² on Day 1) every 4 weeks, and 
Japan Esophageal Cancer Guideline31recommends fluorouracil (700 - 1000 mg/m² on Days 1 - 4 
or 1 - 5) plus cisplatin (70 - 100 mg/m² on Day 1) every 3 or 4 weeks. ESMO guidelines
13do not 
describe any specific dose and schedule of FP regimen to recommend to use as first line treatment 
in locally advanced unresectable and metastatic ESCC. 
At present in Japan, the most commonly used FP regimen is fluorouracil (800 mg/m² on Days 1 - 5) 
plus  cisplatin  (80  mg/m² on  Day  1)  every  4  weeks  based  on  four  Phase  2 studies32,33,34,35
conducted by The Japan Esophageal Oncology Group (JEOG). The same dose and schedule is also 
used in clinical practice in US and Europe due to the similar safety and efficacy outcomes to other 
FP regimens.,36
Therefore,  fluorouracil  (800  mg/m² on  Days  1 - 5)  plus  cisplatin  (80 mg/m² on  Day  1)  every 
4 weeks was selected to be combined with nivolumab 240 mg every 2 weeks (Arm B) and as the 
standard chemotherapy in the control arm (Arm C).
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1.1.6 
Rationale for Dose Selection of Nivolumab in Combination with 
Ipilimumab (Arm A) and Chemotherapy (Arm B) in First-line ESCC 
Subjects
As described in Section 1.1.4, it may be beneficial to administer nivolumab in combination with 
ipilimumab in the treatment of ESCC, as it has demonstrated activity across multiple tumor types, 
including NSCLC  and  melanoma. Nivolumab  3 mg/kg  Q2W  in  combination  with  ipilimumab 
1 mg/kg Q6W was selected for Arm A, as it allows the study of clinical benefit of the addition of 
ipilumumab 1 mg/kg Q6W to nivolumab 3 mg/kg Q2W, which is the dose studied for the treatment 
of  advanced  
line  ESCC  (see Section 1.1.3for  ONO-4538-07 results).  Further,  
this  nivolumab-
ipilimumab  combination  regimen  is  being  tested  in  first-line  NSCLC  subjects  (CA209-227, 
including  Squamous  and  non-Squamous)  due  to  enhanced  tolerability  versus  regimens  using 
ipilimumab Q3W. Finally, weight based dosing is being used in the combination of nivolumab and 
ipilimumab, to be consistent with nivolumab-ipilimumab combination dosing in other tumor types, 
e.g. NSCLC.
Nivolumab 240 mg Q2W in combination with FP chemotherapy was selected for Arm B, as it is 
the  
flat  dose  equivalent  
to  3  mg/kg  Q2W  dosing  
that  has  been  studied  
in  advanced  
line  ESCC 
(ONO-4538-07). Nivolumab 240 mg Q2W was selected based on clinical data and modeling and 
simulation approaches using population pharmacokinetic (PPK) and exposure-response analyses 
of data from studies in multiple tumor types (melanoma, NSCLC, and RCC) where body weight 
normalized dosing (mg/kg) has been used.
PPK analyses have shown that the PK of nivolumab is linear with proportional exposure over a 
dose range of 0.1 to 10 mg/kg, and no differences in PK across ethnicities and solid tumor types 
were  observed.  Nivolumab  clearance  and  volume  of  distribution  were  
found  
to  
increase  as  
the 
body weight increases, but less than proportionally with increasing weight, indicating that mg/kg 
dosing represents an over-adjustment for the effect of body weight on nivolumab PK. Using data 
from  1,544  subjects  from  7  studies  investigating  nivolumab  in  the  treatment of  melanoma, 
NSCLC,  and  RCC,  
the  median  
(minimum - maximum)  weight  was  77  kg  
(35 kg - 160  kg)  and 
thus, an approximately equivalent dose of 3 mg/kg for an 80 kg subject, nivolumab 240 mg Q2W 
was  selected  
for  future  studies. To  predict  
relevant  summary  exposures  of  nivolumab  240  mg 
Q2W,  
the  PPK  model  was  used  
to  simulate  nivolumab  3 mg/kg  Q2W  and  240  mg  Q2W.  The 
simulated  measure  of  exposure  of  interest,  
time-averaged  concentrations  (Cavgss)  for  240 mg 
Q2W are predicted to be similar for all subjects in reference to 80 kg subjects receiving 3 mg/kg 
Q2W. Because  no  differences  
in  PKwere  noted across  ethnicities  and  solid  
tumor types,  
these 
simulated melanoma and NSCLC data will be applicable to subjects with other tumor types. 
It  should  be  noted that  nivolumab  240  mg  Q2W  
is  currently  approved  
in  US  
for  monotherapy 
treatment of NSCLC, RCC, melanoma, UC, HCC, and MSI-H/dMMR CRC and is currently under 
review by other Health Authorities. 
1.1.7 
Rationale for Shorter Infusion Times for Nivolumab and Ipilimumab
Long infusion times place a burden on patients and treatment centers. Establishing that nivolumab 
and ipilimumab can be safely administered using shorter infusion times of 30 minutes’ duration 
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will diminish the burden, provided that there is no change in the safety profile. Previous clinical 
studies  of  nivolumab  and  ipilimumab  monotherapies  and  the  combination  of  nivolumab  and 
ipilimumab  have  used a  60-minute  infusion duration  for  nivolumab  and  a  90-minute  infusion 
duration for ipilimumab (1 - 3 mg/kg dosing for both). However, both nivolumab and ipilimumab 
have been administered at up to 10 mg/kg with the same infusion duration (ie, 60 minutes).
Establishing that nivolumab can be safely administered using a shorter infusion time (30 minutes) 
is under investigation. Previous clinical studies of nivolumab monotherapy have used a 60-minute 
infusion duration  wherein,  nivolumab  has  been  safely  administered  up  
to 10 mg/kg  over  long 
treatment periods. Infusion  
reactions  
including  high-grade  hypersensitivity  
reactions  have  been 
uncommon across nivolumab clinical program. In CA209010, 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 3 mg/kg nivolumab (30% 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. The safety of nivolumab 3 mg/kg administered as a 30-min infusion 
was  assessed  in  CA209153  in  patients  (n = 322)  with  previously  treated  advanced  NSCLC. 
Overall,  there  were  no  clinically  meaningful  differences  in  the  frequency  of 
hypersensitivity/infusion-related  reactions  (of  any  cause  or  treatment-related)  in  patients 
administered nivolumab over a 30-minute infusion compared with that reported for patients with 
the 60-minute infusion. Thus, it was shown that nivolumab can be safely infused over 30 minutes. 
Similarly, ipilimumab at 10 mg/kg has been safely administered over 90 minutes. In subjects with 
advanced Stage II or Stage IV melanoma (CA184022 Study), where ipilimumab was administered 
up to a dose of 10 mg/kg, on-study drug related hypersensitivity events (Grade 1/2) were reported 
in 1 subject (1.4%) in the 0.3 mg/kg and in 2 subjects (2.8%) in the 10 mg/kg group. There were 
no  drug-related  hypersensitivity  events  reported  
in  
the  3  mg/kg  group.  Across  
the  3 treatment 
groups, no Grade 3/4 drug-related hypersensitivity events were reported and there were no reports 
of infusion reactions. Ipilimumab 10 mg/kg monotherapy has also been safely administered as a 
90-minute infusion in a large Phase 3 study in prostate cancer (CA184043) and as adjuvant therapy 
for Stage III melanoma (CA184029), with infusion reactions occurring in subjects. Administering 
3 mg/kg of ipilimumab represents approximately one-third of the 10 mg/kg dose.
Overall, infusion reactions including high-grade hypersensitivity reactions have been uncommon 
across  clinical  studies  of  nivolumab,  ipilimumab,  and  nivolumab/ipilimumab  combinations. 
Furthermore, a 30-minute break after the first infusion for the combination cohort will ensure the 
appropriate safety monitoring before the start of the second infusion. Overall, a change in safety 
profile is not anticipated with 30-minute infusions of nivolumab, ipilimumab or combination.
1.1.8 
Rationale for Including Subjects with PD-L1 and Non PD-L1 Expressing 
Tumors and Stratification by PD-L1 Expression
In ESCC cancer, PD-L1 expression has been suggested as a prognostic marker
24as it is has been 
shown  to  be  associated  with  adverse  survival. In  ONO-4538-07  responses  were  observed 
irrespective of PD-L1 status although numerically higher ORR was  seen  
in  subjects expressing 
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PD-L1 ≥1%  [ORR  23.8  (5/21)]  compared  to  those  with  PD-L1 <1% 12.5%  (2/16). OS  was 
survival  was 11.33  months  in  subjects  with  PD-L1 ≥1%  vs  6.24 months  in  those  with 
PD-L1 < 1%.
23
In  study  CA209012,  56  subjects  with  NSCLC  received  nivolumab  and platinum  based 
chemotherapy.  Activity  was  also  evaluated  by  PD-L1  expression  and  was  observed  
in  subjects 
with both PD-L1 expressing and non-expressing tumors although some enrichment for response 
was seen by PD-L1 status (seeTable 1.1.8-1). At the 1% expression level, the response rate was 
48% and 43% for PD-L1 ≥1% and all comers population respectively, which compared favorably 
to the responses observed with nivolumab monotherapy (28% and 23% for PD-L1 ≥1% and all 
comers,  
respectively).  Similarly,  
for  
the  combination  of  nivolumab  with  
ipilimumab  at  
the  1% 
expression level, the response rate was 57% and 43% for PD-L1 ≥1% and all comers population.
Table 1.1.8-1: 
Efficacy of Nivolumab and Platinum-based Chemotherapy, 
Nivolumab plus Ipilimumab and Nivolumab Monotherapy in 
NSCLC
Nivo + Chemoa
(n = 56)
Nivo + Ipib
(n = 77)
Nivo 3 Q2W
(n = 52)
ORR, % (n/N)
All comers
≥1% PD-L1
43
48 (11/23)
43
57 (26/46)
23
28 (9/32)
mPFS, mo
All comers
≥1% PD-L1
5.7
6
8.0
12.7
3.6
3.5
1-year OS Rate
All comers
≥1% PD-L1
71
70
76
87
73
69
a Pulled analysis of Nivo/Gem/Cis (n = 12), Nivo/Pem/Cis (n = 15), Nivo/Pac/Carbo (n = 29) cohorts.
b Pulled analysis of Nivo 3 Q2W + Ipi Q12W (n = 38) and Nivo 3 Q2W + Ipi 1 Q6W (n = 39).
Nivo + Ipi combination data based on September 2016 database lock; Nivo monotherapy data based on a March 2015 
database lock except for OS data which are based on August 2015 database lock.
Thus for these reasons, in study CA209648 subjects will be enrolled into the study regardless of 
PD-L1 tumor expression with stratification by PD-L1 at the expression level of 1% and the primary 
analysis of PFS/OS will be conducted in subjects with PD-L1 expressing tumor.
1.1.9 
Rationale for Two-Year Duration of Treatment
The optimal duration of immunotherapy is currently unknown. However, because immunotherapy
engages the immune system to control the tumor, continuous treatment as is required with targeted
agents or cytotoxic therapy may not be necessary. Accumulating evidence from different clinical
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trials in different tumors types with nivolumab or nivolumab combined to ipilimumab indicates
that  most  of  the  responses  are  generally  occurring  early,  with a  median  time  to  response  of 
2 - 4 months including in patients with NSCLC,
46,47,48and a recent analysis in a melanoma study 
suggests the  majority  of  patients  who discontinue  nivolumab  and/or  ipilimumab  for  toxicity 
maintain disease control in the absence of further treatment.
37Furthermore, a limited duration of 
ipilimumab including  only  4  induction  doses  resulted  in  long  term  survival  in  patients  with 
metastatic melanoma, with a sustained plateau in survival starting at around Year 3.
22
For these reasons, in study CA209648, treatment with nivolumab or nivolumab with ipilimumab
will be given for up to 24 months in the absence of disease progression or inacceptable toxicity.
Chemotherapy  will  be  given  as  per  the  study  dosing  schedule until  disease  progression  or 
unacceptable toxicity. 
1.2 
Research Hypothesis 
• The  administration  of  nivolumab  plus  ipilimumab will  improve  overall  survival  (OS) 
compared with fluorouracil and cisplatin combination in subjects with unresectable advanced, 
recurrent or metastatic ESCC with PD-L1 expression ≥1%. 
• The administration of nivolumab combined with fluorouracil plus cisplatin will improve OS 
compared  with  fluorouracil  and  cisplatin  combination  alone in  subjects  with  unresectable
advanced, recurrent or metastatic ESCC with PD-L1 expression ≥1%.
• The administration of nivolumab plus ipilimumabwill improve progression free survival (PFS) 
as  assessed  by  a  blinded independent  central review  committee  (BICR) compared  with 
fluorouracil  and  cisplatin  combination in  subjects  with  unresectable advanced,  
recurrent  or 
metastatic ESCC with PD-L1 expression ≥1%. 
• The administration of nivolumab combined with fluorouracil plus cisplatin will improve PFS 
as assessed by a BICR compared with fluorouracil and cisplatin combination alone in subjects 
with unresectable advanced, recurrent or metastatic ESCC with PD-L1 expression ≥1%.
1.3 
Objectives(s)
1.3.1 
Primary Objectives
• To  compare  the  OS  of  nivolumab  plus  ipilimumab  (Arm  A)  to  fluorouracil  and  cisplatin 
combination (Arm C) in subjects with PD-L1 expression ≥1%.
• To  compare  the  OS  of  nivolumab  combined  with  fluorouracil  plus cisplatin  (Arm  B)  to 
fluorouracil and cisplatin combination (Arm C) in subjects with PD-L1 expression ≥1%.
• To  compare  
the  PFS of  nivolumab  plus  ipilimumab  (Arm  A)  
to  fluorouracil  and  cisplatin
combination (Arm C) as assessed by a BICR in subjects with PD-L1 expression ≥1%.
• To  compare  the  PFS of  nivolumab  combined  with  fluorouracil  plus cisplatin  (Arm  B)  to 
fluorouracil and cisplatin combination (Arm C) as assessed by a BICR in subjects with PD-L1 
expression ≥1%.
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1.3.2 
Secondary Objectives
• To compare the OS of  nivolumab plus  
ipilimumab (Arm  A) and  nivolumab combined with 
fluorouracil plus cisplatin (Arm B) to fluorouracil and cisplatin combination (Arm  C)  
in all 
randomized subjects.
• To compare the PFS of nivolumab plus ipilimumab (Arm A) and nivolumab combined with 
fluorouracil  plus  cisplatin  (Arm  B)  to  fluorouracil  and  cisplatin  combination (Arm  C)  as 
assessed by a BICR in all randomized subjects.
• To compare the objective response rate (ORR) of nivolumab plus  
ipilimumab (Arm  A) and 
nivolumab  combined  with  fluorouracil  plus  cisplatin  (Arm  B)  
to fluorouracil  and  cisplatin 
combination (Arm C) as assessed by a BICR in subjects with PD-L1 expression ≥1%.
• To compare the ORR of nivolumab plus ipilimumab (Arm A) and nivolumab combined with 
fluorouracil  plus  cisplatin  (Arm  B)  to  fluorouracil  and  cisplatin  combination (Arm  C)  as 
assessed by a BICR in all randomized subjects.
•
1.3.3 
Exploratory Objectives
• To  assess PFS  of  nivolumab  plus  ipilimumab  (Arm  A)  and  nivolumab  combined  with 
fluorouracil  plus  cisplatin  (Arm  B)  vs fluorouracil  and  cisplatin  combination (Arm  C)  as 
assessed  by  investigators  in  subjects  with  PD-L1  expression ≥1%  and  in  all  randomized 
subjects.
• To  assess ORR of  nivolumab  plus  ipilimumab  (Arm  A)  and  nivolumab combined  with 
fluorouracil  plus  cisplatin  (Arm  B)  vs fluorouracil  and  cisplatin  combination (Arm  C)  as 
assessed  by  investigators  in  subjects  with  PD-L1  expression ≥1% and  in  all  randomized 
subjects.
• To  assess  DOR  of  nivolumab  plus  ipilimumab  (Arm  A)  or  nivolumab  combined  with 
fluorouracil  plus  cisplatin  (Arm  B) vs fluorouracil  and  cisplatin  combination (Arm  C)  as 
assessed  by  BICR and  by  
investigators in  subjects  with  PD-L1  expression ≥1%  and  
in  all 
randomized subjects.
• To  assess  
time  from  randomization  
to  
the  date  of  investigator-defined  documented  second 
objective disease progression or start of second subsequent therapy or death due to any cause, 
whichever  comes  first (PFS2/TSST)  of  nivolumab  plus  
ipilimumab  
(Arm  A)  or  nivolumab 
combined with fluorouracil plus cisplatin (Arm B) vs fluorouracil and cisplatin combination
(Arm  C) as  assessed  by  investigators  in  subjects  with  PD-L1  expression ≥1%  and  in  all 
randomized subjects.
•
• To  assess  
the  overall  safety  and  
tolerability  of  
treatment  with  nivolumab  plus  ipilimumab 
(Arm A) or nivolumab combined with fluorouracil plus cisplatin (Arm B) vs fluorouracil and 
cisplatin combination (Arm C).
• To characterize the PK of nivolumab plus ipilimumab (Arm A) or nivolumab combined with 
fluorouracil plus cisplatin (Arm B).
• To  characterize  
the  
immunogenicity  of  nivolumab  plus  
ipilimumab  (Arm  A)  or  nivolumab 
combined with fluorouracil plus cisplatin (Arm B).
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• To  characterize  immune  correlates  of  nivolumab  plus  ipilimumab  (Arm  A),  nivolumab 
combined with fluorouracil plus cisplatin (Arm B), and fluorouracil and cisplatin combination
(Arm C).
• To  evaluate  the  pharmacodynamic  activity  of  nivolumab  plus  ipilimumab  (Arm  A)  or 
nivolumab combined with fluorouracil plus cisplatin (Arm B) in the peripheral blood.
• To explore potential biomarkers associated with clinical efficacy (OS, PFS, and ORR) and/or 
with  incidence  of  adverse  events  of  nivolumab  plus  ipilimumab  (Arm  A)  or  nivolumab 
combined with  
fluorouracil plus cisplatin (Arm B) by analyzing  biomarker measures within 
the  tumor  microenvironment  and  periphery  (eg,  blood,  serum,  plasma)  in  comparison  to 
clinical  outcomes. These  biomarkers  may  include, but  not  necessarily  be  limited  
to  
tumor 
mutational  burden  (TMB),  tumor  infiltrating  lymphocytes,  inflammatory  signatures, 
microbiome, serum and plasma biomarkers.
• To assess the subject’s overall  health  
status using 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). 
1.4 
Product Development Background
1.4.1 
Mechanism of Action 
1.4.1.1 
Nivolumab Mechanism of Action
Cancer immunotherapy rests on the premise that tumors can be recognized as foreign rather than 
as  self  and  can  be  effectively  attacked  by  an  activated  immune system.  An  effective  immune 
response in this setting is thought to rely on immune surveillance of tumor antigens expressed on 
cancer  cells  that  ultimately  results  in  an  adaptive  immune  response  and  cancer  cell  death. 
Meanwhile, tumor  progression  may  depend  upon acquisition  of  
traits that  allow  cancer  cells  
to 
evade  immunosurveillance  and  escape  effective  innate  and  adaptive  immune  response.38,39,40
Current immunotherapy efforts attempt to break the apparent tolerance of the immune system to 
tumor cells and antigens  by either  
introducing cancer antigens by therapeutic  vaccination or by 
modulating regulatory checkpoints of the immune system. T-cell stimulation is a complex process 
involving  the  integration  of  numerous  positive  as  well  as  negative  co-stimulatory  signals  in 
addition to antigen recognition by the T-cell receptor (TCR).41Collectively, these signals govern 
the balance between T-cell activation and tolerance.
41
PD-1 is a member of the CD28 family of T-cell co-stimulatory receptors that also includes CD28, 
CTLA  4,  ICOS,  and  BTLA.42PD-1  signaling  has  been  shown  to  inhibit  CD-28-mediated 
upregulation of IL-2, IL-10, IL-13, interferon γ (IFN γ) and Bcl-xL. PD-1 expression also been 
noted  
to  
inhibit  T  cell  activation,  and  expansion  of  previously  activated  cells.  Evidence  for  a 
negative regulatory role of PD-1 comes from studies of PD-1 deficient  mice,  which  develop  a 
variety of autoimmune phenotypes.43These results suggest that PD-1 blockade has the potential 
to activate anti-self T-cell responses, but these responses are variable and dependent upon various 
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host genetic factors. Thus, PD-1 deficiency or inhibition is not accompanied by a universal loss of 
tolerance to self-antigens.
In vitro, nivolumab (BMS-936558) binds to PD-1 with high affinity (EC50 0.39-2.62 nM), and 
inhibits the binding of PD-1 to its  
ligands PD-L1 and PD-L2 (IC50 < 1 nM). Nivolumab binds 
specifically to PD-1 and not to related members of the CD28 family such as CD28, ICOS, CTLA-4 
and BTLA. Blockade of the PD-1 pathway by nivolumab results in a reproducible enhancement 
of both proliferation and IFN-γ release in the mixed lymphocytereaction (MLR). Using a CMV 
re stimulation  assay  with  human  Peripheral  Blood  Mononuclear  cells  (PBMC),  the  effect  of 
nivolumab on antigen specific recall response indicates that nivolumab augmented IFN-γ secretion 
from CMV specific memory T cells in a dose-dependent manner versus isotype-matched control. 
In  vivo  blockade  of  PD-1  by  a  murine  analog  of  nivolumab  enhances the  anti-tumor  
immune 
response and result in tumor rejection in several immunocompetent mouse tumor models (MC38, 
SA1/N, and PAN02).44
Immunotherapeutic  approaches  recently  have  demonstrated  clinical  efficacy  in  several  cancer
types, including melanoma, and NSCLC, and RCC.
45,46,47,48Nivolumab (Opdivo®)is approved 
in  multiple  countries  including  the  US  for  treatment  of  previously treated, unresectable  or 
metastatic melanoma and previously treated, metastatic NSCLC, and advanced RCC.49
1.4.1.2 Ipilimumab Mechanism of Action
CTLA-4,  an  activation-induced  T-cell  surface  molecule,  is  a  member  of  the  CD28:B7 
immunoglobulin  superfamily  that  competes  with  CD28  for  B7.  CTLA-4  mediated  signals  are 
inhibitory and turn off T cell-dependent immune responses.
50,51
Ipilimumab is a fully human monoclonal IgG1κ that binds to the CTLA-4 antigen expressed on a 
subset  of  T  cells  
from  human  and  nonhuman  primates.  The  proposed  mechanism  of  action  
for 
ipilimumab  is  interference  of  the  interaction  of  CTLA-4  with  B7  molecules  on  APCs,  with 
subsequent blockade of the inhibitory modulation of T-cell activation promoted by the CTLA 4/B7 
interaction.
1.4.1.3 
Nivolumab-plus-Ipilimumab Mechanism of Action
Preclinical and clinical data indicate that the combination of PD-1 and CTLA-4 receptor blockade 
may  
improve  antitumor  activity.  
In  vitro  combinations  of  nivolumab  plus  
ipilimumab increase 
IFN-γproduction 2- to 7-fold over either agent alone in a mixed lymphocyte reaction. In a murine 
melanoma  vaccine  model,  blockade  with  either  CTLA-4  or  PD-1  antibodies increased the 
proportion  of  CTLA-4- and  PD-1-expressing  CD4/CD8  
tumor-infiltrating  T effector  cells, and 
dual  blockade  increased  tumor infiltration  of  T  effector  cells and  decreased  intratumoral
T regulatory cells, as compared to either agent alone.52
In the Phase 1 dose escalation Study CA209004, the combination of nivolumab and ipilimumab
has been studied in subjects with unresectable or metastatic melanoma. In this study, a safe dose
level  for  the  combination  of  ipilimumab  and  nivolumab  was  established  for  the  treatment  of
advanced melanoma. At this dose level, 3 mg/kg ipilimumab plus 1 mg/kg nivolumab, an ORR of 
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53% was observed. This dose level has been approved in subjects with advanced melanoma in the 
US based on the Phase 3 Study CA209067.53
1.4.2 
Summary of Clinical Pharmacology
1.4.2.1 
Nivolumab 
The  pharmacokinetics  (PK) of  nivolumab  was  studied  in  subjects over  a  dose  
range  of  0.1  
to 
20 mg/kg  administered  as  a  single  dose or  as  multiple  doses of  nivolumab  every  2  or  3 weeks. 
Based on a population pharmacokinetic (PPK) analysis using data from patients with various tumor 
types, including melanoma, NSCLC, and RCC and a time varying CL model, nivolumabclearance 
was  shown  to  decrease  over  
time,  with  a  median  maximal  reduction  from  baseline values  of 
approximately 25% resulting in a geometric mean steady state clearance (CLss) (% coefficient of 
variation [CV%]) of 8.2 mL/h [53.9%]. The decrease  
in CLss  
is  not considered to be clinically 
relevant. The geometric mean [CV%] volume of distribution at steady state (Vss) is 6.8 L (27.3%), 
and elimination half-life (t1/2) is 25 days (77.5%). Steady-state concentrations of nivolumab were 
reached by approximately 12 weeks when administered at 3 mg/kg every 2 weeks, and systemic 
accumulation  was  approximately  3.7-fold.  The  exposure  to  nivolumab increased  dose 
proportionally over the dose range of 0.1 to 10 mg/kg administered every 2 weeks. The clearance 
of  nivolumab  increased  with  increasing  body  weight.  The PPK  analysis suggested  that  the 
following  factors  had  no  clinically  
important  effect  on  
the  clearance  of nivolumab:  age  
(29  
to 
87 years), gender, race, baseline LDH, PD-L1, solid tumor type, baseline tumor size, and hepatic 
impairment. Although ECOG status, baseline glomerular filtration rate (GFR), albumin, and body 
weight  had  an  effect on  nivolumab  CL,  
the  effect  was  not  clinically meaningful.  PPK  analysis 
suggested  
that  nivolumab  CL  in  subjects  with  cHL  was  approximately 32%  lower  relative  to 
subjects with NSCLC; however, the lower CL in cHL subjects was not considered to be clinically 
relevant as nivolumab exposure was not a significant predictor for safety risks for these patients. 
When  nivolumab  is  administered  in  combination  with  ipilimumab, the  CL  of  nivolumab  was 
increased by 24%, whereas there was no effect on the clearance of ipilimumab. Additionally, PPK 
and exposure response analyses have been performed to support use of 240 mg Q2W dosing  
in 
addition to the 3 mg/kg Q2W regimen. Using the PPK model, exposure of nivolumab at 240 mg 
flat  dose  was  identical  to  a  dose  of  3 mg/kg  for  subjects  weighing  80  kg,  which  was  the 
approximate median body weight in nivolumab clinical trials (see 
Section 1.1.5). Additional details 
are provided in the investigator brochure.
1.4.2.2 Ipilimumab 
The PPK of ipilimumab was studied in 785 subjects (3,200 serum concentrations) with advanced
melanoma in 4 Phase 2 studies (CA184004, CA184007, CA184008, and CA184022),541Phase3 
study (CA184024), and 1 Phase 1 study (CA184078). The PPK analysis demonstrated that the PK 
of ipilimumab is linear, the exposures are dose proportional across the tested dose range of 0.3 to 
10 mg/kg,  and  the  model  parameters  are  time-invariant,  similar  to  that  determined  by 
noncompartmental analyses.
Upon  
repeated  dosing  of  
ipilimumab,  administered  Q3W,  minimal  systemic  accumulation  was
observed by an accumulation index of 1.5-fold or less, and ipilimumab steady-state concentrations 
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were achieved by the third dose. The ipilimumab CL of 16.8 mL/h from PPK analysis is consistent 
with  that  determined  by  noncompartmental  PK  analysis.  The  terminal  T-HALF  and  Vss  of 
ipilimumab  calculated  from the  model were 15.4 days  and  7.47 L,  respectively,  which  are 
consistent with that determined by noncompartmental analysis. Volume of central compartment 
(Vc) and peripheral compartment were found to be 4.35 and 3.28 L, respectively, suggesting that 
ipilimumab first distributes into plasma volume and, subsequently, into extracellular fluid space. 
CL of  
ipilimumab and Vc were found to increase with  
increase  
in BW. However, there was no 
significant increase in exposure with increase in BW when dosed on a milligram/kilogram basis, 
supporting dosing of ipilimumab based on a weight normalized regimen. The PK of ipilimumab is 
not  affected  by  age, gender,  race,  and  immunogenicity  (anti-drug  antibody  [ADA]  status); 
concomitant use of chemotherapy; prior therapy; BW; performance status; or tumor type. Other 
covariates  had effects  
that  were  either  not  statistically  significant  or  were  of  minimal  clinical 
relevance.
In subjects with mild and moderate renal impairment, the CL of ipilimumab was similar to that of 
subjects with normal renal function. No specific dose adjustment is necessary in subjects with mild 
to moderate renal impairment. Likewise, the CL of ipilimumab in subjects with mild and moderate 
hepatic impairment was similar to that of subjects with normal hepatic function. 
Additional details are provided in the investigator brochure (IB).
1.4.3 
Safety Summary
Nivolumab  has  been  studied  in  over  12,300  subjects  and  is  widely  approved  in  multiple 
indications. Extensive details on the safety profile of nivolumab are available in the IB, and will 
not be repeated herein.
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 
Maximum  Tolerated  Dose  
(MTD) reached  at  any  dose tested  up to  10  mg/kg.  Most  AEs  were 
low-grade (Grade 1 to 2) with relatively few related high-grade (Grade 3 to 4) AEs. There was no 
pattern in the incidence, severity, or causality of AEs with respect to nivolumab dose level.
A pattern of immune-related AEs has been defined, for which management algorithms have been 
developed; these are provided in Appendix 1. Most high-grade events were manageable with the 
use of corticosteroids or hormone replacement therapy (endocrinopathies) as  
instructed in these 
algorithms.
Additional details on the safety profiles of nivolumab and ipilimumab, including results from other 
clinical studies, are also available in the respective nivolumab and ipilimumab IBs.
1.5 
Overall Risk/Benefit Assessment
Subjects with unresectable advanced, recurrent or metastatic ESCC represent an important unmet 
medical need. There is robust clinical data available to suggest the potential to improve clinical 
outcomes in ESCC:
• Clinical activity of nivolumab monotherapy in heavily treated ESCC patients in ONO-07 Japan 
Phase 2 study was observed with durable tumor responses and survival benefit (ORR by central 
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review 17.2%, mOS 10.78 months, and mPFS 1.51 months). The mOS of 10.78 is comparable 
to the OS with standard of care FP chemotherapy (6-10 months). Enhanced efficacy outcomes 
were  seen  in  patients  with  PD-1  expression ≥1%.  
In  
this  population, the  safety  profile  of 
nivolumab was shown to be favorable. 
• Clinical activity of nivolumab plus ipilimumab in first line NSCLC patients was observed in 
study CA209012 regardless of PD-L1 expression, although enrichment for response was seen 
in patients with PD-1 expression ≥1%, with an overall acceptable safety profile.
• Clinical activity of nivolumab plus platinum-based chemotherapy in first line NSCLC patients 
was observed in study CA209012 study regardless of PD-L1 expression, although enrichment 
for response was seen in patients with PD-1 expression ≥1%, with manageable toxicities.
Based on this clinical experience, subjects will be enrolled into the CA209648 regardless of PD-L1 
tumor  expression  with  stratification  by  PD-L1  at  
the  expression  level  of  1%  and  
the  primary 
analysis of PFS/OS will be conducted in subjects with PD-L1 expressing tumor.
Overall the safety profile of nivolumab and ipilimumab is well characterized from a large safety
database at different dose and schedules as monotherapy or in combination. Additional details on 
the safety profiles of nivolumab and ipilimumab, including results from other clinical studies, are 
also available in the respective nivolumab and ipilimumab IBs. Consistent with the mechanism of
action of nivolumab and ipilimumab, the most frequently reported drug-related AEs observed in 
clinical trials are those associated with activation of the immune system. The most common types 
of  immune-mediated  adverse events  include  endocrinopathies,  diarrhea/colitis,  hepatitis, 
pneumonitis, nephritis and rash. In the combination regimen, the frequency and intensity of these 
events may vary and depend on the specific dose and schedule used. In the combination dosing 
schedule selected for this study (nivolumab 3 mg/kg mg Q2W plus ipilimumab 1 mg/kg Q6W), 
immune-mediated  adverse  events  were mostly  low  grade  and  manageable  with  prompt  use  of 
corticosteroids.
In order to assure an ongoing favorable risk/benefit assessment for subjects treated in CA209648, 
the following safety measures will be employed throughout the conduct of the study:
• An independent Data Monitoring Committee (DMC) will be utilized to monitor the safety and 
clinical activity of nivolumab plus ipilimumab and nivolumab combined with fluorouracil plus 
cisplatin versus standard chemotherapy (FP regimen). 
• Rigorous safety monitoring by BMS to ensure subjects’ safety including regular and systematic 
review  of  safety  data,  close  follow-up  of  reported  safety  events,  intensive  site  and study 
investigator  training/education  on  the  implementation  of  the  nivolumab  and  ipilimumab 
management algorithms as well as regular safety conference calls with study investigators. 
• Open label drug administration of study drugs to allow for prompt and accurate assessment of 
the unique toxicities associated with study treatments.
In  conclusion,  
the  overall  
risk-benefit  of  nivolumab  plus  
ipilimumab  and  nivolumab  combined 
with  
fluorouracil  plus cisplatin  and  
fluoruracil  
in  unresctable advanced,  
recurrent  or  metastatic 
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first-line ESCC is deemed acceptable and subjects will be randomized to 1 of 3 arms: nivolumab 
plus  ipilimumab (Arm  A),  nivolumab  combined  with  fluorouracil  plus  cisplatin (Arm  B),  or 
fluorouracil plus cisplatin (Arm C).
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  Council on  Harmonisation  (ICH)  and  in  accordance  with  the  ethical  principles 
underlying  European  Union  Directive  2001/20/EC  and  the  United  States  Code  of  Federal 
Regulations, Title 21, Part 50 (21CFR50) and applicable local requirements.
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 Sponsor or designee immediately. A breach of 
the conditions and principles of GCP (occurring in any country) in connection with that study or 
the  protocol related  
to  
the  study which  is  likely  to  affect  
to  a significant  degree  
the  safety  or 
physical or mental integrity of 1 or more 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 shouldprovide 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  the  Health  Insurance  Portability  and  Accountability  Act  (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
This is a randomized Phase 3 study of nivolumab plus ipilimumab or nivolumab combined with 
fluorouracil  plus  cisplatin  compared  with  fluorouracil  and  cisplatin  combination in  adult 
(≥18 years) male and female subjects with unresectable advanced, recurrent or metastatic ESCC. 
The total number of subjects to be randomized is expected to be approximately 939 subjects.
After  signing  the  informed  consent  form,  and upon confirmation  of  the  subject’s  eligibility, 
subjects with unresectable advanced, recurrent or metastatic ESCC will be randomized in a 1:1:1 
ratio to one of the following open-label treatments (Arms A, B andC):
• Arm A: Subjects will receive treatment with nivolumab 3 mg/kg as a 30-minute infusion every 
2 weeks and ipilimumab as a 30-minute infusion 1 mg/kg every 6 weeks.
• Arm  B:  Subjects  will  receive  treatment  with  nivolumab  240  mg  as  a  30-minute  infusion
on Day 1  and  Day 15,  
fluorouracil  800  mg/m²/day as  an IV  continuous infusion  on  Day 1 
through Day 5 (for 5 days), and cisplatin 80 mg/m² as a 30- to 120-minute infusion* on Day 1 
of 4-week cycle.
• Arm C: Subjects will receive treatment with fluorouracil 800 mg/m²/day as an IV continuous 
infusion from Day 1 through Day 5 (for 5 days), and cisplatin 80 mg/m² as a 30- to 120-minute 
infusion* on Day 1 of 4-week cycle.
*Subjects are allowed to receive treatment with cisplatin 80 mg/m² as an IV infusion over a period 
of longer than 120 min if it is in accordance with local standard of care/local label.
Stratification factors:
1. 1.  PD-L1 status (≥1% vs < 1% [including indeterminate])*
2. 2.  Region (East Asia [Japan, Korea, Taiwan] vs Rest of Asia vs Rest of world [RoW])
3. 3.  Eastern Cooperative Oncology Group (ECOG) performance status (0 vs 1).
4. 4.  Number of organs with metastases (≤1 vs ≥2).
*The  proportions  of  subjects  with  or  without  PD-L1  
tumor  expression  will  be  monitored  and 
reassessed  as  needed  
to  ensure  
that the  sample  size  of  
randomized  subjects  with  PD-L1  
tumor 
expression ≥1% is adequate for analysis (ie, approximately 50% of all comers).
The study design schematic is presented inFigure 3.1-1.
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Figure 3.1-1: 
Study Design Schematic
Treatment with nivolumab or nivolumab with ipilimumab will be given for up to 24 months in the 
absence of disease progression  or inacceptable toxicity.  Chemotherapy will  be given as per the 
study dosing schedule until disease progression or unacceptable toxicity (see Section 4.5.5.2).
Baseline and all subsequent scans will be submitted to a BICR for analysis and archiving, once the 
subject is randomized and throughout the study
 period.
This study will consist of 3 phases: screening, treatment, and follow-up. 
3.1.1 
Screening Phase
• Begins by establishing the subject’s initial eligibility and signing of the informed consent.
• Subject is enrolled using the Interactive Response Technology (IRT) system.
• Subjects  must  have  PD-L1  immunohistochemistry  (IHC) testing,  with  evaluable  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 if available,  must be submitted for biomarker evaluation prior to randomization. The 
tumor  tissue  sample  may  be  fresh  or  archival  if  obtained  within 6months prior to 
randomization,  and  
there  can  have  been  no  systemic  
therapy  
(eg,  adjuvant)  given  after  
the 
sample  was  obtained.  Tissue  must  be  a  core  needle  biopsy,  excisional  or  
incisional  biopsy. 
Fine  needle  biopsies  or  drainage  of  pleural  effusions  with  cytospins  are  not  considered 
adequate for biomarker review and randomization. Biopsies of bone lesions that do not have a 
soft tissue component or decalcified bone tumor samples are also not acceptable. If insufficient 
tumor  
tissue  is  provided  for  analysis,  acquisition  of  additional  tumor  
tissue  (block  and/or 
slides) for the biomarker analysis is required. 
• Note that subjects  with  PD-L1  result  will  be  randomized,  but only subjects  with  PD-L1 
expression ≥1% will be assessed as part of the primary objective. 
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nivolumab
This study permits the re-enrollment of a subject that has discontinued the study as a pre-treatment 
failure (ie,  
if subject has not been randomized). If re-enrolled, the subject must be re-consented 
and a new subject number must be assigned.
Subject is assessed for study eligibility according to the inclusion (Section 3.3.1) and exclusion 
(Section 3.3.2) criteria. The detailed procedures are described in Table 5.1-1. 
3.1.2 
Treatment Phase
The treatment phase begins when the treatment is assigned in the IRT. 
Study treatment must begin within 3 calendar days of randomization.
• Adverse  event  assessments  should  be  documented  at each  clinic  visit  and  Women  of
Child-bearing Potential (WOCBP) must have a negative pregnancy test within 24 hours of first 
dose and then every 4 weeks (±7days).
• Treated subjects will be evaluated for tumor assessments every 6 weeks (±7 days) starting on 
Week 7 up to and including Week 48, then every 12 weeks (±7 days) thereafter.
• Biomarker sampling will follow the protocol-defined schedule (Table 5.6-1).
• Patient-reported  outcomes  (PRO)  questionnaires  EQ-5D-3L  and  FACT-E  will be  collected
prior to other procedures on Cycle 1 Day 1 and then every 2 weeks until Week 7 and every 
6 weeks thereafter.
Study assessments are to be collected as outlined in Section 5.
Treatment with nivolumab or nivolumab with ipilimumab (Arms A and B) will be given for up to 
24 months in the absence of disease progression or inacceptable toxicity. Chemotherapy (Arms B, 
and C) will be given as per the study dosing schedule until disease progression or unacceptable 
toxicity (see Section 4.5.5.2). Then, the subject will enter the Follow-up Phase (Table 5.1-5).
3.1.2.1 
Nivolumab plus Ipilimumab (Arm A)
• Nivolumab 3 mg/kg will be administered IV on Day 1 and then every 2 weeks.
• Ipilimumab 1 mg/kg will be administered IV on Day 1 and then every 6 weeks following the 
administration of nivolumab.
• When both nivolumab and ipilimumab are to be administered on the same day, nivolumab is 
to be administered first. The second infusion will always be ipilimumab, and will start at least 
30 minutes after completion of the nivolumab infusion.
• Treatment beyond initial, investigator-assessed, RECIST 1.1-defined progression is permitted 
if the subject has investigator-assessed clinical benefit and is tolerating treatment, as specified 
inSection 4.5.6.
• PK and IMG sampling data will be collected as indicated inTable 5.5-1.
3.1.2.2
Nivolumab Combined with Fluorouracil plus Cisplatin (Arm B)
• Nivolumab  combined  with  fluorouracil  and  cisplatin  will  be  administered  IV  
in  a  4-week
cycle.  Nivolumab  240  mg  will  be  administered  
IV  every  2  weeks  on Day 1  and  Day 15 of 
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each cycle. Fluorouracil 800 mg/m²/day will be administered as an IV continuous infusion on 
Day 1 through Day 5 (for 5 days) and cisplatin 80 mg/m² will be administered IV on Day 1 of 
4-week cycle .
• When both nivolumab and fluorouracil and cisplatin combination are to be administered on the 
same day, nivolumab is to be administered first. Infusion of fluorouracil and cisplatin will start 
at least 30 minutes after completion of the nivolumab infusion.
• Treatment  with  nivolumab beyond  initial,  investigator-assessed, RECIST  1.1-defined 
progression  is permitted  if  the  subject  has  investigator-assessed  clinical  benefit  and  is 
tolerating treatment, as specified inSection 4.5.6.
• PK and IMG sampling data will be collected as indicated inTable 5.5-1.
3.1.2.3 
Fluorouracil and Cisplatin Combination (Arm C)
• Fluorouracil  800  mg/m²/day will  be  administered  as  an IV  continuous  infusion  on  Day 1 
through Day5 (for 5 days) and cisplatin 80 mg/m² will be administered IV on Day 1 of 4-week 
cycle.
3.1.3 
Follow-up Phase
• Begins  when  
the  decision  
to  discontinue  a  subject  from  study  
therapy  is  made  (no  further 
treatment with study therapy).
−FU1 = 30 days  
from  
last dose (±7 days) or coinciding with the date of discontinuation 
(±7 days) if date of discontinuation is greater than 35 days after last dose
−FU2 = 84 days from FU1 (±7 days). 
• Subjects who discontinue treatment for reasons other than tumor progression will continue to 
have  
tumor  assessments  as  per the  schedule  
for the  assigned  
treatment  arm  until  confirmed 
disease progression, withdrawal of consent or lost to follow-up.
• Subjects  will  be  followed  for  all  AEs until  
these  
resolve,  
return  
to  baseline  or  are  deemed 
irreversible.  All  AEs will  be  documented  
for  a  minimum  of  100  days  after the  
last  dose of 
study treatment.
• After completion of the first two follow-up visits, subjects will  be  
followed every 3 months
(±14 days) for  survival  via  
in-person  visit  or phone.  Ad  hoc  survival  data  
requests  may  be 
made  during  the  study  as  well,  particularly  during  database  locks. Additional  subsequent 
cancer therapy details such as regimen, setting of the regimen, line of therapy, start date and 
end date of each regimen, best response to the regimen and date of progression after second 
line therapy will be collected.
• The PRO questionnaires collection and biomarker sampling will continue as per time and event 
schedule. Study follow-up assessment data are to be collected as outlined inTable 5.1-5.
The start of the trial is defined as first visit for first subject screened . End of trial is defined as the 
last visit or scheduled procedure shown in the Time & Events schedule for the last subject. Study 
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completion is defined as the final date on which data for the primary endpoint was or is expected 
to be collected, if this is not the same.
3.2 
Post Study Access to Therapy
At  
the  conclusion  of  the  study,  subjects  who continue  to  demonstrate  clinical  benefit  will  be 
eligible to receive BMS supplied study drug for the maximum treatment duration allowed by the 
study protocol. Study drug will be provided via an extension of the study, a rollover study requiring 
approval by responsible health authority and ethics committee or through another mechanism at 
the discretion of BMS. BMS reserves the right to terminate access to BMS supplied study drug if 
any of the following occur: a) the marketing application is rejected by responsible health authority; 
b) the  study  
is  
terminated  due  
to  safety concerns;  c)  
the  subject  can  obtain  medication  from  a 
government sponsored or private health program; or d) therapeutic alternatives become available 
in the local market.
3.3 
Study Population
For entry into the study, the following criteria MUST be met.
3.3.1 
Inclusion Criteria
• Signed Written Informed Consent
a) Subjects must have signed and dated an IRB/IEC approved written informed consent form 
in accordance with regulatory and  
institutional guidelines. This  must be obtained before 
the performance of any protocol-related procedures that are not part of normal subject care.
b) Subjects  must  be  willing  and  able  
to  comply  with  scheduled  visits,  
treatment  schedule, 
laboratory tests and other requirements of the study.
• Target Population
c) Subjects must have histologically confirmed squamous cell carcinoma or adenosquamous 
cell  carcinoma  (predominant  squamous  differentiation)  of  esophagus  (per  AJCC 
7th edition,55see Appendix 4).
d) Subjects must have unresectable advanced, recurrent or metastatic ESCC (per AJCC 7th 
edition,
48see Appendix 4).
e) Subjects must not be amenable to curative approaches such as definitive chemoradiation 
and/or surgery.
f) No prior systemic anticancer therapy given as primary therapy for advanced or metastatic 
disease
i) Prior  adjuvant,  neoadjuvant,  or  definitive,  chemotherapy/ radiotherapy/
chemoradiotherapy for ESCC is permitted if given as part of curative intent regimen 
and completed before enrollment. A recurrence-free period  
is required  
for 24 weeks 
after  completion  of  neoadjuvant  or  adjuvant  chemotherapies,  or after  completion  of 
multimodal therapies (chemotherapies and chemoradiotherapies) for locally advanced
diseases
g) ECOG Performance Status of ≤1 (Appendix 3)
h) Subjects must have at least one measurable lesion by CT or MRI per RECIST 1.1 criteria; 
radiographic tumor assessment must be performed within 28 days prior to randomization.
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i) Tumor tissue  must be provided  
for biomarker analyses. Either 1  
formalin-fixed paraffin 
embedded  (FFPE)  tumor  tissue  block  or  15 unstained  tumor  tissue slides,  with  an 
associated pathology report if available, must besubmitted for biomarker evaluation prior 
to study drug administration The tumor tissue sample may be fresh or archival if obtained 
within 6 months prior to randomization, and there can have been no systemic therapy (eg, 
adjuvant)  given  after  the  sample  was  obtained.  Tissue  must  be  a  core  needle  biopsy, 
excisional or incisional biopsy. Fine needle biopsiesor drainage of pleural effusions with 
cytospins are not considered adequate for biomarker review and randomization. Biopsies 
of bone lesions that do not have a soft tissue component or decalcified bone tumor samples 
are also not acceptable. 
2) In order to be randomized, a subject must have an evaluable PD-L1 expression classification 
≥1% or < 1%, or indeterminate) as determined by the central lab.
i) Subjects with non-evaluable results will not be allowed to be randomized.
b) Subject  Re-enrollment:  this  study permits  the  re-enrollment  of  a  subject  that  has
discontinued the study as a pre-treatment failure (ie, if subject has not been randomized). 
If  re-enrolled,  the  subject  must  be  re-consented and  a  new  subject  number  must  be 
assigned.
c) All  baseline  laboratory requirements  will  be  assessed  and  should  be  obtained  within 
14 days  prior  
to  study  drug  administration.  Screening  laboratory  values  must  meet  
the 
following criteria
i) White Blood Cells (WBC)
≥2000/uL
ii) Neutrophils
≥1500/uL
iii) Platelets
≥100 x 103/uL
iv) Hemoglobin
≥9.0 g/dL
v) Calculated  creatinine  clearance (CrCl) > 60 mL/min  (using  the  Cockcroft-Gault 
formula)
• Female CrCl = (140- age in years) x weight in kg x 0.85
•                                     72 x serum creatinine in mg/ dL
•
• Male CrCl = (140- age in years) x weight in kg x 1.00
•                                        72 x serum creatinine in mg/ dL,
• or, measured creatinine clearance (CrCl) > 60 mL/min (using a preferred method per local 
Standard of Care)
•
vi) AST
≤3.0 x ULN (or ≤5.0 x ULN if liver metastases are present)
vii) ALT
≤3.0 x ULN (or ≤5.0 x ULN if liver metastases are present)
viii) Total Bilirubin ≤1.5 x ULN (except subjects with Gilbert Syndrome who must have 
a total bilirubin level of < 3.0x ULN)
• Age and Reproductive Status
d) Males and Females≥18 years of age
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e) 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.
f) Women must not be breastfeeding
g) WOCBP  randomized  to  the  nivolumab  -plus  -ipilimumab  arm  or  the 
nivolumab-plus-chemotherapy  arm  must  agree  to  follow  instructions  for  method(s)  of 
contraception for the duration of study treatment and 5 months after the last dose of study 
treatment  (i.e.,  30  days  [duration  of  ovulatory  cycle]  plus  the  time  required  for  the 
investigational drug to undergo approximately five half-lives). 
h) Males  randomized  to  the  nivolumab  plus  ipilimumab  arm  or  the 
nivolumab-plus-chemotherapy arm and who are sexually active with WOCBP must agree 
to follow  
instructions  
for method(s) of contraception  
for the duration of study treatment 
and  7  months  after  the  last  dose  of  study  treatment  (i.e.,  90  days  [duration  of  sperm 
turnover] plus the time required for the investigational drug to undergo approximately five 
half-lives). In addition, male subjects must be willing to refrain from sperm donation during 
this time.
i) WOCBP randomized to the chemotherapy arms must also agree to follow instructions for 
method(s) of contraception from the time of enrollment for the duration of treatment with 
chemotherapy plus 5 half-lives of chemotherapy plus 30 days (duration of ovulatory cycle) 
or a duration specified by the local labels of the chemotherapy drugs received, whichever 
is longer.
j) Males randomized to the chemotherapy arms who are sexually active with WOCBP must 
also  agree  to  follow  instructions  for  method(s)  of  contraception  for  the  duration  of 
treatment with chemotherapy plus 5 half lives of chemotherapy plus 90 days (duration of 
sperm  
turnover)  or  a  duration  specified  by  
the  local  labels  of the  chemotherapy  drugs 
received, whichever is longer. In addition, male subjects must be willing to refrain from 
sperm  donation  during  this  time.  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 on the use of highly effective methods of contraception (Appendix 2), 
which have a failure rate of < 1% when used consistently and correctly.
3.3.2 
Exclusion Criteria
• Target Disease Exceptions
k) Subjects with adenocarcinoma.
a) Patients with any metastasis in the brain or meninx that is symptomatic or requires 
treatment. Patients may be randomized if the metastasis is asymptomatic and requires no 
treatment. 
l) Patients at high risks of bleeding or fistula due to apparent invasion of tumor to organs (the 
aorta or the trachea) adjacent to esophageal lesions.
• Medical History and Concurrent Diseases
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m) Subjects  must have recovered  
from the effects of  major surgery or significant traumatic 
injury at least 14 days before randomization. 
n) Prior malignancy requiring active treatment 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.
o) Subjects  with  active,  known,  or  suspected  autoimmune  disease.  Subjects  with  Type I 
diabetes  mellitus, residual  hypothyroidism due to autoimmune thyroiditis only requiring 
hormone replacement, skin disorders (such as vitiligo, psoriasis, or alopecia) not requiring 
systemic treatment are permitted to enroll. For any cases of uncertainty, it is recommended 
that a BMS medical monitor be consulted prior to signing informed consent.
p) Subjects with a condition requiring systemic treatment with either corticosteroids (> 10 mg 
daily prednisone equivalent) or other immunosuppressive  medications  within  14 days  of 
start of study treatment. Inhaled or topical steroids, and adrenal replacement steroid doses 
> 10 mg daily prednisone equivalent, are permitted in the absence of active autoimmune 
disease.
q) 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.
r) All toxicities attributed to prior anti-cancer therapy other than alopecia and fatigue must 
have  
resolved  
to  Grade  1 (NCI  CTCAE  version  4) or  baseline  before  administration  of 
study drug. 
s) 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 study drug.
t) Patients with uncontrollable, tumor related pain. 
u) Patients  with  significant  malnutrition.  Patients  will  be  excluded  if  they  are  receiving 
intravenous hyperalimentation, or require continuous infusion therapy with hospitalization. 
Patients whose nutrition has been well controlled for ≥28 days prior to randomization may 
be enrolled.
v) Subjects  with  interstitial  lung  disease  that  is  symptomatic  or  may  interfere  with  the 
detection or management of suspected drug-related pulmonary toxicity.
w) Subjects with > Grade 1 peripheral neuropathy.
x) Known  history  of  positive  test  for  human  immunodeficiency  virus  (HIV)  or  known 
acquired immunodeficiency syndrome (AIDS). NOTE: Testing for HIV must be performed 
at sites where mandated locally.
y) Known  medical  condition  that,  in  the  investigator’s  opinion,  would  increase  the  risk 
associated  with  study  participation  or  study  drug  administration  or  interfere  with  the 
interpretation of safety results.
z) Participants who have received a live / attenuated vaccine within 30 days of first treatment.
• Physical and Laboratory Test Findings
aa) Any  positive  
test  
result  
for hepatitis  B  virus  or  hepatitis C virus  
indicating  presence  of 
virus, eg, Hepatitis B surface antigen (HBsAg, Australia antigen) positive, or Hepatitis C 
antibody (anti-HCV) positive (except if HCV-RNA negative)
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• Allergies and Adverse Drug Reaction
bb) History of allergy or hypersensitivity to study drug components
cc) Any contraindications to any of the study drugs of the chemotherapy regimen (fluorouracil
or cisplatin). Investigators should refer to package insert of the chemotherapy drugs.
• Other Exclusion Criteria
dd) Prisoners  or  subjects  who  are  involuntarily  incarcerated. Note:  under  certain  specific 
circumstances a person who has been imprisoned may be included or permitted to continue 
as a subject. Strict conditions apply and Bristol-Myers Squibb approval is required.
ee) Subjects who are compulsorily detained for treatment of either a psychiatric or physical 
(eg, infectious disease) illness.
ff) Participation in any prior clinical study of nivolumab, including participants in comparator 
arms, in which overall survival is listed as the primary or co-primary endpoint and which 
has not completed analysis based on the primary endpoint.
Eligibility criteria for this study have been carefully considered to ensure the safety of the study 
subjects and that the results of the study can be used. It is imperative that subjects fully meet all 
eligibility criteria.
3.3.3 
Women of Childbearing Potential
WOCBP is  defined  as  any  
female  who  has  experienced  menarche  and who  has  not  undergone 
surgical  sterilization  (hysterectomy  or  bilateral  oophorectomy)  and  is  not  postmenopausal. 
Menopause is defined as 12 months of amenorrhea in a woman over age 45 years in the absence 
of other biological or physiological causes. In addition, females under the age of 55 years must 
have a serum follicle stimulating hormone, (FSH) level > 40 mIU/mL to confirm menopause.
*Females  treated  with hormone  replacement  therapy,  (HRT)  are  likely  to  have  artificially 
suppressed  FSH  levels  and  may  require  a  washout  period  in order  to  obtain  a physiologic 
FSH level. The duration of the washout period is a function of the type of HRT used. The duration 
of  the  washout  period  below  are  suggested  guidelines  and  the  investigators  should  use  their 
judgement 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.
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3.4 
Concomitant Treatments
3.4.1 
Prohibited and/or Restricted Treatments
The following medications are prohibited during the study (unless utilized to treat a drug related 
adverse event):
• Immunosuppressive agents
• Immunosuppressive doses of systemic corticosteroids (except as stated in Section3.4.3)
• Any concurrent anti-neoplastic therapy (ie, chemotherapy, hormonal therapy, immunotherapy, 
extensive, non-palliative radiation therapy, or standard or investigational agents for treatment 
of EC).
• Botanical formulations with an approved indication for cancer treatment are [e.g. traditional 
Chinese  medicines];  these should  be  discontinued  (if  used)  at  least  2  weeks  prior  to 
randomization.
• Any  live  /  attenuated  vaccine  (eg  varicella,  zoster,  yellow  fever,  rotavirus,  oral  polio  and 
measles, mumps, rubella (MMR)) during treatment and until 100 days post last dose.
Investigators should refer to the local product labeling for the chemotherapy drugs selected for use 
in Arms B and C for additional prohibited and restricted concomitant medications.
3.4.2 
Other Restrictions and Precautions
Subjects with a condition requiring systemic treatment with either corticosteroids (> 10 mg daily 
prednisone equivalent) or other immunosuppressive medications within 14 days of randomization 
are  excluded.  
Inhaled  or  
topical  steroids,  and  adrenal  
replacement  steroid  doses  > 10 mg  daily 
prednisone equivalent, are permitted in the absence of active autoimmune disease.
Subjects  who  are  
receiving  coumarin-derivative  anticoagulants  such  as  warfarin  concomitantly 
with fluorouracil should be closely monitor patients for INR or prothrombin time in order to adjust 
the anticoagulant dose accordingly.
3.4.3 
Permitted Therapy
Subjects  are  permitted  the  use  of  topical,  ocular,  intra-articular,  intranasal,  and  inhalational 
corticosteroids (with  minimal systemic absorption). Adrenal replacement steroid doses > 10 mg 
daily  prednisone  are  permitted.  A  brief  (less  than  3 weeks)  course  of  corticosteroids  for 
prophylaxis  (eg,  contrast  dye  allergy)  or  for  treatment  of non-autoimmune  conditions 
(eg, delayed-type hypersensitivity reaction caused by a contact allergen) is permitted.
Regular concomitant use of bisphosphonates and RANK-L inhibitors for prevention or reduction 
of skeletal-related events in subjects with bone metastases is allowed if initiated prior to first dose 
of study therapy.
Subjects requiring palliative radiotherapy should be evaluated for objective evidence of disease 
progression prior to the initiation of such therapy, particularly if the most recent tumor assessment 
was  more  than  4 weeks  prior  to  the  start  of  local  therapy.  If  progression  per  RECIST  1.1  is 
identified on any tumor assessments prior to the initiation of palliative local therapy, then subjects 
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must  either  discontinue  study  drug  
treatment  or  
they  must meet  criteria  
to  continue  
treatment 
beyond  progression (Section 4.5.6)in  order  to  resume  immunotherapy  after  palliative  local 
therapy. Palliative radiotherapy may also be permitted prior to discontinuation of study treatment 
in subjects who do not have evidence of overall clinical or radiographic progression per RECIST 
1.1,  provided  
that the lesions  undergoing  palliative  
local  
therapy  are  non-target  
lesions  and  
the
case is discussed with, and approved by, the BMS Medical Monitor. 
In cases where palliative radiotherapy is required for a tumor lesion, then study treatment should 
be  withheld  for  at  
least  1  week  before,  during,  and  1  week  after  
radiation.  Subjects  should  be 
closely  monitored  for  any  potential  
toxicity  during  and  after  receiving  radiotherapy,  and  AEs 
should resolve to Grade ≤ 1 prior to resuming study therapy.
3.5 
Discontinuation of Subjects following any Treatment with Study Drug
Subjects  MUST  discontinue  investigational  product  (and  non-investigational  product  at  the 
discretion of the investigator) for any of the following reasons:
• Subject’s request to stop study treatment
• Any  clinical  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 BMS
• Loss of ability to freely provide consent through imprisonment or involuntarily incarceration 
for treatment of either a psychiatric or physical (eg, infectious disease) illness. (Note: Under 
specific circumstances, a participant who has been imprisoned may be permitted to continue 
as a participant. Strict conditions apply and BMS approval is required.)
• Criteria listed in Section 4.5.5
• Disease progression as assessed by RECIST 1.1 criteria, unless the subject meets criteria for 
treatment beyond progression (Section 4.5.6).
In the case of pregnancy, the investigator must immediately notify the Sponsor or designee of this 
event. In most cases, the study drug will be permanently discontinued in an appropriate manner 
(eg, dose tapering if necessary for subject safety). Please contact the Sponsor or designee within 
24 hours  of  awareness  of  the  pregnancy.  If  the  investigator  determines  a  possible  favorable 
benefit/risk ratio that warrants continuation of study drug, 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).
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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.
All 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. Survival visits are every 3 months from FU2 until 
the end of the study and may be conducted during a clinic visit or via the phone.
3.6 
Post Study Drug Study Follow up
In this study, OS and PFS are 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 outcome and/or survival follow-up data 
as required and in line with Section 5until death or the conclusion of the study.
BMS may request that survival data be collected on all treated/randomized subjects outside of the 
protocol defined window (see Section 5). At the time of this request, each subject will be contacted 
to determine their survival status unless the subject has withdrawn consent for all contacts or is 
lost to follow-up.
3.6.1 
Withdrawal of Consent
Subjects who request to discontinue study drug will remain in the study and must continue to be 
followed for protocol specified follow-up procedures. The only exception to this is when a subject 
specifically  withdraws  consent  for  any  further  contact  with  him/her  or  persons  previously 
authorized by subject to provide this  
information. Subjects should  notify the  
investigator of the 
decision  
to  withdraw  consent  
from  
future  
follow-up in  writing,  
if 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 
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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:
• Nivolumab Solution for Injection
• Ipilimumab Solution for Injection
• Cisplatin Concentrate for Solution for Infusion
• Fluorouracil Solution for Injection.
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,  
the  investigational  products  are  nivolumab solution  for  
injection,  ipilimumab
solution for injection, cisplatin solution for infusion, and fluorouracil solution for injection(Table 
4.1-1).
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Table 4.1-1: 
Study Drugs for CA209648: 
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 Injectiona
100 mg (10 mg/mL)
IP
Open label
10 mL vial. Clear to 
opalescent, colorless to 
pale yellow liquid. May 
contain particles.
2° to 8°C. Protect from 
light and freezing.
Ipilimumab Solution for 
Injection
200 mg (5 mg/mL)
IP
Open label
40 mL vial Clear to 
opalescent, colorless to 
pale yellow liquid. May 
contain particles.
2° to 8°C. Protect from 
light and freezing.
Cisplatin Concentrate for 
Solution for Infusionb,c
100 mg (1 mg/mL)
IP
Open label
Clear, colorless 
solution (100 mL/ vial)
Do not store above 
25°C. Do not 
refrigerate or freeze. 
Store in outer carton.
Fluorouracil Solution for 
Injectionb,c
1g/vial (50 mg/ mL)
IP
Open label
Clear, colorless or 
slightly yellow 
solution. 1 g/20 mL
Do not store above 
25°C. Do not 
refrigerate or freeze. 
Store in outer carton.
a May be labeled as either “BMS-936558-01” or “Nivolumab”
b These products may be obtained as local commercial product in certain countries if allowed by local regulations. In these cases, products may be a different pack
size/potency  
than  
listed  
in  
the  
table.  These  products  should  be  prepared/stored/administered  
in  accordance  with  
the  package  
insert  or  summary  of  product 
characteristics (SmPC).
c Potency, packaging and storage conditions may vary for China. Storage conditions will be indicated on the clinical labels.
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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: any medications used to treat nivolumab or 
ipilimumab infusion-related reactions (eg, steroids). These non-investigational products should be 
sourced by the investigator sites if available and permitted bylocal regulations.
4.3 
Storage of Study Drug
The product storage manager should ensure that the study drug is stored in accordance with the 
environmental conditions (temperature, light, and humidity) as determined by BMS. If concerns 
regarding the quality or appearance of the study drug arise, the study drug should not be dispensed
and contact BMS immediately.
Study drug not supplied by BMS will be stored in accordance with the package insert.
Please refer toSection 9.2.2for guidance on IP records and documentation.
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).
Infusion-related supplies (eg, IV bags, in-line  
filters, 0.9% NaCl solution, or pump) will  not be 
supplied by the sponsor and should be purchased locally if permitted by local regulations.
Please refer to the current versions of the IBs, SpC or package inserts and/or pharmacy manual
for complete storage, handling, dispensing, and infusion/dosing information for nivolumab,
ipilimumab, fluorouracil and cisplatin.
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 the IRT system to obtain the 
subject number. Every subject that signs the informed consent form  must be assigned a subject 
number in the IRT system. Specific instructions for using the IRT system 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 the IRT, subjects that have met all eligibility criteria (including the required tumor 
tissue received and evaluable result obtained by the central  
laboratory and the pathology report 
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approved  by the  
investigator)  will  be  ready  
to  be  randomized  
through  
the  
IRT.  The  
following 
information is required for subject randomization:
• Subject number
• Date of birth
• Gender: male vs female
• Region: East Asia (Japan, Korea, Taiwan) vs Rest of Asia vs rest of world
• ECOG performance status: 0 vs 1
• PD-L1  evaluable  status  (the  result  of  PD-L1  expression  [≥1%  or  <  1%  or  indeterminate] 
inserted by the central  
laboratory vendor  
into the IRT and both the site and the BMS study 
team remain blinded to the result).
• Number of organs with metastases (≤1 vs ≥2).
• Weight
Subjects meeting all eligibility criteria will be randomized in a 1:1:1 ratio to either the nivolumab 
and ipilimumab arm (Arm A), or the nivolumab plus fluorouracil and cisplatin arm (Arm B), or 
the fluorouracil and cisplatin combination arm (Arm C). Randomization will be stratified by the 
following factors:
3) 1.  PD-L1 status (≥1% vs < 1% [including indeterminate])*
4) 2.  Region (East Asia (Japan, Korea, Taiwan) vs Rest of Asia vs rest of world)
5) 3.  ECOG performance status (0 vs 1).
6) 4.  Number of organs with metastases (≤1 vs ≥2)
* During enrollment, the proportion of subjects with or without PD-L1 tumor expression will be 
monitored, and may be re-assessed in case it does not reflect study assumptions (ie, subjects with 
PD-L1 tumor expression ≥1% is approximately 50% of all comers).
The exact procedures for using the IRT will be detailed in the IRT manual.
4.5 
Selection and Timing of Dose for Each Subject
4.5.1 
Dosing
4.5.1.1 
Nivolumab plus Ipilimumab Dosing (Arm A) 
Subjects randomized to Arm A will receive nivolumab at a dose of 3 mg/kg as a 30-minute IV 
infusion, on Day 1 of each treatment cycle every  2 weeks and  
ipilimumab at a dose of 1 mg/kg 
every 3 cycles (ie, every 6 weeks) until progression, unacceptable toxicity, withdrawal of consent,
completion of 24 months of treatment, or the study ends, whichever occurs first.
Subjects should begin study treatment within 3 calendar days of randomization. See Table 4.5.1.1-
1for details on the dosing schedule of nivolumab plus ipilimumab in Arm A.
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Dosing calculations should be based on the body weight assessed at baseline. It is not necessary to 
re-calculate subsequent doses if the subject weight is within 10% of the weight used to calculate 
the  previous  dose.  All  doses  should  be  
rounded  up or to the  nearest  milligram  per  
institutional 
standard.
When  study  treatments  (nivolumab  and  ipilimumab)  are  
to  be  administered  on  
the  same  day, 
nivolumab is to be administered first. Nivolumab infusion must be promptly followed by a flush 
of  diluent  
to  clear  
the  line  of  nivolumab  before  starting  
the  ipilimumab  infusion.  The  second 
infusion will always be the ipilimumab study treatment and will start after the infusion line has 
been  
flushed,  
filters  changed  and  patient  has  been  observed  
to ensure  no  
infusion  
reaction  has 
occurred. 
There will be no dose escalations or reductions of nivolumab and ipilimumab allowed. Subjects 
may be dosed with nivolumabno less than 12 days from the previous dose of nivolumab and may 
be dosed with ipilimumab no less than 37 days from the previous dose of ipilimumab. There are 
no premedications recommended.
Subjects should be carefully monitored for infusion reactions during nivolumab administration. If 
an acute infusion reaction is noted, subjects should be managed according toSection 4.5.8.
Doses of nivolumab and/or ipilimumab may be interrupted, delayed, or discontinued depending 
on  how  well  
the  subject  
tolerates  
the  
treatment. Please  refer  
to Section 4.5.2.1(dose  delays), 
Section 4.5.4.1(resuming treatment) and Section 4.5.5.1(dose discontinuation). 
Table 4.5.1.1-1: 
Dose Schedule of Nivolumab and Ipilimumab in Arm A
Treatment 
Group
Drug Name
Cycle 1 
(Week 1)
Cycle 2a
(Week 3)
Cycle 3a
(Week 5)
Cycle 4a
(Week 7)
Cycle 5a
(Week 9)
Cycle 6a
(Week 11) 
till EOT
Nivolumab 
+ 
Ipilimumab 
Nivolumab 
3 mg/kg
Day 1 
Day 1 
Day 1 
Day 1 
Day 1 
Day 1
Ipilimumabb
1 mg/kg
Day 1
Day 1
a Cycle 2 till EOT: Subsequent nivolumab doses may be administered within 3 days before or after the scheduled 
date if necessary. There should be no less than 12 days between doses.
b Ipilimumab dose is administered Q6W, within 5 days before or after the scheduled date if necessary. There should 
be no less than 37 days between ipilimumab doses.
4.5.1.2 
Nivolumab Combined with Fluorouracil plus Cisplatin Dosing (Arm B)
Subjects  
randomized  
to  Arm  B  will receive  
treatment  with  nivolumab  240  mg  as  a  30-minute 
infusion on Day 1 and Day 15 (ie, every 2 weeks), fluorouracil 800 mg/m²/day as an IV continuous 
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infusion  on Day 1  
through  Day 5  
(for  5  days),  and  cisplatin  80  mg/m²  as  a  30- to  120-minute 
infusion* on Day1 of 4-week cycle. 
*Subjects are allowed to receive treatment with cisplatin 80 mg/m² as an IV infusion over a period 
of longer than 120 min if it is in accordance with local standard of care/local label.
Treatment will continue until progression, unacceptable toxicity, withdrawal of consent, the study 
ends, whichever occurs first. The treatment with nivolumab will be given for up to 24 months in 
the absence of disease progression or unacceptable toxicity. Chemotherapy will be given as per 
the study dosing schedule.
Subjects should begin study treatment within 3 calendar days of randomization. SeeTable 4.5.1.2-
1for  details  on  
the  dosing  schedule  of  nivolumab  combined  with  
fluorouracil  plus  cisplatin  
in 
Arm B.
Dosing calculations of fluorouracil and cisplatin should be based on the body weight assessed at 
baseline. It is not necessary to re-calculate subsequent doses if the subject weight is within 10% of 
the weight used to calculate the previous dose. All doses should be rounded up or to the nearest 
milligram per institutional standard.
When  both nivolumab and  
fluorouracil and cisplatin combination are to be administered on the 
same day, nivolumab is to be administered first. Infusion of fluorouracil and cisplatin will start at 
least 30 minutes after completion of the nivolumab infusion.
Pretreatment hydration for cisplatin can follow local standard of care, or use 1 to 2 liters of fluid 
(per  
local  standards)  infused  IV  for  8  
to  12  hours  prior  
to  cisplatin  infusion  is  recommended. 
Adequate hydration and urinary output must be maintained for at least 24 hours following cisplatin 
administration. Administration and monitoring should be performed according to local standards. 
Use of mannitol following the cisplatin infusion should also follow local standards-of-care.
Premedications for use with fluorouracil/cisplatin: Antiemetic premedication will be administered 
according  
to  
local  standards. Recommended antiemetic  
treatments  are  dexamethasone  (dosing 
according to local standards; an equivalent dose of another corticosteroid may be substituted) and 
a  5-HT3  receptor  antagonist  (type  per  investigator  discretion  and  local  standards-of-care). 
Dexamethasone is allowed as premedication in arm B during the platinum-based chemotherapy. 
Additional use of antiemetic premedications may be employed at the discretion of the Investigator.
Refer to the  
local product label  
for  more detail. There are no premedications recommended  
for 
nivolumab treatment.
Doses  of  fluorouracil and/or  cisplatin  may  be  interrupted,  delayed,  reduced,  or  discontinued 
depending  on  how  well  
the  subject tolerates  
the  
treatment  See the  
following sections for  more
details:4.5.2(dose  delays) and 4.5.3(dose  reductions), 4.5.4(retreatment),  and4.5.5(dose 
discontinuations).
If either fluorouracil or cisplatin is discontinued the other study treatments may be continued for 
the remainder of the cycles. 
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In  subjects  who  required  fluorouracil dose  reduction  due  to  toxicity  during  the
fluorouracil/cisplatin  combination  cycles,  the  dose  of  fluorouracil  may  be  re-escalated  to 
800 mg/m2after the discontinuation of cisplatin, at the investigator’s discretion and according to 
local standards, if the prior toxicity was felt to be related mainly to cisplatin.
All  subjects who will  be receiving cisplatin should have audiometric testing performed prior to 
initiation of therapy and prior to subsequent doses of cisplatin, or as per local standards of care.
Doses  of  nivolumab  may  be  interrupted,  delayed,  or  discontinued  depending  on  how  well  
the 
subject  
tolerates  the  treatment.  There  will  be  no  dose  escalations  or  reductions  of  nivolumab 
allowed. Subjects may be dosed with nivolumab no less than 12 days  
from the previous dose of 
nivolumab. 
Subjects should be carefully monitored for infusion reactions during nivolumab administration. If 
an acute infusion reaction is noted, subjects should be managed according toSection 4.5.8. 
Table 4.5.1.2-1: 
Dose Schedule of Nivolumab plus FP in Arm B
Treatment 
Group
Drug Name
Cycle 1
(Week 1)
Cycle 2
(Week 5)
Cycle 3
(Week 9)
Cycle 4
(Week 13)
Cycle 5
(Week 17)
Cycle 6
(Week 21)
till EOT
Nivolumab
+ 
fluorouracil 
+ cisplatin
Nivolumaba
240 mg
Day 1 and 
Day 15
Day 1 and 
Day 15
Day 1 and 
Day 15
Day 1 and 
Day 15
Day 1 and 
Day 15
Day 1 and 
Day 15
Fluorouracil
800 mg/m²
Days 1, 2, 
3, 4 and 5
Days 1, 2, 
3, 4 and 5
Days 1, 2, 
3, 4 and 5
Days 1, 2, 
3, 4 and 5
Days 1, 2, 
3, 4 and 5
Days 1, 2, 
3, 4 and 5
Cisplatin
80 mg/m²
Day 1 
Day 1 
Day 1 
Day 1 
Day 1 
Day 1
a Cycle 1 on Day 15 till EOT: Subsequent nivolumab doses may be administered within 3 days before or after the 
scheduled date if necessary. There should be no less than 12 days between doses.
4.5.1.3 
Fluorouracil plus Cisplatin Dosing (Arm C)
Subjects randomized to Arm C will receive treatment with fluorouracil 800 mg/m²/day as an IV 
continuous  
infusion  on Day 1  
through  Day 5  (for  5  days),  and  cisplatin  80  mg/m²  as  a  30- to 
120-minute  infusion* on  Day  1  of  4-week  cycle. Treatment  will  continue  until progression, 
unacceptable toxicity, withdrawal of consent, the study ends, whichever occurs first.
*Subjects are allowed to receive treatment with cisplatin 80 mg/m² as an IV infusion over a period 
of longer than 120 min if it is in accordance with local standard of care/local label.
Doses  of  fluorouracil and/or  cisplatin  may  be  interrupted,  delayed,  reduced,  or  discontinued 
depending  on  how  well  
the  subject tolerates  
the  
treatment  See the  
following sections for more
details:4.5.2(dose  delays)  and 4.5.3(dose  reductions), 4.5.4(retreatment),  and 4.5.5(dose 
discontinuations).
If either fluorouracil or cisplatin is discontinued the other study treatments may be continued for 
the remainder of the cycles. 
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In  subjects  who  required  fluorouracil dose  reduction  due  to  toxicity  during  the
fluorouracil/cisplatin  combination  cycles,  the  dose  of  fluorouracil  may  be  re-escalated  to 
800 mg/m2after the discontinuation of cisplatin, at the investigator’s discretion and according to 
local standards, if the prior toxicity was felt to be related mainly to cisplatin.
Subjects should begin study treatment within 3 calendar days of randomization. SeeTable 4.5.1.3-
1for details on the dosing schedule of fluorouracil plus cisplatin in Arm C.
Dosing calculations of fluorouracil and cisplatin should be based on the body weight assessed at 
baseline. It is not necessary to re-calculate subsequent doses if the subject weight is within 10% of 
the weight used to calculate the previous dose. All doses should be rounded up or to the nearest 
milligram per institutional standard.
Pretreatment hydration for cisplatin can follow local standard of care, or use 1 to 2 liters of fluid 
(per  
local  standards)  infused  IV  for  8  
to  12  hours  prior  
to  cisplatin  infusion  is  recommended. 
Adequate hydration and urinary output must be maintained for at least 24 hours following cisplatin 
administration. Administration and monitoring should be performed according to local standards. 
Use of mannitol following the cisplatin infusion should also follow local standards-of-care.
Premedications:  Antiemetic premedication  will  be  administered  according  to  local  standards. 
Recommended antiemetic treatments are dexamethasone (dosing according to local standards; an 
equivalent  dose  of  another  corticosteroid  may  be  substituted)  and  a  5-HT3  
receptor  antagonist 
(type  per  investigator  discretion  and  local  standards-of-care).  Dexamethasone  is  allowed  as 
premedication in arm C during the platinum-based chemotherapy. Refer to the local product label 
for more detail. Additional use of antiemetic premedications may be employed at the discretion of 
the Investigator.
All  subjects who will  be receiving cisplatin should have audiometric testing performed prior to 
initiation of therapy and prior to subsequent doses of cisplatin, or as per local standards of care.
Table 4.5.1.3-1: 
Dose Schedule of FP (Fluorouracil + Cisplatin) in Arm C
Treatment 
Group
Drug Name
Cycle 1 
(Week 1)
Cycle 2 
(Week 5)
Cycle 3 
(Week 9)
Cycle 4 
(Week 13)
Cycle 5
(Week 17)
Cycle 6 
(Week 21) 
till EOT
Fluorouracil 
+ cisplatin
Fluorouracila
800 mg/m²
Days 1, 2, 
3, 4 and 5
Days 1, 2, 
3, 4 and 5
Days 1, 2, 
3, 4 and 5
Days 1, 2, 
3, 4 and 5
Days 1, 2, 
3, 4 and 5
Days 1, 2, 
3, 4 and 5
Cisplatina
80 mg/m²
Day 1 
Day 1 
Day 1 
Day 1 
Day 1 
Day 1
a Fluorouracil and cisplatin will be given every 4 weeks. FP dose on Day 1 is administered within 3 days before or 
after the scheduled date if necessary
.
4.5.2 
Dose Delay Criteria
4.5.2.1 
Dose Delay Criteria for Nivolumab and/or Ipilimumab (Arms A and B)
Nivolumab and/or ipilimumab administration should be delayed for the following: 
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• Any Grade ≥2 non-skin, drug-related AE, with the following exception:
−Grade 2 drug-related fatigue does not require a treatment delay.
• Grade 2 drug-related creatinine, 
• Any Grade ≥ 3 skin, drug-related AE
• Any  Grade  3  drug-related  laboratory  abnormality,  with  the  following  exceptions  for 
lymphopenia, AST, ALT, or total bilirubin and asymptomatic amylase or lipase abnormalities:
−Grade 3 lymphopenia does not require dose delay
−If a subject has a baseline AST, ALT, or total bilirubin that is within normal limits, delay 
dosing for drug-related Grade ≥ 2toxicity
−If a  subject has  baseline  AST, ALT, or total  bilirubin within the  grade  1  
toxicity  
range, 
delay dosing for drug-related Grade ≥ 3 toxicity
−Any  Grade ≥3  drug-related  amylase  or  lipase  abnormality  that  is  not  associated  with 
symptoms or clinical manifestations of pancreatitis does not require dose delay.
• Any  AE,  laboratory  abnormality,  or  intercurrent illness  which,  in  the  judgment  of  the 
investigator, warrants delaying the dose of study medication.
Subjects who have drug-related toxicities that meet the criteria for dose delay should have both 
drugs (ipilimumab and nivolumab) delayed until retreatment criteria are met(exceptions apply to 
the retreatment criteria after dose delay of ipilimumab and nivolumab for Grade ≥ 3 amylase and 
lipase  abnormalities  that  are  not  associated  with  symptoms  or  clinical  manifestations  of 
pancreatitis and that are attributed to ipilimumab alone).
Subjects who require delay of nivolumab and ipilimumab should be re-evaluated weekly or more 
frequently  if  clinically  indicated  and  resume  nivolumab  and/or ipilimumab  dosing  when 
re-treatment criteria are met.
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.
Rescheduling:
•
Nivolumab  may  be  delayed  until the  next  planned  
ipilimumab  dose  
if  
the  next  
ipilimumab 
dose is scheduled within the next 12 days. This will permit periodic ipilimumab dosing to be 
synchronized with nivolumab dosing.
• Ipilimumab should be dosed at the specified interval regardless of any delays in intervening 
nivolumab doses. However, in order to maintain periodic synchronized dosing of ipilimumab 
and  nivolumab,  
the  dosing  days  of  nivolumab  and  
ipilimumab  may be  adjusted  within  
the 
permitted ±5-day window, as long as consecutive nivolumab doses are given at least 12 days 
apart. Ipilimumab may be delayed beyond the 5-day window if needed to synchronize with the 
next nivolumab dose.
• If  an  ipilimumab  dose  is  delayed  beyond  6 weeks  from  the  prior  ipilimumab  dose,  then 
subsequent  ipilimumab  doses  should  rescheduled  
to  maintain  
the 6-week  interval  between 
consecutive ipilimumab doses. 
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• Dosing delays of ipilimumab which results in an interruption of ipilimumab dosing > 12 weeks 
requires discontinuation ipilimumab, with exceptions as noted in Section 4.5.5.1.
4.5.2.2 
Dose Delay Criteria for Fluorouracil and Cisplatin Combination (Arm C)
In  Arms  B  and  C,  dosing  of  both  drugs  
in  
the  fluorouracil  and  cisplatin  combination selected 
should be delayed for any of the following on the Day 1 of each cycle:
• Absolute neutrophil count (ANC) < 1500/μL
• Platelets < 100,000/mm
3
• Any  Grade ≥2  non-skin,  non-hematologic,  drug-related  adverse  event  (excluding  Grade  2 
alopecia, Grade 2 fatigue, and Grade 2 laboratory abnormalities)
• Any Grade ≥3 skin, drug-related adverse event
• Any Grade ≥3 drug-related laboratory abnormality, with the following exceptions:
−Grade 3 lymphopenia does not require dose delay.
−If a subject has a baseline AST. ALT or total bilirubin that is within normal limits, delay 
dosing for drug-related Grade ≥2 toxicity
−If a subject has baseline AST, ALT, or total bilirubin within the Grade 1 toxicity range, 
delay dosing for drug-related Grade ≥3 toxicity
• Any adverse event, laboratory abnormality, or intercurrent illness which, in the judgment of 
the investigator, warrants delaying the dose of study medication. Investigators should consult 
local  labeling  for  the  chemotherapy  drugs  being  administered  to  any  given  subject  for 
additional guidance on dose delays.
Rescheduling:
If any non-hematologic adverse event meeting the dose delay criteria above is felt to be related to 
only one particular agent in the  
fluorouracil and  cisplatin combination regimen, then that agent 
alone  may  be  omitted  for  that  cycle  while  the  other  agent  is  given.  In  order  to  maintain 
synchronized dosing of the regimen, the omitted agent should be resumed with the next scheduled 
cycle once the AE has improved and retreatment criteria are met. Please refer to Section 4.5.3to 
determine if dose reduction of the resumed agent is required.
If both drugs in fluorouracil and cisplatin combination regimen are delayed, then the subject should 
be re-evaluated weekly or more frequently if clinically indicated until re-treatment criteria are met 
(as per Section 4.5.4).
4.5.2.3 
Dose Delay Criteria for Nivolumab Combined with Fluorouracil plus 
Cisplatin Platinum in Arm B
In  Arm  B,  dosing  of  all  drugs  should  be  delayed  if  any  criteria in Sections 4.5.2.1(Arm  A, 
nivolumab and/or ipilimumab) or4.5.2.2(Arm C, fluorouracil and cisplatin combination) are met.
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That  is,  nivolumab  should  be  delayed  if  criteria  for  delay  of  chemotherapy are  met,  and 
chemotherapy should be delayed if criteria for delay of nivolumab are met.
4.5.3 
Dose Reductions
4.5.3.1 
Dose Reductions for Nivolumab or Ipilimumab
There will be no dose reductions for nivolumab or ipilimumab.
4.5.3.2 
Dose Reductions for Fluorouracil and Cisplatin combination
Dose reductions of fluorouracil and cisplatin combination may be required, and will be performed 
according toTable  4.5.3.2-1. The  dosing  reduction  criteria  will  apply  to  Arms  B  and  C. 
Chemotherapy  dose  reductions  are  permanent;  once  the  dose  of  any  chemotherapy  agent  is 
reduced, it may not be re-escalated in subsequent cycles. The dose reductions for each agent in the 
fluorouracil and cisplatin combination regimen are not linked and may be adjusted independently 
as summarized below.
In  subjects  who  required  fluorouracil dose  reduction  due to  toxicity  during  the
fluorouracil/cisplatin  combination  cycles,  the  dose  of  fluorouracil  may  be  re-escalated  to 
800 mg/m2after the discontinuation of cisplatin, at the investigator’s discretion and according to 
local standards, if the prior toxicity was felt to be related mainly to cisplatin.
If either fluorouracil or cisplatin is discontinued the other study drugs may be continued for the 
remainder of the cycles.
Table 4.5.3.2-1: 
Dose Modifications of FP
Dose Level
Fluorouracil
Cisplatin
Starting dose
800 mg/m²
80 mg/m²
First dose reduction
600 mg/m² 
(25% reduction)
60 mg/m²
(25% reduction)
Second dose reduction
400 mg/m²
(50% reduction)
40 mg/m²
(50% reduction)
Third dose reduction
Discontinue
Discontinue
Any  subjects  with  2 prior  dose  
reductions  
for one  agent  who  experiences  a toxicity  
that  would 
cause a third dose reduction must be discontinued from that agent.
Criteria for dose reduction due to postponement of starting a treatment cycle
If the patient does not meet the criteria for starting a treatment at the start of a treatment cycle and 
has to postpone the start of the cycle: 
• The dose of cisplatin and 5-FU will be the same as those used in the previous cycle when a 
treatment cycle is resumed by Day 15 of postponement (Day 1 is defined as the planned day 
of starting the next cycle of FP therapy). However, when a treatment cycle is resumed between
Day 9 and Day 15 (Day 1 is defined as the planned day of starting the next cycle of FP therapy) 
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for two consecutive cycles, the dose of attributable agent(s) should be reduced by 1 level in 
the second of such cycles. 
• When  a  
treatment  cycle  
is  
resumed  between  Day  16  and  Day  29  
(Day  1  
is  defined  as  
the 
planned  day  of  starting  
the  next  cycle  of  FP  
therapy),  
the  dose  of  
the  attributable  agent(s)
should be reduced by 1 level.
4.5.3.2.1 Fluorouracil and Cisplatin - Dose Reductions for Hematologic Toxicity 
Dose modifications for hematologic toxicities (according to CTCAE version 4) are summarized in
Table  4.5.3.2.1-1.  Dose  adjustments  are  based  on  nadir  blood  counts  (assessed  as  per  local 
standards) since the preceding drug administration. Dose  
level adjustments  
for fluorouracil and 
cisplatin  combination are  relative  to  that  of  the  preceding  administration.  Generally,  both 
chemotherapy agents in the fluorouracil and cisplatin combination regimen should be dose reduced 
together for hematologic toxicity. After the first cycle, G-CSF may be used to assist hematologic 
recovery.  Use  local  standards  of  care  in  the  use  of  these  supportive  measures.  Additionally, 
prophylactic  antibiotics  may  be  used  according  to  local  standards  of  care.  Please  report  any 
antibiotic or growth factor use on the eCRF.
Table 4.5.3.2.1-1: 
Dose Modifications for Hematologic Toxicity (Arms B and C)
Toxicitya
Fluorouracil
Cisplatin
Neutrophils (ANC) < 500/mm3 lasting ≥5 days
Reduce one dose level 
Reduce one dose level
Febrile neutropenia (body temperature ≥38.5°C
and ANC < 1,000/mm3)
Reduce one dose level 
Reduce one dose level
Platelet < 25,000/mm3
Reduce one dose level 
Reduce one dose level
Platelets < 50,000/mm3 with significant bleeding
or requiring blood transfusion
Reduce one dose level 
Reduce one dose level
Grade 4 hemoglobin (< 6.5 g/100 mL)
Reduce one dose level 
Reduce one dose level
a If considered in the best interest of the subject, and consistent with local practice, investigators may
 decide to use 
supportive measures/treatment, and/or secondary prophylaxis instead of dose reductions for the next cycle. Also, if 
toxicity can clearly be attributed to one of the drugs, the investigator may choose to only dose reduce one of the
cytotoxic agents.
4.5.3.2.2 Fluorouracil and Cisplatin - Dose Reductions for Non-hematologic 
Toxicity
Dose adjustments for fluorouracil and cisplatin combination for non-hematologic toxicities during 
treatment  are  described inTable  4.5.3.2.2-1.  All  dose  
reductions  
should  be  made  based  on  
the 
worst  CTCAE  grading.  Subjects  experiencing  any  of  
the  
toxicities  detailed  inSection 4.5.2.2
during the previous cycle  should  have their chemotherapy delayed until retreatment criteria are
met  (per Section 4.5.4and  then  reduced  for  all  subsequent  cycles  by  1  or  2  dose  level  or 
discontinued  as  appropriate.  Dose  levels  for the  two  drugs  in  the  fluorouracil  and  cisplatin 
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combination regimen are not linked and may be reduced independently, as summarized in the table 
below.
Table 4.5.3.2.2-1: 
Dose Modifications for Non-hematologic Toxicity (Arms B and C)
Toxicitya
Fluorouracil
Cisplatin
Febrile Neutropenia
Grade ≥3
Reduce one dose level
Reduce one dose level
DiarrheaGrade ≥3
Reduce one dose level
Reduce one dose level
StomatitisGrade ≥3
Reduce one dose level
Reduce one dose level
Neuropathy
Grade 2 lasting >7days OR
Grade 3 lasting ≤7days
No change
Reduce two dose level
Neuropathy
Grade 3 lasting >7days OR
Grade 4
No change
Discontinue
Nephrotoxicity
50-59 mL/min or Grade 3 Creatinine
No change
(Consider reduction in severe 
renal toxicity)
Reduce two dose level
(< 50 mL/min or Grade 4 
creatinine requires Discontinue)b
Total bilirubin > 1.5 x ULN
50% of previous dose
No change
Total bilirubin > 2.5 x ULN
25% of previous dose
No change
Total bilirubin > 4.0 x ULN
Discontinue
No change
Other Grade ≥3toxicity (except for 
fatigue and transient arthralgia and 
myalgia)
Adjust as medically indicated 
Adjust as medically indicated
Allergic reactionc
Grade ≥3
Discontinue
Discontinue
a If considered in the best interest of the subject, and consistent with local practice, investigators may
 decide to use 
supportive measures/treatment, and/or secondary prophylaxis instead of dose reductions for the next cycle. Also, if 
toxicity can clearly be attributed to one of the drugs, the investigator may choose to only dose reduce one of the
cytotoxic agents.
b Unless corrected within ±7 days of the scheduled dosing. CrCl should be determined consistently with the exact 
same  method  used  
to  determine  eligibility  ie  either  
the  Cockcroft-Gault  formula or  
the  preferred  method  for 
measured CrCl determination per local standard of care.
c Only  the  drug(s)  causing  the  hypersensitivity  reaction  or  acute  infusion  reaction  (≥Grade  3)  require(s) 
discontinuation. All other drugs may be continued.
4.5.4 
Criteria to Resume Dosing
4.5.4.1 
Criteria to Resume Nivolumab or Ipilimumab (Arms A and B)
Subjects may resume treatment with study drug when the drug-related AE(s) resolve to Grade ≤1 
or baseline value, with the following exceptions:
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• Subjects may resume treatment in the presence of Grade 2 fatigue
• Subjects who have not experienced a Grade 3 drug-related skin AE may resume treatment in 
the presence of Grade 2 skin toxicity
• For subjects with Grade 2 AST, ALT, or total bilirubin 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 BMS Medical Monitor.
• Subjects  with  Grade  <  4 drug-related  endocrinopathies  adequately  controlled  with  only 
physiologic hormone  replacement  may  resume treatment  after  consultation  with  the  BMS 
Medical Monitor.
If dose delay is necessary, both nivolumab and ipilimumab must be delayed until treatment can 
resume.  However,  if  a  nivolumab-related  infusion  reaction  prevents  subsequent  infusion  of 
ipilimumab on the same day, the dose of ipilimumab should be replaced as soon as possible. In 
such instances, at least 37 days must elapse between the replacement dose of ipilimumab and the 
administration of the next dose of nivolumab combined with ipilimumab.
4.5.4.2 
Criteria to Resume Fluorouracil and Cisplatin Combination (Arm C)
• Subjects may resume treatment when the ANC returns to ≥1500/μl, the platelet count returns 
to ≥100,000/mm
3.
• All  other  drug-related  
toxicities  have  returned  
to  baseline  or Grade ≤1  (or  Grade ≤2  for 
alopecia and fatigue).
• Subjects who have not experienced a Grade 3 drug-related skin AE may resume treatment in
the presence of Grade 2 skin toxicity.
• Subjects with baseline Grade 1 AST/ALT or total bilirubin who require dose delays for reasons 
other than a 2-grade shift in AST/ALT or total bilirubin may resume treatment in the presence 
of Grade 2 AST/ALT OR total bilirubin.
• Subjects  with  combined  Grade 2  AST/ALT  AND  total  bilirubin  values  meeting 
discontinuation parameters (Section 4.5.5.2) should have treatment permanently discontinued.
• Drug-related  pulmonary  
toxicity, diarrhea,  or  colitis,  must  have  
resolved  
to  baseline  before
treatment is resumed.
• If a subject fails to meet criteria for re-treatment, then re-treatment should be delayed, and the 
subject should be re-evaluated weekly or more frequently as clinically indicated. Any subject 
who  fails  
to  recover  from  
toxicity  attributable  
to  fluorouraciland  cisplatin  combination to 
baseline or Grade ≤1 (except Grade 2 alopecia and fatigue) within 8 weeks from the last dose 
given should discontinue the drug(s) that caused the delay.
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When resuming fluorouracil and cisplatin combination treatment, please follow the dose reduction 
recommendations in Section 4.5.3.2.
4.5.4.3 
Criteria to Resume Nivolumab Combined with Fluorouracil and 
Cisplatin (Arm B)
Subjects  
in  Arm  B  may  
resume  dosing  only  when  criteria  
for  BOTH resumption of nivolumab 
(Section 4.5.4.1)  AND  chemotherapy (Section 4.5.4.2)  are  met.  That  is,  nivolumab  and 
chemotherapy must  be  administered  together  until  treatment  discontinuation  criteria 
(Section4.5.5).
4.5.5 
Treatment Discontinuation Criteria
4.5.5.1 
Nivolumab and/or Ipilimumab Treatment Discontinuation (Arms A
and B)
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 ≥2  pneumonitis with  or  without  a  causal relationship  to  nivolumab and/or 
ipilimumab
• Any Grade 3 non-skin, drug-related adverse event lasting > 7 days or recurs, with the following 
exceptions  for  laboratory  abnormalities, diarrhea,  colitis,  neurologic  toxicity,  drug-related 
uveitis,  pneumonitis, bronchospasm,  hypersensitivity  reactions, infusion  reactions,  and 
endocrinopathies:
−Grade  3  drug-related  diarrhea,  colitis,  neurologic  toxicity,  myocarditis,  uveitis, 
bronchospasm,  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
−Grade  3  drug-related  laboratory  abnormalities  do  not  
require treatment  discontinuation 
except:
♦Grade 3 drug-related thrombocytopenia > 7 days or associated with bleeding requires 
discontinuation
♦Any drug-related liver function test (LFT) abnormality that meets the following criteria 
require discontinuation:
o Grade ≥3 drug-related AST, ALT or Total Bilirubin requires discontinuation
o Concurrent AST or ALT > 3 x ULN and total bilirubin > 2x ULN
• Any  Grade  4  drug-related  AE  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. 
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−Isolated Grade 4 electrolyte imbalances/abnormalities that are not associated with clinical 
sequelae and are corrected with supplementation/appropriate management within 72 hours 
of their onset
• Any  drug-related  Grade  4  endocrinopathy  and  Grade  3 adrenal  insufficiency  requires 
discontinuation
• Any treatment delay resulting in an interruption in nivolumab dosing > 8 weeks, or interruption 
in ipilimumab > 12 weeks, , with the following exceptions:
−Dosing  delays  to  allow  for prolonged  steroid  tapers  to  manage  drug-related  AEs  are 
allowed.
−Dosing  delays  
lasting  >8  weeks  
for  nivolumab  and  >12 weeks  
for  
ipilimumabfrom  
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 > 8 weeks, the BMS medical 
monitor must be consulted. Tumor assessments should continue as per protocol even if dosing is 
delayed. Periodic study visits to assess safety and laboratory studies should also continue every 
6 weeks or more frequently if clinically indicated during such dosing delays.
Any AE, laboratory abnormality, or intercurrent illness which, in the judgment of the Investigator, 
presents a substantial clinical risk to the subject with continued nivolumab dosing.
The assessment for discontinuation of ipilimumab should be made separately from the assessment 
made  for  discontinuation  of  nivolumab.  Although  there  is  overlap  among  the discontinuation 
criteria, if discontinuation criteria are met for ipilimumab but not for nivolumab, treatment with 
nivolumab may continue if ipilimumab is discontinued.
In nivolumab plus ipilimumab combination treatment (Arm A), if a subject meets the criteria for 
discontinuation of ipilimumab but not nivolumab, treatment with nivolumab may not resume until 
the  AE  has  fully  resolved  and  
the  subject  has  discontinued  steroids,  if  
they  were  required  for 
treatment  of  
the  AE.  The  
relationship  
to  
ipilimumab  should  be  well  documented  
in  
the  source 
documents. Nivolumab should be resumed at a dose of 3 mg/kg every 2 weeks.
If  a  subject  meets  the  criteria  for  discontinuation  of  nivolumab  but  not  for  ipilimumab,  both 
nivolumab and ipilimumab must be discontinued due to the lack of clinical efficacy of ipilimumab 
monotherapy (Section 1.1.6).
If  a  subject  in  the  nivolumab and  ipilimumab  combination  arm (Arm  A) meets  criteria  for 
discontinuation and investigator is unable to determine whether the event is related to both or one 
study drug, the subject should discontinue both nivolumab and ipilimumab and be taken off the 
treatment phase of the study.
4.5.5.2 
Fluorouracil and Cisplatin Dose Discontinuation (Arms B and C)
Except  where  specified  below,  both  chemotherapy  drugs  in  the  fluorouracil  and  cisplatin 
combination regimen should be discontinued for any of the following (applies to Arms B and C):
• Any  drug-related  Grade  4  toxicity  including  laboratory  abnormalities  the  subject  will  be
discontinued from the relevant study drug, with the following exceptions:
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−Isolated  Grade  4  electrolyte  abnormalities  not  associated  with clinical  sequelae  and  are
adequately managed and corrected within 72 hours of onset
−Grade 4 neutropenia≤7 days
−Grade 4 lymphopenia
• Any  Grade  3  non-skin,  drug-related  adverse  event  lasting  >  7  days,  with  the  following
exceptions:
−Grade  3  drug-related  
laboratory  abnormalities  do  not  
require  
treatment  discontinuation,
except for the following scenarios:
♦Grade ≥3  drug-related  thrombocytopenia  associated  with  clinically  significant 
bleeding requires discontinuation
♦Any drug-related liver function test (LFT) abnormality that meets the following criteria 
requires discontinuation:
• AST or ALT > 8 x ULN
• Total bilirubin > 5 x ULN
• Concurrent AST or ALT > 3 x ULN and total bilirubin > 2 x ULN
♦Any cisplatin-related decrease in creatinine clearance to < 50 mL/min (using the 
Cockcroft Gault formula or any chosen measured creatinine clearance method)
requires discontinuation of cisplatin, unless corrected within ±7 days of the 
scheduled dosing
• Grade 3 lasting > 7 days OR Grade 4 peripheral neuropathy
• Any  drug-related  adverse  event  which  recurs  after  
two  prior  dose  reductions  for  
the  same 
drug-related  adverse  event  (as  specified  in Section 4.5.3.2)  requires  discontinuation  of  
the 
drug(s) which was/were previously dose reduced.
• Any  Grade ≥3  drug-related  hypersensitivity  reaction  or  infusion  reaction  requires 
discontinuation of the drug(s) felt to be causing the reaction. The drug not felt to be related to 
the hypersensitivity reaction or infusion reaction may be continued.
• Any event that leads to delay in dosing of any study drug(s) for > 8 weeks from the previous 
dose requires discontinuation of that drug(s) with the following exception:
−Dosing  delays  >  8 weeks  that  occur  for  non-drug-related  reasons may  be  allowed  if
approved by the BMS Medical Monitor. Prior to re-initiating treatment in a subject with a
dosing  delay  lasting  >  8 weeks,  
the  BMS  Medical  Monitor  must  be consulted.  Tumor 
assessments should continue as per protocol even if dosing is delayed.
• Any adverse event, laboratory abnormality, or intercurrent illness which, in the judgment of
the Investigator, presents a substantial clinical risk to the subject with continued treatment.
Subjects could be discontinued from any or both of the study drugs on the FP regimen if, in the 
opinion of the investigator it is inappropriate to continue on the basis of safety or efficacy.
Subjects  who  discontinue  one  of  the  study drugs  on  
the  FP regimen  may  at  
the investigators 
discretion  continue  administration  of  the  other  study  drugs.  For  example,  if  Cisplatin is
discontinued, 5FU may be continued at the intended dose and schedule.
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For subjects in Arm B, if the investigator is unable to determine whether an adverse event is due 
to nivolumab or to fluorouracil and cisplatin combination, then all drugs must be discontinued.
The assessments for discontinuation of chemotherapy and/or nivolumab in Arm B should be made
separately. It is allowed to continue nivolumab alone when chemotherapy has been discontinued. 
Chemotherapy doublet or single drug is allowed to continue if nivolumab met its discontinuation 
criteria.
4.5.6 
Treatment Beyond Disease Progression
Accumulating evidence indicates a minority of subjects treated with immunotherapy may derive 
clinical benefit despite initial evidence of PD.56
Subjects  will  be  permitted  
to  continue  on  nivolumab alone  or  
in combination  with ipilimumab 
(Arm A) or chemotherapy (Arm B) for treatment beyond initial RECIST 1.1 defined PD, assessed 
by the investigator up to a maximum of 24 months from date of first dose as long as they meet the 
following criteria:
• Investigator-assessed clinical benefit.
• Tolerance of study drug
• Stable performance status
• Treatment beyond progression  will  not  delay  an  imminent  intervention  to  prevent  serious 
complications of disease progression (eg, CNS metastases)
• Subject provides written informed consent prior to receiving additional nivolumab alone or in 
combination with ipilimumab (Arm A) or chemotherapy (Arm B). All other elements of the 
main  consent  
including  description  of  
reasonably  
foreseeable  
risks  or  discomforts, or other 
alternative treatment options will still apply.
A radiographic  assessment/scan  should  be  performed  within  6 weeks  of  initial 
investigator-assessed progression to determine whether there has been a decrease in the tumor size 
or continued PD. The assessment of clinical benefit should be balanced by clinical judgment as to 
whether the subject is clinically deteriorating and unlikely to receive any benefit from continued 
treatment  with  nivolumab or  nivolumab  plus  ipilimumab or  nivolumab  plus  fluorouracil  and 
cisplatin.
If the investigator feels that the subjects treated with nivolumab or nivolumab plus ipilimumab or 
nivolumab  plus  fluorouracil  and  cisplatin continues  to  achieve  clinical  benefit  by  continuing 
treatment, the subject should remain on the trial and continue to receive monitoring according to 
the Time and Events Schedule in Section 5.1.
For the subjects in Arms A or B who continue nivolumab alone or in combination with ipilimumab 
(Arm  A)  or  chemotherapy (Arm B) beyond  progression,  further  progression  is  defined  as  an 
additional 10% increase in tumor burden with a minimum 5 mm absolute increase from time of 
initial  PD and  an  appearance  of  another  new  lesion.  This  includes  an  increase  in  the  sum  of 
diameters of all target lesions and/ or the diameters of new measurable lesions compared to the 
time of initial PD. Nivolumab alone or in combination with ipilimumab (Arm A) or chemotherapy
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(Arm B) treatment  should  be  discontinued  permanently  upon  documentation  of  further 
progression.
New lesions are considered measureable at the time of initial progression if the longest diameter 
is at least 10 mm (except for pathological lymph nodes which must have a short axis of at least 
15 mm).  Any  new  lesion  considered  non-measureable  at  the  time  of  initial progression  may 
become measureable and therefore included in the tumor burden if the longest diameter increases 
to at least 10 mm (except for pathological lymph nodes which must have a short axis of at least 
15 mm). In situations where the relative  
increase in total tumor burden by 10%  
is solely due to 
inclusion  of  new  lesions  which  become  measurable,  these  new  lesions  must  demonstrate  an 
absolute increase of at least 5 mm.
4.5.7 
Management Algorithms for Immuno-oncology Agents
Immuno-oncology (I-O) agents are associated with  AEs that can differ  
in severity and duration 
than  AEs  caused  by  other therapeutic  classes.  Nivolumab  and  
ipilimumab  
is  considered  an  
I-O
agent in this protocol. Early recognition and management of AEsassociated with I-O agents may 
mitigate severe toxicity. Management Algorithms have been developed to assist investigators in 
assessing and managing the following groups of AEs:
• Gastrointestinal
• Renal
• Pulmonary
• Hepatic
• Endocrinopathy
• Skin
• Neurological
The above algorithms are found in the nivolumab Investigator Brochure and Appendix 1 of this 
protocol.
4.5.8 
Treatment of Nivolumab or Ipilimumab Related Infusion Reactions
Since nivolumab and  
ipilimumab contains only  human  
immunoglobulin protein sequences, it is 
unlikely to be immunogenic and induce infusion or hypersensitivity reactions. However, if such a 
reaction  were  to  occur,  it  might  manifest  with  fever,  chills,  rigors,  headache,  rash,  pruritus, 
arthralgias, hypotension, hypertension, bronchospasm, or other allergic-like reactions. All Grade 3 
or  4  infusion reactions  should be  reported  within  24  hours  
to  
the  study  medical  monitor  and 
reported as an SAE if it meets the criteria. Infusion reactions should be graded according to NCI 
CTCAE version 4 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):
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• Remain  at  bedside  and  monitor  subject  until  recovery  from  symptoms.  The  following 
prophylactic premedications are recommended for future infusions: diphenhydramine 50 mg 
(or equivalent) and/or acetaminophen/paracetamol 325 to 1000 mg at least 30 minutes before 
additional nivolumab or ipilimumab administrations.
For Grade 2 symptoms: (moderate reaction required therapy or infusion interruption but responds 
promptly  
to  symptomatic  
treatment  
(eg,  antihistamines,  non-steroidal anti-inflammatory drugs, 
narcotics,  corticosteroids,  bronchodilators,  IV  fluids);  prophylactic  medications  indicated  for 
≤24 hours):
• Stop the nivolumab or ipilimumab infusion, begin an IV infusion of normal saline, and treat 
the subject with diphenhydramine 50 mg IV (or equivalent) and/or acetaminophen/paracetamol 
325  to  1000 mg;  remain  at  bedside  and  monitor  subject  until  resolution  of  symptoms. 
Corticosteroid and/or bronchodilator therapy may also be administered as appropriate. If the 
infusion  is  interrupted,  
then  restart  
the  infusion  at  50%  of  
the  original  infusion  rate  when 
symptoms  resolve;  if  no  further  complications  ensue  after  30 minutes,  the  rate  may  be 
increased to 100% of the original infusion rate. Monitor subject closely. If symptoms recur, 
then no further BMS-936558 will be administered at that visit.
• For  future  infusions,  the  following prophylactic  premedications  are  recommended: 
diphenhydramine 50  mg (or equivalent) and/or acetaminophen/paracetamol 325 to 1000 mg 
should  be  administered  at  least  30  minutes  before  nivolumab  or ipilimumab  infusions.  If 
necessary, corticosteroids (up to 25 mg of hydrocortisone or equivalent) may be used.
For Grade 3 or 4 symptoms: (severe reaction, Grade 3: prolonged [ie, not rapidly responsive to 
symptomatic medication and/or brief interruption of infusion]; recurrence of symptoms 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 or ipilimumab. Begin an IV infusion of normal 
saline and treat the subject as follows: Recommend bronchodilators, epinephrine 0.2 to 1 mg 
of a 1:1000 solution for subcutaneous administration or 0.1 to 0.25 mg of a 1:10,000 solution 
injected  slowly  for  IV  administration,  and/or  diphenhydramine  50mg  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 or  
ipilimumab
will be permanently discontinued. Investigators should follow their institutional guidelines for 
the  
treatment  of  anaphylaxis.  Remain  at  bedside  and  monitor  subject  until  
recovery  of  
the 
symptoms.
In case of late-occurring hypersensitivity symptoms (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
Not applicable.
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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 or Return of Investigational Product
For this study, IP (those supplied 
by BMS, a vendor or sourced by the investigator) such as partially 
used study drug containers, vials and syringes may be destroyed on site. 
If...
Then...
IP supplied by BMS (including its vendors) 
Any unused IP supplied by BMS can only be 
destroyed after being inspected and reconciled 
by the responsible Study Monitor unless IP 
containers must be immediately destroyed as 
required for safety, or to meet local 
regulations (eg, cytotoxics or biologics).
If IP will be returned, the return will be 
arranged by the responsible Study Monitor.
IP sourced by site, not supplied by BMS (or 
its vendors) (examples include IP sourced 
from the sites stock or commercial supply, or 
a specialty pharmacy)
It is the investigator’s or designee’s 
responsibility to dispose of all containers 
according to the institutional guidelines and 
procedures.
It is the investigator’s or designee’s responsibility to arrange for disposal, provided that procedures
for  proper  disposal  have  been  established  according  to  applicable  federal,  state,  local,  and 
institutional guidelines and procedures, and provided that appropriate records of disposal are kept. 
The following minimal standards must be met:
• On-site disposal practices must not expose humans to risks from the drug.
• On-site  disposal  practices  and  procedures  are  in  agreement  with  applicable  laws  and 
regulations, including any special requirements for controlled or hazardous substances.
• Written procedures for on-site disposal are available and  
followed. The procedures must be 
filed with the site’s Standard Operating Procedures (SOP) and a copy provided to BMS upon 
request.
• Records  are  maintained  that  allow  for  traceability  of  each  container,  including  the  date 
disposed of, quantity disposed, and identification of the person disposing the containers. The 
method of disposal, ie, incinerator, licensed sanitary landfill, or licensed waste disposal vendor 
must be documented.
• Accountability and disposal records are complete, up-to-date, and available for the Monitor to 
review throughout the clinical trial period.
•
It is the investigator’s or designee’s responsibility to arrange for disposal of all empty containers.
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If conditions for destruction cannot be met the responsible Study Monitor will make arrangements 
for return of IP provided by BMS (or its vendors). Destruction of non-IP sourced by the site, not 
supplied by BMS, is solely the responsibility of the investigator or designee.
Please refer to Section 9.2.2for additional guidance on IP records and documentation.
4.9 
Retained Samples for Bioavailability / Bioequivalence
Not applicable.
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5 
STUDY ASSESSMENTS AND PROCEDURES
5.1 
Flow Chart/Time and Events Schedule 
Table 5.1-1: 
Screening Procedural Outline - All Subjects (CA209648)
Procedure
Screening
Visit
Notes
Eligibility Assessments
Informed Consent
X
Contact IRT to obtain study subject number. Study allows for re-enrollment of 
a subject that has discontinued the study as a pre-treatment failure (ie, if subject 
has not been randomized). If re-enrolled, the subject must be re-consented and 
assigned a new subject number from IRT.
Inclusion/Exclusion Criteria
X
All inclusion/exclusion criteria should be assessed during screening and 
confirmed prior to randomization.
Disease Status
Medical History
X
Tumor Tissue Samples
X
Recent sample or archival. Sufficient tumor tissue (either a FFPE tissue block 
or minimum 15 slides*) must be available within 6 months prior to 
randomization and sent to a central laboratory for biomarker analysis. PD-L1 
status must be assessed prior to randomization.
Tissue must be a core needle biopsy, excisional or incisional biopsy. Fine 
needle biopsies are not considered adequate for biomarker review and 
randomization. Biopsies of bone lesions that do not have a soft tissue 
component or decalcified bone tumor samples are also not acceptable. 
* If, despite best efforts, a minimum 15 slides are not obtainable, discuss with 
Sponsor.
Safety Assessments
Physical Examination
X
Within 14 days prior to randomization.
Including audiometric assessment if required as per local standards of care.
Physical Measurements
X
Include Height, Weight and BSA
Within 14 days prior to randomization.
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Table 5.1-1: 
Screening Procedural Outline - All Subjects (CA209648)
Procedure
Screening
Visit
Notes
Vital Signs 
X
Including BP, HR and 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.
Assessment of Signs and Symptoms
X
Within 14 days prior to randomization.
Serious Adverse Event (SAE)
X
After informed consent is signed
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, albumin, Na, Ca, K, Cl, glucose and phosphate 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 (HBsAg, HCV antibody or HCV RNA), 
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 prior 
to first dose of study therapy
. 
For females under the age of 55 years a serum follicle stimulating hormone, 
(FSH) level > 40 mIU/mL is required to confirm menopause.
Efficacy Assessment
Baseline Tumor Imaging Assessment
X
CT Chest, CT/MRI scan of abdomen, pelvis, and any clinically indicated sites 
within 28 days prior to randomization. CT/MRI scan prior to ICF signature 
might be acceptable if performed within 28 days prior to randomization.  
IRT
IRT 
X
IRT must be contacted for subject number assignment at the time informed 
consent is obtained.
Some of the assessments referred to in this section may not be captured as data in the eCRF. They are intended to be used as safety monitoring by the treating 
physician. Additional testing or assessments may be performed as clinically necessary or where required by institutional or local regulations.
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Table 5.1-2: 
On-treatment Assessments - Subjects in Nivolumab 3 mg/kg and Ipilimumab 1 mg/kg - Arm A in 
CA209648
Procedure
Cycle 1
(2 Weeks 
Cycle) 
Day 1
Each 
Subsequent 
Cycle
Day 1
Note
A cycle refers to nivolumab every 2 weeks 
Safety Assessments
Physical Examination
X
X
To be performed within 72 hours of nivolumab dosing
Vital Signs
X
X
Obtain vital signs within 72 hours prior to nivolumab dose. Including BP, HR, 
and temperature.
Weight and ECOG Performance Status 
X
X
Within 72 hours of dosing See protocol appendices for ECOG Performance 
Status scale
Adverse Events Assessment
Continuously
Serious Adverse Event (SAE)
Continuously
Review of concomitant medications
X
X
Laboratory Tests
X 
See Note
Within 72 hours prior to each nivolumab dose through Week 23 visit and every 2 
cycles thereafter. 
Include CBC w/differential, ALT, AST, ALP, T-Bil, BUN or serum urea level, 
creatinine, Ca, Na, K, Cl, LDH, glucose and phosphate. 
TSH (with reflexive Free T4 and Free T3: Total T3/T4 are acceptable if Free 
T3/T4 are not available) every 6 weeks starting on first cycle. Note: Laboratory 
tests do not need to be repeated on C1D1 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 
and then every 4 weeks (± 1 week) regardless of dose delays; if collected with a 
dosing visit, then obtain within 24 hrs prior to administration of study drug: urine 
or serum.
PK and Immunogenicity Sampling
PK and immunogenicity blood samples
SeeTable 5.5-1for details regarding specific sample timing
Efficacy Assessments
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Table 5.1-2: 
On-treatment Assessments - Subjects in Nivolumab 3 mg/kg and Ipilimumab 1 mg/kg - Arm A in 
CA209648
Procedure
Cycle 1
(2 Weeks 
Cycle) 
Day 1
Each 
Subsequent 
Cycle
Day 1
Note
A cycle refers to nivolumab every 2 weeks 
Tumor Imaging Assessment
See Note
CT Chest, CT/MRI scan of abdomen, pelvis and all clinical indicated sites. 
Subjects with a history of brain metastasis should have surveillance MRI 
approximately every 12 weeks from the date of first dose, or sooner if clinically 
indicated.
Every 6 weeks (±7 days) from first dose up to and including Week 48, then 
every 12 weeks (±7 days) regardless of treatment schedule until disease 
progression (unless treatment beyond progression is permitted, see Section 
4.5.6).
Use same imaging method as was used at screening/baseline
Collection of biomarker sampling
See Table 5.6-1for Biomarker Sampling Schedule
Outcomes Research Assessments
FACT-E
X 
See Note
Assessed on Cycle 1 Day 1 and then every 2 weeks, up to Week 7 and every 6 
weeks (± 3 days) thereafter; regardless of treatment schedule; if administered on 
a dosing day, assessment should take place prior to any other study procedures.
PRO administrations not coinciding with another study assessment visit can be 
done via a phone contact
EQ-5D
X 
See Note
Health Care Resource Utilization
X
X
Assessed and completed by the site at every dosing visit
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Table 5.1-2: 
On-treatment Assessments - Subjects in Nivolumab 3 mg/kg and Ipilimumab 1 mg/kg - Arm A in 
CA209648
Procedure
Cycle 1
(2 Weeks 
Cycle) 
Day 1
Each 
Subsequent 
Cycle
Day 1
Note
A cycle refers to nivolumab every 2 weeks 
Study Drug
Dispense Study Treatment
X
X
First dose to be administered within 3 calendar days after randomization.
Nivolumab 3 mg/kg and ipilimumab 1 mg/kg doses may be administered within 
5 days before or after the scheduled date if necessary. Interval between 
ipilimumab doses should not be less than 37 days and 12 days in between 
nivolumab doses.
Every 3 cycles, Ipilimumab 1 mg/kg is administered.  
Vials may be assigned up to 3 calendar days prior to every dose date.
Some of the assessments referred to in this section may not be captured as data in the eCRF. They are intended to be used as safety monitoring by the treating 
physician. Additional testing or assessments may be performed as clinically necessary or where required by institutional or local regulations.
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Table 5.1-3: 
On-Treatment Assessments - Subjects in Nivolumab 240 mg Combined with Fluorouracil plus 
Cisplatin - Arm B in CA209648
Procedure
Cycle 1 
Day 1
Cycle 1 
Day 15
Cycles 2
and beyond 
Day 1
Cycles2
and beyond 
Day 15
Note
A cycle (4 weeks) refers to the nivolumab 
Q2W + FP Q4W 
Safety Assessments
Physical Examination
X
X
X
X
To be performed within 72 hours of nivolumab dosing
Including audiometric assessment if required as per local 
standards of care.
Vital Signs
X
X
X
X
Obtain vital signs within 72 hours prior to nivolumab dose. 
Including BP, HR, and temperature.
Weight, BSA and 
ECOG Performance 
Status
X
X
X
X
Within 72 hours prior to nivolumab dosing See protocol 
appendices for ECOG Performance Status scale
Adverse Events 
Assessment
Continuously
Assessed using NCI CTCAE v. 4
Serious Adverse Event 
(SAE)
Continuously
Assessed using NCI CTCAE v. 4
Review of concomitant 
medications
X
X
X
X
Laboratory Tests
X
See Note
Within 72 hours prior to each nivolumab dose through Week 
23 visit and every 2 nivolumab doses thereafter. 
Include CBC w/differential, ALT, AST, ALP, T-Bil, BUN or 
serum urea level, creatinine, Ca, Na, K, Cl, LDH, glucose and 
phosphate. 
TSH (with reflexive Free T4 and Free T3: Total T3/T4 are 
acceptable if Free T3/T4 are not available) every 6 weeks. 
Note: Laboratory tests do not need to be repeated on C1D1 if 
performed within 14 days prior to first dose.
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Table 5.1-3: 
On-Treatment Assessments - Subjects in Nivolumab 240 mg Combined with Fluorouracil plus 
Cisplatin - Arm B in CA209648
Procedure
Cycle 1 
Day 1
Cycle 1 
Day 15
Cycles 2
and beyond 
Day 1
Cycles2
and beyond 
Day 15
Note
A cycle (4 weeks) refers to the nivolumab 
Q2W + FP Q4W 
Pregnancy Test 
(WOCBP only)
X
See Note
Serum or urine within 24 hours prior to the initial 
administration of study drug and then every 4 weeks 
(± 1 week) regardless of dose delays; if collected with a dosing 
visit, then obtain within 24 hrs prior to administration of study 
drug: urine or serum.
PK and Immunogenicity Sampling
PK and immunogenicity 
blood samples
SeeTable 5.5-2for details regarding specific sample timing
Efficacy Assessments
Tumor Imaging 
Assessment
See Note
CT Chest, CT/MRI scan of abdomen, pelvis and all clinical 
indicated sites. Subjects with a history of brain metastasis 
should have surveillance MRI approximately every 12 weeks 
from the date of first dose, or sooner if clinically indicated.
Every 6 weeks (± 7 days) from first dose up to and including 
Week 48, then every 12 weeks (±7 days) regardless of 
treatment schedule until disease progression (unless treatment 
beyond progression is permitted, see Section 4.5.6).
Use same imaging method as was used at screening/baseline
Collection of biomarker 
sampling
See Table 5.6-1for Biomarker Sampling Schedule
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Table 5.1-3: 
On-Treatment Assessments - Subjects in Nivolumab 240 mg Combined with Fluorouracil plus 
Cisplatin - Arm B in CA209648
Procedure
Cycle 1 
Day 1
Cycle 1 
Day 15
Cycles 2
and beyond 
Day 1
Cycles2
and beyond 
Day 15
Note
A cycle (4 weeks) refers to the nivolumab 
Q2W + FP Q4W 
Outcomes Research Assessments
FACT-E
X
See Note
Assessed on Cycle 1 Day 1 and then every 2 weeks, up to 
Week 7, and every 6 weeks (± 3 days) thereafter; regardless of 
treatment schedule; if administered on a dosing day, 
assessment should take place prior to any other study 
procedures.PRO administrations not coinciding with another 
study assessment visit can be done via a phone contact
EQ-5D
X
See Note
Health Care Resource 
Utilization
X
X
Assessed and completed by the site at every dosing visit
Study Drug
Dispense Study 
Treatment
X
X
X
X
First dose to be administered within 3 calendar days after 
randomization.
Subsequent nivolumab 240 mg + FP doses may be 
administered within 3 days before or after the scheduled date if 
necessary. Subjects may be dosed no less than 12 days 
between nivolumab doses.
Vials may be assigned up to 3 calendar days prior to every 
dose date.
Some of the assessments referred to in this section may not be captured as data in the eCRF. They are intended to be used as safety monitoring by the treating 
physician. Additional testing or assessments may be performed as clinically necessary or where required by institutional or local regulations.
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Table 5.1-4: 
On-Treatment Assessments - Subjects in Fluorouracil and Cisplatin (FP) - Arm C in CA209648
Procedure
Cycle 1 
Day 1
Cycles 2 and beyond 
Day 1
Note
A cycle ( 4 weeks) refers to the FP Q4W 
Safety Assessments
Physical Examination
X
X
To be performed within 72 hours of cisplatin dosing
Including audiometric assessment if required as per local standards of 
care.
Vital Signs
X
X
Obtain vital signs within 72 hours prior to fluorouracil dose. Including BP, 
HR, and temperature.
Weight, BSA and ECOG 
Performance Status
X
X
Within 72 hours prior to dosing See protocol appendices for ECOG 
Performance Status scale
Adverse Events Assessment
Continuously
Assessed using NCI CTCAE v. 4
Serious Adverse Event (SAE)
Continuously
Assessed using NCI CTCAE v. 4
Review of concomitant 
medications
X
X
Laboratory Tests
X
See Note
Within 72 hours prior to each fluorouracil dose.
Include CBC w/differential, ALT, AST, ALP, T-Bil, BUN or serum urea 
level, creatinine, Ca, Na, K, Cl, LDH, glucose\ and phosphate. 
Note: Laboratory tests do not need to be repeated on C1D1 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 and then every 4 weeks (± 1 week) regardless of dose delays; if 
collected with a dosing visit, then obtain within 24 hrs prior to 
administration of study drug: urine or serum.
Efficacy Assessments
Tumor Imaging Assessment
See Note
CT Chest, CT/MRI scan of abdomen, pelvis and all clinical indicated sites. 
Subjects with a history of brain metastasis should have surveillance MRI 
approximately every 12 weeks from the date of first dose, or sooner if 
clinically indicated.
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Table 5.1-4: 
On-Treatment Assessments - Subjects in Fluorouracil and Cisplatin (FP) - Arm C in CA209648
Procedure
Cycle 1 
Day 1
Cycles 2 and beyond 
Day 1
Note
A cycle ( 4 weeks) refers to the FP Q4W 
Every 6 weeks (± 7 days) from first dose up to and including Week 48, then
every 12 weeks (±7 days) regardless of treatment schedule until disease 
progression, unless treatment beyond progression is permitted.
Use same imaging method as was used at screening/baseline
Collection of biomarker sampling
See Table 5.6-1for Biomarker Sampling Schedule
Outcomes Research Assessments
FACT-E
X
See Note
Assessed on Cycle 1 Day 1 and then every 2 weeks, up to week 7, and 
every 6 weeks (±3 days) thereafter; regardless of treatment schedule; if 
administered on a dosing day, assessment should take place prior to any 
other study procedures..
PRO administrations not coinciding with another study assessment visit 
can be done via a phone contact
EQ-5D
X
See Note
Health Care Resource Utilization 
X
X
Assessed and completed by the site at every dosing visit
Study Drug
Dispense Study Treatment
X
X
First dose to be administered within 3 calendar days after randomization.
Subsequent FP doses may be administered within 3 days before or after 
the scheduled date (Day 1) if necessary. Subjects may be dosed no less 
than 26 days between cisplatin doses.
Vials may be assigned up to 3 calendar days prior to every dose date.
Some of the assessments referred to in this section may not be captured as data in the eCRF. They are intended to be used as safety monitoring by the treating 
physician. Additional testing or assessments may be performed as clinically necessary or where required by institutional or local regulations.
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Table 5.1-5: 
Follow-Up Procedural Outline - All subjects (CA209648)
Procedure
Follow-up Phase Visits
FU1a- 30 Days 
(±7 Days) after Last 
Dose
FU2 - 84 Days 
(±7 Days) after FU1
Survival Phase Visits
Every 3 Months 
(±14 days) from FU2
Notes
Safety Assessments
Targeted Physical Examination
X
Adverse Events Assessment
X
Assessed using NCI CTCAE v. 4
Review of Subsequent Cancer Therapy
X
X
Laboratory Tests
X
Include CBC w/differential, ALT, AST, ALP, T-Bil, 
BUN or serum urea level, creatinine, albumin, Na, Ca, 
K, Cl, LDH, glucose. 
If there are ongoing AE, monthly lab tests will be 
conducted till FU2.
Pregnancy Test (WOCBP only)
X
See Note
Serum or urine
Only for FU1, unless testing is required for a longer 
period per local regulations
Efficacy Assessments
Tumor Imaging Assessment
See Note
See Note
For subjects who discontinue study treatment for 
reasons other than radiographic PD, follow-up scans 
should be performed every 6 weeks (±7 days) up to and 
including Week 48, then every 12 weeks until PD, lost 
to follow-up, or withdrawal of consent.
CT Chest, CT/MRI scan of abdomen, pelvis and any 
clinical indicated sites. 
Use same imaging method as was used at 
screening/baseline.
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Table 5.1-5: 
Follow-Up Procedural Outline - All subjects (CA209648)
Procedure
Follow-up Phase Visits
FU1a- 30 Days 
(±7 Days) after Last 
Dose
FU2 - 84 Days 
(±7 Days) after FU1
Survival Phase Visits
Every 3 Months 
(±14 days) from FU2
Notes
Outcomes Research Assessments
FACT-E
X
After FU1 and FU2, every 3 months (±14 days), during 
a clinic visit or via a phone contact.
ECS
X
FACT-G7
X
EQ-5D
X
Health Care Resource Utilization
X
Collection of biomarker sampling
See Table 5.6-1for Biomarker Sampling Schedule
Subject Status
Collection of Survival Status and 
Subsequent Therapy Information
X
X
Every 3 months (±14 days) or more frequently as 
needed after FU2, may be performed by phone contact 
or office visit, to include subsequent anticancer therapy.
Additional subsequent cancer therapy details such as 
regimen, setting of the regimen, line of therapy, start 
date and end date of each regimen, best response to the 
regimen and date of progression after second line 
therapy will be collected.
aOr coinciding with the date of discontinuation (±7 days) if date of discontinuation is greater than 35 days after last dose.
Some of the assessments referred to in this section may not be captured as data in the eCRF. They are intended to be used as safety monitoring by the treating 
physician. Additional testing or assessments may be performed as clinically necessary or where required by institutional or local regulations.
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5.1.1 
Retesting During Screening 
Retesting of laboratory parameters and/or other assessments within any single Screening 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  
treatment 
assignment) and is the valueby which study inclusion will be assessed, as it represents the subject’s 
most current, clinical state.
Laboratory parameters and/or assessments that are included inTable 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
• Nivolumab Investigator Brochure
• Ipilimumab Investigator Brochure
• Pharmacy Binder
• Imaging Manual
• Laboratory  Manuals  
for  collection  and  handling of  blood samples (including biomarker and 
immunogenicity samples) and tissue specimens.
• Site manual for operation of IRT system, including enrollment/randomization worksheets
• Manual for entry of local laboratory data
• Pregnancy Surveillance Forms
• Subject Questionnaires: FACT-E, EQ-5D, FACT-G7, and ECS
• AJCC Cancer Staging Manual for Esophageal Cancers, See Appendix 4
• NCCN Guidelines for Esophageal and Esophagogastric Junction Cancers
• ESMO Clinical Practice Guidelines for Oesophageal Cancer.
5.3 
Safety Assessments
5.3.1 
Screening Safety Assessments
At screening, a  medical  history will  be obtained to capture relevant underlying conditions. The 
screening  examinations  should  include  physical  examination,  weight,  height, BSA, ECOG 
Performance Status, blood pressure (BP), heart rate (HR), and temperature. 
Screening  local  laboratory  assessments  should  be  done  within  14days  prior  to  treatment 
assignment and  are  
to  
include:  CBC  with  differential,  Chemistry  panel  including  LFTs  (ALT, 
AST, total bilirubin, alkaline phosphatase), BUN or serum urea level, creatinine, albumin, Ca, Na, 
K, Cl, phosphate, LDH and glucose.
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Screening  pregnancy  
tests  for  WOCBP  must  be  performed  within  24  hours  prior  
to  
the  
initial 
administration of study drug. For females under the age of 55 years a serum follicle stimulating 
hormone, (FSH) level > 40 mIU/mL is required to confirm menopause.
The  following  screening  local  laboratory  assessments  should  be done  within  28 days  prior  
to 
treatment  assignment: Thyroid  panel  including  TSH,  free  T3,  and  free  T4,  Hepatitis B andC 
testing (HBsAg and HCV Ab or HCV RNA).
5.3.2 
On-Treatment Safety Assessments
While on-study the following local laboratory assessments are to be done within 3 calendar days 
prior to each nivolumab dose: CBC with differential, LFTs (ALT, AST, total bilirubin, alkaline 
phosphatase), BUN or serum urea level, creatinine, Ca, Na, K, Cl, phosphate, LDH and glucose
Thyroid  
function  
testing  
(TSH  with  
reflexive  
fT3  and  
fT4)  
is  
to  be done  every  6  weeks  
(every 
3 cycles)  
for subjects receiving  nivolumab at 3mg/kg q2w (i.e. Arm  A), and every 6 weeks for 
subjects receiving nivolumab at 240 mg q2w (Arm B). Total T3/T4 are acceptable if free T3/T4 
are not available. 
On treatment pregnancy tests should be performed as per the schedule in the Time & Events table.
Subjects will  be evaluated for safety  
if they have received any study drug. Toxicity assessments 
will be continuous during the treatment phase as well as during the first two safety follow-up visits. 
Once subjects reach the survival follow-up phase, either in-person visits or documented telephone 
calls/email correspondence to assess the subject’s status are acceptable.
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. 
Physical  examinations  are  to  be  performed  as  clinically  indicated.  If  there  are  any  new  or 
worsening  clinically  significant  changes  since  
the  
last  exam,  
report  changes  on  
the  appropriate 
non-serious or serious adverse event page.
On  
treatment  
local  
laboratory  assessments  are  
to be  completed  within  3  calendar  days  prior  
to 
nivolumab dosing.
Additional  measures,  including  non-study  required  laboratory  tests,  should  be  performed  as 
clinically indicated or to comply with local regulations. Laboratory toxicities (eg, suspected drug 
induced liver enzyme evaluations) will be monitored during the follow-up phase via on site/local 
labs until all study drug related toxicities resolve, return to baseline, or are deemed irreversible.
If  a  subject  shows  pulmonary-related  signs  
(hypoxia,  
fever)  or symptoms  
(eg.  dyspnea,  cough, 
fever)  consistent  with  possible  pulmonary  adverse  events,  the  subject  should  be  immediately 
evaluated  to  rule  out  pulmonary  toxicity,  according  to  the  suspected  pulmonary  toxicity 
management algorithm in the BMS-936558 (nivolumab) IB.
Some of the assessments referred to in this section may not be captured as data in the eCRF. They 
are  intended  to  be  used  as  safety  monitoring  by  the  treating  physician.  Additional  testing  or 
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assessments may be performed as clinically necessary or where required by institutional or local 
regulations.
5.3.3 
Follow-up Safety Assessments
Adverse events will be assessed and subsequent cancer therapy will  be reviewed as indicated in
Table  5.1-5.  A  physical  examination  will  be  performed  at  FU1  and  FU2 visit. Laboratory  and 
pregnancy tests will be performed as described inTable 5.1-5.
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. At the sponsor’s discretion, scans may be collected for review.
Any  additional  imaging  
that  may demonstrate  
tumor  response  or  progression  (including  scans 
performed at unscheduled timepoints and/or at an outside institution) should be collected for tumor 
assessment and submitted to the BICR.
5.4 
Efficacy Assessments
Study evaluations will take place in accordance with the flow charts inSection 5.1.Baseline tumor 
assessments  should  be  performed  within  28 days  prior  
to  randomization.  In  addition  
to  chest, 
abdomen,  pelvis,  clinically  
indicated  sites as  determined  by  
the  
treating  
investigator  should  be 
assessed at baseline. Subjects with  brain  metastasis adequately treated at least 2 weeks prior to 
treatment assignment must be reassessed by brain Magnetic resonance imaging (MRI) at baseline.
Subsequent assessments should include all sites that were assessed at baseline and should use the 
same imaging method as was used at baseline. 
Subjects  will  be  evaluated  for  disease  progression  every  6  weeks  from  the date  of  first  dose 
(± 7 days) up to and including Week 48, and then every 12 weeks (± 7 days) thereafter, regardless 
of treatment schedule, until disease progression or the subject discontinues the study, whichever 
comes first. Subjects with a history of brain metastasis (eg, a CR case treated prior to treatment 
assignment) should have surveillance MRI approximately every 12 weeks from the date of first 
dose, or sooner if clinically indicated.
Contrast-enhanced CT with PO/IV contrast or contrast-enhanced MRI are the preferred imaging 
modalities for assessing radiographic tumor response. If a subject has a known allergy to contrast 
material, local prophylaxis standards may be used to obtain the assessment with contrast if at all 
possible,  or  use  the  alternate  modality.  In  cases  where  contrast  is  strictly  contraindicated,  a 
non-contrast  scan  will  suffice.  Should  a  subject  have  a  contraindication  for  CT  IV  contrast,  a 
non-contrast CT of the chest and a contrast enhanced MRI of the  abdomen,  pelvis,  clinically 
indicated sites may  be obtained. Every attempt should  be  made to image each subject using an 
identical acquisition protocol and the same method for all imaging time points.
Tumor measurements should be made by the same investigator or radiologist for each assessment 
whenever possible. Change  
in tumor measurements and tumor response  will  be  assessed  by  
the 
Investigator using the RECIST 1.1 criteria. See Appendix 5.
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All radiologic images from the study will be submitted to a central imaging core lab for analysis 
by  a  BICR. The  BICR  will  review  tumor  images  in  all  randomized  subjects  to  determine 
RECIST 1.1 response for the analyses of PFS and ORR.
Details of the BICR responsibilities and procedures will be specified in the BICR charter.
5.5 
Pharmacokinetic Assessments
Pharmacokinetic (PK) and immunogenicity (IMG) assessment data will be collected from study 
subjects assigned to the nivolumab-plus-ipilimumab (Arm A) and nivolumab-plus-chemotherapy 
arm  
(Arm  B)  at  
the  
time  points  
indicated  
in Table  5.5-1, andTable  5.5-2.  All  
time  points  are 
relative to the start of study drug administration. All on-treatment time points are intended to align 
with days on which study drug is administered; if dosing occurs on a different day, the PK and 
IMG sampling should be adjusted accordingly. If it is known that a dose is going to be delayed, 
then the predose sample should be collected just prior to the delayed dose. However, if a predose 
sample is collected but the dose is subsequently delayed, an additional predose sample should not 
be collected. 
Further details of sample collection, processing, and shipment will be provided in the laboratory 
procedures manual. PK samples will be analyzed for nivolumab/ipilimumab by a validated ligand 
binding  assay.  Immunogenicity  samples  will  be  analyzed  for  anti-nivolumab/anti-ipilimumab
antibodies by a validated immunogenicity assay; samples may also be analyzed for neutralizing 
antibodies by a validated method. Serum samples may be analyzed by an exploratory method that 
measures anti-drug antibodies for technology exploration purposes; exploratory results will not be 
reported.  Serum  samples  designated  for  PK  or  biomarker  assessments  may  also  be  used  for 
immunogenicity  analysis  if  required  (eg, insufficient  volume  for  complete  immunogenicity 
assessment or to follow up on suspected immunogenicity related AE).
PKand  immunogenicity  assessments  will  be  collected  from  study  subjects  assigned  to  the 
nivolumab 3 mg/kg and ipilimumab 1 mg/kg arm (Arm A) at the time points indicated inTable 
5.5-1. 
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Table 5.5-1: 
Pharmacokinetic and Immunogenicity Sampling Schedule for Nivolumab and Ipilimumab in Arm A
Study Cycle/Day
One Cycle = Every 2 weeks
(Nivo administered every 
2 weeks, Ipi every 6 weeks)
Event 
(Relative to 
Start of 
Infusion)
Time 
(Relative to Start 
of Nivolumab 
Infusion)
Hour:Min
Nivolumab PK 
Blood Samples
Nivolumab 
Immunogenicity 
Blood Samples 
Ipilimumab PK 
Blood Samples 
Ipilimumab 
Immunogenicity 
Blood Sample
Cycle 1 Day 1 
Predosea,b
00:00
X
X
X
X
Cycle 2 Day 1
Predosea,b
00:00
X
X
X
X
Cycle 4 Day 1
Predosea,b
00:00
X
X
X
X
Cycle 5 Day 1
Predosea,b
00:00
X
X
X
X
Cycle 7 Day 1
Predosea,b
00:00
X
X
X
X
Cycle 15 Day 1
Predosea,b
00:00
X
X
X
X
Cycle 23 Day 1
Predosea,b
00:00
X
X
X
X
Cycle 35 Day 1
Predosea,b
00:00
X
X
X
X
Cycle 47 Day 1
Predosea,b
00:00
X
X
X
X
a If ipilimumab is discontinued and nivolumab continues, ipilimumab PK and ADA should be collected only for the next 2 time points (corresponding to nivolumab 
sample collection) according to the PK table
b Predose samples should be collected just before the administration of the first drug (preferably  within 30 minutes). If it is known that a dose is going to be 
delayed, then the predose sample should be collected  
just prior to the delayed dose.  However, if a predose sample is collected but the dose is subsequently 
delayed, an additional predose sample should not be collected.
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PKand immunogenicity assessments will be collected from study subjects assigned to nivolumab 
240 mg combined with fluorouracil and cisplatin, Arm B at the time points indicated inTable 
5.5-2. 
Further details of sample collection, processing, and shipment will be provided in the laboratory 
procedures manual.
Table 5.5-2: 
Pharmacokinetic and Immunogenicity Sampling Schedule for the 
Nivolumab + Chemotherapy Arm B
Study Cycle/Day
One Cycle = Every 4 weeks
Nivolumab= every 2 weeks
Event 
(Relative to Start 
of Nivolumab 
Infusion)
Time 
(Relative to Start of 
Nivolumab Infusion)
Hour:Min
Nivolumab 
PK Blood 
Sample
Nivolumab 
IMG Blood 
Sample
Cycle 1 Day 1 
Predosea,b
00:00
X
X
Cycle 2 Day 1
Predosea,b
00:00
X
X
Cycle 3 Day 1
Predosea,b
00:00
X
X
Cycle 7 Day 1
Predosea,b
00:00
X
X
Cycle 9 Day 1
Predosea,b
00:00
X
X
Cycle 17 Day 1
Predosea,b
00:00
X
X
Cycle 25 Day 1
Predosea,b
00:00
X
X
a If nivolumab is discontinued and chemotherapy continues, nivolumab PK and ADA should be collected only for 
the next 2 time points according to the PK table
b Predose samples should be collected just before the administration of the first drug (preferably within 30 minutes). 
If it is known that a dose is going to be delayed, then the predose sample should be collected just prior to the delayed 
dose. However, if a predose sample is collected but the dose is subsequently delayed, an additional predose sample 
should not be collected.
5.6 
Biomarker Assessments
Tumor  tissue, blood, and  stool  samples  will  be  collected  prior  
to  
treatment.  Peripheral  blood 
samples will also be collected at selected timepoints on treatment. If a biopsy or surgical resection 
is performed at the time of progression or suspected progression, tumor samples (block or slides) 
should  be  submitted  for  analysis.  If  biomarker  samples  are  drawn  but  study  drug(s)  is  not 
administered, samples will be retained. A detailed description of each assay system is described 
below and a schedule of pharmacodynamic evaluations is provided inTable 5.6-1. 
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Table 5.6-1: 
Biomarker Sampling Schedule
Collection Timinga
Tumor
Whole Blood
DNA
Plasma 
Serum 
PBMC  
Stool
Screening
Xb
Day 1 (D1Wk1) 
X
X
X
Xc
X
Day 15 (D1Wk3)
X
X
X
Day 43 (D1Wk7)
X
X
X
Day 85 (D1Wk13)
X
X
X
Upon Progression
Xb
X
X
X
a Biomarker sampling occurs prior to dosing of study drug and can occur ±7 days from the scheduled time but must 
be prior dosing.
b Tumor tissue prior to therapy is mandatory. If a recent as defined by protocol archived biopsy is not available at 
screening,  a  
tumor  
tissue  will  be  
taken  at  any  point  prior  
to  
treatment  and  will  be  
formalin  
fixed  and  paraffin 
embedded. Tumor tissue during study therapy (eg, at suspected tumor progression) is optional.
c Peripheral blood samples will be taken at designated time points for PBMC preparation, except at sites where the 
stability  of the samples after shipment to the central laboratory cannot be guaranteed. Samples must be shipped 
within 48 hours to a BMS-designated central laboratory for processing.
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  
to the  central  
lab  prior  
to treatment  assignment.  
In  situations 
where on-treatment biopsies or surgeries are performed, tumor samples should be sent for central 
pathology reading. The tissue submitted will be assessed for quality with an H&E stain and only 
those participants who have met tissue quality thresholds can be assigned study drug.
A tumor tissue obtained within 6 months prior to randomization with no prior systemic therapy 
administered  in  the  interval  time  between  sample  collection  and  randomization is  required  to 
ensure that biomarker analysis of the tumor sample is not impacted by effects of prior therapy, age 
of specimen or insufficiency of tissue.
5.6.1.1 
Tumor Sample Collection Details
Collection  of  tumor  tissue  at  diagnostic  surgery  is  required  for  study  eligibility.  If  clinically 
appropriate, additional biopsies obtained at any time, eg, if progression is suspected, may also be
collected.
An assessment of tissue quality  by a local pathologist  
is strongly encouraged at the time of the 
procedure. The tumor tissue that is obtained will be formalin fixed and paraffin-embedded.
Detailed  instructions  of  
the  obtaining,  processing,  
labeling,  handling,  storage  and  shipment  of
specimens will be provided in a separate Procedure Manual at the time of study initiation.
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5.6.1.2 
Characterization of Tumor Infiltrating Lymphocytes (TILs) and Tumor 
Antigens
IHC  or  equivalent  methods  will  be  used  to  assess  the  number  and  composition  of  immune
infiltrates in order to define the immune cell subsets present within FFPE tumor tissue before and 
after exposure to therapy. These IHC analyses may include, but not necessarily be limited to, the 
following markers: CD4, CD8, FOXp3, PD-1, PD-L1, and PD-L2.
5.6.1.3 
Characterization of T cell Repertoire
As described above, DNA sequencing may be performed on pre-and post-treatment tumor tissue
to assess the composition of the T cell repertoire.
5.6.1.4 
Gene Expression Profiling
Tumor tissue will be examined for mRNA gene expression to detect expression of selected cancer 
and immune related genes.
5.6.1.5 
Tumor Genotyping, Mutational Analysis, and Tumor Antigen Profiling
RNA  and  DNA  from  tumor samples  will  be  analyzed  using  whole-exome  and  transcriptome
sequencing to determine the number of mutations found within a given sample relative to a normal 
host  
tissue,  such  as  adjacent  non-transformed  cells  or  PBMC.  
In  addition  
to  
tumor  mutational 
burden (TMB), mutational analyses of cancer related genes and genes relevant for immunotherapy 
may be performed. Mutations that are detected may be analyzed for their ability to bind the major 
histocompatibility  complex  
(MHC) I  and  MHC II  proteins  using  prediction algorithms,  such  as 
NetMHC. Evaluating the ability of tumor mutations to bind MHC molecules will provide evidence 
that  these  mutations  are  serving  as  antigens  that  are  recognized  the immune  system  and  are 
potential rejection antigens.
5.6.1.6 
Microsatellite instability status
Microsatellite  
instability  
(MSI)  
is  emerging  as  a  predictive  biomarker  
for  checkpoint  blockade 
therapy. Different from gastric cancer, esophageal cancer, especially ESCC, has much lower MSI 
prevalence. MSI status may be determined where possible.
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  taken  from  all  subjects  prior  to  or during 
treatment.  Data from  these  investigations  will  be  evaluated  for  associations  with  response,
survival, and/or safety (adverse event) data. Several analyses will be completed and are described 
briefly below.
5.6.2.1 
Soluble Biomarkers
Soluble factors, such as cytokines, chemokines, soluble receptors, and antibodies to tumor antigens 
will  be characterized and quantified  by  
immunoassays  
in serum. Analyses  may  
include, but not 
necessarily be limited to, soluble CD25, soluble PD-1, soluble LAG-3, and CXCL-9.
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Collected serum samples may also be used for the assessment of tumor antigen-specific responses 
elicited  following  treatment  with  monotherapy  and  combination  therapy  to  explore which 
antitumor  antibodies  are  most  associated  with clinical  
response.  Antibody  
levels  
to  cancer test 
antigens may be assessed.
5.6.2.2 Immunophenotyping
The  proportion  of  specific  lymphocyte  subsets  and  expression  levels  of T-cell co-stimulatory
markers in PBMC preparations will be quantified. Analyses may include, but not necessarily be 
limited  
to,  
the  proportion  of  T,  B, and NK  cells,  granulocytes, the  proportion  of  memory  and 
effector T-cell subsets, and expression levels of PD-1, PD-L1, other B7 family members, ICOS, 
and Ki67.
5.6.2.3 
T cell Repertoire Analysis
Low diversity of the peripheral T cell compartment has been shown to correlate with poor overall 
survival in metastatic breast cancer. A standing theory in immuno-oncology suggests a diverse and 
activated  immune  environment  is  better  adept  at  eradicating  tumor  compared  to  a skewed 
repertoire of naïve and tolerized T cells. In order to explore whether a diverse T cell repertoire is 
predictive  of  response  
to  
therapy,  
the  composition  of  
the  T  cell  repertoire  prior  
to  and  during 
therapy may be assessed.
5.6.2.4 
Whole Blood for Germline DNA
Whole blood will be collected from all subjects prior to treatment to generate genomic DNA for
genetic variant analyses and to serve as a reference for tumor genomic testing. These analyses will 
focus on genetic variant within genes associated with PD1 and other immunoregulatory signaling 
pathways  to  determine  if  natural  variation  within  those  genes  is associated  with  response  to 
nivolumab and/or with adverse events during treatment.
5.6.2.5 
Plasma for circulating tumor DNA
The presence of cell-free DNA in circulating blood is a well-documented phenomenon. Fragments 
of DNA are shed into the blood stream from dividing cells during cell proliferation or cell death. 
In participants with cancer, a fraction of this DNA is tumor-derived and is termed circulating tumor 
DNA  (ctDNA).  Several  studies  have  detected  mutations  in  ctDNA  that  exactly  correspond  
to 
mutations  from  the  parent  tumor.  Early  decrease  in  ctDNA  following  treatment  with 
immunotherapy was associated with  
improved outcomes
57. Plasma samples will  be analyzed to 
determine the presence and frequency of ctDNA.
5.6.2.6 
Stool for microbiome
The  gut  microbiome  influences  cancer  development  and  response  to  
therapy.  The  efficacy  of 
cancer immunotherapy with checkpoint blockade could be diminished with the administration of 
antibiotics. Clinical efficacy has been associated with microbiome composition and the presence 
of specific microbe species.58, 59, 60The association of microbiome with efficacy and safety will 
be evaluated using stool samples collected before treatment.
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5.7 
Outcomes Research Assessments
Subjects  will  be  asked  
to  complete  
the  EQ-5D-3L  and  FACT-E  on each  Cycle  1  Day  1 every 
2 weeks until Week 7 and every 6 weeks thereafter, 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, FACT-E, and the FACT-G7.
The questionnaires will be provided in the subject’s preferred language, if 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, and 
FACT-G7, though subjects will be provided with hard copies of these questionnaires to take home 
and use as visual aids during telephone interviews. Section 5.1provides information regarding the 
timing of patient-reported outcomes assessments.
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) for patients.  
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  
to the  FACT-G, 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 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 for each Cohort, which provides an overall indicant of generic HRQL. The FACT-G 
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and  ECS  scores  can  be  combined  to  produce  a  
total  score  for  
the  FACT-E,  which  provide  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. However, to minimize subject response and administrative burden, only the  FACT-G7 
and ECS will be administered during the survival follow-up phase.
In addition to the aforementioned patient-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 
Additional research collection
This protocol will include residual sample storage for additional research (AR).
For All US sites: 
Additional research participation is required for all investigational sites in the US. 
For non-US Sites:
Additional research is optional for all study participants, except where retention and/or collection 
is prohibited by local laws or regulations, ethics committees, or institutional requirements. 
This collection for additional research is intended to expand the translational R&D capability at 
Bristol-Myers  Squibb,  and  will  support  as  yet  undefined  research  aims  that  will  advance our 
understanding of disease and options for treatment. It may also be used to support health authority 
requests for analysis, and advancement of pharmacodiagnostic development to better target drugs 
to the right patients. This may also include genetic/genomic exploration aimed at exploring disease 
pathways, progression and response to treatment etc. 
All requests for access to samples or data for additional research will be vetted through a diverse 
committee of the study sponsor’s senior  
leaders  
in Research and Development (or designee) to
ensure the research supports appropriate and well-defined scientific research activities.
Residual blood, serum and tumor tissue will also be retained for additional research purposes 
Samples kept for future research will be stored at the BMS Biorepository in Hopewell, NJ, USA 
or an independent, BMS-approved storage vendor. 
• The manager of these samples will ensure they are properly used throughout their usable life 
and will destroy the samples at the end of the scheduled storage period, no longer than 15 years 
after the end of the study or the maximum allowed by applicable law. 
• Transfers  of  samples  by  research  sponsor  
to  
third  parties  will be  subject  
to  
the  recipient’s 
agreement to establish similar storage procedures. 
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Samples will be stored in a coded fashion, and no researcher will have access to the key. The key
is securely held by the Investigator at the clinical site, so there is no direct ability for a researcher 
to connect a sample to a specific individual. 
Further details of sample collection and processing will be provided to the site in the procedure 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:
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.)
Sponsor  or  designee will  be  reporting  adverse  events  to  regulatory  authorities  and  ethics 
committees according to local applicable laws including European Directive 2001/20/EC and FDA 
Code of Federal Regulations 21 CFR Parts 312 and 320.
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, 
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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 6.6for 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 Section6.1.1
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 6.1.1for reporting details).
NOTE: 
The following hospitalizations are not considered SAEs in BMS clinical studies: 
−a visit to the emergency room or other hospital department < 24 hours, that does not result 
in admission (unless considered an important medical or life-threatening event)
−elective surgery, planned prior to signing consent
−admissions as per protocol for a planned medical/surgical procedure
−routine  health  assessment  requiring  admission  for  baseline/trending  of  health  status 
(eg, routine colonoscopy)
−medical/surgical admission other than to remedy ill health and planned prior to entry into 
the study. Appropriate documentation is required in these cases
−admission encountered for another life circumstance that carries no bearing on health status 
and requires no medical/surgical intervention (eg, lack of housing, economic inadequacy, 
caregiver respite, family circumstances, administrative reason)
−Admission  for  administration  of  anticancer  therapy  in  the  absence  of  any  other  SAEs 
(applies to oncology protocols).
6.1.1 
Serious Adverse Event Collection and Reporting
Sections  5.6.1  and 5.6.2 in  the  Investigator  Brochure (IB)  represent  the  Reference  Safety 
Information  to  determine  expectedness  of  serious  adverse  events  for  expedited  reporting. 
Following the subject’s written consent to participate in the study, all SAEs, whether related or not 
related to study drug, must be collected, including those thought to be associated with protocol-
specified procedures. All SAEs must be collected that occur during the screening period and within 
100 days of discontinuation of dosing. For subjects randomized/assigned to treatment and never 
treated  with  study  drug,  SAE  information  should  be  collected  for  30  days  from  the  date  of 
randomization.
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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.
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 Sponsor 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  Directive  2001/20/EC  and  FDA  Code  of  Federal 
Regulations  21  CFR  Parts  312  and  320.  A  SUSAR  (Suspected,  Unexpected  Serious  Adverse 
Reaction) is a subset of SAEs and will be reported to the appropriate regulatory authorities and 
investigators following local and global guidelines and requirements.
6.2 
Nonserious Adverse Events
Anonserious adverse eventis an AE not classified as serious.
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6.2.1 
Nonserious Adverse Event Collection and Reporting
The collection of nonserious AE information should begin at initiation of study drug. Nonserious 
AE information  should  also  be  collected  from  the  start  of  a  placebo  lead-in  period  or  other 
observational period intended to establish a baseline status for the subjects.
Nonserious  AEs  should  be  followed  
to  
resolution  or  stabilization,  or  
reported  as  SAEs  
if  
they 
become  serious  (see Section  6.1.1).  Follow-up  is  also  required  for  nonserious  AEs  
that  cause 
interruption or discontinuation of study drug and for those present at the end of study treatment 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.
All nonserious adverse events (not only those deemed to be treatment-related) should be collected 
continuously during the treatment period and for a minimum of 100 days following discontinuation 
of study treatment. 
Every adverse event must be assessed by the investigator with regard to whether it is considered 
immune-mediated. For events which are potentially immune-mediated, additional information will 
be collected on the subject’s case report form.
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 electronic) as appropriate. Paper forms are only intended as a back-up 
option when the electronic system is not functioning.
• Any laboratory test result that is clinically significant or meets the definition of an SAE 
• Any laboratory 
test result abnormality that required the 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.
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In most cases, the study drug will be permanently discontinued in an appropriate manner (eg, dose 
tapering  
if  necessary  
for subject safety). Please call the Sponsor or designee within 24 hours of 
awareness of the pregnancy.
The investigator must immediately notify the Sponsor or designee of this event and complete and 
forward a Pregnancy Surveillance Form to Sponsor or designee within 24 hours of awareness of 
the event and in accordance with SAE reporting procedures described in Section 6.1.1. 
Follow-up  
information  
regarding  
the  course of  
the  pregnancy,  
including  perinatal  and  neonatal 
outcome  and,  where  applicable,  offspring  information  must  be  reported  on  the  Pregnancy 
Surveillance Form.
Any pregnancy that occurs in a female partner of a male study participant should be reported to 
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  this 
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 6.1.1for 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 6.1.1for reporting details).
Potential drug induced liver injury is defined as: 
• AT (ALT or AST) elevation > 3 times upper limit of normal (ULN)
7) AND
• Total bilirubin > 2 times ULN, without initial findings of cholestasis (elevated serum alkaline 
phosphatase),
8) AND
• 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.
6.7.1 
Adverse Events of Interest
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 
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which were exacerbated by the induction of autoimmunity. Information supporting the assessment 
will be collected on the subject’s case report form.
7 
DATA MONITORING COMMITTEE AND OTHER EXTERNAL 
COMMITTEES
7.1 
Data Monitoring Committee
An independent Data Monitoring Committee (DMC) will be utilized. A DMC will be established 
to provide oversight of safety and efficacy considerations in CA209648. 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  plus  ipilimumab and 
nivolumab plus fluorouracil and cisplatin. 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. 
DMC will review the safety data from the study when approximately (dependent on the accrual 
speed) 45 subjects (about 5% of subjects) have been treated and followed for at least 4 weeks.
Details of the DMC responsibilities and procedures will be specified in the DMC charter.
7.2 
Independent Review of Progression at the Time of Investigator-
Assessed Progression
At the time of investigator-assessed initial radiographic progression per RECIST 1.1 in any given 
subject, the site must request the blinded independent review of progression from the third party 
radiology vendor.
Tumor  assessments  for  each  subject  should  be  submitted  
to  
the  radiology  vendor  as  
they  are 
performed  on  an  ongoing  basis.  The  blinded,  
independent radiologists  will  
review  all  available 
tumor assessments for that given subject and determine if RECIST 1.1 criteria for progression have 
been met. The independent assessment of whether or not the given subject met RECIST 1.1 criteria 
for progression will be provided to the site. Subjects whose disease progression is not confirmed 
centrally will  be  
required  
to  continue  
tumor assessments (if clinically  
feasible) according to the 
protocol-specified schedule. Subsequent tumor assessments must be submitted to the third party 
radiology  vendor  for  subsequent  review  and  may  be  discontinued when  the  investigator  and 
independent radiologists both assess the subject to have met RECIST 1.1 criteria for progression.
In addition,  subjects  
receiving  
treatment  beyond  progression  must  continue  
tumor  assessments 
until such treatment has been discontinued. 
If clinically acceptable, subsequent therapy should begin only after RECIST 1.1 progression has 
been  assessed  by  Blinded Independent  Central  Review.  For  subjects  who  start  palliative  local 
therapy  or  subsequent  
therapy  without  prior  assessment  of  RECIST  1.1  progression  by  central 
review, the Investigator must continue tumor assessments (if clinically feasible) according to the 
protocol-specified schedule and submit them to the third-party radiology vendor. When RECIST 
1.1  progression  is  assessed  by  the investigator  (whether  assessed  before  or  after  the  start  of 
palliative local therapy or subsequent therapy), the Blinded Independent Central Review must be 
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requested. Tumor assessments may be discontinued when the independent radiologist assesses the 
subject to have met RECIST 1.1 criteria for progression.
8 
STATISTICAL CONSIDERATIONS
8.1 
Sample Size Determination
It  
is  now  established  
that time-to-events  endpoints  
in  
I-O  clinical  
trials  
tend to  display  specific 
characteristics.  First,  there  may  be  long-term  survival  benefits  in  patients  treated  with 
immunotherapy - observed as a long lasting plateau towards the tail of the survival curve (“cure”). 
Second,  some  
results  also  suggested  a  delayed  effect  
- observed as  
late  separation  of  survival 
curves  between  experimental  and  control  arms.  Both  long-term  survival  and  delayed  onset  of 
benefit may be linked to the mechanisms of action of I-O drugs. As these phenomena are expected 
to be observed in the current disease setting as well, a piecewise mixture cure rate model was used 
for the design setup. 
Sample size calculations assume that the prevalence of subjects with PD-L1 tumor expression level 
≥1% is approximately 50%. (During enrollment, the proportion of subjects with or without PD-L1 
tumor  expression  will  be  monitored,  and  may  be  re-assessed  in  case  it  does  not  
reflect  study 
assumptions.)
In addition, proportion of patients in the chemotherapy arm who receive I-O as subsequent therapy 
will be monitored; protocol may be amended accordingly.
The sample size is based on the primary objectives, ie, on the comparisons of the PFS/OS 
distributions of subjects with PD-L1 expressing tumorsbetween those who were randomized 
to receive nivolumab plus ipilimumab vs those randomized to receive chemotherapy, and between 
those  who  were  randomized  
to  receive  nivolumab  plus  chemotherapy  vs  
those  randomized  
to 
receive chemotherapy. 
For both experimental arms, the same OS distributions and the same PFS distributions are assumed 
(seeTable 8.1-1). As a result, for each of the nivolumab plus  
ipilimumab vs chemotherapy and 
nivolumab plus chemotherapy vs chemotherapy comparisons:
• 250  PFS  events  
in  approximately  313  subjects  with  PD-L1  expressing  
tumors  will provide 
approximately  90%  power  to  detect  an  average  HR  of  0.62  with  a Type  I  error  of  1.5% 
(two-sided);
• 250  OS  events  in  approximately  313  subjects  with  PD-L1  expressing  
tumors  will provide 
approximately  90%  power  to  detect  an  average  HR  of  0.6  with  a  Type  I  error  of  1% 
(two-sided).
To  have  approximately  313 randomized  subjects  with  PD-L1  expressing  tumors  for  each 
comparison, approximately 470 subjects with PD-L1 expressing tumors need to be randomized in 
in a 1:1:1 ratio in the 3 arms. Which therefore translates to a total of approximately 939 subjects 
(with any PD-L1 result) to be randomized  
in a 1:1:1 ratio to the nivolumab plus  
ipilimumab or 
nivolumab plus chemotherapy or chemotherapy arms. Assuming a piecewise constant accrual rate, 
it is estimated that these 939 subjects will be accrued within 29months.
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Although for the comparison of both experimental arms with the control arm, the same treatment 
effect is assumed, observed treatment effects may vary. Therefore, the events of interest (OS, PFS) 
observed in the chemotherapy arm onlywill be used for determining the timing of the interim and 
final efficacy analyses. Final PFS analysis is planned when 136 PFS events per BICR are observed 
among the PD-L1 expressing subjects in the chemotherapy arm. This  
is expected to be reached 
after approximately 33 months. If the planned number of PFS events is unlikely to be reached for 
any  unforeseen  reasons,  
the  final  PFS  analysis  may  occur  when  at  
least  12  months  minimum 
follow-up (defined as the time from the date when the last patient was randomized to the clinical 
cutoff date) is reached. Should this scenario occur, corresponding to PFS events of 110 and 121, 
the power would be 80% and 85%, respectively (details of this scenario are discussed in Appendix 
7 of  
the  SAP).  Final  OS  analysis  
is  planned  when  140 events  are  observed  among  
the  PD-L1 
expressing subjects in the chemotherapy arm. This is expected to be reached after approximately 
49 months. (At  the  time  of  the  final  PFS  analysis,  a  formal  interim  analysis  for  OS  will  be 
conducted, see Section 8.5.)
Details of the sample size calculations for the subjects whose tumors express PD-L1 are provided 
inTable 8.1-1.
Table 8.1-1: 
Subjects  whose  Tumors  Express  PD-L1 - Summary  of  Sample  Size 
Parameters and Schedule of Analyses (Nivolumab plus Ipilimumab 
vs  Chemotherapy  and  Nivolumab  plus  Chemotherapy  vs 
Chemotherapy)
OS
PFS
# of randomized subjects
≈313 (total in the 3 arms: ≈470)
Hypothesized delayed effect
3 months
1 month
Hypothesized cure rate in 
experimental arms
15%
0
Hypothesized HR after delayed 
effect, in non-cure subjects
0.65
0.55
Hypothesized median: control vs 
experimental
9 months* vs 14.4 months
4 months vs 6.4 months
Significance level
0.01
0.015
FINAL ANALYSIS
Criteria for time of LPLV
140 events are observed among the 
PD-L1 expressing subjects in the 
chemotherapy arm
136 events are observed among the 
PD-L1 expressing subjects in the 
chemotherapy arm
Projected time of LPLV (from 
randomization)
49 months
33 months
Projected # of events
250
250
Significance level
[0.009]a
0.015
Power
90%
90%
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Table 8.1-1: 
Subjects  whose  Tumors  Express  PD-L1 - Summary  of  Sample  Size 
Parameters and Schedule of Analyses (Nivolumab plus Ipilimumab 
vs  Chemotherapy  and  Nivolumab  plus  Chemotherapy  vs 
Chemotherapy)
OS
PFS
Hypothesized overall HR
0.6
0.62
Critical HR (b) / Minimal 
difference in median (c)
0.72 / 3.5 months
0.73 / 1.4 months
INTERIM ANALYSIS for OS
Criteria for time of LPLV 
At the time of PFS final analysis
N/A
Projected # of events
≈175 (70% of all events)
N/A
Significance level
[0.002] (a)
N/A
Probability of crossing boundary
29%
N/A
Hypothesized overall HR
0.67
N/A
Critical HRb/ Minimal 
difference in medianc
0.62 / 5.6 months
N/A
a For OS, significance levels will be recalculated based on the actual number of deaths at interim analysis
b Largest observed HR at which a statistically significant difference would be observed
c Difference in median, corresponding to a minimal clinically significant effect size
* Asia: 10 months, RoW: 6 months
Analyses on OS and PFS in all randomized subjects will be carried out at the time of the primary 
analysis (in subjects whose tumors express PD-L1); OS and PFS in all randomized subjects are 
expected to be mature by that time. They will be tested only if significance level is passed on them. 
Details of the related power calculations are provided inTable 8.1-2.
Table 8.1-2: 
All Randomized Subjects - Summary of Power Calculation 
Parameters and Schedule of Analyses (Nivolumab plus Ipilimumab 
vs Chemotherapy and Nivolumab plus Chemotherapy vs 
Chemotherapy)
OS
PFS
# of randomized subjects
626 (total in the 3 arms: 939)
Hypothesized delayed effect
3 months in PD-L1+, 4 months in 
PD-L1-
1 month in PD-L1+, 2 months in 
PD-L1-
Hypothesized cure rate in 
experimental arms
15% in PD-L1+, 10% in PD-L1-
0
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Table 8.1-2: 
All Randomized Subjects - Summary of Power Calculation 
Parameters and Schedule of Analyses (Nivolumab plus Ipilimumab 
vs Chemotherapy and Nivolumab plus Chemotherapy vs 
Chemotherapy)
OS
PFS
Hypothesized HR after delayed 
effect, in non-cure subjects
0.65 in PD-L1+, 0.85 in PD-L1- 
0.55 in PD-L1+, 0.75 in PD-L1-
Hypothesized median: control vs 
experimental
9 months* vs 12.3 months
4 months vs 5.5 months
Significance levela
0.01
0.015
FINAL ANALYSIS
Criteria for time of LPLV
At the time of the PD-L1+ LPLV 
At the time of the PD-L1+ LPLV
Projected # of events
≈514
≈512
Significance levela
[0.009]b
0.015
Powerc
94%
90%
Hypothesized overall HR
0.68
0.72
Critical HRd/ Minimal difference in 
mediane
0.80 / 2.3 months
0.81 / 0.9 months
INTERIM ANALYSIS for OS
Criteria for time of LPLV
At the time of PFS final analysis
N/A
Projected # of events
≈362 (70.4% of all events)
N/A
Significance levela
[0.002] (a)
N/A
Probability of crossing boundaryc
33%
N/A
Hypothesized overall HR
0.75
N/A
Critical HRb/ Minimal difference in 
mediane
0.74 / 3.1 months
N/A
Accrual rate per month
Gradually increasing accrual rates (max = 45 subjects per months)
Accrual Duration
29 months
a In case the significance level from the corresponding primary endpoint is passed. (Note that endpoint-specific [i.e. 
initially allocated] significance level is 0.)
b For OS, significance levels will be recalculated based on the actual number of deaths at interim analysis
c Not accounting for hierarchy
d Largest observed HR at which a statistically significant difference would be observed
e Difference in median, corresponding to a minimal clinically significant effect size
* Asia: 10 months, RoW: 6 months
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Simulations were conducted in R-v3.1.3.
8.2 
Populations for Analyses
• The following definitions of populations will be applicable for subjects whose tumors express 
PD-L1 and also for subjects regardless of PD-L1 expression.
• All Enrolled Subjects: All subjects who signed an informed consent form and were registered 
into the IRT
• All Randomized Subjects: All enrolled subjects who were randomized to any treatment arm in 
the study 
• All Treated Subjects: All randomized subjects who received at least one dose of study drug 
during the study
• PK Subjects: All randomized subjects with available serum time-concentration data.
• Outcome  Research  subjects:  All  randomized  subjects  who  have  an assessment  at 
screening/baseline and at least 1 follow-up assessment
• Immunogenicity  subjects:  All  randomized  subjects  who  have  an  assessment  at 
screening/baseline and at least 1 follow-up assessment
• Biomarker subjects: All randomized subjects with available biomarker data.
8.3 
Endpoints
8.3.1 
Primary Endpoint
• Overall survival (OS)  
in subjects with PD-L1 expressing tumors. OS  
is defined as the 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. 
• Progression-free  Survival  
(PFS)  
(as  assessed  by  BICR) in  subjects  with  PD-L1  expressing 
tumors. PFS is defined as the time from randomization to the date of the first documented PD 
per BICR or death due to any cause. Subjects who die without a reported prior PD per BICR 
(and die without start of subsequent therapy) will be considered to have progressed on the date 
of death. Subjects who did not have documented PD per BICR per RECIST1.1 criteria and 
who did not die, will be censored at the date of the last evaluable tumor assessment on or prior 
to  
initiation  of  
the  subsequent  anti-cancer therapy. Subjects  who  did  not  have  any  on-study 
tumor  assessments  and  did  not  die  (or  died  after  initiation  of  the  subsequent  anti-cancer 
therapy)  will  be  censored  at  
the  randomization  date.  Subjects  who  started  any  subsequent 
anti-cancer therapy without a prior reported PD per BICR will be censored at the last tumor 
assessment on or prior to initiation of the subsequent anti-cancer therapy. 
8.3.2 
Secondary Endpoint(s)
• Overall  survival  
(OS)  
in  All  Randomized  subjects.  OS  
is  defined  
the  same  way  as  for  
the 
primary endpoint (for subjects with PD-L1 expressing tumors). 
• Progression-free Survival (PFS) (as assessed  by  BICR)  
in  All  Randomized subjects. PFS is 
defined the same way as for the primary endpoint (for subjects with PD-L1 expressing tumors). 
• Objective  Response  Rate  
(ORR)  
(as  assessed  by  BICR)  
in  subjects  with  PD-L1  expressing 
tumors and All Randomized subjects. It is defined as the number of subjects with a best overall 
response (BOR) of CR or PR divided by the number of randomized subjects in the population 
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for each treatment group. BOR is defined as the best response designation as determined by 
BICR,  
recorded  between  
the  date of  
randomization  and  
the date of objectively  documented 
progression (per RECIST 1.1 as determined by BICR) or the date of subsequent anti-cancer 
therapy (including tumor-directed radiotherapy and tumor-directed surgery), whichever occurs
first.  For  subjects  without  documented  progression  or  subsequent  anti-cancer  therapy,  all 
available response designations will contribute to the BOR determination.
8.3.3 
Exploratory Endpoint(s) 
• Progression-free  Survival  (PFS)  (as  assessed  by  investigator)  in  subjects  with  PD-L1 
expressing  tumors  and  All  Randomized  subjects.  PFS  is  defined  the  same  way  as  for  
the 
primary and secondary endpoints (as assessed by BICR) - except that only PD assessments by 
investigator will be taken into account.
• Objective  Response Rate  (ORR)  (as  assessed  by  investigator)  in  subjects  with  PD-L1 
expressing  
tumors  and  All  Randomized  subjects.  ORR is  defined  
the  same  way  as  for  
the 
primary and secondary endpoints (as assessed by BICR) - except that only tumor assessments 
by investigator will be taken into account.
• Duration of Response (DOR) (as assessed by BICR and as assessed by investigator) is defined 
as the time between the date of first documented response (CR or PR) to the date of the first 
disease progression, per RECIST 1.1 or death due to any cause, whichever occurs first. For 
subjects who neither progress nor die, the duration of objective response will be censored at 
the same time they were censored for the primary definition of PFS.
• PFS2/TSST in  subjects  with  PD-L1  expressing tumors  and  all  randomized  subjects. 
PFS2/TSST  is  defined  as  the  time  from  randomization  to  
the  date  of  investigator-defined 
documented  second  objective  disease  progression  or  start  of  second  subsequent  
therapy  or 
death due to any cause, whichever comes first. Clinical deterioration will not be considered as 
progression. Details for censoring will be provided in the SAP. 
• Safety and tolerability objective will be measured by the incidence of adverse events (AEs), 
serious adverse events (SAEs), deaths, and laboratory abnormalities.
• PK will be measured using serum concentration-time data.
Assessments  for  other  exploratory  endpoints  are  discussed in  other  sections  of  the  protocol, 
including biomarker analysis (Section 5.6), immunogenicity (Section 5.5), and outcomes research 
(Section 5.7). Corresponding endpoints will be detailed in the statistical analysis plan(s) (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  subjects  with  PD-L1  expressing  
tumors  and  for  all  randomized 
subjects.
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8.4.2 
Efficacy Analyses
Primary Endpoints
Progression free survival (PFS) in subjects with PD-L1 expressing tumors will be compared 
• Between nivolumab plus ipilimumab vs chemotherapy using a two-sided log rank test and an 
endpoint-specific (i.e. initially allocated) significance level of 1.5%; and
• Between nivolumab plus chemotherapy vs chemotherapy using a two-sided log rank test and 
an endpoint-specific significance level of 1.5%. 
OS in subjects with PD-L1 expressing tumors will be compared 
• Between nivolumab plus ipilimumab vs chemotherapy using a two-sided log rank test and an 
endpoint-specific overall significance  
level  of  1%  defined  for  
the  groups  sequential  
testing 
procedure (see Section 8.5); 
• Between nivolumab plus chemotherapy vs chemotherapy using a two-sided log rank test and 
an endpoint-specific overall significance level of 1% defined for the groups sequential testing 
procedure (see Section 8.5). 
All tests will be stratified by region (East Asia [Japan, Korea, Taiwan] vs Rest of Asia vs RoW), 
ECOG status (0 vs 1), and number of organs with metastases (≤1 vs ≥2) as recorded in the IRT.
Endpoint-specific significance levels are split based on the conservative Bonferroni method and 
may be updated through graphical approach where the family-wise error rate will be protected in 
the  strong  sense.  Rules  for  updating  endpoint-specific significance  levels following the 
Bonferroni-based graphical approach by Maurer and Bretz (2013)61will be detailed in the SAP.
For  each  comparison,  
the  HR  with  
its  associated  
two-sided  100*(1  
- adjusted α)%  confidence 
intervals (CI) will be estimated via a stratified Cox model with treatment arm as the only covariate 
in the  model. Both PFS and OS  
for each treatment arm will  be estimated and plotted using the 
Kaplan-Meier  (KM)  product-limit  method.  Median  survival  time  along  with  95%  CI  will  be 
constructed based on a log-log transformed CI for the survival function.
Secondary Endpoints
Time-to-event endpoints (OS and PFS as assessed by BICR  
in all randomized subjects) will  be 
estimated and plotted using the KM product-limit method for each treatment arm. Median survival 
time along with 95% CI will  be  constructed based on a log-log transformed CI for the survival 
function. The HR with its associated two-sided 95% CI will be estimated via a stratified Cox model 
with treatment arm as the only covariate in the model. 
Overall  Survival  and  PFS  
in  all  
randomized  subjects  will  be  
tested  only  
if  significance  
level  
is 
passed on them. Rules for passing on significance levels will be defined together with the graphical 
approach  in  the  SAP.  Comparisons  will  use a  two-sided  log  rank  test,  stratified  by  the  same 
stratification  factors  as  the  primary  endpoint  and by  PD-L1  status  (≥1%  vs  < 1%  [including 
indeterminate]) as recorded in IRT. 
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ORR as assessed by BICR and by investigator in subjects with PD-L1 expressing tumors and in 
all randomized subjects will be computed in each treatment group along with the exact 95% CI
using Clopper-Pearson method. An estimate of the difference in ORRs, and corresponding 95% 
CI will be calculated using Cochran-Mantel-Haenszel (CMH) methodology and adjusted by the 
randomization stratification  factors.  The  stratified odds  ratios  (Mantel-Haenszel  estimator) 
between the treatments will be provided along with the 95% CI.
ORR  as  assessed  by  BICR  in  subjects  with  PD-L1  expressing  tumors  and  in  all  randomized 
subjects will  be  tested  only  if  significance  level  is  passed  on them.  Rules  for  passing  on 
significance levels will be defined together with the graphical approach in the SAP. Comparisons 
will use a two-sided CMH test.
Exploratory Endpoints
Progression free survival, PFS2/TSST, and ORR as assessed by investigator (in subjects with PD-
L1 expressing tumors and in all randomized subjects) will be described using the same methods 
as the corresponding secondary endpoints.
Duration  of  Response  
(as  assessed  by  BICR  and  as  assessed  by  
investigator)  
in  each  
treatment 
group  will  be  estimated  using  KM  product-limit  method  for  subjects  who  achieve  PR  or  CR. 
Median values along with two-sided 95% CI will be calculated.
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 by treatment group. All on-study AEs, treatment-related 
AEs,  SAEs,  and  
treatment-related  SAEs  will  be  
tabulated  using  worst  grade  per  NCI  CTCAE 
version  4  criteria  by  system  organ  class  and  preferred  term  (PT).  On-study  lab  parameters 
including  hematology,  chemistry,  liver  function,  and  renal  function  will  be  summarized  using 
worst grade NCI CTCAE version 4 criteria.
8.4.4 
Pharmacokinetic Analyses
The  nivolumab  and/or  ipilimumab  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/or  
ipilimumab  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
Details for biomarker analyses will be described in the SAP(s). These analyses will be descriptive 
and not adjusted for multiplicity.
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8.4.6 
Outcomes Research Analyses
The analysis of EQ-5D-3L and FACT-E (including 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. The 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-3L data will be described by treatment group as randomized in the following ways:
• EQ-5D-3L 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-3L 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-3L 
health state (ie, 5-digit vector), EQ-5D-3L index score, and EQ-VAS score will be provided.
From the beginning of the on-treatment phase through follow-up Visit 2, data for the FACT-E will 
be described by treatment group as randomized in the following ways:
• ECS, FACT-G7, 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-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.
During  the  survival  follow-up  phase,  data  for  the  ECS  and  FACT-G7  will  be  described  by 
treatment group as randomized 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 
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immunogenicity on safety, efficacy, biomarkers and PK may be explored. Additional details will 
be described in the SAP.
8.5 
Interim Analysis
At the time  of  
the  
final  PFS  analysis, a formal  
interim  analysis for  OS  
in  subjects  with  PD-L1 
expressing tumors is planned. If no superiority is claimed at interim of OS, the trial will continue 
(regardless of the final PFS analysis results), and a final OS analysis will take place. Lan-DeMets 
α  spending  function  with  O’Brien  and  Fleming  type  of  boundary  will  be  used.  The  stopping 
boundary  will  depend  on  
the  actual  number  of  deaths  at  
the  
time  of  
the  interim  analysis. For 
example,  if  the  interim  analysis  is performed  at  175 deaths (70%  of  all  expected  deaths), 
endpoint-specific  significance  level  at  the  interim  analysis  will  be 0.002.  An  independent 
statistician external to BMS will perform the analysis; results will be evaluated by the DMC.
The endpoint-specific significance  
level  
for the final look after 250 deaths would be 0.009. All 
events in the database at the time of the lock will be used. 
In addition to the formal planned interim analysis for OS, the DMC will have access to periodic 
unblinded interim reports of efficacy and safety to allow a risk/benefit assessment. No formal test 
will be performed and the study will not stop for superiority. Details will be included in the DMC 
charter.
9 
STUDY MANAGEMENT
9.1 
Compliance
9.1.1 
Compliance with the Protocol and Protocol Revisions
The  investigator  should  not  implement  any  deviation  or  change  to  
the  protocol  without  prior 
review and documented approval/favorable opinion of an amendment from the IRB/IEC (and if 
applicable,  also  by  local  health  authority)  except  where  necessary  to  eliminate  an  immediate 
hazard(s) to study subjects. If a deviation or change to a protocol is implemented to eliminate an 
immediate  hazard(s)  prior  
to  obtaining  
relevant  approval/favorable  opinion(s),  
the  deviation  or 
change will be submitted as soon as possible to:
• IRB/IEC 
• Regulatory Authority(ies), if applicable by local regulations per national requirements)
Documentation  of  approval/favorable  opinion  signed  by  the  chairperson  or  designee  of  the 
IRB(s)/IEC(s)  and  if  applicable,  also  by  local  health  authority, must be sent to BMS. If an 
amendment substantially alters the study design or increases the potential risk to the 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).
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9.1.2 
Monitoring
BMS or designee representatives will review data centrally to identify potential issues to determine 
a schedule of on-site visits for targeted review of study records.
Representatives of BMS must be allowed to visit all study site locations periodically to assess the 
data quality and study integrity. On site they will review study records and directly compare them 
with source documents, discuss the conduct of the study with the investigator, and verify that the 
facilities  
remain  acceptable.  Certain  CRF  pages  and/or  electronic  
files  may  serve  as  
the  source 
documents:
In  addition, the  study  may  be  evaluated  by  BMS or  designee  
internal  auditors  and  government 
inspectors who must be allowed access to CRFs, source documents, other study files, and study 
facilities. BMS audit reports will be kept confidential.
The investigator must notify BMS promptly of any inspections scheduled by regulatory authorities, 
and promptly forward copies of inspection reports to BMS or designee. 
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. 
9.2 
Records
9.2.1 
Records Retention
The  investigator  (or  head  of  
the  study  site  in  Japan) must  retain  all  study  records  and  source 
documents  for  the  maximum  period  required  by  applicable  regulations  and  guidelines,  or 
institution procedures, or for the period specified by BMS or designee, whichever is longer. The 
investigator (or head of the study site in Japan) must contact BMS or designee prior to destroying 
any records associated with the study.
BMS or designee will notify the investigator (or head of the study site in Japan) when the study 
records are no longer needed.
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If  the  investigator  withdraws  from  the  study  (eg,  relocation,  retirement),  
the  records  shall  be 
transferred to a mutually agreed upon designee (eg, another investigator, study site, IRB). Notice 
of such transfer will be given in writing to BMS or designee.
9.2.2 
Study Drug Records 
Records for IP (whether supplied by BMS, its vendors, or the site) must substantiate IP integrity 
and  traceability  from  receipt,  preparation,  administration,  and  through  destruction  or  return. 
Records must be made available for review at the request of BMS/designee or a Health Authority.
If
Then
Supplied by BMS (or its vendors):
Records or logs must comply with applicable 
regulations and guidelines and should include:
• amount received and placed in storage 
area
• amount currently in storage area
• label identification number or batch 
number
• amount dispensed to and returned by each 
subject, including unique subject 
identifiers
• amount transferred to another area/site for 
dispensing or storage
• nonstudy disposition (e.g., lost, wasted) 
• amount destroyed at study site, if 
applicable
• amount returned to BMS
• retain samples for 
bioavailability/bioequivalence, if 
applicable 
• dates and initials of person responsible for 
Investigational Product 
dispensing/accountability, as per the 
Delegation of Authority Form.
Sourced by site, and  not supplied  by  BMS or 
its vendors (examples include IP sourced from 
the  sites  stock  or  commercial  supply,  or  a 
specialty pharmacy)
The investigator or designee accepts 
responsibility for documenting traceability 
and study drug integrity in accordance with 
requirements applicable under law and the 
SOPs/standards of the sourcing pharmacy. 
These records should include:
• label identification number or batch 
number 
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If
Then
• amount dispensed to and returned by each 
subject, including unique subject 
identifiers
• dates and initials of person responsible for 
Investigational Product 
dispensing/accountability, as per the 
Delegation of Authority Form.
BMS or designee will provide forms to facilitate inventory control if the investigational site does 
not have an established system that meets these requirements.
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  Sponsor  or  designee electronic  data  capture tool,  electronic  CRFs  will  be 
prepared for all data collection fields except for fields specific to SAEs and pregnancy, which will 
be  reported  on  the  electronic  SAE  form  and  Pregnancy  Surveillance  form,  respectively. If 
electronic SAE  
form  
is not available, a paper SAE form can be used. Spaces may  be  
left blank 
only in those circumstances permitted by study-specific CRF completion guidelines provided by 
Sponsor of designee. 
The confidentiality of records that could identify subjects must be protected, respecting the privacy 
and confidentiality rules in accordance with the applicable regulatory requirement(s).
The investigator will maintain a signature sheet to document signatures and initials of all persons 
authorized to make entries and/or corrections on CRFs. 
The completed CRF, SAE/pregnancy CRFs, must be promptly reviewed, signed, and dated by the 
investigator or qualified physician who is a subinvestigator and who is delegated this task on the 
Delegation of Authority Form. Subinvestigators in Japan may not be delegated the CRF approval 
task. For electronic CRFs, review and approval/signature is completed electronically through the 
BMS  electronic  data  capture  
tool. The investigator  must  retain  a copy  of  
the  CRFs  including 
records of the changes and corrections.
Each  
individual electronically signing electronic  CRFs  must  meet Sponsor or designee training 
requirements  and  must only  access  
the  BMS  electronic  data  capture tool  using  
the  unique  user
account provided by Sponsor or designee. User accounts are not 
to be shared or reassigned to other 
individuals.
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9.3 
Clinical Study Report and Publications
A Signatory Investigator must be selected to sign the clinical study report. 
For this protocol, the Signatory Investigator will be selected as appropriate based on the following 
criteria:
• External Principal Investigator designated at protocol development
• Other criteria (as determined by the study team)
The  data  collected  during  
this  study  are  confidential  and proprietary  
to  BMS or  designee.  Any 
publications or abstracts arising from this study must adhere to the publication requirements set 
forth in the clinical trial agreement (CTA) governing [Study site or Investigator] participation in 
the study. These requirements include, but are not limited to, submitting proposed publications to 
BMS or designee at the earliest practicable time prior to submission or presentation and otherwise 
within the time period set forth in the CTA.
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10 
GLOSSARY OF TERMS
Term
Definition
Complete Abstinence
Complete Abstinence is defined as complete avoidance of heterosexual 
intercourse and 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. Women must continue to have pregnancy tests.
Acceptable alternate methods of highly or less effective contraception’s 
must be discussed in the event that the subject chooses to forego complete 
abstinence.
PD-L1 Evaluable Status 
Sufficient quantity of tissue sample available for analysis
PD-L1 Indeterminate Status  
Inconclusive result
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11 
LIST OF ABBREVIATIONS
Term
Definition
AE
adverse event
ADA
Anti Drug Antibody
AIDS
Acquired Immunodeficiency Syndrome
AST
aspartate aminotransferase
AT
aminotransaminases
AUC
area under the concentration-time curve
BICR
Blinded Independent Central Review 
BLQ
below limit of quantification 
BMI
body mass index
BMS
Bristol-Myers Squibb
BP
blood pressure
BSA
Body surface area
BSC
Best Supportive Care
BUN
blood urea nitrogen
C
Celsius
Ca++
calcium
Cavg
average concentration
CBC
complete blood count
CFR
Code of Federal Regulations 
CI
confidence interval
C1-
chloride
CrCl
creatinine clearance
CLR
renal clearance
CLT
total body clearance
cm
centimeter
Cmax, CMAX 
maximum observed concentration
Cmin, CMIN 
trough observed concentration
CNS
Central nervous system
CRF
Case Report Form, paper or electronic
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Term
Definition
CV
coefficient of variation
CR
Complete response
CT
computerized tomography
DCR
Disease Control rate
dL
deciliter
DILI
Drug Induced Liver Injury
EAC
Esophageal Adenocarcinoma
EBV
Epstein-Barr Virus
EC
Esophageal Cancer
ECOG
Eastern Cooperative Oncology Group
eCRF
Electronic Case Report Form
ECS
Esophageal Cancer Subscale
EDC
Electronic Data Capture
eg
exempli gratia (for example)
EoT
End of treatment
ESCC
Esophageal Squamous Cell Cancer
ESMO
European Society of Medical Oncology
FA
final analysis
FACT-G7 
Functional Assessment of Cancer Therapy - General
FACT-Ga 
Functional Assessment of Cancer Therapy - Gastric
FACT-E
Functional Assessment of Cancer Therapy - Esophageal
FDA
Food and Drug Administration
FFPE
Formalin-Fixed Paraffin-Embedded
FSH
follicle stimulating hormone
g
gram
GaCS
Gastric Cancer Subscale
GC
Gastric Cancer
GCP
Good Clinical Practice
GEC
Gastric-Esophageal Junction Cancer
GERD
Gastro-Esophageal Reflux Disease
GFR
glomerular filtration rate
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Term
Definition
h
hour
HBsAg
hepatitis B surface antigen
HBV
hepatitis B virus
hCG
Human chorionic gonadotropin
HCV
hepatitis C virus
HIPAA
Health Insurance Portability and Accountability Act
HIV
Human Immunodeficiency Virus
HR
heart rate
hazard ratio
HRT
hormone replacement therapy
IA
interim analysis
IB
Investigator Brochure
ICH
International Conference on Harmonisation 
ie
id est (that is)
IEC
Independent Ethics Committee
IFN
Interferon
IMG
Immunogenicty
IMP
investigational medicinal products
IND
Investigational New Drug
IO
Immuno-Oncology
IRB
Institutional Review Board
IRCC
Immune related Response Criteria
IRT
Interactive Response Technology
IU
International Unit
IV
intravenous
K+
potassium
kg
kilogram
L
liter
LDH
lactate dehydrogenase
mg
milligram
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Term
Definition
Mg++
magnesium
min
minute
mL
milliliter
MLR
Mixed Lymphocytes reaction
mmHg
millimeters of mercury
mOS
Median overall survival
mDOR
Median duration of response
MRI
Magnetic resonance imaging
MSI
Microsatellite Instability
MTD
maximum tolerated dose
μg
microgram
N
number of subjects or observations
Na+
sodium
N/A
not applicable
NCCN
National Comprehensive Cancer Network
ng
nanogram
NIMP
non-investigational medicinal products 
NSCLC
Non Small Cell Lung Cancer
OS
Overall Survival
ORR
Objective Response Rate
PBMC
Peripheral Blood Mononuclear cell
PD
Disease Progression
PD-L1
Programmed Death Ligand 1
PFS
Progression Free Survival
PK
pharmacokinetics
PPK
Population pharmacokinetic
PRO
Patient Reported Outcomes
QxW
Every x weeks
QoL
Quality of Life
RCC
Renal Cell Carcinoma
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Term
Definition
RECIST
Response Evaluation Criteria In Solid Tumors
RT PCR
Real-time Polymerase Chain Reaction
SAE
serious adverse event
SAP
statistical analysis plan
SD
standard deviation
SNP
Single Nucleotide Polymorphism
SOC
Standard of Care
SOP
Standard Operating Procedures
SPC
Summary of Product Characteristic
Subj
subject
t
temperature
T
time
T-HALF 
Half life
TCR
T-cell receptor
TMB
Tumor mutational burden
TSST
Time to second subsequent therapy
TTP
Time to progression
TTR
Time to response
Vc
Volume of Central compartment
Vss/F (or Vss) 
apparent volume of distribution at steady state
Vz
Volume of distribution of terminal phase (if IV and  
if  multi-exponential 
decline)
WBC
white blood cell
WHO
World Health Organization
WOCBP
women of childbearing potential
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12 
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54 Ipilimumab population  pharmacokinetics  and  exposure-response  analyses  in  subjects  with 
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APPENDIX 1 
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 2 
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  for  female  participants  of  childbearing  potential  treated  with  nivolumab  plus 
ipilimumab,  and  5  half-lives  plus  30  days,  or  the  duration  specified  by  the  local  labels  of 
chemotherapy drugs received, whichever is longer.
Local  laws  and  regulations  may  require  use  of  alternative  and/or  additional  contraception 
methods.
Highly Effective Contraceptive Methods That Are User Dependent 
Failure rate of <1% per year when used consistently and correctly.a
• Combined (estrogen- and progestogen-containing) hormonal contraception associated with 
inhibition of ovulation
b 
−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 
ovulationb
• Intrauterine hormone-releasing system (IUS)
c
• Intrauterine device (IUD)
c
• Bilateral tubal occlusion
• Vasectomizedpartner 
A vasectomized partner is a highly effective contraception method provided that the partner is 
the sole male sexual partner of the WOCBP and the absence of sperm has been confirmed. If 
not, an additional highly effective method of contraception should be used. 
• Sexual abstinence
Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study drug. The 
reliability of sexual abstinence needs to be evaluated in relation to the duration of the study 
and the preferred and usual lifestyle of the participant.
• It is not necessary to use any other method of contraception when complete abstinence  
is 
elected. 
• WOCBP  participants who  choose  complete  abstinence  must  continue to  have  pregnancy 
tests, as specified in Section 2. 
• Acceptable  alternate  methods  of  highly  effective  contraception must  be  discussed  in  
the 
event that the WOCBP participants chooses to forego complete abstinence 
NOTES: 
a Typical use failure rates may differ from those when used consistently and correctly. Use should be consistent 
with  local  regulations  regarding  the  use  of  contraceptive  methods  for  participants  participating  in  clinical 
studies. 
b Hormonal contraception may be susceptible to interaction with the study drug, which may reduce the efficacy 
of the contraceptive method. Hormonal contraception is permissible only when there is sufficient evidence that 
the  IMP  and  other  study  medications  will  not  alter  hormonal  exposures  such  that  contraception  would  be 
ineffective  or  result  in  increased  exposures  that  could  be  potentially  hazardous.  In  this  case,  alternative 
methods of contraception should be utilized. 
c Intrauterine devices and intrauterine hormone releasing systems are acceptable methods of contraception in the 
absence of definitive drug interaction studies when hormone exposures from intrauterine devices do not alter 
contraception effectiveness
Unacceptable Methods of Contraception
• Male or female condom with or without spermicide. Male and female condoms cannot be 
used simultaneously
• Diaphragm with spermicide
• Cervical cap with spermicide
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• Vaginal Sponge with spermicide
• Progestogen-only  oral  hormonal  contraception,  where  inhibition of  ovulation  is  not  the 
primary mechanism of action
• Periodic abstinence (calendar, symptothermal, post-ovulation methods)
• Withdrawal (coitus interruptus).
• Spermicide only
• Lactation amenorrhea method (LAM)
CONTRACEPTION GUIDANCE FOR MALE PARTICIPANTS WITH PARTNER(S) OF 
CHILD BEARING POTENTIAL.
Male participants with female partners of childbearing potential are eligible to participate if they 
agree to the following during the treatment and until the end of relevant systemic exposure.
• Inform  any  and  all  partner(s)  of  
their  participation  
in  a  clinical  drug  study  and  
the  need  
to 
comply with contraception instructions as directed by the investigator.
• Male participants are required to use a condom for study duration and until end of relevant 
systemic  exposure  defined  as  7  months  after  the  end  of  study  treatment  if  treated  with 
nivolumab  plus  
ipilimumab,  and  5  half-lives  plus  90  days  or  a  duration  specified  by  
local 
labels of chemotherapy, whichever is longer. 
• Female  partners  of  males  participating  
in  
the  study  
to  consider  use  of  effective  methods  of 
contraception until the end of relevant systemic exposure as defined above. 
• 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  
the  end of  
relevant  systemic  exposure  as  defined 
above. 
• Refrain from donating sperm for the duration of the study treatment until the end of relevant 
exposure  period  defined  as: 7  months  after  the  end  of  study  treatment  if  treated  with 
nivolumab  plus  
ipilimumab,  and  5  half-lives  plus  90  days  or  a  duration  specified  by  
local 
labels of chemotherapy, whichever is longer.
COLLECTION OF PREGNANCY INFORMATION
Guidance for collection of Pregnancy Information and outcome of pregnancy on the Pregnancy 
Surveillance Form is provided in Section 6.4and the Appendix for Adverse Events and Serious 
Adverse Events Definitions and procedures for Evaluating, Follow-up and Reporting.
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APPENDIX 3 
ECOG PERFORMANCE STATUS
ECOG PERFORMANCE STATUS
0 
Fully active, able to carry on all pre-disease performance without restriction
1 
Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature, e.g., light house work, office work
2 
Ambulatory and capable of all selfcare but unable to carry out any work 
activities. Up and about more than 50% of waking hours
3 
Capable of only limited selfcare, confined to bed or chair more than 50% of 
waking hours
4 
Completely disabled. Cannot carry on any selfcare. Totally confined to bed or 
chair
5 
Dead
Source:  Oken  MM,  Creech  RH,  Tomey  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 4 
7TH EDITION OF THE AJCC CANCER STAGING MANUAL : 
ESOPHAGUS AND ESOPHAGOGASTRIC JUNCTION
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Source: Ann Surg Oncol 2010;17:1721-1724 DOI 10.1245/s10434-010-1024-1
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APPENDIX 5 
RADIOLOGIC EVALUATION CRITERIA IN SOLID TUMOURS 
VERSION 1.1 (RECIST CRITERIA 1.1)
1 
ASSESSMENT OF OVERALL TUMOR BURDEN AND MEASURABLE 
DISEASE
To assess objective response or future progression, it is necessary to estimate the overall tumor
burden at baselineand  use  this  as  a  comparator  for  subsequent  measurements.  Measurable 
disease  is  defined  by  the  presence  of  at  least  1 measurable  tumor  lesion.  When  computed 
tomography  (CT) scans  have slice  thickness  greater  than  5  mm,  the  minimum  size  for  a 
measurable lesion should be twice the slice thickness.
At baseline, tumor lesions/lymph nodes will be categorized measurable or nonmeasurable, which 
are discussed below.
1.1 
Measurable Lesions
Measurable lesions must be accurately measured in at least 1 dimension (longest diameter in the 
plane of the measurement to be recorded) with a minimum size of:
• 10  mm  by  CT/magnetic  
resonance  
imaging  
(MRI) scan  
- (CT/MRI  scan slice  
thickness  no 
greater than 5 mm)
• 10 mm caliper measurement by clinical exam (lesions which cannot be accurately measured 
with calipers should be recorded as nonmeasurable)
• 20 mm by chest x-ray
• Malignant lymph nodes: To be considered pathologically enlarged and measurable, a lymph 
node  must  be ≥15  mm  in  short  axis  when  assessed  by  CT  scan  (CT  scan  slice  
thickness 
recommended to be no greater than 5 mm). At baseline and in follow-up, only the short axis 
will be measured and followed.
1.2 
Non-measurable Lesions
• All other lesions,  
including small  
lesions (longest diameter < 10 mm or pathological  
lymph 
nodes with ≥10 to < 15 mm short axis), as well as truly non-measurable lesions
• Lesions  considered  
truly  nonmeasurable  
include:  
leptomeningeal disease,  ascites,  pleural  or 
pericardial effusion, inflammatory breast disease, lymphangitic involvement of skin or lung, 
and abdominal  masses/abdominal  organomegaly  identified  by physical  exam  that  is not 
measurable by reproducible imaging techniques.
1.3 
Special Considerations Regarding Lesion Measurability
1.3.1 
Bone Lesions
• Bone  scan, positron emission  tomography  (PET) scan, or  plain  films  are  not  considered 
adequate  imaging  techniques  to  measure  bone  lesions.  However,  these  techniques  can  be 
used to confirm the presence or disappearance of bone lesions. 
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• Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue components that 
can  be  evaluated  by  cross  sectional  imaging  techniques  such  as  CT  or  MRI,  can  be 
considered measurable  lesions  if  the  soft  tissue  component  meets  the  definition  of 
measurability described above.
• Blastic bone lesions are nonmeasurable.
1.3.2 
Cystic Lesions
• Lesions  that  meet  the  criteria  for  radiographically  defined  simple  cysts  should  not  be 
considered  as  malignant  
lesions  
(neither  measurable  nor  nonmeasurable)  since  
they  are,  by 
definition, simple cysts. 
• ‘Cystic  lesions’  thought  to  represent  cystic  metastases  can  be considered  as  measurable 
lesions  
if they  meet the definition of  measurability described above. However, if  non-cystic 
lesions are present in the same subject, these are preferred for selection as target lesions.
1.3.3 
Lesions with Prior Local Treatment
Tumor lesions  situated  in  a  previously  irradiated  area  or  in  an area  subjected  to  other 
locoregional therapy are usually not considered measurable, unless there has been demonstrated 
progression  in  
the  
lesion.  Measurable  lesions  may be  in  an  irradiated  field  as  
long  as  
there  
is 
documented progression, and the lesion(s) can be reproducibly measured.
1.4 
Specifications by Methods of Measurements
1.4.1 
Measurement of Lesions
All  measurements should  be recorded in  metric  notation (mm). All  baseline  evaluations should 
be performed as close as possible to the treatment start and never more than 30 days before the 
beginning of the treatment.
1.4.2 
Method of Assessment
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. Imaging-based evaluation should 
always  be  done  
rather than  clinical  examination, unless  
the  
lesion(s)  being  
followed  cannot  be 
imaged but are assessable by clinical exam.
1.4.2.1 
CT/MRI Scan
CT/MRI is the best currently available and reproducible method to measure lesions selected for 
response assessment. Measurability of  
lesions on CT/MRI scan is based on the assumption that 
CT/MRI slice thickness is 5 mm or less. When CT scans have slice thickness greater than 5 mm, 
the minimum size for a measurable lesion should be twice the slice thickness.
1.4.2.2 
Chest X-ray
Chest CT is preferred over chest X-ray, particularly when progression is an important endpoint,
since  CT  is  more  sensitive  than  X-ray in  identifying new  lesions.  However,  lesions  on  chest 
X-ray may be considered measurable if they are clearly defined and surrounded by aerated lung.
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1.4.2.3 
Clinical Lesions
Clinical  lesions  will  only  be  considered  measurable  when  they  are  superficial  and ≥10  mm 
diameter  as  assessed  using  calipers.  For  the  case  of  skin  lesions,  documentation  by  color 
photography including a ruler to estimate the size of the lesion is suggested. As previously noted, 
when  lesions  can  be  evaluated  by  both  clinical  examination and  imaging,  imaging  evaluation 
should be undertaken since it is more objective and may also be reviewed at the end of the study.
1.4.2.4 
Ultrasound
Ultrasound  is notuseful  in  assessment  of  lesion  size  and  should  not  be  used  as  a  method  of 
measurement. If new lesions are identified by ultrasound in the course of the study, confirmation 
by CT or MRI is advised. 
1.4.2.5 
Endoscopy, Laparoscopy
The utilization of these techniques for objective tumor evaluation is notadvised.
1.4.2.6 
Tumor Markers
Tumor markers alonecannot be used to assess objective tumor response.
2 
BASELINE DOCUMENTATION OF ‘TARGET’ AND ‘NON-TARGET’
LESIONS
2.1 
Target Lesions
When  more  
than  1 measurable  lesion  is  present  at  baseline, all  lesions  up  
toa  maximum  of 
5 lesions total (and a maximum of 2 lesions per organ) representative of all involved organs 
should be identified as target lesionsand will be recorded and measured at baseline.
Target lesions should be selected on the basis of their size (lesions with the longest diameter), be 
representative  of  all  involved  organs,  and should  lend  themselves  to reproducible repeated
measurements.
A sum of the diameters(longest for non-nodal lesions, short axis for nodal lesions) for all target 
lesions will be calculated and reported as the baseline sum diameters.If lymph nodes are to be 
included in the sum, then as noted below, only the shortaxis is added into the sum. The baseline 
sum diameters will be used as reference to further characterize any objective tumor regression in 
the measurable dimension of the disease.
2.1.1 
Lymph Nodes
Lymph  nodes merit special  mention since they  are normal anatomical structures which  may  be 
visible  by  imaging  even  if  not  involved  by  tumor.  Pathological nodes, which  are  defined  as 
measurable  and  may  be  
identified  as  
target  
lesions, must  meet  
the  criterion  of  a short  axis  of 
≥15 mm  by  CT  scan.  Only  
the  short axis  of  
these  nodes  will contribute  
to  
the  baseline  sum. 
Nodes that have a short axis < 10 mm are considered nonpathological and should not be recorded 
or followed.
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2.2 
Non-target Lesions
All other lesions (or sites of disease), including pathological lymph nodes, should be identified as 
non-target lesionsand should also be recorded at baseline. Measurements are not required, and 
these  lesions  should  be  followed  as ‘present’,  ‘absent’,  or  in  rare  cases, ‘unequivocal 
progression’.In addition, it is possible to record multiple non-target lesions involving the same 
organ  as  a  single  
item  on  
the  case  
record  
form  
(eg, ‘multiple  enlarged  pelvic  
lymph  nodes’  or 
‘multiple liver metastases’).
3 
TUMOR RESPONSE EVALUATION
3.1 
Evaluation of Target Lesions
• Complete  Response  (CR):Disappearance  of  all  target  lesions. Any  pathological  lymph 
nodes (whether target or nontarget) must have reduction in short axis to < 10 mm.
• Partial Response (PR): At least a30% decrease in the sum of diameters of target lesions,
taking as reference the baseline sum diameters.
• Progressive  Disease  (PD): At  least  a 20%  increase  in  the  sum  of  diameters  of  target 
lesions, taking as reference the smallest sum on study(this includes the baseline sum if that 
is  the  smallest  on  study).  In  addition  to  the  relative  increase  of  20%,  the  sum  must  also 
demonstrate an absolute increase of at least 5 mm. (Note:The appearance of 1 or more new 
lesions is also considered progression).
• Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest sum on study.
3.1.1 
Special Notes on the Assessment of Target Lesions
3.1.1.1 
Lymph Nodes
Lymph  nodes merit special  mention since they  are normal anatomical structures which  may  be 
visible  by  imaging  even  if  not  involved  by  tumor.  Pathological nodes, which  are  defined  as 
measurable  and  may  be  
identified  as  
target  
lesions, must  meet  
the  criterion  of  a short  axis  of 
≥15  mm  by  CT  scan.  Only  
the  short axis  of  
these  nodes  will contribute to the  baseline  sum. 
Nodes that have a short axis <10 mm are considered nonpathological and should not be recorded 
or followed.
3.1.1.2 
Target Lesions That Become ‘Too Small to Measure’
All  lesions  (nodal  and  nonnodal)  recorded  at  baseline  should  have  their  actual  measurements 
recorded at each subsequent evaluation, even when  very small (eg, 2 mm). If the radiologist is 
able to provide an actual measurement, that should be recorded even if it is below 5 mm.
However, when such a lesion becomes difficult to assign an exact measure to then:
• If it is the opinion of the radiologist that the lesion has likely disappeared, the measurement 
should be recorded as 0 mm.
• If the lesion  
is believed to be present and is faintly seen but too small to measure, a default 
value of 5 mm should be assigned (Note: In case of a lymph node believed to be present and 
faintly  seen  but  
too  small  
to  measure,  a  default  value  of  5  mm should  be  assigned  in  
this 
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circumstance as  well).  This default  value  
is  derived  
from  
the  5  mm  CT slice thickness (but 
should not be changed with varying CT slice thickness).
3.1.1.3 
Target Lesions that Split or Coalesce on Treatment
• When  non-nodal  
lesions  
fragment, the  
longest  diameters  of  
the  
fragmented  portions  should 
be added together to calculate the target lesion sum.
• As  
lesions  coalesce,  a  plane  between  
them  may  be  maintained  
that  would  aid  
in  obtaining 
maximal diameter measurements of each individual lesion. If the lesions have truly coalesced 
such  
that  
they  are  no  longer  separable,  
the  vector  of  
the  longest  diameter  
in  
this  instance 
should be the maximal longest diameter for the ‘coalesced lesion’
3.2 
Evaluation of Non-target Lesions
While  some  non-target  lesions  may  actually  be  measurable,  they need  not  be  measured  and 
instead should be assessed only qualitatively at the time points specified in the protocol. 
• CR: Disappearance  of  all  non-target  
lesions.  All  lymph  nodes  must  be  nonpathological  in 
size (< 10 mm short axis).
• PD: Unequivocal progression of  existing  non-target lesions.  
(Note:The  appearance  of  1 or 
more new lesions is also considered progression).
• NonCR/NonPD: Persistence of 1or more non-target lesion(s).
3.2.1 
Special Notes on Assessment of Non-target Lesions
The  concept  of  progression  of  non-target  disease  requires  additional  explanation  as  discussed 
below.
3.2.1.1 
When the Subject Also has Measurable Disease
• To achieve unequivocal progression on the basis of the non-target disease, there must be an 
overall level of substantial worsening in non-target disease, such that even in presence of SD 
or  PR  in  target  disease,  the  overall  tumor  burden  has  increased  sufficiently  to  merit 
discontinuation of therapy.
• A  modest  
‘increase’  
in  
the  size  of  1 or  more  non-target  
lesions is  usually  not  sufficient  
to 
quality for unequivocal progression status.
3.2.1.2 
When the Subject has Only Non-measurable Disease
• To achieve unequivocal progression on the basis of the non-target disease, there must be an 
overall  level  of  substantial  worsening, such  that  the  overall  tumor  burden  has  increased 
sufficiently to merit discontinuation of therapy.
• A  modest  increase in  the  size  of  1 or  more  non-target  lesions  is usually  not  sufficient  to 
qualify for unequivocal progression status.
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• Because  worsening  in  non-target  disease  cannot  be  easily  quantified  (by  definition,  if  all 
lesions  are  nonmeasurable), a  useful  test  that  can  be  applied  when  assessing  subjects  for 
unequivocal progression is to consider if the increase in overall disease burden based on the 
change in non-measurable disease is comparable in magnitude to the increase that would be 
required to declare PD for measurable disease,  
ie, an  
increase  
in tumor burden representing
an additional 73%  
increase  
in  volume (which  
is equivalent to a 20% increase diameter in  a 
measurable lesion). Examples include an increase in a pleural effusion from ‘trace’ to ‘large’, 
an  increase  in  lymphangitic  disease  from  localized  
to  widespread,  or  may  be  described  in 
protocols as ‘sufficient to require a change in therapy’.
• If unequivocal progression is seen, the subject should be considered to have had overall PD 
at that point. 
3.2.1.3 
Tumor Markers
Tumor markers will not be used to assess objective tumor responses.
3.3 
New Lesions
The  appearance  of  new  malignant  lesions  denotes  disease progression. The  finding  of  a  new 
lesion  should  be  unequivocal,  that  is, not  attributable  to  differences  in  scanning  technique, 
change  
in  
imaging  modality, or  
findings  
thought  
to  
represent  something  other  
than  
tumor  
(for 
example, some new bone lesions may be simply healing or flare of preexisting  
lesions). This  
is 
particularly important when the subject’s baseline lesions show PR or CR. For example, necrosis 
of a liver lesion may be reported on a CT scan report as a new cystic lesion, which it is not.
A  lesion  identified  on  a  follow-up  study  in  an  anatomical  location  that  was notscanned  at 
baseline is considered a new lesion and will indicate disease progression. An example of this is 
the subject who has visceral disease at baseline and while on study, has a CT or MRI brain scan
ordered that reveals metastases. The subject’s brain metastases are considered to be evidence of 
PD even if he/she did not have brain imaging at baseline.
If  a  new  lesion  is  equivocal,  for  example  because  of  its  small size,  continued  therapy  and 
follow-up evaluation will clarify if it represents truly new disease. If repeat scans confirm there 
is definitely a new lesion, then progression should be declared using the date of the initial scan.
4 
RESPONSE CRITERIA
4.1 
Time Point Response
A response assessment should occur at each time point specified in the protocol.
For subjects who have measurable disease at baseline, Table 4.1-1provides a summary of the 
overall response status calculation at each time point.
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Table 4.1-1: 
Subjects with Target (+/– Non-target) Disease
Target Lesions 
Non-target Lesions
New Lesions 
Overall Response
CR
CR
No
CR
CR
NonCR/nonPD
No
PR
CR
Not evaluated
No
PR
PR
NonPD or not all evaluated
No
PR
SD
NonPD or not all evaluated
No
SD
Not all evaluated
NonPD
No
NE
PD
Any
Yes or No
PD
Any 
PD
Yes or No
PD
Any
Any 
Yes
PD
Abbreviations:  CR = complete  response,  PR = partial  response,  SD = stable  disease,  PD = progressive  disease, 
NE = not evaluable.
4.1.1 
Missing Assessments and Not Evaluable Designation
When  no  
imaging/measurement  
is  done  at  a  particular  
time  point, the  subject isnot  evaluable 
(NE)at that time point. If only a subset of lesion measurements are made at an assessment, the 
case is also considered NE at that time point, unless a convincing argument can be made that the 
contribution of the individual missing lesion(s) would not have changed the assigned time point 
response.
4.1.2 
Confirmation Scans
Verification of Response: Confirmation of PR and CR is required at least after 4 weeks from the 
initial  scan  reporting  response  to  ensure  that  the  responses  identified  are  not  the  result  of 
measurement error.
4.2 
Best Overall Response: All Time Points
The best overall response is determined once all the data for the subject is known. It is the best 
response  recorded from  
the  start  of  
the  study  
treatment  until  
the  end  of  
treatment, taking  into 
account  any  
requirement  
for  confirmation. The  subject’s  best  overall  
response  assignment  will 
depend on the findings of both target and non-target disease and will also take into consideration 
the appearance of new lesions.
Best response is defined as the best response across all time points with subsequent confirmation. 
CRs or  PRs may  be  claimed  only  
if  
the  criteria  
for  each  are  met  at  a  subsequent time  point  as 
specified in the protocol (generally 4 weeks later).
In  
this  circumstance,  
the  best  overall  response  can  be  interpreted  as specified inTable  4.2-1. 
When  SD  is  believed  
to  be  best response,  it  must  meet  
the  protocol  specified  minimum  
time 
from  baseline. Measurements  must have  met the SD criteria at  
least once after study entry at a 
minimum interval (in general not less than 6 to 8 weeks). For this protocol best response of SD 
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can  be  made after the  
subject  
is  on  
study  
for  a  minimum of  6  weeks (42 days)±7 days with a 
minimum on study time of 35 days.
Table 4.2-1: 
Best Overall Response When Confirmation of CR and PR is 
Required
Overall Response
Overall Response
Best Overall Response
First Time Point
Subsequent Time Point
CR
CR
CR
CR
PR
SD, PD, or PRa
CR
SD
SD provided minimum criteria for 
SD duration met, otherwise, PD
CR
PD
SD provided minimum criteria for 
SD duration met, otherwise, PD
CR
NE
SD provided minimum criteria for 
SD duration met, otherwise NE
PR
CR
PR
PR
PR
PR
PR
SD
SD
PR
PD
SD provided minimum criteria for 
SD duration met, otherwise, PD
PR
NE
SD provided minimum criteria for 
SD duration met, otherwise NE
NE
NE
NE
a Abbreviations:  CR = complete  response,  PR = partial  response,  SD = stable  disease,  PD = progressive  disease, 
NE = not evaluable.
If a CR is truly met at first time point, then any disease seen at a subsequent time point, even disease meeting PR 
criteria  
relative  
to  baseline,  makes  
the  disease  PD  at  
that  point  (since  disease  must  have  
reappeared  after  CR). 
Best response would depend on whether minimum duration for SD was met. However, sometimes ‘CR’ may be 
claimed when subsequent scans suggest small lesions were likely still present and in fact the subject had PR, not 
CR  at  
the  first  
time  point.  Under  
these  circumstances,  
the  original  CR  should  be  changed  
to  PR  and  
the  best 
response is PR.
4.3 
Duration of Response
4.3.1 
Duration of Overall Response
The duration of overall response is measured from the time measurement criteria are first met for 
CR/PR  
(whichever  
is  first  
recorded)  until  
the  first  date  
that  
recurrent  or  progressive  disease  
is 
objectively  documented  (taking  as  reference  for  PD the  smallest measurements  recorded  on 
study).
The  duration  of  overall  complete response  
is  measured  
from  
the time  measurement  criteria  are 
first met for CR until the first date that recurrent disease is objectively documented.
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4.3.2 
Duration of Stable Disease
SD is measured from the start of the treatment (in randomized trials, from date of randomization) 
until  
the  criteria  for  progression  are  met,  
taking  as  
reference  
the  smallest  sum  on  study  (if  
the 
baseline sum is the smallest, this is the reference for calculation of PD).
Reference: Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: revised 
RECIST guideline (version 1.1). Eur J Cancer 2009;45:228-247.
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APPENDIX 6 
REVISED PROTOCOL SUMMARY OF CHANGE HISTORY
Overall Rationale for the Revised Protocol 04, 12-Sep-2018
The  
revised  protocol  
restricts  study  entry  
to  participants  of  previous  nivolumab  clinical  studies 
where  overall  survival  was listed  as  a  primary  or  co-primary  endpoint  since  participation  in 
CA209-648  could  confound  the  interpretation  of  efficacy  results  in  these  studies.  Live 
/attenuated  vaccines  were  prohibited  to  address  any  potential  safety  risks  and  the  inclusion 
criterion related to the assessment of renal function was expanded to allow the consideration of 
measured  creatinine  clearance  instead  of  calculated  creatinine clearance  per  Cockcroft-Gault 
formula  on  the  basis  that  measured  creatinine  clearance  represents  an  accurate estimation  of 
GFR. Cisplatin  infusion  
times  longer  
than  120  minutes  were  allowed  if  deemed  necessary  by 
investigator  per  local  standard  of  care/local  label. PFS2/TSST was  added  as  an  exploratory 
endpoint to help understand the relevance of  meaningful  
improvements  
in PFS. The section on 
biomarker  assessments  was  revised  
to  
reflect  current  prioritizations  in  
the  biomarker  analyses 
plan. Additionally, program updates were added and internal inconsistencies were corrected.
SUMMARY OF KEY CHANGES FOR REVISED PROTOCOL 04
Section Number & Title 
Description of Change 
Brief Rationale
Section 1.3.3, Exploratory Objectives, 
bullet 4
Bullets 9 - 12
An exploratory objective was 
added.
Revised biomarker 
exploratory objectives.
PFS2/TSST is included as an 
exploratory objective to help 
understand the relevance of 
meaningful improvements in PFS.
Biomarker objectives were revised to 
reflect current prioritizations in the 
biomarker analyses plan.
Section 2.1, Good Clinical Practice
Minor revisions to 
paragraph 2.
Revised to align with the most recent 
language for BMS studies
Section 3.1, Study Design and Duration; 
Section 4.5.1.2, Nivolumab Combined 
with Fluorouracil plus Cisplatin Dosing 
(Arm B); Section 4.5.1.3, Fluorouracil 
plus Cisplatin Dosing (Arm C); 
Synopsis
Added a note to allow for 
longer cisplatin infusion 
times. 
The duration of cisplatin infusion 
may exceed 120 minutes if required 
by local standard of care/local label 
in order to prevent/reduce potential 
toxicities.
Section 3.1.3, Follow-up Phase, bullet 4
Additional study assessments 
were added to bullet 4.
Added study assessments pertinent to 
PFS2/TSST.
Section 3.3.1, Inclusion Criteria, 
2) Target Population, i) v) Calculated 
creatinine clearance
Added measured creatinine 
clearance (CrCl)
Measured CrCl represents an 
accurate estimate of GFR and can be 
used instead of the Cockcroft-Gault 
formula if preferable and feasible.
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SUMMARY OF KEY CHANGES FOR REVISED PROTOCOL 04
Section Number & Title 
Description of Change 
Brief Rationale
Section 3.3.2, Exclusion Criteria, 
2) Medical History and Concurrent 
Diseases;
Section 3.4.1, Prohibited and/or 
Restricted Treatments
Added  exclusion criterion 
2) n)
Added bullet 5 
Alignment with current BMS 
standards for studies using 
nivolumab. This restriction is based 
on theoretical risk of adverse effects 
for nivolumab and ipilimumab and 
not on clinical or safety data. The 
administration of live vaccines is 
contraindicated in patients receiving 
cisplatin and fluorouracil 
chemotherapy.
Section 3.3.2, Exclusion Criteria, 
5) Other Exclusion Criteria, c)
Added to exclude 
participation in any prior 
clinical study of nivolumab.
Study participation may confound 
OS results in other nivolumab 
studies.
Section 3.5, Discontinuation of Subjects 
following any Treatment with Study 
Drug, bullet 4
Added a note to bullet 4.
Revised to align with the most recent 
language for BMS studies
Table 4.5.3.2.2-1, Dose Modifications 
for Non-hematologic Toxicity (Arms B 
and C)
Revised footnote b. 
To clarify that CrCl should be 
assessed prior to dose with the same 
method used to determine eligibility
Section 4.5.5.1, Nivolumab and/or
Ipilimumab Treatment Discontinuation 
(Arms A and B)
Revised dash-bullet 1, under 
bullet 3, to include 
myocarditis.
Removed asterisk-and 
corresponding statement 
regarding Grade 3 AST or 
ALT elevation.
Nivolumab and or ipilimumab dose 
discontinuation criteria were updated 
for safety and to align with program 
standards.
Section 4.5.5.2, Fluorouracil and 
Cisplatin Dose Discontinuation (Arms B 
and C) 
Revised diamond-bullet 3, 
under bullet 2.
To allow measured creatinine in 
addition to calculated creatinine by
the Cockcroft Gault formula.
Table 5.1-5, Follow-Up Procedural 
Outline - All subjects (CA209648), 
Subject Status
Revised survival status to 
include subsequent therapy 
information. 
Additional data collection for PFS 2 
analyses.
Section 5.6, Biomarker Assessments, 
Table 5.6-1, Biomarker Sampling 
Schedule
Revised content regarding 
samples collected. 
Biomarker collections were revised 
to reflect current prioritizations in the 
biomarker analyses plan. 
Biomarker Sections 5.6.1.1 -
Section 5.6.2.6 
Section 5.6.1.1 -
Section 5.6.1.5 were revised.
Section 5.6.1.6 was added.
Section 5.6.2.1 -
Section 5.6.2.4 were revised.
Section 5.6.2.5 and 
Section 5.6.2.6 were added.
Biomarker assessments sections were
revised to reflect current 
prioritizations in the biomarker 
analyses plan and sections were 
added regarding microsatellite 
instability, plasma for circulating 
tumor DNA, and stool for 
microbiome.
Section 8.3.3, Exploratory Endpoint(s);
Section 8.4.2, Efficacy Analyses, 
Exploratory Endpoints
Added bullet 4.
Revised paragraph 1.
PFS2/TSST was added to the 
exploratory endpoints.
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SUMMARY OF KEY CHANGES FOR REVISED PROTOCOL 04
Section Number & Title 
Description of Change 
Brief Rationale
Appendix 1, Hepatic Adverse Event 
Management Algorithm
Footnote *, regarding delay 
of I-O therapy was deleted.
Hepatic algorithm updated to align 
with most recent guidance in the IB.
Appendix 2, Women of Childbearing 
Potential Definitions and Methods of 
Contraception, Highly Effective 
Methods That Are User Independent
Revised bullet 2. 
To align with program standards.
All
Minor formatting and 
typographical corrections.
Minor, therefore have not been 
summarized
Overall Rationale for the Revised Protocol 03, 02-Feb-2018
The  optimal  duration  of  immunotherapy  is  an  important  question  and  continues  to  be 
investigated.  Clinical  trials  across  different  tumors  types  in the  nivolumab  and  ipilimumab 
development  program  indicate  that  most  of  the  responses  occur  early,  with  a  median  time  to 
response  of  2-4  months,  and  emerging  data  suggests  that  benefit  can  be  maintained  in  the 
absence of continued treatment. A recent analysis in a melanoma study suggests the majority of 
patients  who  discontinue  nivolumab  and/or  
ipilimumab  
for  
toxicity  maintain  disease  control  
in 
the  absence  of  further  
treatment  
(Schadendorf  et  al.,  2016).  Furthermore,  a  
limited  duration  of 
ipilimumab,  including  only  4  induction  doses,  resulted  in  long term  survival  in  patients  with 
metastatic  melanoma, with a sustained plateau in survival  starting around 2 years after the start 
of treatment (Schadendorf et al., 2015).
Accumulating data suggest that 2 years of PD-1 checkpoint inhibitor treatment may be sufficient 
for  
long term benefit. CA209003, a dose-escalation cohort expansion trial evaluating the safety 
and  clinical  activity  of  nivolumab  in  patients  with  previously treated  advanced  solid  tumors 
(including  129  subjects  with  NSCLC),  specified  a  maximum  treatment  duration  of  2  years.  
Among 16 subjects with non-small cell lung cancer (NSCLC) who discontinued nivolumab after 
completing 2 years of treatment, 12 subjects were alive >5 years and remained progression-free 
without  any subsequent  therapy.  In  the  CA209003  NSCLC  cohort,  the  overall  survival  (OS) 
curve  begins  
to  plateau  after  2  years,  with  an  OS  rate  of  25%  at  2  years  and  18%  at  3  years 
(Brahmer  et  al.,  2017).  These  survival  outcomes  are  similar  to phase  3  studies  in  previously 
treated NSCLC, in which nivolumab treatment was continued until progression or unacceptable 
toxicity (2 year OS rates of 23% and 29%, and 3 year OS rates of 16%-18% for squamous and 
non-squamous NSCLC respectively) (Felip et al., 2017).
Similar results have been reported in clinical studies of pembrolizumab, another PD-1 inhibitor. 
Keynote-010 was a randomized phase 3 trial of pembrolizumab (at either 2 mg/kg or 10 mg/kg 
every  3  weeks)  versus  docetaxel  
in  subjects  with  previously  
treated,  PD-L1-positive,  advanced 
NSCLC which specified a maximum treatment duration of 2 years for pembrolizumab. OS was 
significantly  longer  with  both  pembrolizumab  2  mg/kg  (HR  0.72, p  =  0.00017)  and 
pembrolizumab  10  mg/kg  
(HR  0.60,  p  <  0.00001)  compared  
to  docetaxel,  with  an  OS  plateau 
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developing  beyond  2  years  in  both  pembrolizumab  arms.  Among  690  patients  who  received 
pembrolizumab,  47  patients  completed  2  years  of  pembrolizumab  and  stopped treatment.  Most 
were  able  
to  maintain  
their  
response,  
including  
those  with  stable  disease,  with  only  2  patients 
(4%) having confirmed progression after stopping at 2 years (Herbst et al., 2016). 
Keynote-006 was a randomized phase 3 study of pembrolizumab versus  
ipilimumab  
in patients 
with  advanced  melanoma,  which  also  specified  a  maximum  2  year  duration  of  pembrolizumab 
treatment. 104  (19%)  of  556  patients  randomized  to  pembrolizumab  completed 2 years of 
treatment.  With  a  median  follow-up  of  9  months  after  completion  of  pembrolizumab,  the 
estimated risk of progression or death was 9% in these patients (Robert et al., 2017).
Taken together, these data suggest that treatment beyond 2 years is unlikely to confer additional 
clinically  meaningful  benefit  and  
that the  
risk  of  progression after  discontinuing  
treatment  at  2 
years is low.
In contrast, a shorter duration of nivolumab of only 1 year was associated with increased risk of 
progression in previously treated patients with NSCLC, suggesting that treatment beyond 1 year 
is  likely  needed.  In  CA209153,  patients  with  previously  treated  advanced  NSCLC  who 
completed  1  year  of  nivolumab  
therapy  were  
randomized  
to  either  continue  or  stop  
treatment, 
with the option of retreatment upon progression. Among 163 patients still on treatment at 1 year 
and  without  progression,  those  who  were  randomized  to  continue nivolumab  had  significant 
improvement in progression-free survival (PFS) compared to those who were randomized to stop 
treatment,  with  median  PFS  (post-randomization)  not  reached  vs 10.3  months,  respectively; 
HR=0.42 (95% CI, 0.25 to 0.71). With a median follow-up of 14.9 months post-randomization, 
there also was a trend for patients on continued treatment to live longer (OS HR = 0.63 [95% CI: 
0.33,  1.20]).  Of  note,  the  PFS  curves  in both  groups  plateau  approximately  1  year  after 
randomization  (i.e.,  2  years  after  treatment  initiation),  suggesting  that  there  may  be  minimal 
benefit in extending treatment beyond a total of 2 years (Spigel et al., 2017).
Collectively,  these  data  suggest  that  there  is  minimal  if  any  benefit  derived  from  continuing 
immuno-oncology  treatment  beyond  2  years  in  advanced  tumors.  However,  even  though 
immunotherapy is well tolerated, patients will be at risk for additional toxicity with longer term 
treatment. Therefore, in this  study, treatment will be given  
for a  maximum of 2  years  
from the 
start of study treatment.
This revised protocol applies to all patients in Study CA209-648
SUMMARY OF KEY CHANGES FOR REVISED PROTOCOL 03
Section Number & Title 
Description of Change 
Brief Rationale
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SUMMARY OF KEY CHANGES FOR REVISED PROTOCOL 03
Section Number & Title 
Description of Change 
Brief Rationale
Synopsis
Investigational Product(s), Dose and 
Mode of Administration, Duration of 
Treatment with Investigational 
Product(s)
Section 1.1.9
Rationale for Two-Year Duration of 
Treatment
Section 3.1
Study Design and Duration
Section 3.1.2
Treatment Phase
Removed treatment 
reinitiation procedures after 
disease progression for up to 
1 additional year.
There is minimal, if any, benefit 
derived from continuing immuno-
oncology treatment beyond two years 
in advanced tumors. Treatment 
beyond 2 years is no longer allowed 
in studies with nivolumab.
Section 4.5.6
Treatment Beyond Disease Progression
Added language for the 24 
month maximum duration of 
treatment for nivolumab
There is minimal, if any, benefit 
derived from continuing immuno-
oncology treatment beyond two years 
in advanced tumors. Treatment 
beyond 2 years is no longer allowed 
in studies with nivolumab.
Overall Rationale for the Revised Protocol 02, 25-Oct-2017
Protocol  was  amended  to  rectify  inconsistencies,  add  clarifications  and  implement  changes 
requested by health authorities
SUMMARY OF KEY CHANGES OF REVISED PROTOCOL 02
Section Number & Title 
Description of Change 
Brief Rationale
Section 1: Introduction and Study 
Rationale
Clarified terminology in 
description of study subjects, 
replacing “inoperable” with 
“unresectable” advanced, 
recurrent or metastatic
esophageal squamous cell 
carcinoma
Revised to ensure consistency of 
terminology used across the study 
protocol
Section 1.1.6: Rationale for Dose 
Selection of Nivolumab in 
Combination with Ipilimumab 
(Arm A) and Chemotherapy (Arm 
B) in First-line ESCC Subjects
Expanded the rationale for 
dose selection in Arms A and 
B 
The dose and schedule of the combination 
of nivolumab and ipilimumab tested in 
other tumor types and perceived to be safe 
and efficacious is been tested in this 
ESCC trial as well.
Rationale for Arm B updated to reflect 
current approval by FDA of nivolumab 
240mg for a variety of tumor types 
including melanoma UC and MSI-
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SUMMARY OF KEY CHANGES OF REVISED PROTOCOL 02
Section Number & Title 
Description of Change 
Brief Rationale
H/dMMR CRC, in addition to the tumor 
types already stated in the previous 
protocol version. Furthermore this dose is 
under review by other health authorities.
Section 3.1.1: Screening Phase
Clarified that an evaluable 
PD-L1 IHC test result by 
central lab would be required 
for randomization 
Revised to specify the term “evaluable” 
(Sufficient quantity of tissue sample 
available for analysis) versus an 
indeterminate test conclusion 
(inconclusive results)
Section 3.1.1: Screening Phase; 
Section 5.1, Table 5.1-1 
Screening Procedural Outline -
All Subjects (CA209648); 
Section 5.3.1: Screening Safety 
Assessments
Removed the 28 day window 
for performance of screening 
assessments and procedures
Each screening assessment will have its 
own window and it is detailed in 
Table 5.1-1. 
Section 3.1.3: Follow-up Phase; 
Section 3.5: Discontinuation of 
Subjects following any Treatment 
with Study Drug; Table 5.1-5: 
Follow-Up Procedural Outline -
All subjects (CA209648)
Follow up 1 criteria date of 
discontinuation is greater 
than 30 days after last dose 
changed to 35 days 
Correction of a protocol inconsistency: 
aligning with Section 3.5 
Section 3.3.1: Inclusion Criteria
Clarified that an evaluable 
PD-L1 IHC test result by 
central lab would be required 
for subject randomization
Revised to clarify that a non-evaluable test 
result will not be accepted for subject 
randomization
Section 3.3.1: Inclusion Criteria
Revised length of 
contraception adherence for 
subjects of child bearing 
potential randomized to 
chemotherapy arms: duration 
of study treatment plus 5 
half-lives of chemotherapy 
plus an additional 30 days for 
women and 90 days for men 
or per local chemotherapy 
drugs label, whichever is 
longer
Revised to meet requirements for duration 
of contraception as set by local labels for 
the chemotherapy drugs 
Section 3.4.1: Prohibited and/or 
Restricted Treatments
Prohibited the use of 
botanical formulations 
approved for the treatment of 
cancer and added a wash out 
window period of 2 weeks 
prior to randomization 
Botanical formulations approved for the 
treatment of cancer may potentially 
interfere with the interpretation of the 
study results therefore added to the 
prohibited medication list. A wash out 
period of two weeks prior to 
randomization is deemed adequate due to 
the low likelihood of DDI. 
Section 3.4.1: Prohibited and/or 
Restricted Treatments
Added language to refer 
investigators to the local 
product labeling for the 
Raise awareness and ensure investigator 
compliance to the local product labeling 
information for the chemotherapy drugs 
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SUMMARY OF KEY CHANGES OF REVISED PROTOCOL 02
Section Number & Title 
Description of Change 
Brief Rationale
chemotherapy drugs for 
additional prohibited and 
restricted concomitant 
medications
with regards additional prohibited and 
restricted concomitant medications not 
explicitly stated in the study protocol. 
Section 3.4.3: Permitted Therapy
Clarified that regular 
concomitant use of 
bisphosphonates and RANK-
L inhibitors for prevention or 
reduction of skeletal-related 
events in subjects with bone 
metastases is allowed if 
initiated prior to first dose of 
study therapy
Specified circumstances were the use of 
bisphosphonates and RANK-L inhibitors
is allowed taking into consideration that 
these agents might be necessary for the 
prevention or reduction of skeletal-related 
events in patients with bone metastases
Section 3.4.3: Permitted Therapy
Added instructional text 
regarding subjects requiring 
concurrent palliative 
radiotherapy
Considering that the study has a PFS co-
primary end-point and measurable disease 
is an inclusion criterion, palliative 
radiotherapy would permitted for non-
target lesions only since this will lessen 
the chances of rendering a subject 
unevaluable per RECIST 1.1. Where 
palliative radiotherapy is required for a 
tumor lesion, then study treatment should 
be withheld for at least 1 week before, 
during, and 1 week after radiation and 
AEs should resolve to Grade ≤ 1 prior to 
resuming study therapy in order to 
minimize toxicities.
Section 4.5.1.1: Nivolumab plus 
Ipilimumab Dosing (Arm A
Removed the text referring to 
the 30 minute timeframe 
between infusions of 
nivolumab and ipilimumab
The detailed instructions are removed as 
they can be found in the pharmacy manual
Section 4.5.1.1, Table 4.5.1.1-1 
Dose Schedule of Nivolumab and 
Ipilimumab in Arm A; Section 
5.1. Table 5.1-2: On-treatment 
Assessments - Subjects in 
Nivolumab 3 mg/kg and 
Ipilimumab 1 mg/kg - Arm A in 
CA209648
Dosing of ipilimumab Q6W, 
window was extended from 
within 3 days before or after 
the scheduled date if 
necessary to 5 days
Increased window flexibility for 
ipilimumab to taking into account that 
drug is administered every 6 weeks to 
permit better synchronization with 
nivolumab dosing
Section 4.5.2.1: Dose Delay 
Criteria for Nivolumab and/or 
Ipilimumab (Arms A and B)
Removed dose delay for 
Grade 2 and 3 AST, ALT or 
Total Bilirubin abnormalities
Removed as this criterion is explicated 
under the ‘Laboratory abnormalities’ 
bullet point further below in the same 
section 
Section 4.5.2.1: Dose Delay 
Criteria for Nivolumab and/or 
Ipilimumab (Arms A and B); 
Section 4.5.5.1: Nivolumab 
and/or Ipilimumab Treatment 
Changed the dose delay 
requiring discontinuation of 
ipilimumab from > 8 weeks 
to > 12 weeks 
> 8 weeks dose delay resulting to 
discontinuation would be too restrictive 
taking into consideration that ipilimumab 
is dosed every 6 weeks
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SUMMARY OF KEY CHANGES OF REVISED PROTOCOL 02
Section Number & Title 
Description of Change 
Brief Rationale
Discontinuation (Arms A and B)
Section 4.5.4.2: Criteria to 
Resume Fluorouracil and 
Cisplatin Combination (Arm C)
Changed the timing criteria 
for discontinuation of 
treatment due to failure of 
recovery of chemotherapy 
toxicity from 6 weeks to 8 
weeks 
To correct a typo; duration was already 
stated 8 weeks elsewhere in the protocol 
Section 4.5.5.1: Nivolumab 
and/or Ipilimumab Treatment 
Discontinuation (Arms A and B)
Added colitis, neurologic 
toxicity, as exceptions for 
discontinuation due to 
adverse events lasting > 7
days or recurring  
Revised to align with the nivolumab IB 
Section 4.5.5.1: Nivolumab 
and/or Ipilimumab Treatment 
Discontinuation (Arms A and B)
Added instructional text 
regarding discontinuation for 
Grade≥ 3 AST, ALT and 
bilirubin elevations and 
investigator consideration of 
abnormal ALT, AST and 
bilirubin values 
Revised to align with the nivolumab IB 
Section 5.1, Table 5.1-1: 
Screening Procedural Outline -
All Subjects (CA209648); Table 
5.1-2: On-treatment Assessments 
- Subjects in Nivolumab 3 mg/kg 
and Ipilimumab 1 mg/kg - Arm A 
in CA209648; Table 5.1-3:On-
Treatment Assessments - Subjects 
in Nivolumab 240 mg Combined 
with Fluorouracil plus Cisplatin -
Arm B in CA209648; Table 5.1-
4: On-Treatment Assessments -
Subjects in Fluorouracil and 
Cisplatin (FP) - Arm C in 
CA209648; Table 5.1-5: Follow-
Up Procedural Outline - All 
subjects (CA209648); 5.3.1: 
Screening Safety Assessments; 
5.3.2: On-Treatment Safety 
Assessments
Amylase and lipase removed 
from laboratory tests 
Amylase and Lipase elevations have been 
observed with nivolumab or nivolumab 
plus ipilimumab treatment. However very 
few subjects reported associated 
symptoms (eg, abdominal pain) or 
radiographic findings (eg, stranding) 
consistent with pancreatitis. Thus, there 
does not seem to be clinical significance 
to the elevated laboratory values and 
therefore there is no evidence suggesting 
that routine monitoring of amylase and 
lipase is required 
Section 5.1, Table 5.1-1: 
Screening Procedural Outline -
All Subjects (CA209648); 5.3.1: 
Screening Safety Assessments
Added a required serum 
follicle stimulating hormone, 
(FSH) level > 40 mIU/mL 
result for females under the 
age of 55 years to confirm 
menopause.
To be consistent with the instructions in 
Section 3.3.3. 
Section 5.1, Table 5.1-2: On-
treatment Assessments - Subjects 
in Nivolumab 3 mg/kg and 
Ipilimumab 1 mg/kg - Arm A in 
Removed procedures in 
column for every 3 cycles 
(every 6 weeks) 
To simplify the table (details are entered 
in the note column)
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SUMMARY OF KEY CHANGES OF REVISED PROTOCOL 02
Section Number & Title 
Description of Change 
Brief Rationale
CA209648
Section 5.1, Table 5.1-2: On-
treatment Assessments - Subjects 
in Nivolumab 3 mg/kg and 
Ipilimumab 1 mg/kg - Arm A in 
CA209648; Table 5.1-3:On-
Treatment Assessments - Subjects 
in Nivolumab 240 mg Combined 
with Fluorouracil plus Cisplatin -
Arm B in CA209648; Table 5.1-
4: On-Treatment Assessments -
Subjects in Fluorouracil and 
Cisplatin (FP) - Arm C in 
CA209648
Outcomes research 
assessments FACT-E and 
EQ-5D to be assessed at set 
time points post cycle 1 d1 
visit regardless of treatment 
schedule. PRO 
administrations not 
coinciding with another study 
assessment visit can be done 
via a phone contact. Health 
care resource utilization will 
be assessed at every dosing 
visit
Clarified schedule of PROs and health 
care assessment administration
Section 5.1, Table 5.1-3:On-
Treatment Assessments - Subjects 
in Nivolumab 240 mg Combined 
with Fluorouracil plus Cisplatin -
Arm B in CA209648; 
Table 5.1-4:On-Treatment 
Assessments - Subjects in 
Fluorouracil and Cisplatin (FP) -
Arm C in CA209648
Removed all procedures in 
column for cycle 1 days 2-5 
and removed procedure 
dispense study treatment 
from cycles 2 and beyond 
days 2-5
This is a correction to an error in the study 
protocol, no assessments have to be 
performed from D2 to D5 as the subject 
will not necessarily come to the hospital
Section 5.3.1: Screening Safety 
Assessments
Physical examinations added 
to screening assessments
Correction to be consistent with the table 
in Section 5.1
Section 5.3.4: Imaging 
Assessment for the Study
Added text to account for the 
collection of additional 
imaging that may 
demonstrate tumor response 
or progression for tumor 
assessment and subsequent 
submission to the BICR.
To be consistent with Section 4.5.6
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SUMMARY OF KEY CHANGES OF REVISED PROTOCOL 02
Section Number & Title 
Description of Change 
Brief Rationale
Section 5.6.1 Tumor Samples
Added text stating that tissue 
samples submitted be 
assessed for quality with an 
H&E stain and only 
participants who have met 
tissue quality thresholds be 
assigned study drug
To be consistent with the clarification 
made in Section 3.3.1 and 3.1.1
Section 8.5: Interim Analysis
Text removed regarding 
number of final events 
exceeding the number 
specified per protocol (250 
deaths) and that final 
boundary would not be 
recalculated using updated 
information fraction at 
interim.
As the number of deaths is a random 
number, details regarding the final 
boundary in case number of final events 
exceeds 250 will be specified in a separate 
document.
Section 10 GLOSSARY OF 
TERMS
Added definitions for PD-L1 
Evaluable Status and PD-L1 
Indeterminate Status
To be consistent with the clarification 
made in Sections 3.3.1, 3.1.1, and 5.6.1
All
Updated End Note reference 
numbering throughout
Duplicates and unnecessary references 
removed
All
Minor formatting and 
typographical corrections
Clarifications to minor formatting and 
typographical corrections
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SAP_001.pdf: 
Official Title of Study: 
A Randomized Phase 3 Study of Nivolumab plus Ipilimumab or Nivolumab Combined with 
Fluorouracil plus Cisplatin versus Fluorouracil plus Cisplatin in Subjects with Unresectable 
Advanced, Recurrent or Metastatic Previously Untreated Esophageal Squamous Cell Carcinoma 
 
 
NCT Number: NCT03143153 
Document Date (Date in which document was last revised): February 23, 2021 


STATISTICAL ANALYSIS PLAN
FOR CLINICAL STUDY REPORT
A RANDOMIZED PHASE 3 STUDY OF NIVOLUMAB PLUS IPILIMUMAB OR 
NIVOLUMAB COMBINED WITH FLUOROURACIL PLUS CISPLATIN VERSUS 
FLUOROURACIL PLUS CISPLATIN IN SUBJECTS WITH UNRESECTABLE 
ADVANCED, RECURRENT OR METASTATIC PREVIOUSLY UNTREATED 
ESOPHAGEAL SQUAMOUS CELL CARCINOMA
PROTOCOL CA209648
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TABLE OF CONTENTS
STATISTICAL ANALYSIS PLAN FOR CLINICAL STUDY REPORT ...................................1
TABLE OF CONTENTS............................................................................................................2
LIST OF TABLES......................................................................................................................5
LIST OF FIGURES ....................................................................................................................5
1
BACKGROUND AND RATIONALE......................................................................6
2
STUDY DESCRIPTION ..........................................................................................7
2.1
Study Design ............................................................................................................7
2.2
Treatment Assignment............................................................................................10
2.3
Blinding and Unblinding.........................................................................................10
2.4
Protocol Amendments.............................................................................................11
2.5
Independent Review of Progression........................................................................11
2.6
Data Monitoring Committee ...................................................................................12
3
OBJECTIVES ........................................................................................................12
3.1
Primary...................................................................................................................12
3.2
Secondary...............................................................................................................13
3.3
Exploratory.............................................................................................................13
4
ENDPOINTS..........................................................................................................14
4.1
Primary Endpoints..................................................................................................14
4.1.1
Overall Survival in All PD-L1 Expressing Subjects.................................................14
4.1.2
Progression-Free Survival per BICR in All PD-L1 Expressing Subjects..................15
4.2
Secondary Endpoints ..............................................................................................17
4.2.1
Overall Survival in All Randomized Subjects ..........................................................17
4.2.2
Progression-Free Survival per BICR in All Randomized Subjects ...........................17
4.2.3
Objective Response Rate per BICR in All Randomized Subjects..............................17
4.3
Exploratory Endpoints............................................................................................17
4.3.1
Efficacy Exploratory Endpoints ..............................................................................17
4.3.2
Safety Exploratory Endpoints..................................................................................18
4.3.3
Outcomes Research Exploratory Endpoints ............................................................19
4.3.4
Pharmacokinetics Exploratory Endpoints...............................................................21
4.3.5
Immunogenicity Exploratory Endpoints..................................................................21
4.3.6
Biomarker Exploratory Endpoints ..........................................................................21
5
SAMPLE SIZE AND POWER...............................................................................23
6
STUDY PERIODS, TREATMENT REGIMENS AND POPULATIONS 
FOR ANALYSES ..................................................................................................27
6.1
Study Periods..........................................................................................................27
6.2
Treatment Regimens...............................................................................................28
6.3
Populations for Analyses ........................................................................................28
7
STATISTICAL ANALYSES..................................................................................29
7.1
General Methods ....................................................................................................29
7.1.1
General Methods: Efficacy .....................................................................................30
7.2
Study Conduct........................................................................................................31
7.2.1
Accrual...................................................................................................................31
7.2.2
Relevant Deviations................................................................................................31
7.3
Study Population ....................................................................................................32
7.3.1
Subject Disposition.................................................................................................32
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7.3.2
Demographics and Other Baseline Characteristics.................................................32
7.3.3
Medical History......................................................................................................33
7.3.4
Prior Therapy Agent...............................................................................................33
7.3.5
Baseline Examinations............................................................................................34
7.3.6
Discrepancies between IRT Stratification Factors and Other Datasets ...................34
7.4
Extent of Exposure .................................................................................................34
7.4.1
Administration of Study Therapy.............................................................................34
7.4.2
Modification of Study Therapy................................................................................37
7.4.3
Concomitant Medications.......................................................................................38
7.5
Efficacy..................................................................................................................38
7.5.1
Protection of Type I Error Across Primary and Secondary Endpoints.....................38
7.5.2
Primary Efficacy Endpoints....................................................................................41
7.5.3
Secondary Efficacy Endpoints.................................................................................45
7.5.4
Exploratory Efficacy Endpoints ..............................................................................46
7.6
Safety.....................................................................................................................47
7.6.1
Deaths ....................................................................................................................47
7.6.2
Serious Adverse Events...........................................................................................47
7.6.3
Adverse Events Leading to Discontinuation of Study Therapy.................................47
7.6.4
Adverse Events Leading to Dose Modification........................................................48
7.6.5
Adverse Events .......................................................................................................48
7.6.6
Select Adverse Events .............................................................................................49
7.6.7
Immune Modulating Medication .............................................................................50
7.6.8
Multiple Events.......................................................................................................51
7.6.9
Other Events of Special Interest..............................................................................51
7.6.10
Immune Mediated Adverse Events...........................................................................51
7.6.11
Clinical Laboratory Evaluations.............................................................................52
7.6.12
Vital Signs ..............................................................................................................54
7.6.13
Immunogenicity Analysis ........................................................................................54
7.6.14
Pregnancy ..............................................................................................................54
7.6.15
Adverse Events by Subgroup...................................................................................54
7.7
Pharmacokinetic Analysis.......................................................................................54
7.8
Biomarker Analysis ................................................................................................55
7.8.1
PD-L1 Expression ..................................................................................................55
7.8.2
PD-L1 by Combined positive score (CPS)  and Microsatellite Instability 
(MSI) Status............................................................................................................56
7.9
Outcomes Research Analyses .................................................................................56
7.10
COVID-19 Related Analyses..................................................................................58
8
Analysis to Evaluate the Contribution of Ipilimumab Component in the N+I 
regimen in the Summary of Clinical Efficacy (SCE)...............................................58
9
CONTENT OF REPORTS .....................................................................................58
9.1
Within-Trial Analyses Performed To Date..............................................................58
10
CONVENTIONS....................................................................................................59
11
CONTENT OF REPORTS .....................................................................................60
12
DOCUMENT HISTORY........................................................................................60
APPENDIX 1............................... APPENDIX: EXAMPLE FOR SEQUENTIALLY REJECTIVE 
PROCEDURE ........................................................................................................63
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APPENDIX 2..............MISSING AND PARTIAL RADIOTHERAPY AND SURGERY DATES 
IMPUTATION ALGORITHMS.............................................................................68
APPENDIX 3................ TIME-TO ONSET AND TIME-TO RESOLUTION DEFINITION AND 
CONVENTIONS FOR SELECT ADVERSE EVENTS, IMMUNE-
MEDIATED ADVERSE EVENTS AND EVENTS OF SPECIAL 
INTEREST.............................................................................................................70
APPENDIX 4..................................... IMMUNOGENICITY ANALYSIS: BACKGROUND AND 
RATIONALE.........................................................................................................72
APPENDIX 5.....................................................................................ANALYSES OF DATA FROM 
CHINA...................................................................................................................75
APPENDIX 6................................................................................ R PROGRAM FOR THE STUDY 
DESIGN.................................................................................................................76
APPENDIX 7........................................................ CHANGE OF THE TRIGGER FOR PFS FA/OS 
IA...........................................................................................................................91
13
REFERENCES.......................................................................................................93
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LIST OF TABLES
Table 2.4-1:
Relevant Protocol Amendments..............................................................11
Table 4-1:
Overview of Major Efficacy Endpoints...................................................14
Table 4.3.3-1:
Time Windows for EQ-5D-3L and FACT-E Assessments ......................20
Table 5-1:
Subjects whose Tumors Express PD-L1 - Summary of Sample Size 
Parameters and Schedule of Analyses (N+I vs CT and N+C vs CT)........24
Table 5-2:
All Randomized Subjects - Summary of Power Calculation 
Parameters and Schedule of Analyses (N+I vs CT and N+C vs CT)........25
Table 7.4.1-1:
Administration of Study Therapy in the N+I Arm - Definition of 
Parameters..............................................................................................36
Table 7.4.1-2:
Administration of Study Therapy in the N+C and CT Arms....................36
Table 7.4.2.1-1:
Dose Delays ...........................................................................................37
Table 10-1:
Step1: Time 1, Rejection of PFS PDL1+ for N+I vs. CT.........................64
Table 10-2:
Step2: Time 1, Rejection of PFS AC for N+I vs. CT...............................65
Table 10-3:
Step3: Time 2, Rejection of OS PDL1+ for N+I vs. CT ..........................66
Table 10-4:
Step4: Time 2, Rejection of OS AC for N+I vs. CT ................................67
Table 10-5:
Derivation of clustered AE .....................................................................71
LIST OF FIGURES
Figure 2.1-1:
Study Scheme...........................................................................................8
Figure 4.1.2-1:
Graphical Representation of the Primary PFS Definition ........................16
Figure 7.5.1-1:
Graphical Representation of the Testing Strategy for the Primary 
and Secondary Endpoints........................................................................39
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1
BACKGROUND AND RATIONALE
CA209648 is a randomized, global Phase 3 study of nivolumab plus ipilimumab or nivolumab in 
combination with fluorouracil plus cisplatin versus fluorouracil and cisplatin chemotherapy as first 
line-therapy in inoperable advanced, recurrent or metastatic esophageal squamous cell carcinoma 
(ESCC). This study will determine if nivolumab plus ipilimumab and nivolumab combined with 
fluorouracil plus cisplatin improve overall survival (OS) and/or progression free survival (PFS) 
over fluorouracil and cisplatin standard of care chemotherapy (further: chemotherapy) in subjects 
with ESCC whose tumors express PD-L1. Additional objectives include further characterization 
of the efficacy, adverse event profile, pharmacokinetics (PK), patient reported outcomes, and 
potential predictive biomarkers of nivolumab in combination with ipilimumab or nivolumab in 
combination with fluorouracil and cisplatin in subjects with ESCC.
Research Hypothesis:  
•
The administration of nivolumab plus ipilimumab will improve OS compared with fluorouracil 
and cisplatin combination in subjects with unresectable advanced, recurrent or metastatic 
ESCC with PD-L1 expression ≥ 1%.
•
The administration of nivolumab combined with fluorouracil plus cisplatin will improve OS 
compared with fluorouracil and cisplatin combination alone in subjects with unresectable 
advanced, recurrent or metastatic ESCC with PD-L1 expression ≥ 1%.
•
The administration of nivolumab plus ipilimumab will improve PFS as assessed by a blinded 
independent central review committee (BICR) compared with fluorouracil and cisplatin 
combination in subjects with unresectable advanced, recurrent or metastatic ESCC with PD-L1 
expression ≥ 1%.
•
The administration of nivolumab combined with fluorouracil plus cisplatin will improve PFS 
as assessed by a BICR compared with fluorouracil and cisplatin combination alone in subjects 
with unresectable advanced, recurrent or metastatic ESCC with PD-L1 expression ≥ 1%.
Schedule of Analyses:
In this study, two formal efficacy analyses are planned:
•
Final PFS analysis and Interim OS analysis: For superiority of PFS in subjects who were 
randomized to nivolumab plus ipilimumab vs. subjects who were randomized to chemotherapy 
and in subjects who were randomized to nivolumab in combination with chemotherapy vs. 
subjects who were randomized to chemotherapy only. Analysis will be performed when 136 
PFS events per BICR are observed or when a 12-month minimum follow-up (defined as the 
time from the date of the last patient was randomized to the clinical cutoff date) is reached if 
the planned number of events is unlikely to be reached among the PD-L1 expressing subjects 
in the chemotherapy arm. By design, 136 PFS events among the PD-L1 expressing subjects in 
the chemotherapy arm are expected to be reached approximately 33 months after first patient 
randomized. At the same time, formal interim analysis of OS will be also conducted (in case 
of significant results, study may be stopped). All the events observed in the locked database 
will be used in the final analysis of PFS, following intention-to-treat principle (Section 5).
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•
Final OS analysis: For superiority of OS in subjects who were randomized to nivolumab plus 
ipilimumab vs. subjects who were randomized to chemotherapy and in subjects who were 
randomized to nivolumab in combination with chemotherapy vs. subjects who were 
randomized to chemotherapy only. Analysis will be performed when 140 OS events are 
observed among the PD-L1 expressing subjects in the chemotherapy arm. This is expected to 
be reached approximately 49 months after first patient randomized. In the case that the 
observed number of OS events exceed the pre-planned number, all the events observed in the 
locked database will be used in the final analysis of OS, following intention-to-treat principle 
(Section 5).
Since each of the formal efficacy analyses will be triggered by the pre-planned number of events 
among the PD-L1 expressing subjects in the chemotherapy arm, the external independent statistical 
group supporting DMC review (Axio Research) will be utilized to conduct unblinded event 
tracking (the tracking plan is documented separately).
2
STUDY DESCRIPTION
2.1
Study Design
This is a randomized Phase 3 study of nivolumab plus ipilimumab or nivolumab combined with 
fluorouracil plus cisplatin compared with fluorouracil and cisplatin combination in adult 
(≥18 years) male and female subjects with unresectable advanced, recurrent or metastatic ESCC. 
After signing the informed consent form, and upon confirmation of the subject’s eligibility, 
subjects with unresectable advanced, recurrent or metastatic ESCC will be randomized in a 1:1:1 
ratio to one of the following open-label treatments:
•
Nivolumab-plus-ipilimumab (N+I) arm: Subjects will receive treatment with nivolumab 
3mg/kg as a 30-minute infusion every 2 weeks and ipilimumab as a 30-minute infusion 1mg/kg 
every 6 weeks.
•
Nivolumab-plus-chemotherapy (N+C) arm: Subjects will receive treatment with nivolumab 
240mg as a 30-minute infusion on Day 1 and Day 15, fluorouracil 800mg/m层/day as an IV 
continuous infusion on Day 1 through Day 5 (for 5 days), and cisplatin 80mg/m层as a 30 to 
120-minute infusion on Day 1 of 4-week cycle.
•
Chemotherapy (CT) arm: Subjects will receive treatment with fluorouracil 800mg/m²/day as 
an IV continuous infusion from Day 1 through Day 5 (for 5 days), and cisplatin 80mg/m层as a 
30- to 120-minute infusion on Day 1 of 4-week cycle.
Treatment with nivolumab or nivolumab with ipilimumab will be given for up to 24 months in the 
absence of disease progression (PD) or unacceptable toxicity. Chemotherapy will be given as per 
the study dosing schedule until PD or unacceptable toxicity.
Baseline and all subsequent scans will be submitted to a BICR for analysis and archiving, once the 
subject is randomized and throughout the study period.
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Figure 2.1-1:
Study Scheme
This study will consist of 3 phases: screening, treatment, and follow-up:
Screening Phase
•
Begins by establishing the subject’s initial eligibility and signing of the informed consent.
•
Subject is enrolled using the Interactive Response Technology (IRT) system.
•
Subjects must have PD-L1 IHC testing, with evaluable 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 if available, must be submitted for biomarker 
evaluation prior to randomization. The tumor tissue sample may be fresh or archival if obtained 
within 6 months prior to randomization, and there can have been no systemic therapy 
(eg, adjuvant) given after the sample was obtained.
•
All subjects with PD-L1 result will be randomized, but only subjects with PD-L1 expression 
≥ 1% will be assessed as part of the primary objective. 
•
Subject is assessed for study eligibility according to the inclusion and exclusion criteria. All 
screening assessments and procedures must be performed within 28 days prior to 
randomization unless otherwise specified.
Treatment Phase
•
The treatment phase begins when the treatment is assigned in the IRT. Study treatment must 
begin within 3 calendar days of randomization.
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•
Treated subjects will be evaluated for tumor assessments every 6 weeks (± 7 days) starting on 
Week 7 up to and including Week 48, then every 12 weeks (± 7 days) thereafter.
•
Treatment with nivolumab with ipilimumab or nivolumab (Arms A and B) will be given for 
up to 24 months in the absence of PD or unacceptable toxicity. Chemotherapy (Arms B and C) 
will be given as per the study dosing schedule until PD or unacceptable toxicity. Then, the 
subject will enter the Follow-up Phase.
Dosing in the N+I arm:
•
Nivolumab 3mg/kg will be administered IV on Day 1 and then every 2 weeks.
•
Ipilimumab 1mg/kg will be administered IV on Day 1 and then every 6 weeks following the
administration of nivolumab.
•
When both nivolumab and ipilimumab are to be administered on the same day, nivolumab is
to be administered first. The second infusion will always be ipilimumab, and will start at least
30 minutes after completion of the nivolumab infusion.
•
Treatment beyond initial, investigator-assessed, RECIST 1.1-defined progression is permitted
if the subject has investigator-assessed clinical benefit and is tolerating treatment.
Dosing in the N+C arm:
•
Nivolumab combined with fluorouracil and cisplatin will be administered IV in a 4-week cycle. 
Nivolumab 240mg will be administered IV every 2 weeks on Day 1 and Day 15 of each cycle. 
Fluorouracil 800mg/m²/day will be administered as an IV continuous infusion on Day 1 
through Day 5 (for 5 days) and cisplatin 80mg/m² will be administered IV on Day 1 of 4-week 
cycle.
•
When both nivolumab and fluorouracil and cisplatin combination are to be administered on the 
same day, nivolumab is to be administered first. Infusion of fluorouracil and cisplatin will start 
at least 30 minutes after completion of the nivolumab infusion.
•
Treatment with nivolumab beyond initial, investigator-assessed, RECIST 1.1-defined PD is 
permitted if the subject has investigator-assessed clinical benefit and is tolerating treatment.
Dosing in the CT arm:
•
Fluorouracil 800mg/m²/day will be administered as an IV continuous infusion on Day 1
through Day 5 (for 5 days) and cisplatin 80mg/m² will be administered IV on Day 1 of 4-week
cycle.
Follow-up Phase
•
Begins when the decision to discontinue a subject from study therapy is made (no further
treatment with study therapy).
−
FU1 = 30 days from last dose (± 7 days) or coinciding with the date of discontinuation
(± 7 days) if date of discontinuation is greater than 35 days after last dose
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−
FU2 = 84 days from FU1 (± 7 days).
•
Subjects who discontinue treatment for reasons other than tumor progression will continue to
have tumor assessments as per the schedule for the assigned treatment arm until confirmed PD
by BICR, withdrawal of consent or lost to follow-up. (For details on discontinuation of tumor 
assessments, see Section 2.5.)
•
Subjects will be followed for all AEs until these resolve, return to baseline or are deemed
irreversible. All AEs will be documented for a minimum of 100 days after the last dose of
study treatment.
•
After completion of the first two follow-up visits, subjects will be followed every 3 months
(± 14 days) for survival via in-person visit or phone. Ad hoc survival data requests may be
made during the study as well, particularly during database locks. Additional subsequent 
cancer therapy details such as regimen, setting of the regimen, line of therapy, start date and 
end date of each regimen, best response to the regimen and date of progression after second 
line therapy will be collected.
•
The PRO questionnaires collection and biomarker sampling will continue as per time and event 
schedule.
2.2
Treatment Assignment
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 the IRT system to obtain the 
subject number. Every subject that signs the informed consent form must be assigned a subject 
number in the IRT system. 
Once enrolled in the IRT, subjects that have met all eligibility criteria (including 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 IRT. 
Subjects meeting all eligibility criteria will be randomized in a 1:1:1 ratio to either the N+I arm, 
or the N+C arm, or the CT arm. Randomization will be stratified by the following factors:
1) PD-L1 status (≥1% vs. < 1% [including indeterminate])*
2) Region (East Asia (Japan/Korea/Taiwan [J/K/T]) vs Rest of Asia vs rest of world [RoW])
3) ECOG performance status (0 vs. 1).
4) Number of organs with metastases (≤1 vs. ≥2)
* During enrolment, the proportion of subjects with or without PD-L1 tumor expression will be 
monitored, and may be re-assessed in case it does not reflect study assumptions (i.e., subjects with 
PD-L1 tumor expression ≥1% is approximately 50% of all comers).
2.3
Blinding and Unblinding
Not applicable.
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2.4
Protocol Amendments
Global amendments incorporated in the protocol with relevant changes are described in Table 2.4-
1. 
Table 2.4-1:
Relevant Protocol Amendments
Amendments
Date of Issue
Summary of Major Changes
Revised Protocol 
05
29-Oct-2020
This revised protocol allows for the final PFS analysis to be triggered 
when 136 PFS events per BICR are observed among the PD-L1 
expressing subjects in the chemotherapy arm or when at least 12 
months minimum follow up is reached, if the target number of PFS 
events is unlikely to be reached.
Revised Protocol 
04
12-Sep-2018
This revised protocol restricts study entry to participants of previous 
nivolumab clinical studies where overall survival was listed as a 
primary or co-primary endpoint. Live /attenuated vaccines were 
prohibited and the inclusion criterion related to the assessment of renal 
function was expanded to allow the consideration of measured 
creatinine clearance. Cisplatin infusion times longer than 120 minutes 
were allowed if deemed necessary by investigator per local standard of 
care/local label. PFS2/TSST was added as an exploratory endpoint. 
The section on biomarker assessments was revised. Program updates 
were added and internal inconsistencies were corrected.
Revised Protocol 
03
02-Feb-2018
This revised protocol removed the procedures for the reinitiation of 
nivolumab ± ipilimumab treatment after disease progression for up to 1 
additional year.  In addition, it added clarification to the treatment 
beyond progression procedures to limit treatment to a maximum 
duration of 24 months.
Revised Protocol 
02
25-Oct-2017
To align the protocol with the latest SmPC, simplify procedures, and 
provide clarifications in the protocol. 
Revised Protocol 
01
21-Dec-2016
Incorporates Amendment(s) 02
Amendment 02
21-Dec-2016
Expansion of the esophageal cohort into a 3-arm randomized Phase 3 
study in first line squamous esophageal cancer. The study now 
includes a nivolumab plus chemotherapy arm (fluorouracil and 
cisplatin) and a chemotherapy alone arm in addition to the existing 
nivolumab and ipilimumab arm. The gastric cohort was removed.
2.5
Independent Review of Progression
At the time of investigator-assessed initial radiographic progression per RECIST 1.1 in any given 
subject, the site must request the blinded independent central review (BICR) of progression from 
the third party radiology vendor.
Tumor assessments for each subject should be submitted to the radiology vendor as they are 
performed on an ongoing basis. The blinded, independent radiologists will review all available 
tumor assessments for that given subject and determine if RECIST 1.1 criteria for progression have 
been met. The independent assessment of whether or not the given subject met RECIST 1.1 criteria 
for progression will be provided to the site. Subjects whose disease progression is not confirmed 
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centrally will be required to continue tumor assessments (if clinically feasible) according to the 
protocol-specified schedule. Subsequent tumor assessments must be submitted to the third party 
radiology vendor for subsequent review and may be discontinued when the investigator and 
independent radiologists both assess the subject to have met RECIST 1.1 criteria for 
progression. In addition, subjects receiving treatment beyond progression must continue tumor 
assessments until such treatment has been discontinued.
If clinically acceptable, subsequent therapy should begin only after RECIST 1.1 progression has 
been assessed by BICR. For subjects who start palliative local therapy or subsequent therapy 
without prior assessment of RECIST 1.1 progression by central review, the Investigator must 
continue tumor assessments (if clinically feasible) according to the protocol-specified schedule 
and submit them to the third-party radiology vendor. When RECIST 1.1 progression is assessed 
by the investigator (whether assessed before or after the start of palliative local therapy or 
subsequent therapy), the BICR assessment must be requested. Tumor assessments may be 
discontinued when the independent radiologist assesses the subject to have met RECIST 1.1 
criteria for progression.
2.6
Data Monitoring Committee
An independent Data Monitoring Committee (DMC) will be utilized. A DMC will be established 
to provide oversight of safety and efficacy considerations in CA209648. 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 plus ipilimumab and 
nivolumab plus fluorouracil and cisplatin. 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.
DMC will review the safety data from the study when approximately (dependent on the accrual 
speed) 45 subjects (about 5% of subjects) have been treated and followed for at least 4 weeks.
The DMC will be reviewing safety data every approximately six months and will be also 
responsible for reviewing and making recommendations at Final PFS analysis and Interim OS 
analysis. (Section 1).
3
OBJECTIVES
3.1
Primary
•
To compare the OS of nivolumab plus ipilimumab to fluorouracil and cisplatin combination in 
subjects with PD-L1 expression ≥1%.
•
To compare the OS of nivolumab combined with fluorouracil plus cisplatin to fluorouracil and 
cisplatin combination in subjects with PD-L1 expression ≥1%.
•
To compare the PFS of nivolumab plus ipilimumab to fluorouracil and cisplatin combination 
as assessed by a BICR in subjects with PD-L1 expression ≥1%.
•
To compare the PFS of nivolumab combined with fluorouracil plus cisplatin to fluorouracil 
and cisplatin combination as assessed by a BICR in subjects with PD-L1 expression ≥1%.
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3.2
Secondary
•
To compare the OS of nivolumab plus ipilimumab and nivolumab combined with fluorouracil 
plus cisplatin to fluorouracil and cisplatin combination in all randomized subjects.
•
To compare the PFS of nivolumab plus ipilimumab and nivolumab combined with fluorouracil 
plus cisplatin to fluorouracil and cisplatin combination as assessed by a BICR in all 
randomized subjects.
•
To compare the objective response rate (ORR) of nivolumab plus ipilimumab and nivolumab 
combined with fluorouracil plus cisplatin to fluorouracil and cisplatin combination as assessed 
by a BICR in subjects with PD-L1 expression ≥1%.
•
To compare the ORR of nivolumab plus ipilimumab and nivolumab combined with 
fluorouracil plus cisplatin to fluorouracil and cisplatin combination as assessed by a BICR in 
all randomized subjects.
3.3
Exploratory
•
To assess PFS of nivolumab plus ipilimumab and nivolumab combined with fluorouracil plus 
cisplatin vs fluorouracil and cisplatin combination as assessed by investigators in subjects with 
PD-L1 expression ≥1% and in all randomized subjects.
•
To assess ORR of nivolumab plus ipilimumab and nivolumab combined with fluorouracil plus 
cisplatin vs fluorouracil and cisplatin combination as assessed by investigators in subjects with 
PD-L1 expression ≥1% and in all randomized subjects.
•
To assess Duration of Response (DOR) of nivolumab plus ipilimumab or nivolumab combined 
with fluorouracil plus cisplatin vs fluorouracil and cisplatin combination as assessed by BICR 
and by investigators in subjects with PD-L1 expression ≥1% and in all randomized subjects.
•
To assess time from randomization to the date of investigator-defined documented second 
objective disease progression or start of second subsequent therapy or death due to any cause, 
whichever comes first (PFS2/TSST) of nivolumab plus ipilimumab (Arm A) or nivolumab 
combined with fluorouracil plus cisplatin (Arm B) vs fluorouracil and cisplatin combination 
(Arm C) as assessed by investigators in subjects with PD-L1 expression ≥1% and in all 
randomized subjects.
•
To assess the overall safety and tolerability of treatment with nivolumab plus ipilimumab or 
nivolumab combined with fluorouracil plus cisplatin vs.
fluorouracil and cisplatin 
combination.
•
To characterize the PK of nivolumab plus ipilimumab or nivolumab combined with 
fluorouracil plus cisplatin.
•
To characterize the immunogenicity of nivolumab plus ipilimumab or nivolumab combined 
with fluorouracil plus cisplatin.
•
To characterize immune correlates of nivolumab plus ipilimumab, nivolumab combined with 
fluorouracil plus cisplatin, and fluorouracil and cisplatin combination.
•
To evaluate the pharmacodynamic activity of nivolumab plus ipilimumab or nivolumab 
combined with fluorouracil plus cisplatin in the peripheral blood.
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•
To explore potential biomarkers associated with clinical efficacy (OS, PFS, and ORR) and/or 
with incidence of adverse events of nivolumab plus ipilimumab or nivolumab combined with 
fluorouracil plus cisplatin by analyzing biomarker measures within the tumor 
microenvironment and periphery (e.g., blood, serum, plasma) in comparison to clinical 
outcomes.
•
To assess the subject’s overall health status using 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).
4
ENDPOINTS
A summary of the efficacy endpoints is presented in Table 4-1.
Table 4-1:
Overview of Major Efficacy Endpoints
N+C vs CT
N+I vs CT
All PDL1-
Expressing 
Subjects
All Randomized 
Subjects
All PDL1-
Expressing 
Subjects
All Randomized 
Subjects
Primary Endpoints
OS, PFS by BICR
OS, PFS by BICR
Secondary 
Endpoints
ORR by BICR
OS
PFS by BICR
ORR by BICR
ORR by BICR
OS
PFS by BICR
ORR by BICR
Exploratory 
Endpoints
PFS by investigator
ORR by investigator
DOR*
PFS2/TSST by 
investigator
PFS by investigator
ORR by investigator
DOR*
PFS2/TSST by 
investigator
PFS by investigator
ORR by investigator
DOR*
PFS2/TSST by 
investigator
PFS by investigator
ORR by investigator
DOR*
PFS2/TSST by 
investigator
* By BICR and by investigator
For the definition of All PD-L1 Expressing Subjects and All Randomized Subjects, see 
Section 6.3.
4.1
Primary Endpoints
Primary endpoints are OS and PFS in All PD-L1 expressing subjects. 
4.1.1
Overall Survival in All PD-L1 Expressing Subjects
OS is defined as the 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.
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4.1.2
Progression-Free Survival per BICR in All PD-L1 Expressing Subjects
For the purposes of the primary endpoints, PFS is as assessed by BICR in subjects with PD-L1 
expressing tumors. 
PFS is defined as the time from randomization to the date of the first documented PD per BICR or 
death due to any cause. Subjects without any baseline scan will be censored at the randomization 
date (regardless of death). Subjects who did not have any on-study tumor assessments and did not 
die (or died after initiation of the subsequent anti-cancer therapy) will be censored at the 
randomization date. Subjects who die without a reported prior PD per BICR (and die without start 
of subsequent therapy) will be considered to have progressed on the date of death. Subjects who 
did not have documented PD per BICR per RECIST1.1 criteria and who did not die, will be 
censored at the date of the last evaluable tumor assessment on or prior to initiation of the 
subsequent anti-cancer therapy. Subjects who started any subsequent anti-cancer therapy without 
a prior reported PD per BICR will be censored at the last tumor assessment on or prior to initiation 
of the subsequent anti-cancer therapy.
See Figure 4.1.2-1 for the graphical representation of this definition.
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Figure 4.1.2-1:
Graphical Representation of the Primary PFS Definition
rand = randomization, subs = subsequent therapy
PFS Primary 
Definition
No: baseline Scan
Censored at rand 
(regardless of 
Death) 
Yes: baseline scan
No: on-study 
scans
Yes: Death
Death with prior 
subsequent 
therapy
Censored at 
randomization
Death without 
prior subsequent 
therapy
Event at Death 
date
No:Death
Censored at 
randomization
Yes:  on-study 
scans
No PD, 
No death
Yes: subsequent 
therapy
Censored at max( rand, 
last tumor scan <=the 
subs date)
No: subsequent 
therapy
Censored at last 
tumor scan date
Yes: PD or Death 
or both
Yes: subs < PD or 
death or min (PD, 
death)
Censored at 
max(rand, last tumor 
scan <= subs date)
No: subs < PD or 
death or min (PD, 
death date)
Event at PD or  
death or min (PD, 
death date)
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4.2
Secondary Endpoints
4.2.1
Overall Survival in All Randomized Subjects
Overall survival in All Randomized subjects is defined the same way as for the primary endpoint 
(for subjects with PD-L1 expressing tumors).
4.2.2
Progression-Free Survival per BICR in All Randomized Subjects
Progression-free survival in All Randomized subjects is defined the same way as for the primary 
endpoint (for subjects with PD-L1 expressing tumors).
4.2.3
Objective Response Rate per BICR in All Randomized Subjects
Objective response rate as assessed by BICR in subjects with PD-L1 expressing tumors and in All 
Randomized subjects are secondary endpoints for this study.
It is defined as the number of subjects with a best overall response (BOR) of CR or PR divided by 
the number of randomized subjects in the population for each treatment group. BOR is defined as 
the best response designation as determined by BICR per RECIST 1.1, recorded between the date
of randomization and the date of objectively documented progression or the date of subsequent 
anti-cancer therapy (including tumor-directed radiotherapy and tumor-directed surgery), 
whichever occurs first. For subjects without documented progression or subsequent anti-cancer 
therapy, all available response designations will contribute to the BOR determination. For subjects 
who continue treatment beyond progression, the BOR will be determined based on response 
designations recorded up to the time of the initial RECIST 1.1-defined progression.
4.3
Exploratory Endpoints
4.3.1
Efficacy Exploratory Endpoints
Progression-Free Survival per Investigator
Progression-free Survival as assessed by investigator in subjects with PD-L1 expressing tumors 
and in All Randomized subjects is defined similarly as the corresponding (primary) endpoints as 
assessed by BICR - except that only tumor assessments by investigator will be taken into account.
Objective Response Rate per Investigator
Objective response rate as assessed by investigator in subjects with PD-L1 expressing tumors and 
in All Randomized subjects is defined similarly as the corresponding (primary) endpoints as 
assessed by BICR - except that only tumor assessments by investigator will be taken into account.
Duration of Response
Duration of Response (as assessed by BICR and as assessed by investigator) is defined as the time 
between the date of first documented response (CR or PR) to the date of the first disease 
progression, per RECIST 1.1 or death due to any cause, whichever occurs first. For subjects who 
neither progress nor die, the duration of objective response will be censored at the same time they 
were censored for the primary definition of PFS. DOR will be evaluated only for subjects whose 
BOR is CR or PR.
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Survival rate, PFS rate and duration of Stable Disease (SD) are not positioned as objectives per 
protocol, but will be evaluated. 
Survival Rate
Overall survival rate at different timepoints, e.g. at 18, 24, and 36 months is defined as the 
probability that a subject is alive at 18, 24, and 36 months, respectively, following randomization.
Overall survival rates at other timepoints are defined similarly.
PFS Rate
PFS rate at different timepoints, e.g. at 6, 12, 18 and 24 months is defined as the probability that a 
subject has not progressed and is alive at 6, 12, 18 and 24 months, respectively, following 
randomization. PFS rates at other timepoints are defined similarly.
Duration of Stable Disease
Duration of SD is defined as the time between the randomization date and the date of the first 
documented tumor progression (per RECIST 1.1) or death due to any cause, whichever occurs 
first. Censoring rules will be the same as for DOR analysis. It will be evaluated only for subjects 
whose BOR is SD.
PFS2/TSST
PFS on next-line therapy (PFS2) / Time To Second Subsequent Therapy (TSST) is defined as the 
time from randomization to the documented progression (radiographic or clinical progression) per 
investigator assessment after the next line of systemic therapy or start of the second next line 
systemic therapy or death from any cause, whichever occurs first. Subjects who were alive and 
without the second progression and without the second next line systemic therapy will be censored 
at last known alive date. 
The following censoring rules will be applied for PFS2/TSST:
•
Subjects who did not receive any subsequent anti-cancer systemic therapy:
−
Subjects who died, the death date is the event date;
−
Else the subject’s PFS2/TSST is censored at the last known alive date.
•
Subjects who received at least one subsequent anti-cancer systemic therapy:
−
Subjects who had a disease progression after the start of the first subsequent anti-cancer 
systemic therapy, this disease progression date is the event date;
−
Else if a subject died or start of the second next line systemic therapy, the date of min 
(death, start date of the second next line systemic therapy) is the event date;
−
Else the subject’s PFS2/TSST is censored at the last known alive date.
4.3.2
Safety Exploratory Endpoints
The assessment of safety will be based on the incidence of adverse events (AEs), serious adverse 
events (SAEs), adverse events leading to discontinuation, adverse events leading to dose 
modification, select adverse events (select AEs) for EU/ROW Submissions, immune-mediated 
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AEs (IMAEs) for US Submission, other events of special interest (OEOSI), and deaths. The use 
of immune modulating concomitant medication will be also summarized. In addition clinical 
laboratory tests, and immunogenicity (i.e. development of anti-drug antibody) will be analyzed.
4.3.3
Outcomes Research Exploratory Endpoints
EQ-5D-3L
Subjects’ reports of general health status will be assessed using the EuroQoL Group’s EQ-5D-3L. 
EQ-5D-3L essentially has 2 components: the descriptive system and the visual analogue scale 
(VAS).
The instrument’s descriptive system consists of 5 dimensions:  mobility, self-care, usual activities, 
pain/discomfort, and anxiety/depression. Each dimension has 3 levels, reflecting "no health 
problems," "moderate health problems," and "extreme health problems." A dimension for which 
there are no problems is said to be at level 1, while a dimension for which there are extreme 
problems is said to be at level 3.  Thus, the vectors 11111 and 33333 represent the best health state 
and the worst health state, respectively, described by the EQ-5D-3L. Altogether, the instrument 
describes 35 = 243 health states. Empirically derived weights can be applied to an individual’s 
responses to the EQ-5D-3L descriptive system to generate an index measuring the value to society 
of his or her current health. Such preference-weighting systems have been developed for Japan,
UK, US, Spain, Germany, and numerous other populations. For this study, EQ-5D-3L utility index 
values will be computed using a scoring algorithm based on the United Kingdom Time-Trade-Off 
(UK TTO) value set1
In addition, the EQ-5D-3L includes a VAS, which allows respondents to rate their own current 
health on a 101-point scale ranging from 0=”worst imaginable” health to 100=“best imaginable” 
health state 2.
A change from baseline of 0.08 for the EQ-5D-3L utility index score and of 7 for the EQ-5D-3L 
VAS are considered minimally important differences for the EQ-5D-3L3.
FACT-E
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) for patients.
The FACT-E includes the 27-item FACT-General (FACT-G) generic cancer-related core measure, 
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 to the FACT-G, the FACT-E also includes a 17-item disease-specific Esophagus 
Cancer Subscale (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 
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is rated on a five-point scale ranging from 0 (not at all) to 4 (very much).  The FACT-E also 
includes the single-item GP5 item, which assesses the overall bother associated with the side 
effects of treatment.  
Scores for the PWB, FWB, SWB, and EWB subscales can be combined to produce a FACT-G 
total score for each Cohort, which provides an overall indicant of generic HRQL. The FACT-G 
and ECS scores can be combined to produce a total score for the FACT-E, which provide a 
composite measure of general and targeted HRQL. The PWB, FWB and ECS scores can be 
combined to produce a Trial Outcome Index (TOI).  Higher scores on all scales indicate reduced 
symptoms and better HRQL. The full FACT-E will be administered to subjects during the on-
treatment phase and at follow up visits 1 and 2. However, to minimize subject response and 
administrative burden, only the FACT-G7 and ECS will be administered during the survival 
follow-up phase.
All questionnaires completed at baseline and on-study will be assigned to a time-point according 
to the windowing criteria in Table 4.3.3-1 and included in the analysis. In case a subject has two 
on-study assessments within the same window, the assessment closest to the time-point will be 
used. And, in the case of two assessments at a similar distance to the time-point, the latest one will 
be chosen. In the event where the subject has no assessment at all in a specific window, the 
observation will be treated as missing for that time-point.
Table 4.3.3-1:
Time Windows for EQ-5D-3L and FACT-E Assessments
Nominal Time-Point
Time Window
all treatment groups
Baselinea
On or prior to first dose on Day 1b
Week 3
Nominal Day 15 (Day 2 through Day 22, inclusive)
Week 5
Nominal Day 29 (+7 days/-6 days, inclusive)
Every Week 7
Nominal Day 43 (+21 days/-6 days,  inclusive)
Every 6 weeks thereafter
Nominal Day (+21 days/-20 days,  inclusive)
Follow-Up 1a, c, d
Post last dose and within 72 days after last dose Date
(If date of discontinuation is within 35 days after last 
dose)
Post last dose and within 42 days of the date of
discontinuation (If date of discontinuation is after 35
days after last dose)
Follow-Up 2a, c
Post 72 days of last dose and within 159 days after last 
dose Date (If date of discontinuation is within 35 days 
after last dose)
Post 42 days of the date of discontinuation and within 
129 days of the date of discontinuation (If date of 
discontinuation is after 35 days after last dose) 
Survival Visit ie
Survival Follow-Up 1
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Table 4.3.3-1:
Time Windows for EQ-5D-3L and FACT-E Assessments
Nominal Time-Point
Time Window
Post 159 days of last dose and within 249 days after
last dose Date (If date of discontinuation is within 35 
days after last dose)
Post 129 days of the date of discontinuation and within 
219 days of the date of discontinuation (If date of 
discontinuation is after 35 days after last dose) 
Subsequent Survival Follow-Up visits i=2, 3....
Post 249+(i-2)*90 days of last dose and within 249+(i-
1)*90 days after last dose Date (If date of 
discontinuation is within 35 days after last dose)
Post 219+(i-2)*90 days of the date of discontinuation
and within 219+(i-1)*90 days of the date of 
discontinuation (If date of discontinuation is after 35 
days after last dose)
a For subjects randomized and not treated: Baseline will be defined as “On or prior to randomization date”. Any 
assessment after the randomization date will be considered as follow-up visit. “Last dose” date reference in Follow-
Up 1 and Follow-Up 2 Time Window derivation will be replaced by randomization date.
b First dose date considers as Day 1 of Week 1. So Week 3 corresponds to 2 weeks of Treatment.
c These Time Window definitions are based on the definition of Follow-up visits definition in the study protocol (See 
Section 5, Table 5.1-5).
d Any assessment post last dose will be slotted to Follow-Up visit.
e Survival visits = every 3 months (i.e. 90 days assumed in calculation) from Follow-Up 2. 
4.3.4
Pharmacokinetics Exploratory Endpoints
PK will be measured using serum concentration-time data.
4.3.5
Immunogenicity Exploratory Endpoints
Serum samples collected will be analyzed by a validated immunogenicity assay. Selected serum 
samples may be analyzed by an exploratory orthogonal method that measures Nivolumab and 
Ipilimumab. 
In addition, ad hoc serum samples designated for pharmacokinetic or biomarker assessments may 
also be used for immunogenicity analysis if required (e.g., insufficient volume for complete 
immunogenicity assessment or to follow up on suspected immunogenicity related AE).
Further details on immunogenicity background and rationale, definitions, population for analyses 
and endpoints are described in APPENDIX 4.
4.3.6
Biomarker Exploratory Endpoints
The source of the biomarker data in this section will be from the lab.
Tumor Cell PD-L1 expression
For subjects with an available tumor biopsy specimen(s), the following will be considered:
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•
Tumor cell PD-L1 expression is defined as the percent of tumor cell membrane staining in a 
minimum of 100 evaluable tumor cells per validated Dako PD-L1 IHC assay unless otherwise 
specified. This is referred as quantifiable PD-L1 expression. If the PD-L1 staining could not 
be quantified, it is further classified as:
•
Indeterminate: Tumor cell membrane staining hampered for reasons attributed to the biology 
of the tumor biopsy specimen and not because of improper sample preparation or handling 
•
Not evaluable: Tumor biopsy specimen was not optimally collected or prepared (e.g. PD-L1 
expression is neither quantifiable nor indeterminate) (In this study, we do not expect to have 
such patients.)
PD-L1 status will consider three cutoffs 1%, 5% or 10% and PD-L1 status categories used for 
these analyses are: 
•
Each PD-L1 status subgroup 
−
PD-L1 ≥1%: ≥ 1% PD-L1 expression 
−
PD-L1 < 1%: < 1% PD-L1 expression
−
PD-L1 ≥5%: ≥ 5% PD-L1 expression 
−
PD-L1 < 5%: < 5% PD-L1 expression
−
PD-L1 ≥10%: ≥ 10% PD-L1 expression 
−
PD-L1 < 10%: < 10% PD-L1 expression
•
PD-L1 status indeterminate, not evaluable or missing subgroup
Subjects without an available tumor biopsy specimen for PD-L1 evaluation will be considered as 
PD-L1 expression missing.
PD-L1 by Combined Positive Score (CPS)  
PD-L1 by combined positive score (CPS) is defined as the number of PD-L1 staining cells (tumor 
cells, lymphocytes, macrophages) divided by the total number of viable tumor cells, multiplied by 
100. Exploratory PD-L1 by CPS data is generated by rescoring PD-L1 slides previously stained at 
the time of randomization. The PD-L1 by CPS status subgroups will consider three cutoffs, 1, 5 
and 10 and CPS categories used for these analyses are:
•
CPS status subgroups
−
PD-L1 by CPS ≥1
−
PD-L1 by CPS < 1
−
PD-L1 by CPS ≥ 5
−
PD-L1 by CPS < 5
−
PD-L1 by CPS ≥10
−
PD-L1 by CPS < 10
•
PD-L1 by CPS indeterminate, not evaluable or missing subgroup
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Microsatellite Instability (MSI) Status
MSI refers to instability at the microsatellite tracts: gain or loss of nucleotides from DNA elements 
composed of short repeating motifs. MSI is determined by using whole exome sequencing. MSI 
status will be categorized to:
•
MSI-H (High levels of Microsatellite Instability)
•
MSS (Microsatellite Stable)
•
unknown including not tested and invalid
5
SAMPLE SIZE AND POWER
It is by now established that time-to-events endpoints in I-O clinical trials tend to display specific 
characteristics. First, there may be long-term survival benefits in patients treated with 
immunotherapy - observed as a long lasting plateau towards the tail of the survival curve (“cure”). 
Second, some results also suggested a delayed effect - observed as late separation of survival 
curves between experimental and control arms. Both long-term survival and delayed onset of 
benefit may be linked to the mechanisms of action of I-O drugs. As these phenomena are expected 
to be observed in the current disease setting as well, a piecewise mixture cure rate model was used 
for the design setup.
Sample size calculations assume that the prevalence of subjects with PD-L1 tumor expression level 
≥ 1% is approximately 50%. (During enrolment, the proportion of subjects with or without PD-L1 
tumor expression will be monitored, and may be re-assessed in case it does not reflect study 
assumptions.)
The sample size is based on the primary objectives, i.e., on the comparisons of the PFS/OS 
distributions of subjects with PD-L1 expressing tumors between those who were randomized 
to receive nivolumab plus ipilimumab vs those randomized to receive chemotherapy, and between 
those who were randomized to receive nivolumab plus chemotherapy vs those randomized to 
receive chemotherapy.
For both experimental arms (N+I, N+C), the same OS distributions and the same PFS distributions 
are assumed (see Table 5-1). As a result, for each of the N+I vs CT and N+C vs CT comparisons:
•
250 PFS events in approximately 313 subjects with PD-L1 expressing tumors will provide 
approximately 90% power to detect an average Hazard Ratio (HR) of 0.62 with a Type I error 
of 1.5% (two-sided);
•
250 OS events in approximately 313 subjects with PD-L1 expressing tumors will provide 
approximately 90% power to detect an average HR of 0.6 with a Type I error of 1%
(two-sided).
To have approximately 313 randomized subjects with PD-L1 expressing tumors for each 
comparison, approximately 470 subjects with PD-L1 expressing tumors need to be randomized in 
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a 1:1:1 ratio in the 3 arms. Which therefore translates to a total of approximately 939 subjects (with 
any PD-L1 result) to be randomized in a 1:1:1 ratio to the N+I or N+C or CT arms. Assuming a 
piecewise constant accrual rate, it is estimated that these 939 subjects will be accrued within 
29 months.
Although for the comparison of both experimental arms with the control arm, the same treatment 
effect is assumed, observed treatment effects may vary. Therefore, the events of interest (OS, PFS) 
observed in the CT arm only will be used for determining the timing of the interim and final 
efficacy analyses. (Note that the number of events in the CT arm will be monitored by an 
independent statistical group.) Final PFS analysis is planned when 136 events are observed among 
the PD-L1 expressing subjects in the CT arm. This is expected to be reached after approximately 
33 months. If the planned number of PFS events per BICR is unlikely to be reached for any 
unforeseen reasons, the final PFS analysis may occur when at least 12 months minimum follow-
up is reached. Should this scenario occur, corresponding to PFS events of 110 and 121, the power 
would be 80% and 85% respectively (details of this scenario are discussed in APPENDIX 7.
Final OS analysis is planned when 140 events are observed among the PD-L1 expressing subjects 
in the CT arm. This is expected to be reached after approximately 49 months (at the time of the 
final PFS analysis, a formal interim analysis for OS will be conducted).
Details of the sample size calculations for the subjects whose tumors express PD-L1 are provided 
in Table 5-1.
Table 5-1:
Subjects whose Tumors Express PD-L1 - Summary of Sample Size 
Parameters and Schedule of Analyses (N+I vs CT and N+C vs CT)
OS
PFS
# of randomized subjects
≈313 (total in the 3 arms: ≈470)
Hypothesized delayed effect
3 months
1 month
Hypothesized cure rate in 
experimental arms (after delay)
15%
0
Hypothesized HR after delayed 
effect, in non-cure subjects
0.65
0.55
Hypothesized median in control arm
9 monthsa
4 months
Significance level
0.01
0.015
FINAL ANALYSIS b
Criteria for time of LPLV
140 events are observed among the 
PD-L1 expressing subjects in the 
CT arm
136 events are observed among the 
PD-L1 expressing subjects in the 
CT arm
Projected time of LPLV (from 
first patient randomized)
49 months
33 months
Projected # of eventsc
250
250
Significance level 
[0.009]d
0.015
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Table 5-1:
Subjects whose Tumors Express PD-L1 - Summary of Sample Size 
Parameters and Schedule of Analyses (N+I vs CT and N+C vs CT)
OS
PFS
Power
90%
90%
Overall HR
0.6
0.62
Median in experimental arm
14.4 months
6.4 months
Critical HRe / Minimal 
difference in medianf
0.72 / 3.5 months
0.73 / 1.4 months
INTERIM ANALYSIS for OS b
Criteria for time of LPLV
At the time of PFS final analysis
N/A
Projected # of eventsc
≈175 (70% of all events)
N/A
Significance level
[0.002]d
N/A
Probability of crossing boundary
29%
N/A
Hypothesized overall HR
0.67
N/A
Critical HRe / Minimal 
difference in medianf
0.62 / 5.6 months
N/A
a Asia: 10 months, RoW: 6 months
b Results based on simulations (except: Criteria for time of LPLV)
c Projected # of events for one comparison (i.e. for N+I vs CT; and for N+C vs CT)
d For OS, significance levels will be recalculated based on the actual number of deaths at interim analysis
e Largest observed HR at which a statistically significant difference would be observed
f Difference in median, corresponding to a minimal clinically significant effect size
Analyses on OS and PFS in all randomized subjects will be carried out at the time of the primary 
analysis (in subjects whose tumors express PD-L1); OS and PFS in all randomized subjects are 
expected to be mature by that time. They will be tested only if significance level is passed on them. 
Details of the related power calculations are provided in Table 5-2.
Table 5-2:
All Randomized Subjects - Summary of Power Calculation 
Parameters and Schedule of Analyses (N+I vs CT and N+C vs CT)
OS
PFS
# of randomized subjects
626 (total in the 3 arms: 939)
Hypothesized delayed effect
3 months in PD-L1+, 4 months in 
PD-L1-
1 month in PD-L1+, 2 months in
PD-L1-
Hypothesized cure rate in 
experimental arms (after delay)
15% in PD-L1+, 10% in PD-L1-
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Table 5-2:
All Randomized Subjects - Summary of Power Calculation 
Parameters and Schedule of Analyses (N+I vs CT and N+C vs CT)
OS
PFS
Hypothesized HR after delayed 
effect, in non-cure subjects
0.65 in PD-L1+, 0.85 in PD-L1-
0.55 in PD-L1+, 0.75 in PD-L1-
Hypothesized median in control arm
9 monthsa
4 months
Significance levelb
0.01
0.015
FINAL ANALYSIS c
Criteria for time of LPLV
At the time of the PD-L1+ LPLV
At the time of the PD-L1+ LPLV
Projected # of eventsd
≈514
≈512
Significance levelb
[0.009]e
0.015
Powerf
94%
90%
Hypothesized overall HR
0.68
0.72
Median in experimental arm
12.3 months
5.5 months
Critical HRg / Minimal difference in 
medianh
0.80 / 2.3 months
0.81 / 0.9 months
INTERIM ANALYSIS for OS b
Criteria for time of LPLV
At the time of PFS final analysis
N/A
Projected # of eventsd
≈362 (70.4% of all events)
N/A
Significance levelb
[0.002] e
N/A
Probability of crossing boundaryf
33%
N/A
Hypothesized overall HR
0.75
N/A
Critical HR g / Minimal difference 
in medianh
0.74 / 3.1 months
N/A
Accrual rate per month
Gradually increasing accrual rates (max = 45 subjects per months)
Accrual Duration
29 months
a Asia: 10 months, RoW: 6 months
b In case the significance level from the corresponding primary endpoint is passed. (Note that endpoint-specific [i.e. 
initially allocated] significance level is 0.)
c Results based on simulations (except: Criteria for time of LPLV)
d Projected # of events for one comparison (i.e. for N+I vs CT; and for N+C vs CT)
e For OS, significance levels will be recalculated based on the actual number of deaths at interim analysis
f Not accounting for hierarchy
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g Largest observed HR at which a statistically significant difference would be observed
h Difference in median, corresponding to a minimal clinically significant effect size
Simulations were conducted in R-v3.1.3.
6
STUDY PERIODS, TREATMENT REGIMENS AND POPULATIONS FOR 
ANALYSES
6.1
Study Periods
•
Baseline period:
−
Baseline evaluations or pre-treatment events will be defined as evaluations or events that 
occur before the date and time of the first dose of study treatment. Evaluations (laboratory 
tests, vital signs, and biomarkers (excluding PD-L1)) on the same date and time of the first 
dose of study treatment will be considered as baseline evaluations. For the stratification 
factors and PD-L1 from lab, baseline evaluations will be defined as evaluations that occur 
before the date  of the randomization. Events (AEs) on the same date and time of the first 
dose of study treatment will not be considered as pre-treatment events.
−
In cases where the time (onset time of event or evaluation time and dosing time) is missing 
or not collected, the following definitions will apply:
♦Pre-treatment AEs will be defined as AEs with an onset date prior to but not including 
the day of the first dose of study treatment;
♦Baseline evaluations (laboratory tests, vital signs and biomarkers) will be defined as 
evaluations with a date (and time if collected) on or prior to the date of first dose of 
study treatment.
−
If there are multiple valid observations in the baseline period, then the latest non-missing 
observation will be used as the baseline in the analyses. If multiple observations exist on 
the latest collection date (and time if collected), the record with the latest data entry date 
and time will be used. If multiple observations exist on the latest collection date (and time 
if collected) and data entry date and time, then the first observation is used as baseline, 
unless otherwise specified.
♦For PD-L1, non-missing is identified as those with quantifiable test result. After 
applying the rule above, if there are no records with a quantifiable test result, then select 
those with indeterminate result (“INDETERMINATE”). If there are no records with 
indeterminate test result, then select those with unavailable result (“NOT 
EVALUABLE”). If there are no records with unavailable test result, then select those 
which are not reported or not available result (all other records). 
♦For Anti-Drug Antibody (ADA), the baseline record of Nivolumab and Ipilimumab 
immunoglobulin (IMG) evaluation must be less than the date and time of the first 
Nivolumab and Ipilimumab dose date and time.
•
Post baseline period:
−
On-treatment AEs will be defined as AEs with an onset date and time on or after the date 
and time of the first dose of study treatment (or with an onset date on or after the day of 
first dose of study treatment if time is not collected or is missing). For subjects who are off 
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study treatment, AEs will be included if event occurred within a safety window of 30 days 
(or 100 days depending on the analysis) after the last dose of study treatment. No 
“subtracting rule” will be applied when an AE occurs both pre-treatment and post-
treatment with the same preferred term and grade.
−
On-treatment evaluations (laboratory tests, and vital signs) will be defined as evaluations 
taken after the day (and time, if collected and not missing) of first dose of study treatment. 
For subjects who are off study treatment, evaluations should be within a safety window of 
30 days (or 100 days depending on the analysis) after the last dose of study treatment.
6.2
Treatment Regimens
The treatment group “as randomized” will be retrieved from the IRT system
•
Arm A in the IRT system: Experimental arm N+I
•
Arm B in the IRT system: Experimental arm N+C
•
Arm C in the IRT system: Control arm CT
The treatment group “as treated” will be, in general, the same as the arm randomized by IRT. 
However, if a subject received the incorrect drug for the entire period of treatment, the subject’s 
treatment group will be defined as the incorrect drug the subject actually received.
6.3
Populations for Analyses
The following definitions of populations will be applicable for subjects whose tumors express 
PD-L1 and also for subjects regardless of PD-L1 expression, except otherwise specified.
•
All Enrolled Subjects: All subjects who signed an informed consent form and were registered 
into the IRT
•
All Randomized Subjects: All enrolled subjects who were randomized to any treatment arm in 
the study
•
All PD-L1 Expressing Subjects: All randomized subjects with tumors expressing PD-L1 
(≥1%)
•
All PD-L1 Negative Subjects: All randomized subjects with tumors PD-L1 expression < 1% 
•
All Treated Subjects: All randomized subjects who received at least one dose of study drug 
during the study
•
All Treated PD-L1 Expressing Subjects: All treated subjects with tumors expressing PD-L1 (≥
1%)
•
PK Subjects: All randomized subjects with available serum time-concentration data.
•
Outcome Research subjects: All randomized subjects who have an assessment at 
screening/baseline and at least 1 follow-up assessment while on treatment.
•
Immunogenicity subjects: All randomized 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 
expression status and other assays).
−
All PD-L1 tested subjects: All enrolled subjects who had a tumor biopsy specimen 
available for assessment of PD-L1 expression. 
−
All randomized PD-L1 subjects: All tested PD-L1 subjects who are randomized to the 
study and with baseline PD-L1 expression (includes non-evaluable [should be none per 
protocol] and indeterminate)
−
All evaluable PD-L1 subjects: All PD-L1 tested subjects who are randomized to the study 
and with quantifiable baseline PD-L1 expression
Unless otherwise specified, the safety analyses will include all treated subjects.
Unless otherwise specified, the efficacy analyses will include all randomized subjects.
7
STATISTICAL ANALYSES
7.1
General Methods
Unless otherwise noted, discrete variables will be tabulated by the frequency and proportion of 
subjects falling into each category, grouped by treatment (with total, as needed). Percentages given 
in these tables will be rounded and, therefore, may not always sum to 100%. Continuous variables 
will be summarized by treatment group (with total, as needed) using the mean, standard deviation, 
median, minimum and maximum values, unless specified otherwise.
Unless mentioned otherwise, outputs will be provided separately for the N+I vs CT analyses
and for the N+C vs CT analyses.
All listings will include PD-L1 status as well.
This study has 4 stratification factors. Each factor has 2 to 3 levels, with 24 strata in total. 
•
region (J/K/T vs. rest of Asia vs. RoW)
•
ECOG performance status (0 vs. 1)
•
number of organs with metastases (< 1 vs. ≥ 2)
•
PD-L1 expression level (≥ 1% vs. < 1% or indeterminate)
Anticipating the study population may not be equally distributed across levels in a given 
stratification factor, it is likely that the number of subjects in some strata may be small. With three 
treatment arms in this study, the stratum size with less than 20 subjects would likely cause 
unreliable estimates in the stratified analyses4, 5, 6, 7.
Therefore the following rule will be used when applicable. 
If the number of subjects in at least one stratum is less than 20 across all randomized subjects, the 
planned stratified analyses will be modified per the following steps. 
•
The marginal distribution of each level of a given stratification factor will be examined.
•
The stratification factor with the lowest prevalence in a level will be excluded from the planned 
stratified analyses. 
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•
After the above step, if there is still at least one stratum with less than 20 subjects, the above 
steps will be repeated for the rest of stratification factors until all the stratum size is at least 20. 
7.1.1
General Methods: Efficacy
Protection of Type I Error
Family-wise Type I error will be protected in the strong sense across all primary and secondary 
endpoints. The p-values from sensitivity analyses for efficacy endpoints are for descriptive purpose 
only and not adjusted for multiplicity.
Stratification Factors
For all stratified analyses, stratification factors will be based on the randomization factors 
(Section 2.2). Specifically, stratification factors used for analyses are as follows:
•
for Subjects Expressing PD-L1:
−
region (J/K/T vs rest of Asia vs. RoW)
−
ECOG performance status (0 vs. 1)
−
number of organs with metastases (≤1 vs. ≥2)
•
for All Randomized Subjects
−
region (J/K/T vs. rest of Asia vs. RoW)
−
ECOG performance status (0 vs. 1)
−
number of organs with metastases (≤1 vs. ≥2)
−
PD-L1 expression level (≥1% vs. < 1% or indeterminate)
Unless otherwise specified, stratification factors are used as entered in the IRT.
In the situation that the stratification factors are adjusted as specified per Section 7.1 General 
Methods, the adjustment will apply to all the stratified analyses in this document.
General Methods for Time-to-event Variables
Time to event distribution (e.g. OS, PFS, DOR) will be estimated using Kaplan-Meier (KM) 
techniques.
Median survival time along with 95% or adjusted confidence interval (CI) will be constructed 
based on a log-log transformed CI for the survivor function S(t)8,9. Rates at fixed timepoints 
(e.g. OS at 6 months) will be derived from the KM estimate and corresponding CI will be derived 
based on Greenwood formula10 for variance derivation and on log-log transformation applied on 
the survivor function S(t)11.
Unless otherwise specified, the stratified log-rank test will be performed to test the comparison 
between time to event distributions. Unless otherwise specified, the stratified HR between 
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2 treatment groups along with CI will be obtained by fitting a stratified Cox model with the 
treatment group variable as unique covariate. 
General Methods for Bivariate Variables
The difference in rates between the two treatment arms along with their two-sided 95% CI will be 
estimated using the following Cochran-Mantel-Haenszel (CMH) method of weighting12, adjusting 
for the stratification factors:
where 
is the rate difference of the ith stratum, 
, and 宱宬宻and 宱宬宼are the 
number of subjects randomized to treatments x and y, respectively, in the ith stratum. Associated 
odds-ratio will be derived.
7.2
Study Conduct
7.2.1
Accrual
The accrual pattern will be summarized per region, country, investigational site and per month for 
all enrolled subjects. No separate outputs are provided for N+I vs. CT and for N+C vs. CT. 
Randomization date, first dosing date, country, investigational site will be presented in a by subject 
listing of accrual.
7.2.2
Relevant Deviations
The relevant Protocol Deviations will be summarized for all randomized subjects and for all PD-
L1 expressing subjects, by treatment group and overall. The following programmable deviations 
from inclusion and exclusion criteria will be considered as relevant protocol deviations. Non-
programmable relevant eligibility and on-treatment protocol deviations, as well as important (both 
programmable and nonprogrammable) eligibility and on-treatment protocol deviations will be 
reported via the Clinical Monitoring system (i.e. clinSIGHT).
At Entrance
•
Subjects without squamous cell carcinoma or adenosquamous cell carcinoma of esophagus
•
Subjects with no unresectable advanced, recurrent or metastatic ESCC
•
Subjects who have received prior systemic therapy for advanced or metastatic disease 
(adjuvant, neoadjuvant, and definitive is allowed)
•
Subject with baseline ECOG performance status > 1.
•
Subjects without any measurable disease at baseline.
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•
Subjects without any tumor cell PD-L1 result. (“Indeterminate” is not a deviation.)
On-treatment
•
Subjects receiving concurrent anti-cancer therapy (chemotherapy, hormonal therapy, 
immunotherapy, curative surgery, non-palliative radiation therapy, standard or investigational 
agents for treatment of gastric cancer).
•
Subjects treated differently as randomized (subjects who received the wrong treatment, 
excluding the never treated). 
A subject listing will also be produced.
7.3
Study Population
7.3.1
Subject Disposition
The total number of subjects enrolled (randomized or not randomized) will be presented along 
with the reason for not being randomized.
Number of subjects randomized but not treated along with the reason will be tabulated by treatment 
group as randomized. This analysis will be performed on all randomized subjects and on all PD-
L1 expressing subjects.
Number of subjects who discontinued study treatment along with corresponding reason will be 
tabulated by treatment group as treated. This analysis will be performed on all treated subjects and 
on treated PD-L1 expressing subjects. 
A subject listing for all randomized subjects will be provided showing the subject’s randomization 
date, first and last dosing date, off study date and reason for going off-study. A subject listing for 
subjects not randomized will also be provided, showing the subject’s race, gender, age, consent 
date and reason for not being randomized.
7.3.2
Demographics and Other Baseline Characteristics
The following baseline characteristics will be summarized by treatment arm as randomized. All 
baseline presentations identify subjects with missing measurements. This analysis will be 
performed on all randomized subjects and on PD-L1 expressing subjects. Listings will also be 
provided.
•
Age (descriptive statistics)
•
Age category (< 65, ≥ 65 and < 75, ≥ 75 and < 85, ≥ 85; ≥ 75, ≥ 65)
•
Gender (male, female)
•
Race (White, Black or African American, Asian Indian, Chinese, Japanese, Asian Other,
American Indian or Alaska Native, Native Hawaiian or Other Pacific Islander, Other)
•
Region (J/K/T, Rest of Asia, RoW) (stratification factor)
•
Region (Asia, Non-Asia)
•
ECOG PS (stratification factor)
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•
Weight (descriptive statistics)
•
Disease stage at initial diagnosis (Stage IA, Stage IB, Stage IIA, Stage IIB, Stage IIIA, Stage 
IIIB, Stage IIIC, Stage IV)
•
Histologic grade at initial diagnosis (Gx, G1, G2, G3, G4, unknown)
•
Histological classification at initial diagnosis (squamous cell carcinoma, adenosquamous cell 
carcinoma, other)
•
Location at initial diagnosis (upper thoracic, middle thoracic, lower thoracic, gastroesophageal 
junction)
•
TNM classification at initial diagnosis:
−
Tumor (Tx, T0, Tis, T1, T2, T3, T4, unknown)
−
Nodes (Nx, N0, N1, N2, N3, unknown)
−
Metastasis (Mx, M0, M1, unknown)
•
Disease status at current diagnosis (recurrent - loco-regional, recurrent - distant, de-novo 
metastatic**, unresectable advanced)
•
Smoking status (current/former, never smoker, unknown)
•
Alcohol use (current/former, never, unknown)
•
All lesions at Baseline (Investigator and BICR): sites of disease, number of disease sites per 
subject, number of subjects with no measurable lesion, number of organs with metastases
•
Target Lesions (Investigator and BICR): Presence of target lesions, site of target lesion, sum
of diameters of target lesions
•
Time from Initial Disease Diagnosis to Randomization (< 6months, 6months - < 1 year, 
1 - < 2 year, 2 - < 3 year, 3 - < 4 year, 4 - < 5 year, ≥ 5 year)
•
Time from randomization to first dose date (≤3days, 4 - 5days, 6 - 7days, 8 - 14days, 15 -
21days, >21days, Not Reported or Not Treated)
For the purposes of baseline characteristic summary, stratification factors will be retrieved from 
the CRF.
** The ‘de-novo metastatic’  implies cancer which is already metastatic (Stage IV) at first 
presentation.
7.3.3
Medical History
General medical history will be listed by subject and pretreatment events will be tabulated. This 
analysis will be performed on all randomized subjects and on PD-L1 expressing subjects.
7.3.4
Prior Therapy Agent
Prior therapy will be summarized for all randomized subjects and on all PD-L1 expressing 
subjects.
Prior anti-cancer therapy:
•
Setting of prior systemic therapy regimen received (adjuvant, neo-adjuvant, definitive CRT).
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•
Time from completion of prior adjuvant/neo-adjuvant/definitive therapy to treatment (for 
subjects who received prior adjuvant/neo-adjuvant therapy), (< 6 months, 6 - < 12month,  
≥ 12 months)
•
Prior surgery related to current cancer (yes or no).
−
type of surgery 
•
Prior radiotherapy (yes or no).
•
Prior systemic therapy classified by therapeutic class and generic name.
Other Prior therapy:
•
Prior/current non-study medication classified by anatomic and therapeutic classes.
Agents and medication will be reported using the generic name. A listing by subject will also be 
provided.
7.3.5
Baseline Examinations
Subjects with abnormal baseline physical examination will be tabulated for all randomized 
subjects and on all PD-L1 expressing subjects, by examination criteria and by treatment group.
7.3.6
Discrepancies between IRT Stratification Factors and Other Datasets
Summary tables (cross-tabulations) by treatment group for stratification factor (except for region
and Number of organs with metastases) will be provided to show any discrepancies between what 
was reported through IRT vs. other data sources at baseline:
•
PD-L1 expression level (≥1% vs. < 1% or indeterminate) (IRT vs. clinical database)
•
ECOG performance status (0 vs. 1) (IRT vs. CRF)
This analysis will be performed on all randomized subjects and on all PD-L1 expressing subjects.
7.4
Extent of Exposure
Analyses in this section will be performed in all treated subjects and in treated PD-L1 expressing 
subjects, by treatment group as treated.
7.4.1
Administration of Study Therapy
For details on the dosing schedule per protocol, see Section 2.1.
The following parameters will be summarized (descriptive statistics) by treatment group:
•
Relative dose intensity (%) using the following categories: < 50%; 50 - < 70%; 70 - < 90%; 
90 - < 110%; ≥ 110%.
•
Number of doses/cycles received (summary statistics).
•
Cumulative dose
•
Duration of treatment 
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−
using a KM curve whereby the last dose date will be the event date for those subjects who 
are off study therapy. Subjects who are still on study therapy will be censored on their last 
dose date. Median duration of treatment and associated 95% CI will be provided.
A by-subject listing of dosing of study medication (record of study medication, infusion details, 
dose change) and a listing of batch number will be also provided.
Key parameters used to characterize dosing data for the N+I arm are defined in Table 7.4.1-1; for 
the N+C and CT arms, in Table 7.4.1-2.
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Table 7.4.1-1:
Administration of Study Therapy in the N+I Arm - Definition of Parameters
Nivolumab
Ipilimumab
Dosing schedule per 
protocol
3mg/kg Q2WK, IV
1mg/kg Q6WK, IV
Dose*
Total dose administered (mg)/most recent weight (kg)
Total dose administered (mg)/most recent weight (kg)
Cumulative Dose
The sum of all doses (mg/kg) administered to a subject during the 
treatment period
The sum of all doses (mg/kg) administered to a subject during the 
treatment period
Relative Dose 
Intensity (%)
Cum dose (mg/kg) / [(Last nivolumab dose date – nivolumab 
Start dose date + 14) x 3 / 14 x 100]
Cum dose (mg/kg) / [(Last ipilimumab dose date – ipilimumab 
Start dose date + 42) x 1 / 42 x 100]
Duration of 
Treatment
Last dose date (of the last administered study therapy) - Start dose date (of the first administered study therapy) + 1
* Dose administered in mg at each dosing date and weight are collected on the CRF
Table 7.4.1-2:
Administration of Study Therapy in the N+C and CT Arms
Nivolumab
Fluorouracil
Cisplatin
Dosing schedule per 
protocol
240mg Q2WK, IV
800mg/m2/day, Q4WK continuous 
infusion on Day1-5 of the cycle
80mg/m2 Q4WK, IV
Dose*
Ratio of Total Volume Infused with Total 
Volume Prepared x 240 in mg
Total dose administered (mg) / most 
recent BSA
Total dose administered (mg) / most recent 
BSA
Cumulative Dose
The sum of all doses (mg) administered to 
a subject during the treatment period
The sum of all doses (mg/m2) 
administered to a subject during the 
treatment period
The sum of all doses (mg/m2) 
administered to a subject during the 
treatment period
Relative Dose 
Intensity (%)
Cumulative dose (mg) / [Last nivolumab 
dose date – nivolumab Start dose date + 
14) x 240 / 14]
Cumulative dose (mg/m2) / [First dose of 
fluorouracil in the last cycle – fluorouracil
Start dose date + 28) x 800 x 5 / 28]**
Cumulative dose (mg/m2) / [First dose of 
cisplatin in the last cycle – cisplatin Start 
dose date + 28) x 80 / 28]
Duration of 
Treatment
Last dose date (of the last administered study therapy) - Start dose date (of the first administered study therapy) + 1
* Dose administered in mg at each dosing date and BSA (computed using recent weight and baseline height) are collected on the CRF.
** 800 x 5 may be replaced by 1000 x 4 for sites that administer over 4 days. 
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7.4.2
Modification of Study Therapy
7.4.2.1
Dose Delays 
Table 7.4.2.1-1:
Dose Delays
Ipilimumab
Nivolumab 3 
mg/kg (a)
Nivolumab 240 
mg (b)
Fluorouracil
Cisplatin
Specifications per Protocol
Dose 
considered as 
actually 
delayed
If the delay is 
exceeding 5
days
If the delay is 
exceeding 3 
days
If the delay is 
exceeding 3 
days
If the delay is 
exceeding 3 
days
If the delay is 
exceeding 3 
days
Maximum 
delay allowed 
between doses
12 weeks
8 weeks
8 weeks
8 weeks
8 weeks
Definitions for the Analysis
Dose Delay
duration of 
preceding cycle 
in days – 42
duration of 
preceding cycle 
in days – 14
duration of 
preceding cycle 
in days – 14
duration of 
preceding cycle 
in days – 28
duration of 
preceding cycle 
in days – 28
Categories of 
dose delays
on-time, 4 - 7 
days, 8 - 14 
days, 15 - 42 
days, 42 - 56 
days, > 56 days
on-time, 4 - 7 
days, 8 - 14 
days, 15 - 42 
days, 42 - 56 
days, > 56 days
on-time, 4 - 7 
days, 8 - 14 
days, 15 - 42 
days, 42 - 56 
days, > 56 days
on-time, 4 - 7 
days, 8 - 14 
days, 15 - 42 
days, 42 - 56 
days, > 56 days
on-time, 4 - 7 
days, 8 - 14 
days, 15 - 42 
days, 42 - 56 
days, > 56 days
(a) N+I arm
(b) N+C arm
The following parameters will be summarized by treatment arm:
•
Number of dose delayed per subject, Length of Delay and Reason for Dose Delay.
Reason for dose delay will be retrieved from CRF dosing pages.
7.4.2.2
Dose Interruptions
Each study therapy may be interrupted. This information will be retrieved from CRF dosing pages. 
The following parameters will be summarized by treatment arm:
•
Number of subject with at least one dose infusion interrupted along with reason for the 
interruptions and number of infusions interrupted per subject.
7.4.2.3
IV Rate Reductions
In this study, it is not allowed that IV rate is reduced.
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7.4.2.4
Dose Reductions
Per protocol, there will be no dose escalations or reductions of nivolumab and ipilimumab. 
However, for chemotherapy, dose reduction is permitted (as specified in the protocol). This 
information will be retrieved from CRF dosing pages.
For subjects treated with chemotherapy, the following will be summarized by treatment group:
•
Number of subjects with at least one dose reduction along with the reason of the dose reduction.
7.4.3
Concomitant Medications
Concomitant medications, defined as medications other than study medications which are taken at 
any time on-treatment (i.e. on or after the first day of study therapy and within 100 days following 
the last dose of study therapy), will be coded using the WHO Drug Dictionary.
The following summary tables will be provided:
•
Concomitant medications (subjects with any concomitant medication, subjects by medication 
class and generic term).
A by-subject listing will accompany the table.
7.4.3.1
Subsequent Therapy
•
Number and percentage of subjects receiving subsequent therapies will be summarized. 
Categories include: 
•
Immunotherapy including commercial Nivolumab (anti-PD1 agents, anti-PD-L1 agents, anti-
CTLA-4 agents and others) by drug name 
•
Other anti-cancer agents excluding all immunotherapy (approved and investigational) by drug 
name 
•
Surgery for treatment of tumors 
•
Radiotherapy  for treatment of tumors
•
Any combination of the above 
A subject listing of follow-up therapy will also be produced for subjects who had any subsequent 
therapy.
7.5
Efficacy
7.5.1
Protection of Type I Error Across Primary and Secondary Endpoints
The primary and secondary endpoints are tested using the Bonferroni-based graphical approach by 
Maurer and Bretz (2013)13: see Figure 7.5.1-1 for the graphical display of the multiple testing 
procedure. In this graph defining the test procedure, hypotheses together with their local 
significance levels are represented by weighted vertices and the propagation rule is represented by 
weighted directed edges.  Algorithm 1 in Maurer and Bretz (2013) provides the rules for updating 
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the local significance levels and the transition weights after rejecting an individual hypothesis. The 
resulting sequentially rejective testing procedure controls family-wise Type I error rate of 5% in 
the strong sense, and is uniquely determined by the graph in Figure 7.5.1-1.
Figure 7.5.1-1:
Graphical Representation of the Testing Strategy for the Primary and 
Secondary Endpoints
OS = Overall survival, PFS = Progression-free survival, ORR = Objective response rate, PDL1+ = PDL1-expressing 
subjects, AC = all randomized subjects
In the graph in Figure 7.5.1-1, each vertex (circle) corresponds to a hypothesis to be tested. The 
vertices on the left hand side represent the hypotheses comparing N+I vs. CT; the vertices on the 
right hand side represent the hypotheses comparing N+C vs. CT. The vertices in the upper row
correspond to the primary endpoints, i.e. OS and PFS in PD-L1 expressing subjects. The vertices 
in the rest of the rows correspond to the secondary endpoints, i.e. OS and PFS in all randomized 
subjects, and ORR in PD-L1 expressing and all randomized subjects. The numbers next to the 
vertices are the initially allocated (endpoint-specific) alpha levels. (Note that it is 0 for all 
secondary endpoints - meaning that they cannot be tested until alpha is passed to them from the 
primary endpoints.) The weight (in rectangular frame) associated with a directed edge (line)
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between any two vertices indicates the fraction of the (local) significance level at the initial vertex 
that is added to the significance level at the terminal vertex, if the hypothesis at the tail is rejected14.
The test procedure is identical for the N+I vs. CT and for the N+C vs. CT comparisons. It is as 
follows.
At the time of the PFS final analysis, all 4 primary endpoints will be tested, with the following 
initially allocated (endpoint-specific) alpha levels:
•
PFS in PD-L1 expressing subjects: 0.015
•
OS in PD-L1 expressing subjects: the overall initially allocated (endpoint-specific) alpha of 
0.01 will be distributed over the interim analysis (IA) and final analysis (FA) based on the 
actual number of deaths for each comparison at OS IA, using Lan-DeMets alpha spending 
function with O’Brien-Fleming boundaries. (If the observed number of OS events at IA for a 
comparison with a given experimental arm is exactly 175 [70% of the target number of OS 
events], the significance levels are 0.002 and 0.009 for OS IA and OS FA, respectively.)
If none of the primary endpoints can be rejected then no secondary endpoints are tested, and the 
study continues to proceed to the final OS analysis. If, however, any of these endpoints can be 
rejected, graph will be updated as per Algorithm 1 of Maurer and Bretz (2013), and those 
secondary endpoints to which alpha is passed can be tested. More specifically, the algorithm 
ensures that in case a primary endpoint (in PDL1-expressing subjects) is rejected, its entire alpha 
level is passed to the corresponding (OS or PFS) endpoint in all randomized subjects. Further, if 
for a given experimental arm (N+I or N+C), both OS endpoints (in PD-L1 expressing subjects and 
in all randomized subjects) are rejected, their significance level is passed to the primary OS 
endpoint of the other experimental arm. For a given experimental arm, if PFS in all randomized 
subjects is rejected, its significance level is split into two: half of it will be passed on to the primary 
OS endpoint, and half of it to ORR in PDL1-expressing subjects. (Note that ORR endpoints [in 
PDL1-expressing and in all randomized subjects] can be tested only in case PFS in all randomized 
subjects is rejected.) Further, there is no direct edge between any two endpoints within all 
randomized subjects: this reflects the intention for any given endpoint to first give chance to the 
primary population to be rejected, and only thereafter for all randomized subjects.
Each time a hypothesis is rejected, and the graph is updated, the alpha levels for IA and FA will 
be recalculated for each remaining OS endpoint. (O’Brien-Fleming alpha spending function will 
be used for the primary OS endpoints [in PDL1-expressing subjects], and Pocock for the secondary 
OS endpoints [in all randomized subjects].)
At the time of the final OS analysis, none of the PFS or ORR endpoints will be tested. (I.e. all 
remaining vertices and the related edges will be deleted from the graph). For the OS analyses, all
events in the database at the time of the lock will be used. 
To illustrate how the sequentially rejective procedure works, a hypothetical example is included 
in the appendix.
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The final OS analysis will be triggered when 140 events are observed among the PD-L1 expressing 
subjects in the chemotherapy arm. At the time of interim analysis, the significance level will be 
calculated according to the actual pooled events number between the treatment arm and the control 
arm at the interim and the estimated pooled events number between the treatment arm and the 
control arms at the final.  At the final analysis, the significance level will be calculated using the 
number of events in the database at time of database lock and will consider the alpha level already 
spent at the interim analysis.
7.5.2
Primary Efficacy Endpoints
Analyses in this section will be performed by treatment group as randomized. 
7.5.2.1
Primary Analyses
Overall survival and PFS as assessed by BICR in All PD-L1 expressing subjects will be compared
between N+I vs CT and between N+C vs CT using a two-sided log rank test, stratified by the 
stratification factors as specified in Section 7.1.1, i.e. by
•
region (J/K/T vs rest of Asia vs RoW),
•
ECOG performance status (0 vs. 1),
•
number of organs with metastases (≤1 vs. ≥2).
For each comparison, the HR with its associated two-sided 100(1-α)% CIs will be estimated via a 
stratified Cox model with treatment arm as the only covariate in the model.
Overall survival and PFS for each treatment arm will be estimated and plotted using the KM
product-limit method. Median survival time along with 95% CI will be constructed based on a log-
log transformed CI for the survival function.8,9
Status of Censored Subjects
The status of subjects who are censored in the OS KM analysis will be tabulated for each 
randomized treatment group using following categories:
•
On-study (on-treatment in follow-up);
•
Off-study (lost to follow-up, withdraw consent, never treated etc.).
The status of subjects who are censored in the PFS KM analysis will be tabulated for each 
randomized treatment group using the following categories:
1) Censored on randomization date
a) no baseline scan
b) no on-study scan and no death (or death with prior subsequent therapy)
2) Censored on date of last tumor scan on-study
a) Received subsequent anti-cancer therapy
b) Still on treatment
c) In follow-up
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d) Off study
i)
lost to follow-up
ii) subject withdrew consent
iii) other
The source of PFS event (death vs. PD) will be summarized by treatment group.
7.5.2.2
Sensitivity Analyses
•
Overall Survival and Progression-Free Survival
•
Stratified analysis using stratification factors as obtained from the baseline CRF pages
(instead of IRT) except for the number of organs with metastases at baseline which will be 
retrieved from IRT. This analysis will be performed only if at least one stratification factor at 
randomization (as per IRT) and baseline are not concordant for at least 10% of All PD-L1 
expressing subjects.
−
region (J/K/T vs rest of Asia vs. RoW) - from CRF
−
ECOG performance status (0 vs. 1) - from CRF
−
number of organs with metastases (≤1 vs. ≥2) - from IRT
•
Analysis using a 2-sided, un-stratified log-rank test, an un-stratified Cox proportional hazards 
model with treatment as the single covariate.
•
Analysis for subjects with no relevant deviation. This analysis will be conducted only if there 
are more than 10% subjects with relevant protocol deviations.
Each of the above analysis will use the same significance level as the corresponding primary 
analysis. Estimate of the HR, its two sided CI (adjusted as for the corresponding primary analysis) 
and p-value will be presented.
•
A multivariate adjusted, stratified (by factors as specified in Section 7.1.1) Cox model will be 
fitted to assess the treatment effect when adjusted for potential prognostic factors. The 
following potential prognostic factors will be included in the model. The list of covariates 
considered in the multivariate cox model may be modified if there are issues with 
multicollinearity among the covariates or other important prognostic factors are identified.
−
Age categorization (< 65 vs. ≥ 65)
−
Gender (Male vs. Female)
−
Race (Asian vs. non-Asian)
−
Weight (< 60kg vs. ≥ 60kg)
−
Disease status at current diagnosis (recurrent vs. de novo metastatic and unresectable 
advanced vs. de novo metastatic)
−
Smoking status (current/former vs. never/unknown)
−
Alcohol use (current/former vs. never/unknown)
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For the multivariate analysis, HR and 95% CI will be provided for treatment variable and all 
covariates. Descriptive p-values will be provided.
•
Analysis for investigating non-proportionality in Kaplan-Meier curves. If the Kaplan-Meier 
curves indicate the HR is not constant over time such as a clear delayed separation, the power 
of the standard logrank test is reduced. In this case, as suggested by the non-proportional 
hazards working group, the Max-Combo test is a promising approach with the flexibility of 
allowing different types of non-proportionality and robustness under model mis-specification. 
The R package nphsim can facilitate such testing procedures. We will apply the Max-Combo 
test to the PFS/OS data with the following parameter setting (rho, gamma) of Fleming-
Harrington class of weights: (rho = 0, gamma = 0) attributes equal weights to all; (rho = 1, 
gamma = 0) emphasizes early difference in survival curves; (rho = 0, gamma = 1) weight more 
for late difference; (rho = 1, gamma = 1) emphasizes middle difference. In the current 
implementation of the R package nphsim, stratification is not available. Therefore, the 
unstratified Max-Combo test in the package will be applied and the resulting p-value will be 
reported, along with estimated HR and adjusted 95% CI. Since the stratification is not involved, 
the results of this sensitivity analysis should only be compared with the original results of the 
unstratified analysis.
Sensitivity analyses for PFS to investigate alternative censoring schemes
•
Analysis accounting for assessment on/after subsequent therapy: PFS will be defined similarly 
to the primary definition except that events (progression or death) and disease assessments that 
occurred on or after subsequent anti-cancer therapy will be considered (no time point 
truncation).  This definition is considered as primary definition by EMA. The PFS accounting
for subsequent therapy (primary definition, Section 4.1.2) is the primary endpoint of the study 
and will be the basis of the primary test to determine statistical significance.
•
PFS accounting for two or more consecutively missing disease assessments prior to PFS event: 
This analysis will be performed only if at least 10% of PFS events have missing prior disease 
assessments. In case a subject has two or more consecutively missing disease assessments, the 
subject will be censored at the last disease assessment date prior the PFS event.
•
Analysis in which progression-free subjects who are lost to follow-up for any cause will be 
considered as having an event at the time of the last tumor assessment date prior to loss to 
follow-up.
Each of the above analysis will use the same significance level as the corresponding primary 
analysis. Estimate of the HR, its two sided 100(1-α)% CI and p-value will be presented.
7.5.2.3
Consistency of Treatment Effect in Subsets
To assess consistency of treatment effects in different subsets, a “forest” plot of the OS and PFS 
unstratified HR (and 95% CI) will be produced for the following subgroups.
•
Age category (< 65, ≥ 65 and < 75, ≥ 75, ≥ 65)
•
Gender (male, female)
•
Race (Asian, non-Asian)
•
Region (J/K/T, Rest of Asia, RoW) (stratification factor)
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•
Region (Asia, Non-Asia)
•
ECOG PS (stratification factor)
•
Weight (< 60kg, ≥ 60kg)
•
Disease stage at initial diagnosis (Stage I, Stage II, Stage III, Stage IV)
•
Histologic grade at initial diagnosis (Gx, G1, G2, G3, G4, Not Otherwise specified)
•
Histological classification at initial diagnosis (squamous cell carcinoma, adenosquamous cell 
carcinoma, other)
•
Location at initial diagnosis (upper thoracic, middle thoracic, lower thoracic, gastroesophageal 
junction)
•
Disease status at current diagnosis (recurrent - loco-regional, recurrent - distant, de-novo 
metastatic, unresectable advanced)
•
Smoking status (current/former, never/unknown)
•
Alcohol use (current/former, never/unknown)
•
Number of organs with metastases at baseline (≤1 vs. ≥2) (stratification factor)
•
Time from Initial Disease Diagnosis to Randomization (< 1 year, 1 - < 3 year, 3 -< 5 year, 
≥ 5 year)
•
Prior surgery (excluding biopsy) (Yes or No)
•
Prior radiotherapy (Yes or No)
If subset category has less than 10 subjects per treatment group, HR will not be 
computed/displayed. Number of events and median OS/PFS along with 95% CI will be displayed 
for each treatment group.
For the purposes of the subset analyses, stratification factors will be retrieved from the CRF except 
for the number of organs with metastases at baseline which will be retrieved from IRT.
7.5.2.4
Subjects follow-up
The extent of follow-up is defined as the time between randomization date and last known date 
alive (for subjects who are alive) or death date (for subjects who died) will be summarized 
descriptively for all subjects randomized.
The currentness of follow-up for OS is defined as the time between last OS contact (i.e., last known 
date alive or death date) and data cut-off date. Subjects who died and subjects with last known 
alive date after data cut-off date will be considered as current for this analysis.
The currentness of follow-up for PFS is defined as the time between last tumor assessment date 
(regardless of initiation of subsequent therapy) and cut-off date. Subjects who have a PFS event 
(regardless of initiation of subsequent therapy) and subjects with last tumor assessment date on or 
after data cut-off will be considered as current for this analysis. 
The currentness of follow-up for OS and PFS will be summarized by treatment group, and will be 
categorized in categories.
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7.5.2.5
Survival Rates
Overall survival and PFS rates at 6, 12, 18, 24, 36, 48 months and at 5 year will also be estimated 
using KM estimates on the OS and PFS curves for each randomized arm. Minimum follow-up 
must be approximately longer than or equal to timepoint to generate the rate. Associated two-sided 
95% CIs will be calculated using the Greenwood’s formula.8,9
7.5.3
Secondary Efficacy Endpoints
Secondary endpoints are: OS and PFS by BICR in All Randomized Subjects, ORR by BICR in All 
PD-L1 expressing subjects and in All Randomized subjects.
Analyses for each of these endpoints will be performed by treatment group as randomized. 
7.5.3.1
Overall Survival and PFS by BICR in All Randomized Subjects
As specified by Figure 7.5.1-1, if any of the primary endpoints is significantly superior, the 
corresponding secondary endpoint in all randomized subjects will be compared using a two-sided 
log rank test at the allocated significance level, stratified by the stratification factors as specified 
in Section 7.1.1. (I.e. by the same stratification factors as the primary endpoints plus by PD-L1 
status [≥1% vs. < 1%] as recorded in IRT.)
For each comparison, the HR with its associated two-sided 95% CI (in case the given endpoint is 
formally tested, also with the 100(1-α)% CI) will be estimated via a stratified Cox model with 
treatment arm as the only covariate in the model. OS and PFS for each treatment arm will be 
estimated and plotted using the KM product-limit method. Median survival time along with 95% 
CI will be constructed based on a log-log transformed CI for the survival function.8,9
Additional Analyses for OS and PFS in All Randomized Subjects
The same additional analyses will be carried out for OS and PFS in All randomized Subjects as 
for OS and PFS in All PD-L1 expressing subjects, i.e.:
•
Status of censored subjects (Section 7.5.2.1)
•
All sensitivity analyses (Section 7.5.2.2)
•
Analyses by subsets (Section 7.5.2.3)
•
Extent of follow-up and currentness of follow-up (Section 7.5.2.4)
•
Survival rates (Section 7.5.2.5)
7.5.3.2
Objective Response Rate by BICR
All analyses in this section will be carried out for All PD-L1 expressing subjects and for All 
Randomized subjects as well.
Best Overall Response will be summarized by response category for each treatment group. 
ORR (as assessed by BICR) in subjects with PD-L1 expressing tumors and in all randomized 
subjects will be tested only if significance level is passed on them. For rules for passing on 
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significance levels, see Section 7.5.1. Comparisons will use a two-sided CMH test (as detailed in 
Section 7.1.1). 
ORR will be computed in each treatment group along with the exact 95% CI using Clopper-
Pearson method15. An estimate of the difference in ORRs and corresponding 95% CI (in case the 
given endpoint is formally tested, also with the 100(1-α)% CI) will be calculated using CMH 
methodology and adjusted by the stratification factors as specified in Section 7.1.1. The stratified 
(source: IRT) odds ratios (Mantel-Haenszel estimator) between the treatments will be provided 
along with the 95% CI (in case the given endpoint is formally tested, also with the 100(1-α)% CI).
For additional analysis related to ORR by BICR, see Section 7.5.4.3.
7.5.4
Exploratory Efficacy Endpoints
Analyses in this section will be performed in all randomized subjects and in All PD-L1 expressing 
subjects, by treatment group as randomized.
7.5.4.1
Progression-Free Survival by Investigator
Hazard ratio (N+C vs CT and N+I vs CT) with its associated two-sided 95% CI will be estimated 
via a stratified Cox model with treatment arm as the only covariate in the model. PFS for each 
treatment arm will be estimated and plotted using the KM product-limit method. Median survival 
time along with 95% CI will be constructed based on a log-log transformed CI for the survival 
function.8,9
The PFS rates, the source of PFS event (death vs. PD), and the status of subjects who are censored 
in the PFS KM analysis will be evaluated the same way as for PFS by BICR.
7.5.4.2
PFS2/TSST
Hazard ratio (N+C vs CT; N+I vs CT) with its associated two-sided 95% CI will be estimated via 
a stratified Cox model with treatment arm as the only covariate in the model. PFS2/TSST for each 
treatment arm will be estimated and plotted using the KM product-limit method. Median 
PFS2/TSST time along with 95% CI will be constructed based on a log-log transformed CI for the 
survival function.8,9
The PFS2/TSST rates and the source of PFS2/TSST event (death vs. PD vs. second next line 
systemic therapy) will be evaluated.
7.5.4.3
Endpoints Related to Best Overall Response
Duration of Response and Duration of SD (as assessed by BICR and by investigator) in each 
treatment group will be estimated using KM product-limit method for subjects who achieve PR or 
CR. Median values along with two-sided 95% CI will be calculated.
For DOR, type of event (PD, death) and status of subjects censored (received subsequent therapy, 
ongoing follow-up [current, non-current], off study [withdrew consent] will be presented by 
treatment arm.
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Time to objective response (TTR as assessed by BICR and by investigator): summary statistics 
will be provided for each treatment group for subjects who achieve PR or CR.  Cumulative 
Response Rates will be tabulated for Week 6, Week 12, Month 4, 6, 8, and 12, and overall 
Response Rate will be provided for each treatment group.
7.6
Safety
Analyses in this section will be tabulated for all treated subjects by treatment group as treated, 
unless otherwise specified.
In addition, selected safety analyses (including any adverse events (AE), drug-related AE, serious 
AEs, drug-related SAE, AEs leading to discontinuation, drug-related AE leading to 
discontinuation, death summary) will be summarized by treatment group in all treated PD-L1 
expressing subjects and all treated PD-L1 negative subjects. In all treated PD-L1 expressing 
subjects, the frequency of immune mediated adverse events and other events of special interest
(within 100 days), select AEs and drug-related select AEs (within 30 days) will be summarized by 
treatment group.
7.6.1
Deaths
Deaths will be summarized by treatment group:
•
All deaths, reasons for death.
•
Deaths within 30 days of last dose received, reasons for death.
•
Deaths within 100 days of last dose received, reasons for death.
A by-subject listing of deaths will be provided for the all enrolled subjects population.
7.6.2
Serious Adverse Events
Serious adverse events will be summarized by treatment group:
•
Overall summary of SAEs by worst CTC grade (any grade, grade 3-4, grade 5) presented by 
SOC/PT.
•
Overall summary of drug-related SAEs by worst CTC grade (any grade, grade 3-4, grade 5) 
presented by SOC/PT.
All analyses will be conducted using the 30-day safety window. 
A by-subject SAE listing will be provided for the “enrolled subjects” population.
7.6.3
Adverse Events Leading to Discontinuation of Study Therapy
AEs leading to discontinuation will be summarized by treatment group:
•
Overall summary of AEs leading to discontinuation by worst CTC grade (any grade, grade 
3-4, grade 5) presented by SOC/PT.
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•
Overall summary of drug-related AEs leading to discontinuation by worst CTC grade (any 
grade, grade 3-4, grade 5) presented by SOC/PT.
The analyses will be conducted using the 30-day safety window. 
A by-subject AEs leading to discontinuation listing will be provided.
7.6.4
Adverse Events Leading to Dose Modification
AEs leading to dose delay/reduction will be summarized by treatment group:
•
Overall summary of AEs leading to dose delay/reduction by worst CTC grade (any grade, 
grade 3-4, grade 5) presented by SOC/PT.
•
Overall summary of related AEs leading to dose delay/reduction by worst CTC grade 
(any grade, grade 3-4, grade 5) presented by SOC/PT.
The analysis will be conducted using the 30-day safety window.
A by-subject AEs leading to dose delay/reduction listing will be provided.
7.6.5
Adverse Events
Adverse events will be summarized by treatment group.
The following analyses will be conducted using the 30 days safety window only:
•
Overall summary of any AEs by worst CTC grade (1, 2, 3, 4, 5, not reported) presented by 
SOC/PT. 
•
Overall summary of any AEs presented by worst CTC grade (any grade, grade 3-4, grade 5) 
by SOC/PT. This table will be restricted to events with an incidence greater or equal to 5% in 
any treatment group.
•
Overall summary of any non-serious AEs presented by SOC/PT. This table will be restricted 
to events with an incidence greater or equal to 5% in any treatment group.
•
Overall summary of any AEs that required immune modulating medication by worst CTC 
grade (any grade, grade 3-4, grade 5) presented by SOC/PT.
•
Overall summary of drug-related AEs by worst CTC grade (1, 2, 3, 4, 5, not reported) presented 
by SOC/PT. 
The following analyses will be conducted using the 30 days safety window and repeated using the 
100 days safety window:
•
Overall summary of drug-related AEs by worst CTC grade (any grade, grade 3-4, grade 5) 
presented by SOC/PT.
A by-subject AE listing will be provided. A by-subject listing of any AE requiring immune 
modulating medications will also be provided.
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7.6.6
Select Adverse Events
Unless otherwise specified, analyses will be performed by select AE category. Analyses will also 
be repeated by subcategory of endocrine events.
7.6.6.1
Incidence of Select AE
Select AEs will be summarized by treatment group for each category/subcategory. 
The following analyses will be conducted using the 30-day safety window only:
•
Overall summaries of any select AEs by worst CTC grade (any grade, grade 3-4, grade 5) 
presented by Category or Subcategory/PT.
•
Overall summaries of any drug-related select AEs by worst CTC grade (any grade, grade 3-4, 
grade 5) presented by Category or Subcategory/PT.
•
Overall summaries of any serious select AEs by worst CTC grade (any grade, grade 3-4, grade 
5) presented by Category or Subcategory /PT.
•
Overall summaries of drug-related serious select AEs by worst CTC grade (any grade, grade 
3-4, grade 5) presented by Category or Subcategory /PT.
•
Overall summaries of any select AEs leading to discontinuation by worst CTC grade (any 
grade, grade 3-4, grade 5) presented by Category or Subcategory /PT.
•
Overall summaries of drug-related select AEs leading to discontinuation by worst CTC grade 
(any grade, grade 3-4, grade 5) presented by Category or Subcategory /PT.
•
Summary of frequency of unique select AEs by Category.
A by-subject select AE listing will be provided.
7.6.6.2
Time-to Onset of Select AE
Time-to onset of drug-related select AEs (any grade, grade 3-5) will be summarized for each 
category/subcategory by treatment group.
Time-to onset analyses are restricted to treated subjects who experienced at least one drug-related 
select AE in the category/subcategory. The analyses will be conducted using the 30-day safety 
window.
Additional details regarding the time-to onset definition are described in time-to onset definition 
subsection of APPENDIX 3.
7.6.6.3
Time-to Resolution of Select AE
Time-to resolution of the following specific events will be summarized separately for each 
category/subcategory.
•
Time-to resolution of drug-related select AE (any grade, grade 3-5) by treatment group
•
Time-to resolution of drug-related select AE (any grade, grade 3-5) where immune modulating 
medication was initiated, by treatment group
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Time-to resolution analyses are restricted to treated subjects who experienced the specific events. 
Time-to resolution where immune modulating medication was initiated analyses are restricted to 
treated subjects who experienced the specific events and who received immune modulating 
medication during the longest select AE. 
The analyses will be conducted using the 30-day safety window.
The following summary statistics will be reported: percentage of subjects with resolution of the 
longest select AE, median time-to resolution along with 95% CI (derived from Kaplan-Meier 
estimation) and ranges.
See time-to resolution definition subsection of APPENDIX 3 for additional details.
7.6.7
Immune Modulating Medication
Immune modulating concomitant medications are medications entered on an immune modulating 
medication form or available from the most current pre-defined list of immune modulating 
medications. The list of anatomic class, therapeutic class and generic name used for the selection 
at the time of the database lock will be provided.
The percentage of subjects who received immune modulating concomitant medication for
•
management of adverse event 
•
premedication 
•
other use
•
any use
•
management of drug-related select adverse event (any grade, grade 3-5) by select AE category/ 
subcategory (EU/ROW Submissions)
•
management of IMAEs (any grade, grade 3-5) by IMAE category (US Submission) will be 
reported separately for each treatment group (percentages of treated subjects by medication 
class and generic term).
For each category/subcategory of drug-related select AEs (any grade, grade 3-5) and IMAEs (any 
grade, grade 3-5), the following will be reported for each treatment group:
•
The total immune modulating medication treatment duration (excluding overlaps), duration of 
high dose of corticosteroid, initial dose of corticosteroid, and tapering duration (summary 
statistics)
Duration represents the total duration the subject received the concomitant medication of interest. 
If the subject took the medication periodically, then DURATION in the summation of all use. 
Initial dose represents the dose of the concomitant medication of interest received at the start of 
the event. In the case multiple medications started on the same date, the highest equivalent dose is 
chosen and converted to mg/kg by dividing by the subject’s recent weight.
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These analyses, except the ones related to IMAEs will be conducted using the 30-day safety 
window. The analyses related to IMAEs will be conducted using the 100-day safety window.
7.6.8
Multiple Events
The following summary tables will be provided:
•
A table showing the total number and rate (exposure adjusted) of occurrences for all AEs. 
•
A table showing the total number and rate (exposure adjusted) of occurrences for AEs 
occurring in at least 5% of subjects in any treatment group. 
In addition, the rate (exposure adjusted) and its 95% CI evaluated for different time intervals will 
be displayed graphically for each treatment group. This analysis will be limited to the rate of all 
AEs and all drug-related AEs. The analyses will be conducted using the 30-day safety window.
A listing displaying the unique instances of all AEs, i.e., after duplicates have been eliminated and 
overlapping and contiguous occurrences of the same event (i.e. same PT) have been collapsed will 
be provided. No formal comparisons will be made between treatment groups.
7.6.9
Other Events of Special Interest
OEOSI will be summarized by treatment group for each category.
The following analyses will be conducted using the 100-day safety window:
•
Overall summary of OEOSI by worst CTC grade (any grade, grade 3-4, grade 5) presented by 
Category / PT
•
Overall summary of drug-related OEOSI by worst CTC grade (any grade, grade 3-4, grade 5) 
presented by Category / PT
A by-subject listing of OEOSI will be provided.
7.6.10
Immune Mediated Adverse Events
IMAEs will be summarized by treatment group for each immune-mediated category / PT using the 
100-day safety window:
•
Overall summary of non-endocrine IMAEs by worst CTC grade (any grade, grade 3-4, grade 5) 
where immune modulating medication was initiated presented by Category / PT.
•
Overall summary of endocrine IMAEs by worst CTC grade (any grade, grade 3-4, grade 5) 
presented by Category / PT.
•
Overall summary of non-endocrine IMAEs leading to discontinuation by worst CTC grade 
(any grade, grade 3-4, grade 5) where immune modulating medication was initiated presented 
by Category / PT.
•
Overall summary of endocrine IMAEs leading to discontinuation by worst CTC grade (any 
grade, grade 3-4, grade 5) presented by Category / PT.
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Overall summary of non-endocrine IMAEs leading to dose delay or reduction by worst CTC 
grade (any grade, grade 3-4, grade 5) where immune modulating medication was initiated 
presented by Category / PT
•
Overall summary of endocrine IMAEs leading to dose delay or reduction by worst CTC grade 
(any grade, grade 3-4, grade 5) presented by Category / PT.
•
Summaries of time-to onset and time-to resolution of non-endocrine IMAEs where immune 
modulating medication was initiated presented by Category.
•
Summaries of time-to onset and time-to resolution of endocrine IMAEs presented by Category.
A by-subject listing of IMAEs will be provided. By-subject listings of time-to resolution for 
longest IMAEs cluster (any grade and grade 3-5 in separate summaries) will also be provided. For 
new studies which collect investigator assessment of potential IMAE data, a by-subject listing of 
AEs considered as immune-mediated events per investigator but not qualified for IMAEs 
definition will also be provided.
In addition, for all Nivolumab and/or Ipilimumab treated subjects who experienced at least one 
IMAE, the following data presentation will be provided:
•
Summary of subjects who were re-challenged with Nivolumab and/or Ipilimumab by IMAE 
category, with extended follow-up 
For these, re-challenge is considered to have occurred when last Nivolumab and/or Ipilimumab
infusion was administered after the onset of an IMAE.
7.6.11
Clinical Laboratory Evaluations
The analysis population for each laboratory test is restricted to treated subjects who underwent that 
laboratory test. Laboratory tests (in addition to the tests specified below) with CTC criteria 
collected in the specific studies may also be included in the summaries.
A by-subject listing of differences in categorization of SI and US laboratory test results will be 
provided.
7.6.11.1
Hematology
The following will be summarized by treatment group as worst CTC grade on-treatment per 
subject and as shift table of worst on-treatment CTC grade compared to baseline CTC grade per 
subject: hemoglobin (HB), platelets, white blood counts (WBC), absolute neutrophils count (ANC) 
and lymphocyte count (LYMPH). 
The analyses will be conducted using the 30-day safety window.
A by-subject listing of these laboratory parameters will be provided.
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7.6.11.2
Serum Chemistry
The following will be summarized by treatment group as worst CTC grade on-treatment per 
subject and as shift table of worst on-treatment CTC grade compared to baseline CTC grade per 
subject: ALT, AST, alkaline phosphatase (ALP), total bilirubin and creatinine. 
The analyses will be conducted using the 30-day safety window.
A by-subject listing of these laboratory parameters will be provided.
7.6.11.3
Electrolytes
The following will be summarized by treatment group as worst CTC grade on-treatment per 
subject and as shift table of worst on-treatment CTC grade compared to baseline CTC grade per 
subject: sodium (high and low), potassium (high and low), calcium (high and low), and Glucose 
Serum.
The analyses will be conducted using the 30-day safety window.
A by-subject listing of these laboratory parameters will be provided.
7.6.11.4
Additional Analyses
In addition, further analyses on specific laboratory parameters will be performed by treatment 
group:
Abnormal Hepatic Function Test
The number of subjects with the following laboratory abnormalities from on-treatment evaluations 
will be summarized by treatment group:
•
ALT or AST > 3 x ULN, > 5 x ULN, > 10 x ULN and > 20 x ULN
•
Total bilirubin > 2 x ULN
•
ALP > 1.5 x ULN
•
Concurrent (within 1 day) ALT or AST > 3 x ULN and total bilirubin > 1.5 x ULN
•
Concurrent (within 30 days) ALT or AST > 3 x ULN and total bilirubin > 1.5 x ULN
•
Concurrent (within 1 day) ALT or AST > 3 x ULN and total bilirubin > 2 x ULN
•
Concurrent (within 30 days) ALT or AST > 3 x ULN and total bilirubin > 2 x ULN
The analyses will be conducted using the 30-day safety window.
A by-subject listing of these specific abnormalities will be provided.
Abnormal Thyroid Function Test
The number of subjects with the following laboratory abnormalities from on-treatment evaluations 
will be summarized by treatment group:
•
TSH value > ULN and
−
with baseline TSH value ≤ULN
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−
with at least one FT3/FT4 test value < LLN within 2-week window after the abnormal TSH 
test
−
with all FT3/FT4 test values ≥ LLN within 2-week window after the abnormal TSH test
−
with FT3/FT4 missing within 2-week window after the abnormal TSH test.
•
TSH < LLN and
−
with baseline TSH value ≥LLN
−
with at least one FT3/FT4 test value > ULN within 2-week window after the abnormal 
TSH test
−
with all FT3/FT4 test values ≤ ULN within 2-week window after the abnormal TSH test
−
with FT3/FT4 missing within 2-week window after the abnormal TSH test
The analyses will be conducted using the 30-day safety window.
A by-subject listing of these specific abnormalities will be provided.
7.6.12
Vital Signs
Vital signs collected on the CRF will be provided in separate listings.
7.6.13
Immunogenicity Analysis
Nivolumab-containing arms only. Further details on immunogenicity background and rationale, 
definitions, population for analyses and endpoints are described in APPENDIX 4.
7.6.14
Pregnancy
A by-subject listing of pregnancy tests results will be provided for randomized female subjects.
7.6.15
Adverse Events by Subgroup
Overall summary of any AEs and drug-related AEs by worst CTC grade (any grade, grade 3-4, 
grade 5) presented by SOC/PT and for each treatment group for the following subgroups:
•
Sex (Male vs. Female)
•
Race (Asian vs. non-Asian)
•
Age (< 65 vs. 65 - < 75 vs. 75 - < 85 vs. ≥85 vs. ≥75 vs. ≥65)
•
Region (J/K/T vs rest of Asia vs RoW)
These analyses will be conducted using the 30-day safety window only.
7.7
Pharmacokinetic Analysis
Pharmacokinetics analyses will be performed on the nivolumab-containing arms only.
The nivolumab and/or ipilimumab 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 
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on the PK of nivolumab and/or ipilimumab 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.
7.8
Biomarker Analysis
These analyses will be descriptive and not adjusted for multiplicity.
7.8.1
PD-L1 Expression
Analyses will be performed in all randomized subjects, by treatment group as randomized.
7.8.1.1
Distribution of PD-L1 Expression
Descriptive statistics of PD-L1 expression and PD-L1 status will be provided; 
•
Summary statistics of PD-L1 expression by treatment groups as randomized and overall
•
Frequency of PD-L1 categorization: PD-L1 status (1%, 5% and 10%) by treatment group and 
overall, all randomized PD-L1 subjects 
7.8.1.2
Association between PD-L1 Status and Efficacy
Analyses will be based on all PD-L1 randomized subjects if not otherwise specified. PD-L1 status 
categories (1%, 5% and 10%) will be used for these analyses.
For both OS and PFS per BICR, the following analyses will be provided:
•
Within each category above, curves will be estimated using the KM product limit method for 
each treatment group. Two-sided, 95% CIs for median OS and PFS per BICR will be computed 
by Brookmeyer and Crowley method. 
•
Two-sided log-rank test comparing treatment arms 
•
HR (with corresponding two-sided 95% CI) will be estimated via a Cox model with treatment 
arm as the only covariate in the model (note that for PDL1-expressing subjects, this is one of 
the sensitivity analyses, and won’t be repeated; see Section 7.5.2.2)
•
Forest plot of HR with 95% CIs 
•
For ORR per BICR, the following analyses will be provided: 
•
Within each category above, ORR per BICR will be computed in each treatment group along 
with the exact 95% CI using Clopper-Pearson method16. 
•
An estimate of the difference in ORRs per BICR and corresponding 95% CI will be calculated 
using CMH methodology.
7.8.1.3
Predictive Relationship between PD-L1 Status and Efficacy
Analyses will be based on all evaluable PD-L1 subjects. 
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For both OS and PFS per BICR, a Cox proportional hazards regression model will be fitted with 
treatment, PD-L1 status, and treatment by PD-L1 status interaction. Although the study is not 
designed to have appropriate power to formally test the interaction of the model, an interaction test 
at significance level of 0.2 will warrant further exploration and the following statistics will be 
reported:
•
Interaction p-value
•
HR of treatment vs. control and its associated 95% CI for each of the PD-L1 status subgroup
•
HR PD-L1 ≥1% vs. < 1% and its associated 95% CI within each treatment group.
7.8.2
PD-L1 by Combined positive score (CPS) and Microsatellite Instability 
(MSI) Status
Upon data availability, analyses of exploratory biomarker PD-L1 by CPS and MSI status will be 
performed in all randomized subjects, by treatment group as randomized.
7.8.2.1
Descriptive Statistics of PD-L1 by CPS and MSI
•
Summary of tumor specimen acquisition, characteristics by CPS and MSI respectively
•
Summary of PD- L1 by CPS and MSI status by categories by CPS and MSI respectively
Below analyses are applicable for PD-L1 by CPS
•
Summary statistics of PD-L1 by CPS expression.
•
Waterfall plot of Individual PD-L1 by CPS expression.
7.8.2.2
Association between biomarker Status and Efficacy
OS and PFS per BICR will be analyzed for each biomarker category specified for PD-L1 by CPS 
and MSI:
•
Curves will be estimated using the KM product limit method for each treatment group. Two-
sided, 95% CIs for median PFS per BICR and OS will be computed.
•
HR (with corresponding two-sided 95% CI) will be estimated via a Cox model with treatment
arm as the only covariate in the model.
•
Forest plot of HR with 95% CIs
7.9
Outcomes Research Analyses
The analysis of EQ-5D-3L and FACT-E (including FACT-G7 and ECS) data will be performed in 
all randomized subjects and all PD-L1 expressing subjects who have an assessment at baseline 
(assessment on or prior to first dose on Day 1) and at least 1 subsequent assessment while on 
treatment. The 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-3L data will be described by treatment group as randomized in the following ways:
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•
EQ-5D-3L index scores will be summarized at each assessment time point using descriptive 
statistics (i.e., 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 
(i.e., 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-3L dimensions at each assessment time point. Subjects with missing 
data will be excluded from the analysis.
•
A line graph summarizing the mean changes from baseline for the EQ-5D-3L index and VAS 
scores will be produced.
•
A by-subject listing of the level of problems in each dimension, corresponding EQ-5D-3L 
health state (i.e., 5-digit vector), EQ-5D-3L index score, and EQ-VAS score will be provided.
From the beginning of the on-treatment phase through follow-up Visit 2, data for the FACT-E will 
be described by treatment group as randomized in the following ways:
•
FACT-G7 and FACT-E total and subscale (PWB, FWB, EWB, SWB, ECS, TOI) scores will 
be summarized at each assessment time point using descriptive statistics (i.e., N, mean with 
SD and 95% CI, median, first and third quartiles, minimum, maximum).
•
Changes from baseline in FACT-G7, FACT-E total and subscale (PWB, FWB, EWB, SWB, 
ECS, TOI) scores will be summarized at each post-baseline assessment time point using 
descriptive statistics (i.e., N, mean with SD and 95% CI, median, first and third quartiles.
•
The proportion (N) of subjects reporting each response category will be presented for the 
single-item GP5 item at each assessment time point. A stacked bar graph will be produced for 
GP5 which shows the proportion of subject with each response category at each timepoint.
Subjects with missing data will be excluded from the analysis.
•
A line graph summarizing the mean changes from baseline for the FACT-E total score, ECS 
and FACT-G7 scores will be produced.
•
A by-subject listing of the responses to each item in the FACT-E will be provided (including 
the items also included in the ECS and FACT-G7 during the survival follow-up phase).
During the survival follow-up phase, data for the ECS and FACT-G7 will be described by
treatment group as randomized in the following ways:
•
ECS and FACT-G7 scores will be summarized at each assessment time point using descriptive
statistics (i.e., 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 (i.e., N, mean with SD and 95% CI, median,
first and third quartiles, minimum, maximum).
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7.10
COVID-19 Related Analyses
In this study, in order to evaluate the impact of COVID-19 pandemic, the following CRF pages 
were implemented. 
•
Disposition: The subjects who discontinue the study treatment or discontinue the study due to 
COVID-19
•
Exposure: The subjects who have study therapy modification due to COVID-19 
Listings will be provided based on the data collected on each CRF pages and additional analyses 
may be performed in order to evaluate the impact of COVID-19 on this study.
8
Analysis to Evaluate the Contribution of Ipilimumab Component in the 
N+I regimen in the Summary of Clinical Efficacy (SCE) 
In order to evaluate the treatment effect between two experiment arms of N+I and N+C, similar 
analyses as described in Section 7.5 will be conducted for key efficacy endpoints. The below 
analyses will be conducted for all PD-L1 expressing subjects, all PD-L1 Negative Subjects, and 
all Randomized Subjects. These analyses will help to evaluate the contribution of ipilimumab 
component in the N+I regimen in the Summary of Clinical Efficacy (SCE) and Clinical Overview 
(CO) if applicable.
For Overall survival and PFS as assessed by BICR, the HR between N+I and N+C with its 
associated two-sided 95% CIs will be estimated via a stratified Cox model with treatment arm as 
the only covariate in the model. Overall survival and PFS as assessed by BICR for each of the 
three treatment arms will be estimated and overlayed using the KM product-limit method. Median 
survival time along with 95% CI will be constructed based on a log-log transformed CI for the 
survival function.8,9
ORR assessed by BICR will be computed in each treatment group along with the exact 95% CI 
using Clopper-Pearson method15. An estimate of the difference in ORRs and corresponding 95% 
CI between N+I and N+C will be calculated using CMH methodology and adjusted by the 
stratification factors as specified in Section 7.1.1. The stratified odds ratios (Mantel-Haenszel 
estimator) between N+I and N+C will be provided along with the 95% CI. The KM curves of the 
DOR in each of 3 treatment groups will be overlayed for subjects who achieve PR or CR. Median 
DOR along with two-sided 95% CI will be calculated.
Considering that the survival function of overall survival may potentially have different shapes in 
the N+I arm and N+C arm, the restricted mean survival time (RMST) will be evaluated for N+I 
and N+C arm. The difference of RMST between N+I and N+C with its associated two-sided 95%
CIs will be estimated. The RMST will be estimated by the area under the KM curve up to a time 
point (1 year, 2 years, and 3 years, and maximum of the study follow-up).
9
CONTENT OF REPORTS
9.1
Within-Trial Analyses Performed To Date
Not applicable.
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10
CONVENTIONS
The following conventions may be used for imputing partial dates for analyses requiring dates:
•
For missing and partial adverse event onset dates, imputation will be performed using the 
Adverse Event Domain Requirements Specification17.
•
Missing and partial Non-Study Medication Domain dates will be imputed using the derivation 
algorithm described in 4.3.3 of BMS Non-Study Medication Domain Requirements 
Specification18.
•
Missing and partial radiotherapy and surgery dates will be imputed using algorithm described 
in APPENDIX 2.
For death dates, the following conventions will be used for imputing partial dates:
•
If only the day of the month is missing, the 1st of the month will be used to replace the missing 
day. The imputed date will be compared to the last known date alive and the maximum will be 
considered as the death date.
•
If the month or the year is missing, the death date will be imputed as the last known date alive. 
•
If the date is completely missing but the reason for death is present the death date will be 
imputed as the last known date alive
For date of progression, the following conventions will be used for imputing partial dates:
•
If only the day of the month is missing, the 1st of the month will be used to replace the missing 
day.
•
If the day and month are missing or a date is completely missing, it will be considered as 
missing.
•
In case of the date of death is present and complete, the imputed progression date will be 
compared to the date of death. The minimum of the imputed progression date and date of death 
will be considered as the date of progression.
For other partial/missing dates, the following conventions may be used:
•
If only the day of the month is missing, the 15th of the month will be used to replace the 
missing day.
•
If both the day and the month are missing, “July 1” will be used to replace the missing 
information.
•
If a date is completely missing, it will be considered as missing.
The following conversion factors will be used to convert days to months or years:
1 month = 30.4375 days and 1 year = 365.25 days.
Duration (e.g. DOR, etc) will be calculated as follows:
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Duration = (Last date - first date + 1)
All statistical analyses will be carried out using SAS (Statistical Analysis System software, SAS 
Institute, North Carolina, USA) unless otherwise noted.
11
CONTENT OF REPORTS
All analyses describe in this SAP will be included in the Clinical Study Report except where 
otherwise noted. Refer to the Data Presentation Plan for mock-ups of all tables and listings.
12
DOCUMENT HISTORY
Document History
Version 
Number
Author(s)
Description
1.0
Initial version dated 18-Oct-2017
2.0
Version 2.0 dated 28-Aug-2020
•
Updated the definition for the outcome research exploratory endpoint 
FACT-E and added the analysis window for outcome research 
assessments in Section 4.3.3.
•
Added Max-Combo method as a sensitivity analysis accounting for the 
potential non-proportionality observed from the OS/PFS KM curves in 
Section 7.5.2.2.
•
Added PFS2/TSST as an exploratory endpoint (Section 4.3.1) and the 
corresponding analysis (Section 7.5.4.2).
•
Removed the procedures for the reinitiation of nivolumab ± ipilimumab 
treatment after disease progression for up to 1 additional year.
•
Modified the Safety section (Section 7.6) to incorporate the contents 
from the safety section in the IO CORE SAP. 
•
Added value “Gx” for histologic grade at initial diagnosis and added 
prior surgery and prior radiotherapy in Section 7.5.2.3.
•
Added 5% and 10% as additional subgroups for PD-L1 status in Section 
7.8.1.2.
•
Added analysis to explore the association between ORR and PD-L1 in 
Section 7.8.1.2.
•
Added some additional analyses for EQ-5D-3L and FACT-E in Section 
7.9.
•
Added APPENDIX 5 with analyses of data from China.
•
Added the imputation algorithm for missing and partial radiotherapy 
and surgery dates from IO CORE SAP (APPENDIX 2).
3.0
Version 3.0 dated 29-Oct-2020
•
Added language and rationale to allow for the final PFS analysis to be 
triggered when 136 PFS events per BICR are observed among the PD-L1 
expressing subjects in the chemotherapy arm or when at least 12 months 
minimum follow up is reached, if the target number of PFS events is 
unlikely to be reached in Section 1, Section 5 and APPENDIX 7.
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Document History
Version 
Number
Author(s)
Description
4.0
Version 4.0 dated Feb 12, 2021
Main changes include
•
Added analysis to evaluate relevant treatment effect between N+I vs. N+C 
for key efficacy endpoints in Section 8.
•
Added PD-L1 by CPS and MSI analysis in Section 7.8.2.
•
Add language in section 7.1 to handle the small stratum in the stratified 
analyses.
Other minor changes include
•
Aligned the PFS2/TSST definition with IO Core SAP in Section 4.3.1.
•
Modified the baseline definition for stratification factors as before the date 
of the randomization in Section 6.1.
•
Moved the definition of exploratory biomarker endpoints to Section 4.3.6.
•
Added definition for All PD-L1 Negative Subjects and All Treated PD-L1 
Expressing Subjects in Section 6.3.
•
Added on-treatment curative Surgery as the relevant protocol deviation in 
Section 7.2.2. 
•
Add in Section 7.5.2.2 ‘The list of covariates considered in the multivariate 
cox model may be modified if there are issues with multicollinearity among 
the covariates or other important prognostic factors are identified.’
•
Added limited safety analyses in PD-L1 expressing subjects and PD-L1 
negative subjects in Section 7.6 to assess benefit-risk in PD-L1 subgroups. 
•
Aligned the baseline definition in Section 7.9 with Table 4.3.3-1.
•
Added PRO analysis in All PD-L1 expressing subjects in addition to all 
treated subjects in Section 7.9.
•
Added a stacked bar graph for GP5 in Section 7.9.
•
Added COVID-19 Related Analysis in Section 7.10.
•
Added Section 9.1 there was no within-trial analyses performed to date.
•
Add definition of primary and secondary China subpopulation in 
APPENDIX 5.  Includes ‘Only unstratified analyses will be performed for 
efficacy endpoints and the sensitivity analysis of investigating non-
proportionality in Kaplan-Meier curves will not be performed.’ in
APPENDIX 5.
•
Removed metastatic disease from prior anti-cancer therapy in Section 7.3.4.
•
Modified the subcategories for disease status at current diagnosis in the
multivariate cox model in Section 7.5.2.2.
•
In the Section 7.5.2.3 consistency of treatment effect in subsets, added
region (Asia, non-Asia) and excluded biopsy from prior surgery.
•
Removed safety summary in the 3 arms pooled (total) in Section 7.6 safety.
•
For the odds ratio, in addition to 95% CI, also added ‘(in case the given 
endpoint is formally tested, also with the 100(1-α)% CI)’ in Section 7.5.3.2.
•
In Section 7.3.2 demographics and other baseline characteristics, added race 
(Asia vs. non-Asia)
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Document History
Version 
Number
Author(s)
Description
•
Modified the relative dose intensity formula for fluorouracil in Table 7.4.1-2
•
The time to response would analyzed descriptively only for subjects who 
achieved PR or CR. KM estimate of time to response was removed.  
•
Removed alpha adjusted difference in ORRs in Section 7.8.1.2 Association 
between PD-L1 status and efficacy
•
Add in Section 7.3.2 For the purposes of baseline characteristic summary, 
stratification factors will be retrieved from the CRF.
•
Remove alpha adjusted CI for ORR in Section 7.8.1.2 association between 
PD-L1 status and efficacy.
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APPENDIX 1
APPENDIX: EXAMPLE FOR SEQUENTIALLY REJECTIVE 
PROCEDURE
Section 7.5.1 of this SAP specifies the multiple testing procedure that controls family-wise Type I 
error rate of 5% in the strong sense across all primary and secondary endpoints. After rejecting an 
individual hypothesis, the local significance levels and the transition weights of the edges are 
updated: the rules for that update are determined by Algorithm 1 in Maurer and Bretz (2013). The 
resulting sequentially rejective testing procedure is uniquely determined by the graph in Figure 
7.5.1-1. In order to illustrate the principles of this iterative procedure (summarized in Section 
7.5.1), a simple hypothetical example is provided in this section.
This example considers a hypothetical outcome of the primary and secondary endpoints at the time 
of the PFS analysis (Time 1) and at the final OS analysis (Time 2). At Time 1, per protocol, all 
primary endpoints are formally tested (and thus all observed p-values are available): we assume 
that PFS in PDL1-expressing subjects is significant in the N+I vs. CT comparison at its initially 
allocated alpha. The 4 steps below demonstrate how the alpha will then be passed to the next 
testing based on the pre-specified testing strategy. At each step, a hypothesis is rejected (part A), 
its corresponding vertex and all edges will be removed; the remaining edges and nominal 
significance levels will be updated (part B). In the following, shaded vertices represent those 
hypotheses that are rejected at their nominal significance level at the given step. (For the sake of 
simplicity, examples of observed p-values are not provided.) (Notice the following: although the 
design assumes the same treatment effect and thus observed event numbers for the N+I vs. CT and 
N+C vs. CT comparisons, in the example, the OS information fractions observed at Time 1 are 
slightly different for the two comparisons. This reflects the fact that although the true treatment 
effect is assumed to be the same across comparisons, the observed number of events per 
comparison [N+I vs. CT and N+C vs. CT] is a random number.)
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Step 1: At Time 1, reject primary endpoint PFS in PDL1-expressing subjects for N+I vs. CT (shaded vertex). As a result, the graph is 
updated as follows (see also Part B in table below): 
•
the rejected hypothesis and its outgoing edge is removed;
•
the entire significance level of the rejected hypothesis is passed to the corresponding secondary endpoint in all randomized subjects 
(within the N+I vs. CT comparison).
Table 10-1:
Step1: Time 1, Rejection of PFS PDL1+ for N+I vs. CT
Part A: Reject Hypothesis
Part B: Update Graph after Rejection
* Nominal signifiance levels for Time 1 / Time 2, based on O’Brien-Fleming with 72% observed information fraction at Time 1
** Nominal signifiance levels for Time 1 / Time 2, based on O’Brien-Fleming with 68% observed information fraction at Time 1
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Step 2: Now assume that the secondary endpoint PFS in all randomized subjects for N+I vs. CT (shaded vertex) is significant at Time 1 
at its nominal alpha. As a result, the graph is updated as follows (see also Part B in table below):
•
the rejected hypothesis and its outgoing edges are removed;
•
half of the rejected hypothesis’ significance level is passed to ORR in PDL1-expressing subjects (secondary endpoint) - and thus it 
can be now tested at 0.0075;
•
half of the rejected hypothesis’ significance level is passed to another primary endpoint, OS in in PDL1-expressing subjects - and 
thus latter’s local significance level is updated from 0.01 to 0.0175. The alpha spending function (O’Brien-Fleming with 72% 
information fraction at Time 1) is then re-applied to this updated local significance level.
Table 10-2:
Step2: Time 1, Rejection of PFS AC for N+I vs. CT
Part A: Reject Hypothesis
Part B: Update Graph after Rejection
* Nominal signifiance levels for Time 1 / Time 2, based on O’Brien-Fleming with 72% observed information fraction at Time 1
** Nominal signifiance levels for Time 1 / Time 2, based on O’Brien-Fleming with 68% observed information fraction at Time 1
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Step 3: For the sake of illustration, assume that no more endpoints can be rejected at Time 1, and thus the study continues to Time 2. As 
the PFS and ORR endpoints were not planned to be tested at Time 2, all related vertices and edges are removed from the graph. All OS 
endpoints will now use the nominal significance levels for Time 2, as determined by their alpha spending functions. Assume that we 
can reject primary endpoint OS in PDL1-expressing subjects for N+I vs. CT (shaded vertex) at its nominal significance level of 0.0162. 
As a result, the graph is updated as follows (see also Part B in the table below):
•
the rejected hypothesis and its outgoing edge are removed;
•
The entire local significance level of the rejected hypothesis is passed to its corresponding secondary endpoint in all randomized 
subjects in N+I vs. CT - and thus the secondary endpoint’s local significance level (across timepoints) is updated to 0.0175. The 
alpha spending function (Pocock with 65% information fraction at Time 1) is then applied to this updated alpha level, and it can be 
tested at 0.0078.
Table 10-3:
Step3: Time 2, Rejection of OS PDL1+ for N+I vs. CT
Part A: Reject Hypothesis
Part B: Update Graph after Rejection
* Nominal signifiance levels for Time 1 / Time 2, based on O’Brien-Fleming with 72% observed information fraction at Time 1
** Nominal signifiance levels for Time 1 / Time 2, based on O’Brien-Fleming with 68% observed information fraction at Time 1
*** Nominal signifiance levels for Time 1 / Time 2, based on Pocock with 65% observed information fraction at Time 1
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Step 4: Reject OS in all randomized subjects for N+I vs. CT (shaded vertex) at Time 2. As a result:
•
the rejected hypothesis and its related edges are removed;
•
its entire significance level is passed to the last testable primary endpoint, OS in PDL1-expressing subjects for N+C vs. CT. Thus 
latter’s local significance level is updated to 0.0275. The alpha spending function (O’Brien-Fleming with 68% information fraction 
at Time 1) is then applied to this updated alpha level, and it can be tested at 0.0257.
Table 10-4:
Step4: Time 2, Rejection of OS AC for N+I vs. CT
Part A: Reject Hypothesis
Part B: Update Graph after Rejection
* Nominal signifiance levels for Time 1 / Time 2, based on O’Brien-Fleming with 68% observed information fraction at Time 1
** Nominal signifiance levels for Time 1 / Time 2, based on Pocock with 65% observed information fraction at Time 1
Assuming that OS in PDL1-expressing subjects for N+C vs. CT cannot be rejected, the process stops.
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APPENDIX 2
MISSING AND PARTIAL RADIOTHERAPY AND SURGERY 
DATES IMPUTATION ALGORITHMS
Procedures – Imputation Rules. 
If reported procedure start date is a full valid date then set start date equal to the date part of 
procedure start date. 
In case of partial date use imputation rules described below: 
•
If only day is missing then 
−
If month and year of procedure match month and year of first dose date then impute as date 
of first dose; 
−
If month and year of procedure don't match month and year of first dose date then impute 
as first day of that month and year. 
•
If both day and month are missing, then impute as maximum between 01JAN of the year and 
date of the first dose; 
•
If date is completely missing or invalid then leave missing. 
Note: Imputation is not applicable to data where start date is not collected (for example "PRIOR 
RADIOTHERAPY" CRF). Set start date to missing in this case. 
If reported end date is a full valid date then set end date equal to the date part of the reported end 
date. 
In case of partial date use imputation rules described below: 
•
If reported end date is partial then set end date equal to the last possible reported end date based 
on the partial entered reported end date. 
•
If reported end date is missing, continuing, unknown or invalid then set end date equal to the 
most recent database extraction date. 
If end date was imputed then compare end date to the death date or last known alive date if subject 
is not dead. If posterior then end date should be imputed to death date (or last known alive date if 
subject not dead). 
Note: Imputation of partial dates only applies to data entered on "RADIOTHERAPY” CRF page. 
For other CRF pages in case of partial dates set end date to missing.  
Surgeries – Imputation Rules. 
If reported surgery date is a full valid date then set start date equal to the date part of surgery date. 
In case of partial date, use one of the two imputation rules described below: 
A. For data collected on "PRIOR SURGERY RELATED TO CANCER" CRF page: 
•
If only day is missing then impute as the first day of the month; 
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•
If both day and month are missing then then impute as 01JAN of the year; 
•
If date is completely missing or invalid then leave missing. 
B. For data collected on other CRF pages (deemed to be on-treatment/subsequent surgeries): 
•
If only day is missing then 
−
If month and year of surgery match month and year of first dose date then impute the 
missing date as the date of first dose; 
−
If month and year of surgery don't match month and year of first dose date then impute as 
first day of that month and year; 
•
If both day and month are missing then impute as maximum between 01JAN of the year and 
date of the first dose; 
•
If date is completely missing or invalid then leave missing.
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APPENDIX 3
TIME-TO ONSET AND TIME-TO RESOLUTION DEFINITION AND 
CONVENTIONS FOR SELECT ADVERSE EVENTS, IMMUNE-
MEDIATED ADVERSE EVENTS AND EVENTS OF SPECIAL 
INTEREST
Time-to onset definition
Time-to onset of AE (any grade) for a specific category is defined as the time between the day of 
the first dose of study treatment and the onset date of the earliest AE (of any grade) in this category.
The time-to onset of AE (grade 3-5) for a specific category is defined similarly with an onset date 
corresponding to a grade 3-5 AE.
Time-to onset of drug-related AE (any grade or grade 3-5) for a specific category is defined 
similarly but restricted to drug-related AE.
Time-to onset for a specific subcategory is defined similarly but restricted to event of this 
subcategory.
Time-to resolution definition
In order to derive the time-to resolution, overlapping or contiguous AEs within a specific category 
or subcategory will be collapsed into what will be termed “clustered” AEs. For example, if a 
subject (without pre-treatment AE) experienced an AE from 1st to 5th January, another AE (with 
different PT but within same category) from 6th to 11th January and same AE from 10th to 
12th January, these will be collapsed into one clustered AE from 1st to 12th January. Table 10-5 is 
summarizing key derivation steps for each type of clustered AEs.
Time-to resolution of AE (any grade) for a specific category is defined as the longest time from 
onset to complete resolution or improvement to the grade at baseline among all clustered AEs 
experienced by the subject in this category per adverse event criteria category. Events which 
worsened into grade 5 events (death) or have a resolution date equal to the date of death are 
considered unresolved. If a clustered AE is considered as unresolved, the resolution date will be 
censored to the last known alive date. Improvement to the grade at baseline implies that all 
different events in the clustered adverse event should at least have improved to the corresponding 
(i.e. with same preferred term) baseline grade. This measure is defined only for subjects who 
experienced at least one AE in the specific category.
The time-to resolution of AE (grade 3-5) for a specific category is defined similarly with an onset 
date corresponding to a grade 3-5 AE.
Time-to resolution of drug-related AE (any grade or grade 3-5) for a specific category is defined 
similarly but restricted to drug-related AE.
The time-to resolution of AE (any grade or grade 3-5, drug-related or all) where immune 
modulating medication was initiated is defined similarly. For data presentation not restricted to 
IMAE, the additional condition that the subject started an immune modulating medication during 
the longest AE resolution period will be applied.
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Time-to resolution for a specific subcategory is defined similarly but restricted to event of this 
subcategory.
Table 10-5:
Derivation of clustered AE
Type of clustered AE
Derivation
Any grade
Collapse any on-treatment AE from the same category
Drug-related of any grade
Collapse any on-treatment drug-related
AE from the same category
Grade 3-5
Collapse any on-treatment AE from the same category.
Resolution will be based on the onset date of the earliest grade 3-
5 records (if no grade 3-5 record, clustered AE is excluded)
Drug-related of Grade 3-5
Collapse any on-treatment drug-related AE from the same 
category
Resolution will be based on the onset date of  the earliest grade 
3-5 record (if no Grade 3-5 record, clustered AE is excluded)
The algorithm for collapsing adverse event records is using the following conventions:
For each subject and specified category, the corresponding adverse event records will be collapsed 
when:
1) Multiple adverse event records have the same onset date.
2) The onset date of an event record is either the same day or 1 day later than the resolution date 
of a preceding event record (contiguous events).
3) The onset date of an event record is after the onset date and prior to or on the resolution date 
of a preceding event record (overlapping events).
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APPENDIX 4
IMMUNOGENICITY ANALYSIS: BACKGROUND AND 
RATIONALE
The following summary is from the FDA Guidance for Industry Immunogenicity Assessment for 
Therapeutic Protein Products and White Paper on Assessment and Reporting of the Clinical 
Immunogenicity of Therapeutic Proteins and Peptides – Harmonized Terminology and Tactical 
Recommendations by Shankar et al. The program-level definitions of sample- and subject-level 
ADA status are based on recommendation from the BMS Immunogenicity Council.
Immune responses to therapeutic protein products may pose problems for both patient safety and 
product efficacy. Immunologically based adverse events, such as anaphylaxis and infusion 
reactions, have caused termination of the development of therapeutic protein products or limited 
the use of otherwise effective therapies. Unwanted immune responses to therapeutic proteins may 
also neutralize the biological activity of therapeutic proteins and may result in adverse events not 
only by inhibiting the efficacy of the therapeutic protein product, but by cross-reacting to an 
endogenous protein counterpart, if present. Because most of the adverse effects resulting from 
elicitation of an immune response to a therapeutic protein product appear to be mediated by 
humoral mechanisms, circulating antibody has been the chief criterion for defining an immune 
response to this class of products.
ADA is defined as biologic drug-reactive antibody, including pre-existing host antibodies that are 
cross-reactive with the administered biologic drug (baseline ADA). Titer is a quasiquantitative 
expression of the level of ADA in a sample. By employing a serial dilution-based test method, titer 
is defined as the reciprocal of the highest dilution of the sample (e.g., dilution of 1/100 = titer of 
100). The ADA is also tested, via a cell-based biologic assay or a non cell-based competitive 
ligand-binding assay for a subpopulation of ADA known as neutralizing antibodies (NAb), which 
inhibits or reduces the pharmacological activity of the biologic drug molecule regardless of its in 
vivo clinical relevance. Non-neutralizing ADA (non-NAb) is ADA that binds to the biologic drug 
molecule but does not inhibits its pharmacological activity.
ADA should be tested using sensitive and valid methods and employing an appropriate strategy 
for elucidating immunogenicity. Detection of ADA is typically performed in three tiers (screening, 
confirmatory, and titer) using statistically determined cutpoints and samples testing positive in the 
ADA assay are analyzed for neutralizing activity, especially in late-stage clinical studies. 
“Detection” of ADA implies that drug-specific ADA was confirmed. The ‘drug tolerance” of an 
assay (highest drug concentration that does not interfere in the ADA detection method) is not an 
absolute value and differs between individuals due to the varying avidities of ADA immune 
responses. An ADA sampling strategy of collecting samples at times when the least drug 
concentration is anticipated (trough concentrations) can increase the likelihood of accurate ADA 
detection.
It is useful to present ADA results from clinical studies as (a) characteristics of the ADA immune 
response, (b) relationship of ADA with pharmacokinetics (PK) and, when relevant, 
pharmacodynamics (PD) biomarkers, and (c) relationship of ADA with clinical safety and 
efficacy.
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Clinical consequences of ADA can range from no apparent clinical effect to lack of efficacy 
(primary treatment failure), loss of efficacy (secondary treatment failure) or heightened effect due 
to altered exposure to the biologic drug, adverse drug reactions (administration-related systemic 
or site reactions), and severe adverse drug reactions (anaphylaxis and unique clinical problems 
associated with cross-reactivity and neutralization of endogenous molecules). Thus it becomes 
important to examine any associations between ADA or any of its attributes with the various 
clinical sequelae. The presence of ADA may or may not preclude the administration of drug to 
ADA-positive subjects because the outcome is dependent upon the magnitude of the impact of 
ADA on PK and PD. Hence, the relationship of ADA with PK/PD is an important additional 
consideration, but does not necessarily result in a clinically impactful consequence per se.
Immunogenicity Endpoints
A fundamental metric that informs clinical immunogenicity interpretation is the incidence of ADA 
in a study or across comparable studies. ADA incidence is defined as the proportion of the study 
population found to have seroconverted or boosted their pre-existing ADA during the study period.
Terms and Definitions
Validated ADA test methods enable characterization of samples into ADA-positive vs. ADA-
negative. To classify the ADA status of a subject using data from an in vitro test method, each 
sample from the subject is categorized based on the following definitions:
Sample ADA Status:
•
Baseline ADA-positive sample: ADA is detected in the last sample before initiation of 
treatment
•
Baseline ADA-negative sample: ADA is not detected in the last sample before initiation of 
treatment
•
ADA-positive sample: After initiation of treatment, (1) an ADA detected (positive 
seroconversion) sample in a subject for whom ADA is not detected at baseline, or (2) an ADA 
detected sample with ADA titer to be at least 4-fold or greater (≥) than baseline positive titer
•
ADA-negative sample: After initiation of treatment, ADA not positive sample relative to 
baseline
Next, using the sample ADA status, subject ADA status is defined as follows:
Subject ADA Status:
•
Baseline ADA-positive subject: A subject with baseline ADA-positive sample
•
ADA-positive subject: A subject with at least one ADA positive-sample relative to baseline 
at any time after initiation of treatment
1) Persistent Positive (PP): ADA-positive sample at 2 or more consecutive time points, where 
the first and last ADA-positive samples are at least 16 weeks apart
2) Not PP-Last Sample Positive: Not persistent positive with ADA-positive sample at the last 
sampling time point
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3) Other Positive: Not persistent positive but some ADA-positive samples with the last sample 
being negative
4) Neutralizing Positive: At least one ADA-positive sample with neutralizing antibodies detected
•
ADA-negative subject: A subject with no ADA-positive sample after the initiation of 
treatment.
(Note: 16 weeks was chosen based on a long half-life of IgG4.)
Population for Analyses
Analysis of immunogenicity data will be based on ADA evaluable subjects defined as all treated 
subjects with baseline and at least 1 post-baseline immunogenicity assessment. Analysis dataset 
and data listing will include all available ADA samples. However, subject-level ADA status will 
be defined based on only adequate samples (e.g., excluding 1-hour post-infusion samples when 
clearly indicated).
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APPENDIX 5
ANALYSES OF DATA FROM CHINA
Analysis methods for China
Analyses detailed in SAP will be repeated for the patients randomized in China using the analysis 
sets described in this appendix if feasible for an individual analysis (eg, see the minimal subject 
required in Section 7.5.4.3). The analysis methods for the China subpopulation will be the same 
as for the global population unless otherwise noted. No formal hypothesis testing will be performed 
to evaluate consistency of China subpopulation. Instead, summary statistics and estimates will be 
provided to assess the consistency descriptively. All statistical analyses for China will be 
performed when at least one of the primary endpoints is statistically significant. 
No adjustment for multiplicity will be made.
Only unstratified analyses will be performed for efficacy endpoints and the sensitivity analysis of 
investigating non-proportionality in Kaplan-Meier curves will not be performed.
Definition of analysis sets
Primary China subpopulation 
Primary China subpopulation is defined as certified Greater China subgroup. It should contain 
subjects that are Chinese by race and enrolled from all Mainland China sites, National Medical 
Products Administration (NMPA) certified Taiwan sites and NMPA certified Hong Kong sites. 
Secondary China subpopulation
Secondary China subpopulation is defined as Greater China subgroup. It should contain all 
subjects that are Chinese by race and enrolled from Mainland China, Taiwan and Hong Kong. 
Asian subpopulation
Asian subpopulation is defined as Asian subgroup. It should contain subjects that are Asian by 
race and enrolled from Asian countries which are defined as the combination of J/K/T and Rest of 
Asia.
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APPENDIX 6
R PROGRAM FOR THE STUDY DESIGN
This appendix includes the program (R-v3.1.3) that was used for the study design (as specified in 
the protocol).
#####################################################################
# Program name: CA209648 FINAL DESIGN SAP
# Purpose: Sample size calculation for CA209648 revprot1.0
# Author:
# Date: Dec 2016
# Comment: CA209648 design assumes the same OS/PFS for the two experimental 
arms (N+C and N+I)
#          This program generates datasets for 
#             - both primary endpoints of PFS and OS (generated by separate 
calls of the same macros)
#             - the control vs ONE of the two experimental arms
#                   Consequently, the # of randomized subjects, # of events, 
etc will be understood 
#                   PER COMPARISON (i.e. N+I vs. CT and N+C vs. CT)
# Program Description:
#  I. Set up Macros
#     5 macros: my.summary, Report_Results, Run_iterations, DataCohort, 
PrimaryTest
#     Structure:
#     (#my.summary#: customized summary of simulation results)
#     #Report_results#
#        1. calls #Run_Iterations#: to run simulations and collect results in 
one dataframe; 
#           For each iteration:
#           i. calls #DataCohort#: to generate time to event data for each 
cohort
#           ii. pools cohort results and adds random randomization month/day to 
each subject
#           iii. calls #PrimaryTest#: 
#               a) for each patient, adds censoring;
#               b) runs Cox PH model
#        2. summarizes and structures simulation results for presentation
#  II. Set up calls (for accrual; for OS and PFS)
#############################################################################
#######
#####################################################################
library(msm)          # package to access rpexp (to generate piecewise exp 
function)
library(ldbounds)     # package to calculate significance level given an alpha 
spending function
library(survival)     # coxph, survfit
options(scipen=999)   # to disable scientific format in output
# self-made function for customized summary of simulation results (including 
90% CI)
my.summary <- function(x){
  c(min=round(min(x,na.rm=TRUE),3),
    percent=round(quantile(x, probs=0.05,na.rm=TRUE),3), 
    median=round(median(x,na.rm=TRUE),3),
    mean=round(mean(x,na.rm=TRUE),3),
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    percent=round(quantile(x, probs=0.95,na.rm=TRUE),3), 
    max=round(max(x,na.rm=TRUE),3), 
    N.A=sum(is.na(x)))
}
#############################################################################
#######
######### I. Set up Macros
#############################################################################
#######
#####################################################################
####### DataCohort generate time to event data for each cohort
##### INPUT Parameters
## acc_num:            a vector containing the accrual at each month, can have 
zero element
## ctl_mos, trt_mos:   median of the control/experimental group
## trt_cure_os:        % of patients cured in experimental group
## delay_OS:           length of delayed effect (months)
## nprop_trt:          % of patients randomized to the experimental arm
##### OUTPUT 
#### A data matrix consist of:
## trt:                treatment assignment (0 = control, 1 = experimental)
## OS:                 time to event for given endpoint (without censoring)
#####################################################################
DataCohort = function(acc_num, ctl_mos, trt_mos, trt_cure_os, delay_OS, 
nprop_trt)
{
  DataOutput = NULL
  # calculate parameter for exp distribution: control arm, experimental arm 
before and after delay
  ctl_lambda_os = log(2)/ctl_mos
  trt_lambda_os = log(2)/trt_mos
  # set up empty objects
  trt = matrix(0,acc_num,1)
  OS  = matrix(0,acc_num,1)
  ####### Generate vector of treatment assignments (0 = control, 1 = 
experimental)
      for (i in 1:acc_num){
        # for each cohort, first half of the vector is experimental, the 2nd 
half is control; 
        # if acc_num is uneven, the last element's treatment assignment is 
determined at random
        # this reflects block structure
        if(i<=floor(nprop_trt*acc_num)){
          trt[i,1] =1
        }
        if(i>ceiling(nprop_trt*acc_num)){
          trt[i,1] =0
        }
        if(i==ceiling(nprop_trt*acc_num) 
& 
ceiling(nprop_trt*acc_num)-
floor(nprop_trt*acc_num)>0){
          trt[i,1] =rbinom(1,1,nprop_trt)
        }
        
  ######    Generate time to event
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       #### control group: exponential distribution
        if(trt[i,1]==0){
            OS[i,1] = rexp(1, rate = ctl_lambda_os)  
        }
        #### treatment group
        if(trt[i,1]==1){
          seed1 = runif(1)  # random number to decide of each patient whether 
cure or not
          
          # cured patients: for those who live after delay, very long survival 
is generated
          if(seed1 < trt_cure_os){
            OS[i,1] = rpexp(1, rate = c(ctl_lambda_os, log(2)/(10^6)), 
t=c(0,delay_OS))  
          }
          
          # non-cure patients: for those who live after delay, exponential 
distribution
          if(seed1 >= trt_cure_os){
            OS[i,1] = rpexp(1, rate = c(ctl_lambda_os, trt_lambda_os), 
t=c(0,delay_OS))    
          }
        }
      }
      
DataOutput = cbind(trt, OS)
      colnames( DataOutput)=c("trt", "OS")
return(DataOutput)
}
#####################################################################
####### PrimaryTest: 1. for each patient, adds randomization date and censoring;
#                    2. runs Cox PH model
##### INPUT Parameters
## OS_fraction_pd:  Information fraction for IA in the primary subpopulation 
(If 1 then no IA)
## event_OS_FA_pd: Final number of events in the primary subpopulation (defines 
end of study)
## DataPool:        Output vector from Run_Iterations, after running DataCohort 
for all cohorts, and adding entry dates
## 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
("trt", 
"OS", 
"entry_day","dummy_order","n_percohort1","n_percohort2","n_percohort3","n_per
cohort4", "group_ind","dur_accr","entry_month")
# Note that the 1st 3 parameters for PrimaryTest are identified in the 
Report_results call
##### OUTPUT 
#### A data matrix consist of:
### results of Cox regression:
# event_OS_FA_sim, event_OS_IA_sim, event_OS_FA_pd,     event_OS_IA_pd:      # 
of events at Final and Interim, each for AC and PDL1+, both arms
# event_OS_FA_ctrl,event_OS_IA_ctrl,event_OS_FA_ctrl_pd,event_OS_IA_ctrl_pd: # 
of events at Final and Interim, each for AC and PDL1+, control arm
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# event_OS_FA_trt, event_OS_IA_trt, event_OS_FA_trt_pd, event_OS_IA_trt_pd:  # 
of events at Final and Interim, each for AC and PDL1+, experimental arm
# OS_IA_time, OS_IA_time_pd, OS_FA_time, OS_FA_time_pd:                      time 
of analysis at interim (AC and PDL1+) and at Final (AC and PDL1+), months
# hr_OS_IA, hr_OS_IA_pd, hr_OS_FA, hr_OS_FA_pd:                              simulated 
HR at interim (AC and PDL1+) and at Final (AC and PDL1+)
# 
pvalue_OS_IA, 
pvalue_OS_IA_pd, 
pvalue_OS_FA, 
pvalue_OS_FA_pd:             
simulated p-value at interim (AC and PDL1+) and at Final (AC and PDL1+)
# kmmedian_IA_ctl, kmmedian_IA_pd_ctl, kmmedian_FA_ctl, kmmedian_FA_pd_ctl:  
simulated Kaplan-Meier medians at interim (AC and PDL1+) and at Final (AC and 
PDL1+) - Control arm
# kmmedian_IA_trt, kmmedian_IA_pd_trt, kmmedian_FA_trt, kmmedian_FA_pd_trt:  
simulated Kaplan-Meier medians at interim (AC and PDL1+) and at Final (AC and 
PDL1+) - Experimental arm
### simulated results checking that simulation is correct:
# n_ctrl,n_trt,n_ctrl_pd,n_trt_pd:                     simulated # of randomized 
subjects for control/experimental, each for AC and PDL1+
# n_percohort1,n_percohort2,n_percohort3,n_percohort4: simulated # of total 
randomized subjects within each cohort
# simprop_trt:                                         simulated % of randomized 
patients in the experimental arm
# dur_accr:                                            duration of accrual (the 
same for every iteration - depends on accr_total and N_rand)
#####################################################################
PrimaryTest = function(OS_fraction_pd, event_OS_FA_pd, DataPool){
  
  ##### reading the data sets and generating variables needed for the analysis
  treat = DataPool[,"trt"]
  entry_month = DataPool[,"entry_month"]
  entry_day = DataPool[,"entry_day"]
  OS = DataPool[,"OS"]
  PDL1 = ifelse(DataPool[,"group_ind"]==1 | DataPool[,"group_ind"]==3,1,0)
  group_ind = DataPool[,"group_ind"]
  treat_pd = treat[PDL1==1]
  OS_pd = OS[PDL1==1]
  ##### reading the data sets and generating variables needed only for reporting
  dur_accr=median(DataPool[,"dur_accr"])     
  n_percohort1 = median(DataPool[,"n_percohort1"])  #(same for every value)
  n_percohort2 = median(DataPool[,"n_percohort2"])
  n_percohort3 = median(DataPool[,"n_percohort3"])
  n_percohort4 = median(DataPool[,"n_percohort4"])
  
  ##### calculate which day did the subject joint the study (entry_month and 
entry_day was randomly assigned to each subject in Run_Iterations)
  enter = (entry_month - 1) + entry_day
  
  ##### days up to event/censoring
  OS_day = enter + OS
  OS_day_pd = OS_day[PDL1==1]
  OS_day_sorted = sort(OS_day)
  OS_day_sorted_pd = sort(OS_day_pd)
  ####Determine PDL1+ analysis time 
  # FA
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  OS_FA_time_pd = OS_day_sorted_pd[event_OS_FA_pd] + 0.01
  # IA
  if(OS_fraction_pd==1){OS_IA_time_pd = OS_FA_time_pd}
  if(OS_fraction_pd 
<1){OS_IA_time_pd 
= 
OS_day_sorted_pd[ceiling(event_OS_FA_pd*OS_fraction_pd)] + 0.01}
  # AC analyses are at the time of PDL1+
  OS_IA_time=OS_IA_time_pd
  OS_FA_time=OS_FA_time_pd
  # time from randomization until time of analysis
  follow_OS_IA     = OS_IA_time - enter             # IA in AC
  follow_OS_IA_pd  = OS_IA_time_pd - enter[PDL1==1] # IA in PDL1+    
  follow_OS_FA     = OS_FA_time - enter             # FA in AC
  follow_OS_FA_pd  = OS_FA_time_pd - enter[PDL1==1] # FA in PDL1+
  # set up censoring: OS <= follow_up, event, then censor=1 o.w. censor = 0 
(censored)
  censor_OS_IA = ( OS <= follow_OS_IA ) + 0                  # IA in AC
  censor_OS_IA_pd = ( OS[PDL1==1] <= follow_OS_IA_pd ) + 0   # IA in PDL1+
  censor_OS_FA = ( OS <= follow_OS_FA ) + 0                  # FA in AC
  censor_OS_FA_pd = ( OS[PDL1==1] <= follow_OS_FA_pd ) + 0   # FA in PDL1+
  
  # set up vectors for censored survival time
  OS_IA <- OS_FA <- OS                # IA and FA in AC
  OS_IA_pd <- OS_FA_pd <- OS[PDL1==1] # IA and FA in PDL1+
  # truncate time-to-event until analysis time
  OS_IA[which(OS_IA>follow_OS_IA)] = follow_OS_IA[which(OS_IA>follow_OS_IA)]
  OS_IA_pd[which(OS_IA_pd>follow_OS_IA_pd)] 
= 
follow_OS_IA_pd[which(OS_IA_pd>follow_OS_IA_pd)]
  OS_FA[which(OS_FA>follow_OS_FA)] = follow_OS_FA[which(OS_FA>follow_OS_FA)]
  OS_FA_pd[which(OS_FA_pd>follow_OS_FA_pd)] 
= 
follow_OS_FA_pd[which(OS_FA_pd>follow_OS_FA_pd)]
  ## generating KM medians
  # control arm
  kmmedian_IA_ctl 
<-
quantile(survfit(Surv(OS_IA,censor_OS_IA) 
~ 
treat))[[1]][3]
  kmmedian_IA_pd_ctl 
<-
quantile(survfit(Surv(OS_IA_pd,censor_OS_IA_pd) 
~ 
treat_pd))[[1]][3]
  kmmedian_FA_ctl 
<-
quantile(survfit(Surv(OS_FA,censor_OS_FA) 
~ 
treat))[[1]][3] 
  kmmedian_FA_pd_ctl 
<-
quantile(survfit(Surv(OS_FA_pd,censor_OS_FA_pd) 
~ 
treat_pd))[[1]][3] 
  # experimental arm
  kmmedian_IA_trt 
<-
quantile(survfit(Surv(OS_IA,censor_OS_IA) 
~ 
treat))[[1]][4]
  kmmedian_IA_pd_trt 
<-
quantile(survfit(Surv(OS_IA_pd,censor_OS_IA_pd) 
~ 
treat_pd))[[1]][4]
  kmmedian_FA_trt 
<-
quantile(survfit(Surv(OS_FA,censor_OS_FA) 
~ 
treat))[[1]][4] 
  kmmedian_FA_pd_trt 
<-
quantile(survfit(Surv(OS_FA_pd,censor_OS_FA_pd) 
~ 
treat_pd))[[1]][4] 
  ###### Cox models with log rank test
  # IA, AC
  survtest_OS_IA <- coxph(Surv(OS_IA,censor_OS_IA) ~ treat)  
  event_OS_IA_sim = summary(survtest_OS_IA)$nevent
  hr_OS_IA = summary(survtest_OS_IA)$conf.int[1]
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  pvalue_OS_IA =  summary(survtest_OS_IA)$waldtest[3]
  # IA, PDL1+
  survtest_OS_IA_pd <- coxph(Surv(OS_IA_pd,censor_OS_IA_pd) ~ treat_pd) 
  event_OS_IA_pd = summary(survtest_OS_IA_pd)$nevent
  hr_OS_IA_pd = summary(survtest_OS_IA_pd)$conf.int[1]
  pvalue_OS_IA_pd =  summary(survtest_OS_IA_pd)$waldtest[3]
  # FA, AC
  survtest_OS_FA <- coxph(Surv(OS_FA,censor_OS_FA) ~ treat) 
  event_OS_FA_sim  = summary(survtest_OS_FA)$nevent
  hr_OS_FA  = summary(survtest_OS_FA)$conf.int[1]
  pvalue_OS_FA  =  summary(survtest_OS_FA)$waldtest[3]
  # FA, PDL1+
  survtest_OS_FA_pd <- coxph(Surv(OS_FA_pd,censor_OS_FA_pd) ~ treat_pd) 
  event_OS_FA_sim_pd  = summary(survtest_OS_FA_pd)$nevent
  hr_OS_FA_pd  = summary(survtest_OS_FA_pd)$conf.int[1]
  pvalue_OS_FA_pd  =  summary(survtest_OS_FA_pd)$waldtest[3]
  # number of events by arm (for reporting)
  event_OS_FA_ctrl <- length(censor_OS_FA[censor_OS_FA==1 & treat==0])
  event_OS_FA_trt <- length(censor_OS_FA[censor_OS_FA==1 & treat==1])
  event_OS_IA_ctrl <- length(censor_OS_IA[censor_OS_IA==1 & treat==0])
  event_OS_IA_trt <- length(censor_OS_IA[censor_OS_IA==1 & treat==1])
  event_OS_FA_ctrl_pd 
<-
length(censor_OS_FA_pd[censor_OS_FA_pd==1 
& 
treat_pd==0])
  event_OS_FA_trt_pd 
<-
length(censor_OS_FA_pd[censor_OS_FA_pd==1 
& 
treat_pd==1])
  event_OS_IA_ctrl_pd 
<-
length(censor_OS_IA_pd[censor_OS_IA_pd==1 
& 
treat_pd==0])
  event_OS_IA_trt_pd 
<-
length(censor_OS_IA_pd[censor_OS_IA_pd==1 
& 
treat_pd==1])
  # simulated # of randomized patients (to check simulations)
  n_ctrl <- length(censor_OS_FA[treat==0])           # AC, control arm
  n_trt <- length(censor_OS_FA[treat==1])            # AC, experimental arm 
  n_ctrl_pd <- length(censor_OS_FA_pd[treat_pd==0])  # PDL1+, control arm
  n_trt_pd <- length(censor_OS_FA_pd[treat_pd==1])   # PDL1+, experimental arm
  # simulated % of cured patients (to check simulations)
  simprop_trt <- n_trt/(n_ctrl+n_trt)
  # generate output vector from PrimaryTest, for the ith iteration 
  re=c(event_OS_IA_sim, OS_IA_time, event_OS_IA_pd ,OS_IA_time_pd, OS_FA_time, 
OS_FA_time_pd, 
event_OS_FA_sim,event_OS_FA_pd, 
hr_OS_IA, 
pvalue_OS_IA, 
hr_OS_IA_pd, 
pvalue_OS_IA_pd, 
hr_OS_FA, 
pvalue_OS_FA, 
pvalue_OS_FA_pd,hr_OS_FA_pd, 
       
event_OS_FA_ctrl,event_OS_FA_trt,event_OS_IA_ctrl,event_OS_IA_trt,event_OS_FA
_ctrl_pd,event_OS_FA_trt_pd,event_OS_IA_ctrl_pd,event_OS_IA_trt_pd,
       n_ctrl,n_trt,n_ctrl_pd,n_trt_pd,simprop_trt, dur_accr,
       n_percohort1,n_percohort2,n_percohort3,n_percohort4,
       kmmedian_IA_ctl, 
kmmedian_IA_pd_ctl, 
kmmedian_FA_ctl, 
kmmedian_FA_pd_ctl, 
kmmedian_IA_trt, 
kmmedian_IA_pd_trt, 
kmmedian_FA_trt, 
kmmedian_FA_pd_trt) 
  names(re) = c("event_OS_IA", "OS_IA_time", "event_OS_IA_pd","OS_IA_time_pd", 
"OS_FA_time", 
"OS_FA_time_pd", 
"event_OS_FA_sim","event_OS_FA_pd",  
"hr_OS_IA", "pvalue_OS_IA", "hr_OS_IA_pd", "pvalue_OS_IA_pd", "hr_OS_FA", 
"pvalue_OS_FA", "pvalue_OS_FA_pd", "hr_OS_FA_pd", 
                
"event_OS_FA_ctrl","event_OS_FA_trt","event_OS_IA_ctrl","event_OS_IA_trt","ev
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ent_OS_FA_ctrl_pd","event_OS_FA_trt_pd","event_OS_IA_ctrl_pd","event_OS_IA_tr
t_pd",
                "n_ctrl","n_trt","n_ctrl_pd","n_trt_pd","simprop_trt", 
"dur_accr",
                "n_percohort1","n_percohort2","n_percohort3","n_percohort4",
                "kmmedian_IA_ctl", 
"kmmedian_IA_pd_ctl", 
"kmmedian_FA_ctl", 
"kmmedian_FA_pd_ctl", 
"kmmedian_IA_trt", 
"kmmedian_IA_pd_trt", 
"kmmedian_FA_trt", "kmmedian_FA_pd_trt")
  return(re)
}
#####################################################################
####### Run_Iterations: for each iteration, creates time to event datasets and 
result datasets from Cox PH analyses 
##### INPUT Parameters
# Note that all parameters are identified in the Report_results call
## N_sim:           Number of datasets (iterations) to be simulated
## event3:          Final number of events in the primary subpopulation (defines 
end of study)
## random_seed:     seed used for random generation
## OS_fraction_pd:  Information fraction for IA in the primary subpopulation 
(If 1 then no IA)
## acc_num:         accrual pattern
## N_rand:          # of randomized subjects (will be less than sum(acc_num))
##### OUTPUT 
#### A data matrix generating all output variables from PrimaryTest, but one 
row for each iteration
#####################################################################
Run_Iterations = function(N_sim, event3, random_seed, OS_fraction_pd, acc_num, 
N_rand){
  
  set.seed(random_seed)
  result = NULL
  result_list = list(result)
  # read in parameter values for Datacohort
  group1 
= 
 
list(prop_group1, 
ctl_mos_1, 
trt_mos_1,trt_cure_os_1,delay_OS_1,nprop_trt_1)
  group2 
= 
 
list(prop_group2, 
ctl_mos_2, 
trt_mos_2,trt_cure_os_2,delay_OS_2,nprop_trt_2)
  group3 
= 
 
list(prop_group3, 
ctl_mos_3, 
trt_mos_3,trt_cure_os_3,delay_OS_3,nprop_trt_3)
  group4 
= 
 
list(prop_group4, 
ctl_mos_4, 
trt_mos_4,trt_cure_os_4,delay_OS_4,nprop_trt_4)
  
  # create empty month vector for accrual period (length = # of randomized 
patients)
  entry_month <- matrix(0,N_rand,1)
  n = length(acc_num)                  # # of months in accrual period
  # fill entry_month with values: 
  # each month value (1, ..., n) will be included as many times as many patients 
are randomized during that period
  for (month in 1:n){         
    Mn = acc_num[month]  
  # # of patients randomized in this month
    # generate Mn_cum (= cumulative accrual until beginning of given month)
    if(month==1){Mn_cum=0}
    if(month>1){Mn_cum = sum(acc_num[1:(month-1)])}   
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    # Case#1: all subjects are to be recruited within the given month
    if(Mn_cum+Mn < N_rand){
    if(Mn > 0){entry_month[(Mn_cum+1):min((Mn_cum+Mn),N_rand),1] = month}
    }
    # Case#2 (last month of the accrual): not necessarily all subjects from 
acc_num are needed anymore
    if(Mn_cum+Mn >= N_rand & Mn_cum < N_rand){
    if(Mn > 0){entry_month[(Mn_cum+1):min((Mn_cum+Mn),N_rand),1] = month
               dur_accr = month}
    }
  }
  
  #################################################
  ### SIMULATIONS BEGIN ###########################
  #################################################
  for (NN in 1:N_sim){
    # empty vectors
    entry_day <- dummy_order <- group_ind <- matrix(0,N_rand,1)
    # determine # of subjects per cohort: random sample from multinomial 
distribution
    n_percohort 
<-
rmultinom(n=1, 
size 
= 
N_rand, 
prob 
= 
c(group1[[1]],group2[[1]],group3[[1]],group4[[1]]))
    # retrieve cohort sizes for reporting purposes
    n_percohort1 <- n_percohort[[1]]
    n_percohort2 <- n_percohort[[2]]
    n_percohort3 <- n_percohort[[3]]
    n_percohort4 <- n_percohort[[4]]
    # create variable that indicates cohort assignment for each patient
    group_ind[1:n_percohort[[1]],1] = 1
    
if(n_percohort[[2]]>0){group_ind[(n_percohort[[1]]+1):(n_percohort[[1]]+n_per
cohort[[2]]),1] = 2}
    
if(n_percohort[[3]]>0){group_ind[(n_percohort[[1]]+n_percohort[[2]]+1):(n_per
cohort[[1]]+n_percohort[[2]]+n_percohort[[3]]),1] = 3}
    
if(n_percohort[[4]]>0){group_ind[(n_percohort[[1]]+n_percohort[[2]]+n_percoho
rt[[3]]+1):(n_percohort[[1]]+n_percohort[[2]]+n_percohort[[3]]+n_percohort[[4
]]),1] = 4}
    
    # run DataCohort for each cohort 
      Data_group1 
= 
DataCohort(n_percohort[[1]],group1[[2]],group1[[3]],group1[[4]],group1[[5]],g
roup1[[6]])  
      Data_group2 
= 
DataCohort(n_percohort[[2]],group2[[2]],group2[[3]],group2[[4]],group2[[5]],g
roup2[[6]])
      Data_group3 
= 
DataCohort(n_percohort[[3]],group3[[2]],group3[[3]],group3[[4]],group3[[5]],g
roup3[[6]])
      Data_group4 
= 
DataCohort(n_percohort[[4]],group4[[2]],group4[[3]],group4[[4]],group4[[5]],g
roup4[[6]])
    # pool data
      Data = rbind(Data_group1, Data_group2, Data_group3, Data_group4)
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    # ADD RANDOMIZATION DATE (entry_month, entry_day)
    for (k in 1:N_rand){
      entry_day[k,1] = round(runif(1))  # entry day is random within a month
      dummy_order[k,1] = runif(1)               # this will be used to assign 
each patient to a random randomization month
    }
    Data 
<-
cbind(Data,entry_day,dummy_order,n_percohort1,n_percohort2,n_percohort3,n_per
cohort4, group_ind, dur_accr)
    Data <- Data[order(dummy_order),]
    Data <-
cbind(Data,entry_month)    #added entry_month to the randomly 
ordered dataset
    colnames(Data)=c("trt", 
"OS", 
"entry_day","dummy_order","n_percohort1","n_percohort2","n_percohort3","n_per
cohort4", "group_ind","dur_accr","entry_month")
    
    # run Cox regression on the pooled cohorts
    test=PrimaryTest(event_OS_FA_pd=event3, 
OS_fraction_pd=OS_fraction_pd, 
DataPool=Data)
      
    result_list[[1]] = rbind(result_list[[1]], test)
    if(NN %% 250 == 0) {
      print("Generation of samples is ongoing, latest iteration number:", quote 
= FALSE)
      print(NN)
      }
    
  }
  #################################################
  ### SIMULATIONS END #############################
  #################################################
  
  return(result_list)
}
#####################################################################
####### Report_results: determines significance/power; summarizes and outputs 
all results 
##### INPUT Parameters
# same input parameters as for Run_Iterations; in addition:
## alpha_OS:        Significance level for the analysis based on all randomized 
(secondary), overall across timepoints
## alpha_OS_pd:     Significance level for the analysis based on PDL1+ (primary), 
overall across timepoints
##### OUTPUT 
#### A list including the following elements:
### Elements to display simulation parameters (input):
## sim.par:               Simulation Parameters in function Report_results
## sim.par2:              Simulation Parameters by Cohort
### Elements to check that simulation produces result as expected (summary 
statistics of generated parameters across iterations):
## result_nrand:          Checking Simulation: # of Randomized Subjects
## result_nrandcoh:       Checking Simulation: % Randomized by Cohort
### Elements displaying simulation results, presented in the protocol (summary 
statistics of generated parameters across iterations):
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## powerOS_DFS:           SIMULATED POWER (Reported in Protocol Table 8.1-
1,8.1-2)
## result_hr:             Simulated HR (Protocol Table 8.1-1,8.1-2: 'Hypothesized 
Overall HR')
## max_hr_result:         Maximum Significant HR (Protocol Table 8.1-1,8.1-2: 
'Critical HR')
## min_obs_median_result: Minimum Significant Difference in Medians, months 
(Protocol Table 8.1-1,8.1-2: 'Minimal Difference in Median')
## result_alpha:          Alpha Levels Used in the Simulated Datasets  (Protocol 
Table 8.1-1,8.1-2: 'Significance Level' for IA and FA)
## result_event:          # of Simulated Events (Protocol Table 8.1-1,8.1-2: 
'Projected # of Events')
## result_kmmedian:       Simulated KM Medians, months (Protocol Table 8.1-
1,8.1-2: 'Hypothesized Median...')
## result_dur:            Enrolment Period and Projected Time of Analyses, 
months  (Protocol Table 8.1-1: 'Projected Time of LPLV (from FPFV)')
#####################################################################
Report_results = function(N_sim, seed, alpha_OS, alpha_OS_pd, event_OS_FA_pd, 
OS_fraction_pd, accr_pattern, N_rand){
  
  all_result 
= 
Run_Iterations(N_sim=N_sim, 
event3=event_OS_FA_pd, 
random_seed=seed, 
OS_fraction_pd=OS_fraction_pd, 
acc_num=accr_pattern, 
N_rand=N_rand)
  #SIGNIFICANCE  
  alpha_OS_IA 
<-
alpha_OS_FA 
<-
alpha_OS_IA_pd 
<-
alpha_OS_FA_pd 
<-
rep(0,N_sim)
if(OS_fraction_pd<1){
  bds_nivo_pd<-bounds(t=c(OS_fraction_pd,1), 
iuse=c(1,1), 
alpha=c(alpha_OS_pd/2,alpha_OS_pd/2))
  alpha_OS_IA_pd <- (1-pnorm(bds_nivo_pd[[8]][1]))*2
  alpha_OS_FA_pd <- (1-pnorm(bds_nivo_pd[[8]][2]))*2
}
if(OS_fraction_pd==1){
  alpha_OS_IA_pd <- alpha_OS_pd
  alpha_OS_FA_pd <- alpha_OS_pd
}
OS_fraction2=(all_result[[1]][,"event_OS_IA"]/all_result[[1]][,"event_OS_FA_s
im"])
for(m in 1:N_sim){
  if(OS_fraction2[m]<1){
    bds_nivo<-bounds(t=c(OS_fraction2[m],1), 
iuse=c(1,1), 
alpha=c(alpha_OS/2,alpha_OS/2))
    alpha_OS_IA[m] <- (1-pnorm(bds_nivo[[8]][1]))*2
    alpha_OS_FA[m] <- (1-pnorm(bds_nivo[[8]][2]))*2
  }
  if(OS_fraction2[m]>=1){
    alpha_OS_IA[m] <- alpha_OS
    alpha_OS_FA[m] <- alpha_OS
  }
}
  test_OS_IA = all_result[[1]][,"pvalue_OS_IA"] < alpha_OS_IA
  test_OS_IA_pd = all_result[[1]][,"pvalue_OS_IA_pd"] < alpha_OS_IA_pd
  test_OS_FA = all_result[[1]][,"pvalue_OS_FA"] < alpha_OS_FA
  test_OS_FA_pd = all_result[[1]][,"pvalue_OS_FA_pd"] < alpha_OS_FA_pd
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  #### calculate the power
  power_OS_IA = sum(test_OS_IA) / length(test_OS_IA)
  power_OS_IA_pd = sum(test_OS_IA_pd) / length(test_OS_IA_pd)
  power_OS_FA = sum(test_OS_FA) / length(test_OS_FA)
  power_OS_FA_pd = sum(test_OS_FA_pd) / length(test_OS_FA_pd)
  #### events 
  event_OS_IA_sim= summary(all_result[[1]][,"event_OS_IA"])
  event_OS_IA_pd= summary(all_result[[1]][,"event_OS_IA_pd"])
  event_OS_FA_pd_sim= summary(all_result[[1]][,"event_OS_FA_pd"])
  event_OS_FA_sim= summary(all_result[[1]][,"event_OS_FA_sim"])
  ####events by arm
  event_OS_IA_ctrl= summary(all_result[[1]][,"event_OS_IA_ctrl"])
  event_OS_FA_ctrl= summary(all_result[[1]][,"event_OS_FA_ctrl"])
  event_OS_IA_trt= summary(all_result[[1]][,"event_OS_IA_trt"])
  event_OS_FA_trt= summary(all_result[[1]][,"event_OS_FA_trt"])
  event_OS_IA_ctrl_pd= summary(all_result[[1]][,"event_OS_IA_ctrl_pd"])
  event_OS_FA_ctrl_pd= summary(all_result[[1]][,"event_OS_FA_ctrl_pd"])
  event_OS_IA_trt_pd= summary(all_result[[1]][,"event_OS_IA_trt_pd"])
  event_OS_FA_trt_pd= summary(all_result[[1]][,"event_OS_FA_trt_pd"])
  #### N by arm
  n_ctrl= summary(all_result[[1]][,"n_ctrl"])
  n_trt= summary(all_result[[1]][,"n_trt"])
  n_ctrl_pd= summary(all_result[[1]][,"n_ctrl_pd"])
  n_trt_pd= summary(all_result[[1]][,"n_trt_pd"])
  simprop_trt= summary(all_result[[1]][,"simprop_trt"])
  # to check sample size per cohort
  p_pergroup1 <- summary((all_result[[1]][,"n_percohort1"])/N_rand)
  p_pergroup2 <- summary((all_result[[1]][,"n_percohort2"])/N_rand)
  p_pergroup3 <- summary((all_result[[1]][,"n_percohort3"])/N_rand)
  p_pergroup4 <- summary((all_result[[1]][,"n_percohort4"])/N_rand)
  
  # medians
  kmmedian_IA_ctl = my.summary(all_result[[1]][,"kmmedian_IA_ctl"])
  kmmedian_IA_pd_ctl = my.summary(all_result[[1]][,"kmmedian_IA_pd_ctl"])
  kmmedian_FA_ctl = my.summary(all_result[[1]][,"kmmedian_FA_ctl"])
  kmmedian_FA_pd_ctl = my.summary(all_result[[1]][,"kmmedian_FA_pd_ctl"])
  kmmedian_IA_trt = my.summary(all_result[[1]][,"kmmedian_IA_trt"])
  kmmedian_IA_pd_trt = my.summary(all_result[[1]][,"kmmedian_IA_pd_trt"])
  kmmedian_FA_trt = my.summary(all_result[[1]][,"kmmedian_FA_trt"])
  kmmedian_FA_pd_trt = my.summary(all_result[[1]][,"kmmedian_FA_pd_trt"])
  #### enrolment duration  and time of analyses
  dur_accr = my.summary(all_result[[1]][,"dur_accr"])
  month_OS_IA = my.summary(all_result[[1]][,"OS_IA_time"])
  month_OS_IA_pd = my.summary(all_result[[1]][,"OS_IA_time_pd"])
  month_OS_FA = my.summary(all_result[[1]][,"OS_FA_time"])
  month_OS_FA_pd = my.summary(all_result[[1]][,"OS_FA_time_pd"])
  ####  output HR at each test
  hr_OS_IA = all_result[[1]][,"hr_OS_IA"]
  hr_OS_IA_pd = all_result[[1]][,"hr_OS_IA_pd"]
  hr_OS_FA = all_result[[1]][,"hr_OS_FA"]
  hr_OS_FA_pd = all_result[[1]][,"hr_OS_FA_pd"]
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  #### find the largest HR s.t. cox gives significant result
  max_hr_OS_IA = max(hr_OS_IA[test_OS_IA])
  max_hr_OS_IA_pd = max(hr_OS_IA_pd[test_OS_IA_pd])
  max_hr_OS_FA = max(hr_OS_FA[test_OS_FA])
  max_hr_OS_FA_pd = max(hr_OS_FA_pd[test_OS_FA_pd])
  min_obs_mOS_IA 
=  
median(all_result[[1]][,"kmmedian_IA_ctl"])*(1/max_hr_OS_IA - 1)
  min_obs_mOS_IA_pd 
= 
median(all_result[[1]][,"kmmedian_IA_pd_ctl"])*(1/max_hr_OS_IA_pd - 1)
  min_obs_mOS_FA 
=  
median(all_result[[1]][,"kmmedian_FA_ctl"])*(1/max_hr_OS_FA - 1)
  min_obs_mOS_FA_pd 
=  
median(all_result[[1]][,"kmmedian_FA_pd_ctl"])*(1/max_hr_OS_FA_pd - 1)
  max_hr_result 
= 
c(max_hr_OS_IA, 
max_hr_OS_FA,max_hr_OS_IA_pd, 
max_hr_OS_FA_pd)
  names(max_hr_result) = c("Interim, AC", "Final, AC", "Interim, PDL1+", 
"Final, PDL1+")
  
  min_obs_median_result = c(min_obs_mOS_IA, min_obs_mOS_FA, min_obs_mOS_IA_pd, 
min_obs_mOS_FA_pd)
  names(min_obs_median_result) = c("Interim, AC", "Final, AC", "Interim, 
PDL1+", "Final, PDL1+")
  
  sim.par 
= 
c(N_sim, 
seed, 
 
alpha_OS, 
alpha_OS_pd,event_OS_FA_pd, 
OS_fraction_pd, N_rand)
  names(sim.par) 
= 
c("N_sim", 
"seed", 
"alpha_OS", 
"alpha_OS_pd","event_OS_FA_pd", "OS_fraction_pd", "Total_Rand")
  
  sim.par2 
= 
matrix(c(prop_group1,prop_group2,prop_group3,prop_group4,nprop_trt_1,nprop_tr
t_2, nprop_trt_3, nprop_trt_4,
                      ctl_mos_1, ctl_mos_2,ctl_mos_3,ctl_mos_4,
                      trt_mos_1,trt_mos_2,trt_mos_3,trt_mos_4,
                      delay_OS_1, delay_OS_2,delay_OS_3, delay_OS_4,
                      trt_cure_os_1,trt_cure_os_2,trt_cure_os_3, trt_cure_os_4
  ),ncol=4, byrow=TRUE)
  colnames(sim.par2)=c(label1, label2, label3, label4)
  rownames(sim.par2)=c("% Total Rand by Cohort","% Rand to Experimental Arm", 
"Median in Control, months","Median in Experimental, months", "Delay, 
months","% Cure in Experimental")
  result_nrand = rbind(n_ctrl, n_trt, n_ctrl_pd, n_trt_pd, simprop_trt)
  rownames(result_nrand) = c("# in Control","# in Experimental","# in Control, 
PDL1+","# in Experimental, PDL1+","%Rand to Experimental Arm")
  result_nrandcoh = rbind(p_pergroup1,p_pergroup2,p_pergroup3,p_pergroup4)
  rownames(result_nrandcoh) 
= 
c("%Rand 
Cohort1","%Rand 
Cohort2","%Rand 
Cohort3","%Rand Cohort4")
  
  result_event = rbind(event_OS_FA_sim, event_OS_FA_ctrl, event_OS_FA_trt, 
event_OS_IA_sim, 
event_OS_IA_ctrl, 
event_OS_IA_trt, 
event_OS_FA_pd_sim, 
event_OS_FA_ctrl_pd, event_OS_FA_trt_pd, event_OS_IA_pd, event_OS_IA_ctrl_pd, 
event_OS_IA_trt_pd)
  rownames(result_event) = c("Final, AC, both arms","Final, AC, Control", 
"Final, 
AC, 
Experimental","Interim, 
Ac, 
both 
arms","Interim, 
AC, 
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Control","Interim, Ac, Experimental", "Final, PDL1+, both arms", "Final, PDL1+, 
Control", "Final, PDL1+, Experimental", "Interim, PDL1+, both arms", "Interim, 
PDL1+, Control", "Interim, PDL1+, Experimental")
result_dur = rbind(dur_accr,  month_OS_IA,  month_OS_FA, month_OS_IA_pd, 
month_OS_FA_pd)
rownames(result_dur) = c("Accrual Period", "Analysis IA, AC", "Analysis FA, 
AC", "Analysis IA, PDL1+", "Analysis FA, PDL1+")
result_hr 
= 
rbind(  
summary(hr_OS_IA),summary(hr_OS_FA),summary(hr_OS_IA_pd),summary(hr_OS_FA_pd)
)
rownames(result_hr) 
= 
c("Interim 
All 
Randomized","Final 
All 
Randomized","Interim PDL1+","Final PDL1+")
result_kmmedian = rbind(kmmedian_IA_ctl, kmmedian_IA_pd_ctl, kmmedian_FA_ctl, 
kmmedian_FA_pd_ctl, 
kmmedian_IA_trt, 
kmmedian_IA_pd_trt, 
kmmedian_FA_trt, 
kmmedian_FA_pd_trt) 
rownames(result_kmmedian) = rbind("Control All Randomized, IA", "Control PDL1+, 
IA", "Control All Randomized, FA", "Control PDL1+, FA", "Experimental All Rand, 
IA", "Experimental PDL1+, IA", "Experimental All Rand, FA", "Experimental PDL1+, 
FA") 
  result_alpha 
= 
rbind(summary(alpha_OS_IA), 
summary(alpha_OS_FA), 
summary(alpha_OS_IA_pd), summary(alpha_OS_FA_pd))
  rownames(result_alpha) = c("alpha IA - AC", "alpha FA - AC", "alpha IA-PDL1+", 
"alpha FA-PDL1+")
  powerOS_DFS 
<-
matrix(c(power_OS_IA_pd, 
power_OS_FA_pd, 
power_OS_IA, 
power_OS_FA),
                        byrow=TRUE, ncol=2, nrow=2)
  rownames(powerOS_DFS) <- c("PDL1+","AC")
  colnames(powerOS_DFS) <- c("Interim", "Final")
rownames(all_result)=NULL
  result_list 
= 
list(sim.par, 
sim.par2, 
result_nrand, 
result_nrandcoh, 
powerOS_DFS, result_hr, max_hr_result, min_obs_median_result, result_alpha, 
result_event, result_kmmedian, result_dur)
  names(result_list) 
= 
c("Simulation 
Parameters 
in 
function 
Report_results","Simulation Parameters by Cohort", "Checking Simulation: # of 
Randomized Subjects", "Checking Simulation: % Randomized by Cohort","SIMULATED 
POWER (Reported in Protocol Table 8.1-1,8.1-2)", "Simulated HR (Protocol Table 
8.1-1,8.1-2: 'Hypothesized Overall HR')","Maximum Significant HR (Protocol 
Table 8.1-1,8.1-2: 'Critical HR')", "Minimum Significant Difference in Medians, 
months (Protocol Table 8.1-1,8.1-2: 'Minimal Difference in Median')", "Alpha 
Levels Used in the Simulated Datasets  (Protocol Table 8.1-1,8.1-2: 
'Significance Level' for IA and FA)", "# of Simulated Events (Protocol Table 
8.1-1,8.1-2: 'Projected # of Events')", "Simulated KM Medians, months (Protocol 
Table 8.1-1,8.1-2: 'Hypothesized Median...')", "Enrolment Period and Projected 
Time of Analyses, months  (Protocol Table 8.1-1: 'Projected Time of LPLV (from 
FPFV)')")
  return(result_list)
}
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#############################################################################
#######
######### II. Set up calls for different endpoints
#############################################################################
#######
#############################################################################
#######
#############################ACCRUAL RATE
#note that sum(accr_total) > N_rand; accr_total is to be truncated as needed 
(see Run_Iterations)
#TOTAL accrual rate for the 3 arms:
accr_total = c(3,  3,  6,
6,
9,
9,
12, 
12, 
18, 
27, 
36, 
rep(45,100))
#accrual rate for 2 arms:
accr_total2 = round(accr_total/3*2)
#program assumes that we stratify within these groups
label1="Western PDL1+"
label2="Western PDL1-"
label3="Asia PDL1+"
label4="Asia PDL1-"
prop_group1=0.2*0.5
prop_group2=0.2*0.5
prop_group3=0.8*0.5
prop_group4=0.8*0.5
#randomization ratio
nprop_trt_1=nprop_trt_2=nprop_trt_3=nprop_trt_4=0.5
#############################################################################
#######
#################OS#######################################
# OS median for control
ctl_mos_1=6    #West PDL1+
ctl_mos_2=6       #West PDL1-
ctl_mos_3=10    #Asia PDL1+
ctl_mos_4=10       #Asia PDL1-
# OS median for experimental, after delay (without cure)
trt_mos_1=ctl_mos_1/0.65    #West PDL1+
trt_mos_2=ctl_mos_2/0.85
trt_mos_3=ctl_mos_3/0.65    #Asia PDL1+
trt_mos_4=ctl_mos_4/0.85
# OS delay
delay_OS_1=delay_OS_3=3   #PDL1+
delay_OS_2=delay_OS_4=4   #PDL1-
# OS cure in experimental arm
trt_cure_os_1=trt_cure_os_3=0.15   #PDL1+
trt_cure_os_2=trt_cure_os_4=0.1   #PDL1-
####################
OS_RESULTS <- Report_results(N_sim=10000, seed=13484, 
                              accr_pattern=accr_total2,N_rand=626,
                              alpha_OS=0.01,
                              event_OS_FA_pd=250,OS_fraction_pd=0.7, 
alpha_OS_pd=0.01)  
OS_RESULTS
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#############################################################################
#######
#################PFS######################################
# PFS median for control
ctl_mos_1=4    #West PDL1+
ctl_mos_2=4       #West PDL1-
ctl_mos_3=4    #Asia PDL1+
ctl_mos_4=4       #Asia PDL1-
# PFS median for experimental, after delay
trt_mos_1=ctl_mos_1/0.55    #West PDL1+
trt_mos_2=ctl_mos_2/0.75
trt_mos_3=ctl_mos_3/0.55    #Asia PDL1+
trt_mos_4=ctl_mos_4/0.75
# PFS delay
delay_OS_1=delay_OS_3=1   #PDL1+
delay_OS_2=delay_OS_4=2   #PDL1-
# PFS cure in experimental arm
trt_cure_os_1=trt_cure_os_3=0   #PDL1+
trt_cure_os_2=trt_cure_os_4=0   #PDL1-
####################
PFS_RESULTS <- Report_results(N_sim=10000, seed=13484, 
                              accr_pattern=accr_total2,N_rand=626,
                              alpha_OS=0.015,
                              event_OS_FA_pd=250,OS_fraction_pd=1, 
alpha_OS_pd=0.015)    
PFS_RESULTS
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APPENDIX 7
CHANGE OF THE TRIGGER FOR PFS FA/OS IA
Per the original protocol, the planned interim analysis (PFS final analysis and OS interim analysis) 
was to be triggered when 136 PFS events per blinded independent central review committee 
(BICR) are observed among the PD-L1 expressing subjects in the chemotherapy arm (Arm C).  
The primary PFS endpoint is based on the primary PFS definition (i.e. PFS events truncated at 
subsequent therapy as defined in Section 8.3.1). PFS event tracking is conducted by an independent 
external statistical group (Axio, Inc) which supports statistical analyses and generates reports for 
review by an independent Data Monitoring Committee. Event tracking commenced in July 2020 
and per tracking plan, BMS has been receiving information on the number of PFS events per 
primary and secondary (PFS events not truncated by subsequent therapy, sensitivity analysis in 
Section 7.5.2.2) definitions. BMS remains blinded to the number of PFS events in the experimental 
arms. 
Based on the latest event tracking report (report is stored in eTMF Section 01.03.03 Committee 
report) utilizing the September 16 2020 BICR data transfer (data is stored in unix folder 
“/gbs/prod/clin/data/ca/209/648/stable/blinded/level2”), a total of 102 PFS events per BICR were 
observed by primary definition among the PD-L1 expressing subjects in Arm C.  The PFS events 
per secondary definition was 135 among the PD-L1 expressing subjects in Arm C and upon further 
investigation, it could be determined that the target of 136 PFS events per BICR for triggering the 
interim analysis (IA) per protocol is unlikely to  be reached for the reasons specified below, 
acknowledging that data review is ongoing.
•
Under the 1:1:1 randomization ratio and based on the assumption of 50% (from Protocol
Section 3.1) and 48.3% ( % of patients in the control arm in Table 11.2-1 in the ONO-4538-
24 (CA209473) Primary Clinical Study Report (CSR)19) for prevalence of Tumor PD-L1 
expression ≥1% in advanced ESCC, it is estimated that approximately 158 PD-L1 
expressing subjects would be randomized to the chemotherapy arm.
•
Assuming 158 PD-L1 expressing subjects randomized to the chemotherapy arm and 
considering the number of 102 PFS events observed so far, there would be an additional 158-
102=56 subjects for whom a PFS event may still be expected per primary definition. However, 
per secondary definition which accounts for disease progression after subsequent therapy, a 
total of 135 PFS events per BICR were observed. Therefore, it is evident that for 135-102=33
subjects, PFS events per primary definition should not be expected.
•
Event tracking in all randomized subjects across the three treatment arms indicated there are a 
total of 94 subjects are censored per primary definition due to withdrawal of consent, lost to 
follow-up, no scans or without PD/death after subsequent therapies. Assuming equal subject 
distribution across treatment arms and PD-L1 expression subgroups, it is estimated that 15 of 
these subjects would represent PD-L1 expressing subjects in the chemotherapy arm, thus 
reducing the potential pool of subjects for whom a PFS event could be expected even further.
•
Therefore, among the 56 subjects without observed PFS events (per primary definition), only 
56-33-15=8 subjects may contribute a PFS event per primary definition, whereas an additional 
34 PFS events are needed to trigger the IA.
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Based on the reasons stated above, the IA will be performed when 136 PFS events are observed 
or when a 12-month minimum follow-up (defined as the time from the date the last patient was 
randomized to the clinical cutoff date) is reached if the target number of events is unlikely to be 
reached among the PD-L1 expressing subjects in the chemotherapy arm. The table below provides 
the power based on different numbers of PFS events among PD-L1+ subjects in chemo arm using 
the same protocol assumption.
PFS events among PD-
L1+ in chemo
Total number of PFS events for one 
comparison (i.e. for N+I vs CT; and 
for N+C vs CT)
Power
136
250
90%
121
218
85%
110
195
80%
100
175
75%
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