A Phase 1b, Open-label, Multicenter, Multidose, Dose-escalation Study of BMS-936558 (MDX-1106) in Combination With Ipilimumab in Subjects With Unresectable Stage III or Stage IV Malignant Melanoma
Phase: PHASE1
Conditions: Malignant Melanoma
Sponsor: Bristol-Myers Squibb



Clinical Protocol
CA2099LA
BMS-936558
nivolumab
Date: 10-May-2017
2
to partners to which BMS has transferred obligations, eg, a Contract Research Organization 
(CRO).
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BMS-936558
nivolumab
Date: 10-May-2017
3
DOCUMENT HISTORY
Document
Date of Issue
Summary of Change
Original Protocol
10-May-2017
Not applicable
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BMS-936558
nivolumab
1
SYNOPSIS
Protocol Title: A Study of Nivolumab plus Ipilimumab in Combination with Chemotherapy 
vs Chemotherapy alone as First Line Therapy in Stage IV Non-Small Cell Lung Cancer 
(NSCLC) 
Study Phase: Phase 3
 
 
 
 
 
 
 
 
 
 
 
 
Study Population:
•
Participants with histologically confirmed stage IV non-small cell lung cancer (NSCLC),
squamous or non-squamous histology. (Defined by the 7th International Association for the 
Study of Lung Cancer Classification) 
•
No prior systemic therapy for stage IV disease. 
•
EGFR/ALK wild type and ECOG Performance Status of ≤1
•
Participants are to have tumor tissue sample for biomarker analysis
•
Participants must have PD-L1 IHC testing with results available for randomization or PD-L1 
testing will be performed by the central laboratory during the screening period. 
Objectives and Endpoints
Objectives
Endpoints
Primary
•
To compare the efficacy of nivolumab + ipilimumab 
with chemotherapy vs chemotherapy in participants 
with histologically confirmed stage IV NSCLC
•
Overall survival (OS)
Secondary
•
To compare the efficacy of nivolumab + ipilimumab 
combined with chemotherapy vs chemotherapy in 
•
Progression free survival (PFS) by blinded 
independent central review
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for subsequent disease progression (which occurred during the off-treatment period) and 
administered for up to 1 additional year.
The 2 cycles of histology-based platinum doublet chemotherapy in the treatment arm during 
induction are the same chemotherapy regimens as in the control arm:
•
Squamous histology: carboplatin AUC 6 + paclitaxel 200 mg/m2
•
Non-squamous histology: carboplatin AUC 5 or 6 + pemetrexed 500 mg/m2 or cisplatin 
75 mg/m2 + pemetrexed 500 mg/m2. The investigator must decide prior to randomization 
whether or not the participant with non-squamous histology will receive cisplatin, if eligible.
Control arm: 4 cycles of histology-based platinum doublet chemotherapy.
•
Squamous histology: carboplatin AUC 6 + paclitaxel 200 mg/m2
•
Non-squamous histology: carboplatin AUC 5 or 6 + pemetrexed 500 mg/m2 or cisplatin 
75 mg/m2 + pemetrexed 500 mg/m2. The investigator must decide prior to randomization 
whether or not the participant with non-squamous histology will receive cisplatin, if eligible.
•
Chemotherapy will be on day 1 of each 3 week cycle; participants with non-squamous 
histology who have stable disease or response after induction chemotherapy are permitted to 
receive optional pemetrexed maintenance therapy: 500 mg/m2 pemetrexed on day 1 of each 
3 week cycle until disease progression or unacceptable toxicity, or other reasons specified in 
the protocol.
Number of Participants: 
Approximately 420 participants will be randomized to treatment arm and control arm in a 1:1 ratio.
Study treatment: 
Study Drugs for CA2099LA 
Medication 
Potency 
IP/Non-IP 
Nivolumab
10 mg/ml
IP
Ipilimumab
5 mg/ml
IP
Carboplatin 
10 mg/ml  
IP
Paclitaxel
6 mg/ml
IP
Pemetrexed 
500 mg/vial
IP
Cisplatin
100 mg/vial (1 mg/mL)
IP
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nivolumab
Study Schema for CA2099LA
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2
SCHEDULE OF ACTIVITIES
Table 2-1:
Screening Procedural Outline (CA2099LA)
Procedure
Screening
Visit
Notes
Eligibility Assessments
Informed Consent
X
Inclusion/Exclusion Criteria
X
All inclusion/exclusion criteria should be assessed prior to first dose
Medical History
X
Safety Assessments
Physical Measurements/Physical Examination
X
Include height and weight. Within 28 days prior to first dose
Vital Signs and Oxygen Saturation
X
Including BP, HR, and temperature. Obtain at the screening visit and within 72 hours prior to 
first dose
Assessment of Baseline Signs and Symptoms
X
Within 14 days prior to first dose
Serious Adverse Event Assessment
X
Serious Adverse Events from time of consent. 
 
Pregnancy Test (WOCBP only) 
X
Within 24 hours prior to Day 1. Negative pregnancy test required at Screening. 
(An extension up to 72 hours prior to start of study drug may be permissible in situations 
where results cannot be obtained within the standard 24 hour window).
Laboratory Tests
X
Must be performed within 14 days prior to randomization:
•
CBC w/differential
•
Chemistry panel including: AST, ALT, ALP, T. bili, BUN or serum urea level, 
creatinine, phosphate, albumin, Ca, Mg, Na, K, Cl, LDH, glucose, amylase, lipase,
•
Thyroid panel including TSH, Free T4, Free T3
•
Hep B/C (HBV sAg, HCV antibody or HCV RNA) within 28 days prior to first dose.
•
Testing for HIV must be performed as per local regulations. 
ECG (12-lead) 
X
Obtained only for participants who have met all eligibility criteria
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nivolumab
Table 2-2:
On Study Assessments Treatment Phase- Nivolumab+ Ipilimumab with Platinum-based Doublet 
Chemotherapy Combination vs Chemotherapy
Procedure
Cycle 1 
Day 1
Each 
Subsequent 
Cycle Day1
(± 3 Days)
Every 2 Cycles
Day 1
(± 3 Days)
Notes
1 Cycle = 3 weeks
Nivolumab + ipilimumab + platinum-
doublet chemotherapy (q3 weeks) for 2 
cycles followed by nivolumab q3 weeks
+ ipilimumab q6 weeks
(see note)
q3weeks and ipilimumab 1mg/kg q6 weeks until 
progression or maximum 24 month treatment duration)
Control Arm
Platinum-doublet chemotherapy q 3w 
x4 cycles with optional pemetrexed 
maintenance for non-squamous 
histology 
X
X
3 weeks per cycle x4
Non-squamous histology may have option of pemetrexed 
maintenance therapy until progression or unacceptable 
toxicity
NOTES: 
1) If a dose is delayed, the procedures scheduled for that same time point should be delayed to coincide with when the time point’s dosing actually occur (except 
radiographic tumor assessments) continue until disease progression, discontinuation due to unacceptable toxicity, withdrawal of consent, or study closure.
2)
During retreatment upon progression (with post maximum 24 month therapy), laboratory and tumor assessment schedules will be the same. No PK/PRO 
collection are required. 
3)
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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b Survival Follow-up visits to occur every 3 months (± 14 days) from Follow-up Visit 2. Survival visit may be conducted in person or by telephone. BMS may
request that survival data be collected on all treated participants outside of the 3 month specified window. At the time of this request, each participant will be 
contacted to determine their survival status unless the subject has withdrawn consent for all contact. If retreatment starts, then follow-up visits will cease.
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BMS-936558
nivolumab
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Date: 10-May-2017
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nivolumab
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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4
OBJECTIVES AND ENDPOINTS
Table 4-1:
Objectives and Endpoints
Objectives
Endpoints
Primary
•
To compare the efficacy of nivolumab + ipilimumab 
combined with chemotherapy vs chemotherapy in 
participants with histologically confirmed stage IV 
NSCLC
•
OS
Secondary
•
To compare the efficacy of nivolumab + ipilimumab 
combined with chemotherapy vs chemotherapy in 
participants with histologically confirmed stage IV 
NSCLC
•
PFS by BICR
•
ORR by BICR
•
To evaluate efficacy outcomes in participants with 
histologically confirmed stage IV NSCLC treated 
with
nivolumab + ipilimumab combined with 
chemotherapy vs chemotherapy with different PD-
L1 expression levels 
•
ORR and PFS by BICR and OS in participants 
with different PD-L1 levels
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nivolumab
•
PD-L1 negative (< 1% tumor cell membrane staining in a minimum of a hundred evaluable 
tumor cells)
•
PD-L1 not quantifiable (participants with tumor biopsy specimens without quantifiable PD-L1 
expression)
Participants are to have tumor tissue sample available for PD-L1 IHC testing performed by a
central laboratory during screening period. PD-L1 status is required for randomization. 
The enrollment will end when approximately 420 patients are randomized. IWRS will be used to 
track the enrollment number. Testing of PD-L1 through a central laboratory is required prior to 
randomization. Participants tested but with not quantifiable PD-L1 will stratify with PD-L1 
negative participants. PD-L1 not quantifiable population will be capped to 10% of total 
randomized population. The study design schematic is presented in Figure 5.1-1.
Figure 5.1-1:
Study Design Schematic
Approximately 420 participants will be randomized in a 1:1 ratio to the treatment arm or control 
arm. The stratification factors for randomization are PD-L1 level (≥1% vs < 1%), histology
(squamous vs non-squamous histology), and gender (male vs female). Participants without
quantifiable PD-L1 status can be stratified with PD-L1 < 1% population and capped to 10% of the 
total randomized participants. 
The investigator must decide prior to randomization if participant with non-squamous histology 
will receive cisplatin therapy, based on cisplatin eligibility criteria.
Treatment Arm: Nivolumab will be administered with ipilimumab, plus 2 cycles of 
histology-based platinum doublet chemotherapy: 
•
Squamous histology: carboplatin AUC 6 + paclitaxel 200 mg/m2
•
Non-squamous histology: carboplatin AUC 5 or 6 + pemetrexed 500
mg/m2
or 
cisplatin 75 mg/m2 + pemetrexed 500 mg/m2
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5.1.1
Data Monitoring Committee and Other External Committees
5.1.1.1
Data Monitoring Committee
A DMC will be utilized to provide general oversight and safety considerations for this study 
CA2099LA. The DMC will provide advice to the Sponsor regarding actions the committee deems 
necessary for the continuing protection of participants enrolled in this study. The DMC will be 
charged with assessing such actions in light of an acceptable risk/benefit profile for 
nivolumab/ipilimumab. The DMC will act in an advisory capacity to BMS and will monitor 
participant safety data for the study.
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The DMC will be advisory to the clinical study leadership team. The clinical study leadership will 
have responsibility for overall conduct of the study including managing the communication of 
study data. The group will be responsible for promptly reviewing the DMC recommendations, for 
providing guidance regarding the continuation or termination of the study, and for determining 
whether amendments to the protocol or changes to the study conduct are required.
Details of the DMC responsibilities and procedures will be specified in the DMC charter. 
5.1.1.2
Blinded Independent Radiology Central Review 
Tumor assessments for each participant should be submitted to the radiology vendor as will be
performed on an ongoing basis. At the time of investigator-assessed initial radiographic 
progression per RECIST 1.1 in any given participant, the site must request the Independent Central 
Review from the third party radiology vendor for confirmation of progression. The blinded, 
independent radiologists will review all available tumor assessments for that given participant and 
determine if RECIST 1.1 criteria for progression have been met. The independent assessment of 
whether or not the given participant met RECIST 1.1 criteria for progression will be provided to 
the site. Participants 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 participant to have met RECIST 1.1 criteria for progression.
BICR will review tumor images in all treated participants to determine RECIST 1.1 response for 
analyses of ORR or PFS. Details of the BICR procedures will be specified in the imaging manual.
5.2
Number of Participants
Approximately 420 participants will be randomized to treatment arm and control arm in a 1:1 ratio.
5.3
End of Study Definition
The start of the trial is defined as first visit for first participant screened. End of trial is defined as 
the last visit or scheduled procedure shown in the Schedule of Activities for the last participant.
Study completion is defined as the final date on which data for the primary endpoint was or is 
expected to be collected, if this is not the same.
 
 
 
 
 
 
 
 
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report, must be submitted for biomarker evaluation prior to treatment. The tumor tissue 
sample may be fresh or archival, (archival tissue is to be obtained within 3 months prior to 
enrollment), and there can have been no systemic therapy (eg, adjuvant or neoadjuvant 
chemotherapy) given after the sample was obtained. Tissue must be from a core needle 
biopsy, excisional or incisional biopsy. Fine needle biopsies or drainage of pleural 
effusions with cytospins are not considered adequate for biomarker review. Biopsies of 
bone lesions that do not have a soft tissue component or decalcified bone tumor samples 
are also not acceptable.
i)
Participants must have PD-L1 IHC testing with results performed by a central laboratory
during the screening period. 
j)
Prior palliative radiotherapy to non-CNS lesions must have been completed at least 2 weeks 
prior to treatment. Subjects with symptomatic tumor lesions at baseline that may require 
palliative radiotherapy within 4 weeks of first treatment are strongly encouraged to receive 
palliative radiotherapy prior to treatment.
k) Screening laboratory values must meet the following criteria (using CTCAE v4):
i)
WBC ≥2000/ȣL
ii) Neutrophils ≥1500/ȣL
iii) Platelets ≥100 x 103/ȣL
iv) Hemoglobin ≥9.0 g/dL
v) Serum creatinine ≤1.5 x ULN or calculated creatinine clearance ≥50 mL/min 1(using
the Cockcroft Gault formula)
Female CrCl = (140 - age in years) x weight in kg x 0.85/ 72 x serum creatinine in mg/dL
Male CrCl = (140 - age in years) x weight in kg x 1.00/ 72 x serum creatinine in mg/dL
vi) AST/ALT ≤3.0 x ULN (≤5 x ULN if liver metastases are present)
vii)Total bilirubin ≤1.5 x ULN except subjects with Gilbert Syndrome who must have a
total bilirubin level < 3.0 mg/dL).
Subject Re-enrollment: This study permits the re-enrollment of a subject who has discontinued the 
study as a pre-treatment failure (ie, subject has not been treated). If re-enrolled, the subject must 
be re-consented.
3) Age and Reproductive Status
a) Males and Females, ages ≥18 years of age
b) Women of childbearing potential (WOCBP) must have a negative serum or urine 
pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 
24 hours prior to the start of study drug.
c) Women must not be breastfeeding
d) WOCBP must agree to follow instructions for methods(s) of contraception for the 
duration of treatment with nivolumab and 5 months after the last dose of nivolumab (ie 
30 days [duration of ovulatory cycle] plus the time required for nivolumab to undergo 
approximately five half-lives).
e) Males who are sexually active with WOCBP must agree to follow instructions for 
method(s) of contraception for the duration of treatment with nivolumab and up to 
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7 months after the last dose of nivolumab (ie 90 days [duration of sperm turnover] plus 
the time required for nivolumab to undergo approximately five half-lives).
f)
Azoospermic males and WOCBP who are continuously not heterosexually active are 
exempt from contraceptive requirements. However they must still undergo pregnancy 
testing as described in these sections.
Investigators shall counsel WOCBP and male participants who are sexually active with WOCBP 
on the importance of pregnancy prevention and the implications of an unexpected pregnancy.
Investigators shall advise WOCBP and male participants who are sexually active with WOCBP 
on the use of highly effective methods of contraception. Highly effective methods of contraception 
have a failure rate of < 1% when used consistently and correctly.
6.2
Exclusion Criteria
1) Medical Conditions
a) Participants with known EGFR mutations which are sensitive to available targeted inhibitor 
therapy (including, but not limited to, deletions in exon 19 and exon 21 [L858R] 
substitution mutations) are excluded. All participants with non-squamous histology must 
have been tested for EGFR mutation status. EGFR test is to be done locally. EGFR test is 
not provided by a third party laboratory. Use of a FDA-approved test (PCR based assay 
from tumor tissue) is strongly encouraged. Tests other than PCR or next generation 
sequencing will be requested to repeat using PCR or next generation sequencing based 
methods. Participants of non-squamous histology with unknown or indeterminate EGFR 
status are excluded.
b) Participants with known ALK translocations which are sensitive to available targeted 
inhibitor therapy are excluded. If tested, use of an FDA-approved test is strongly 
encouraged. Participants with unknown or indeterminate ALK status may be enrolled.
c) Participants with untreated CNS metastases are excluded. Participants are eligible if CNS 
metastases are adequately treated and participants are neurologically returned to baseline 
(except for residual signs or symptoms related to the CNS treatment) for at least 2 weeks 
prior to first treatment. In addition, participants must be either off corticosteroids, or on a 
stable or decreasing dose of ≤ 10 mg daily prednisone (or equivalent) for at least 2 weeks 
prior to first treatment.
d) Participants with carcinomatous meningitis.
e) Participants must have recovered from the effects of major surgery or significant traumatic 
injury at least 14 days before first treatment.
f)
Participants with previous malignancies (except non-melanoma skin cancers, and in situ 
cancers such as the following: bladder, gastric, colon, cervical/dysplasia, melanoma, or 
breast) are excluded unless a complete remission was achieved at least 2 years prior to first 
treatment and no additional therapy is required or anticipated to be required during the 
study period.
g) Participants with an active, known or suspected autoimmune disease. Participants with type 
I diabetes mellitus, hypothyroidism only requiring hormone replacement, skin disorders 
(such as vitiligo, psoriasis, or alopecia) not requiring systemic treatment, or conditions not 
expected to recur in the absence of an external trigger are permitted to enroll.
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6.4
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study but are 
not subsequently randomized. A minimal set of screen failure information is required to ensure 
transparent reporting of screen failure participants, to meet the Consolidated Standards of 
Reporting Trials (CONSORT) publishing requirements, and to respond to queries from regulatory 
authorities. Minimal information includes date of consent, demography, screen failure details, 
eligibility criteria, and any serious AEs.
6.4.1
Retesting During Screening Period
This study permits the re-enrollment of a participant that has discontinued the study as a 
pre-treatment failure (ie, participant has not been randomized / has not been treated). If re-enrolled, 
the participant must be re-consented
Retesting of laboratory parameters and/or other assessments within any single screening will be 
permitted (in addition to any parameters that require a confirmatory value).
The most current result prior to randomization is the value by which study inclusion will be 
assessed, as it represents the participant’s most current, clinical state.
7
TREATMENT
Study treatment is defined as any investigational treatment(s), marketed product(s), placebo or 
medical device intended to be administered to a study participant according to the study 
randomization or treatment allocation
Study 
treatment
includes 
both 
Investigational 
[Medicinal] 
Product 
(IP/IMP) 
and 
Non-investigational [Medicinal] Product (Non-IP/Non-IMP) and can consist of the following:
In this protocol, investigational product(s) is/are:
•
Nivolumab 
•
Ipilimumab
•
Carboplatin
•
Pemetrexed
•
Paclitaxel
•
Cisplatin
Other medications used as support or escape medication for preventative, diagnostic, or therapeutic 
reasons, as components of the standard of care for a given diagnosis, may be considered as 
non-investigational products.
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Table 7-1:
Study treatments for CA2099LA
Product Description 
and Dosage Form
Potency
IP/Non-IP
Blinded or 
Open Label
Primary Packaging 
(Volume)/Label Type and 
Secondary Packaging 
(Qty)/Label Type
Appearance
Storage Conditions 
(per label)
BMS-936558-01 
Nivolumab Solution for 
Injectiona
100 mg 
(10 mg/mL)
IP
Open label
10 mL per vial and 5 or 10 
vials per carton
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
(5mg/mL)
IP
Open label
40 mL vial and 4 vials per
carton
Clear to opalescent 
colorless to pale 
yellow liquid. May 
contain particles
2 to 8° C. Protect from 
light and freezing
Carboplatin Solution for 
Injectionb
450 mg/vial 
(10 mg/mL)
IP
Open label
45 mL per vial and 4 vials 
per carton/
Clear, colorless or 
slightly yellow 
solution
Product should be stored 
as per market product 
conditions
Paclitaxel Solution for 
Injectionb
100 mg/vial (6 
mg/mL)
IP
Open label
16.7 mL vial and 4 vials per 
carton
Clear, colorless, or 
slightly yellow viscous 
solution
Product should be stored 
as per market product 
conditions
Pemetrexed Powder for 
Concentrate for Solution 
for Infusionb
500 mg/vial
IP
Open label
500 mg per vial and 1 vial 
per carton
White to either light 
yellow or green-
yellow lyophilized 
powder
Product should be stored 
as per market product 
conditions
Cisplatin Solution for 
Infusionb
100 mg/vial 
(1 mg/mL)
IP
Open label
100 mL per vial and 4 vials 
per carton
Clear, colorless 
solution
Product should be stored 
as per market product 
conditions
NOTES:
a May be labeled as either “BMS-936558-01” or “Nivolumab”
b These products may be obtained by the investigational sites 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).
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7.1
Treatments Administered
The selection and timing of dose for each participant is as follows:
Table 7.1-1:
Treatments Administered
Week 1, 
Cycle 1 Day 1
± 3 Days
Week 4, 
Cycle 2 Day 1
± 3 days
Week 7, 
Cycle 3 Day 1 
± 3 Days
Nivolumab + ipilimumab + platinum-doublet 
chemotherapy q 3wk x 2 cycles followed by
nivolumab (360 mg q 3weeks) + ipilimumab 
(1mg/kg q 6weeks)
Cycle 1 
Nivolumab
+
Ipilimumab
+
Histology-based 
chemotherapy
Cycle 2
Nivolumab
+
Histology-based 
chemotherapy
Cycle 3
Nivolumab
+
Ipilimumab
Platinum doublet chemotherapy q 3wk x 4 
followed by optional maintenance
Pemetrexed for non-squamous histology
Cycle 1
Histology-based 
chemotherapy
Cycle 2
Histology-based 
chemotherapy
Cycle 3 
Histology-based 
chemotherapy
Both nivolumab and ipilimumab should be administered as 30 minute infusions. Nivolumab will 
be administered first. Ipilimumab will be administered after at least 30 minutes after completion 
of the nivolumab infusion. Platinum-doublet will start at least 30 minutes after completion of the 
nivolumab or ipilimumab infusion (if ipilimumab is scheduled to be given). At the investigator’s 
discretion, nivolumab or ipilimumab may be administered over a longer infusion time (60 minutes) 
if the participant developed a prior infusion reaction.
Nivolumab and ipilimumab treatment will continue until disease progression, discontinuation due 
to unacceptable toxicity, withdrawal of consent, or study closure. Participants will be treated up to 
24 months in the absence of disease progression or inacceptable toxicity. Treatment with 
nivolumab and ipilimumab could be reinitiated as per the initial schedule for subsequent disease 
progression after maximum 24 months of treatment and administered for up to 1 additional year. 
Maximum 24 months of treatment also applies to treatment beyond progression.
All participants will be monitored continuously for AEs while on study treatment. Treatment 
modifications (eg, dose delay, reduction, retreatment, or discontinuation) will be based on specific 
laboratory and adverse event criteria, as described in Sections 7.4.1, 7.4.2, 7.4.3, and 8.1.
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7.1.1
Dosing
7.1.1.1
Nivolumab and Ipilimumab Dosing for Treatment Arm
Participants will receive nivolumab and ipilimumab (induction dose and treatment interval will be 
determined by safety lead-in phase in study CA209568), followed by chemotherapy on day 1 of 
every 3 weeks cycle. The 2 cycles of chemotherapy during induction are same regimens as control 
arm (without chemotherapy maintenance) as in Section 7.1.1.2. At the time of completion of 
2 cycles of chemotherapy, participants who have not experienced disease progression will continue 
to receive nivolumab at a dose of 360 mg as 30 minute infusion every 3 weeks, and ipilimumab 
1 mg/kg as 30 minute infusion IV every 6 weeks starting on day 1. Treatment will continue until 
progression, unacceptable toxicity, withdrawal of consent, or the study ends, whichever occurs 
first. Treatment with nivolumab with ipilimumab will be given for up to 24 months in the absence 
of disease progression or inacceptable toxicity. A maximum 24 months of treatment also applies 
to treatment beyond progression. Treatment with nivolumab and ipilimumab could be reinitiated 
as per the initial schedule for subsequent disease progression and administered for up to 
1 additional year (investigators may decide not to re-treat with ipilimumab and nivolumab at 
progression if there is significant risk of recurrent severe toxicity). Ipilimumab and/or nivolumab 
must not be reinitiated if it was permanently discontinued on study due to treatment related 
toxicities. All exceptions must require approval by Medical Monitor. Participants may discontinue 
only ipilimumab and continue treatment with nivolumab if certain circumstances are met 
(Section 8.1.2). 
Ipilimumab is not permitted to continue on study after nivolumab is discontinued. The assessment 
for discontinuation of nivolumab should be made separately from the assessment made for 
discontinuation of ipilimumab. 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. The assessment for discontinuation of 
nivolumab/ipilimumab should be made separately from chemotherapy.
If criteria for 
discontinuation for nivolumab and ipilimumab are met, platinum doublet chemotherapy may 
continue until 2 cycles have been completed. If a participant meets criteria for discontinuation and 
investigator is unable to determine whether the event is related to all or any one study drug, the 
participant should discontinue all study drugs and be taken off the treatment phase of the study. 
7.1.1.2
Chemotherapy Dosing
In control arm, 4 cycles of histology-based platinum doublet chemotherapy options will be selected 
by investigator and administered on day 1 every 3 weeks; participants with non-squamous 
histology may also receive optional maintenance therapy with 500 mg/m2 pemetrexed alone on 
day 1 of each 3 week cycle until disease progression or unacceptable toxicity or other reasons 
specified in the protocol (Section 8.1.3). 
In treatment arm, 2 cycles of chemotherapy during induction are same regimens as control arm 
(without chemotherapy maintenance).
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Histology-based chemotherapy:
•
Squamous histology: carboplatin AUC 6 + paclitaxel 200 mg/m2
•
Non-squamous histology: 
−
carboplatin AUC 5 or 6 + pemetrexed 500 mg/m2
−
cisplatin 75 mg/m2 + pemetrexed 500 mg/m2
All chemotherapy agents’
preparation, premedication, administration, monitoring, and 
management of complications are to follow local prescription guideline and regulation. The dose 
of chemotherapy may be capped per local standards.
Note: The investigator must decide prior to randomization whether or not a
participant with 
non-squamous histology will receive cisplatin, if eligible.
7.1.1.2.1
Paclitaxel and Carboplatin 
Participants will receive paclitaxel 200 mg/m2 as a 180-minute IV infusion with carboplatin at a 
dose of AUC 6 as a 30-minute IV infusion, on Day 1 of a 3-week cycle, or at doses per the local 
prescribing information. The infusion time can follow local institutional standard. 
Paclitaxel dosing calculations should be based on the body surface area calculation. The dose may 
remain the same if the participant’s weight is within 10% of the baseline weight or prior dose 
weight.
Carboplatin should be given following paclitaxel on Day 1 of each cycle, and the carboplatin dose 
will be calculated using the Calvert formula as follows:
•
Carboplatin dose (mg) = target AUC x ([CrCl (ml/min) + 25]
•
Creatinine clearance (CrCl) calculation is based on the Cockcroft-Gault formula) and should 
include the most recent serum creatinine and most recent weight. NOTE: If calculation of the 
CrCl by the Cockcroft-Gault formula yields a result of > 125 mL/min, then a CrCl should be 
calculated by an alternative formula per institutional standards or capped at 125 mL/min.
•
The dose of carboplatin may be capped per local standards.
Premedications for use with paclitaxel
Oral corticosteroid should be given according to local standard at a dose equivalent to 
dexamethasone 20 mg 12 hours and 6 hours prior to paclitaxel administration. Oral or intravenous 
(IV) diphenhydramine (or its equivalent) 50 mg and H2-blocker (per local standard of care) should 
be administered 30 to 60 minutes prior to paclitaxel infusion.
Doses of paclitaxel and/or carboplatin may be interrupted, delayed, reduced, or discontinued 
depending on how well the participant tolerates the treatment. 
7.1.1.2.2
Pemetrexed and Cisplatin
Pemetrexed dosing calculations should be based on the body surface area calculation. The dose 
may remain the same if the participant’s weight is within 10% weight used to calculate the previous 
dose.
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Premedications with pemetrexed use
1) Oral corticosteroid should be given according to local standards at a dose equivalent to 
dexamethasone 4 mg BID on the day prior to, the day of, and the day after the administration 
of pemetrexed. Oral folic acid 350 to 1000 mcg daily should be given starting 1 week prior to 
the first dose of pemetrexed, with at least 5 doses of folic acid administered in the 7 days prior 
to the first dose. Oral folic acid should be continued daily throughout the treatment with 
pemetrexed and for 21 days after the last dose of pemetrexed. Intramuscular (IM) injection of 
vitamin B12 1000 mcg should be given approximately one week prior to the first dose of 
pemetrexed and repeated every 3 cycles thereafter during pemetrexed treatment. Subsequent 
injections of vitamin B12 may be given on the same day as pemetrexed. (Participant with 
non-squamous histology may begin folic acid and vitamin B12 prior to randomization in 
anticipation of pemetrexed)
2) 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). Additional use of antiemetic 
premedications may be employed at the discretion of the Investigator.
Participants will receive pemetrexed at a dose of 500 mg/m2 as a 10 minute IV infusion on day 1 
with cisplatin at a dose of 75mg/m2 infusion as per local standard practice on day 1 of a 3-week 
treatment cycle for up to 2 cycles in treatment arm or 4 cycles in control arm.
Dosing calculations should be based on the body surface area calculation and may be capped per 
local standards. The dose may remain the same if the participant’s weight is within 10% of the 
baseline weight or prior dose weight.
Cisplatin will be administered to participants at least 30 minutes following the end of the 
pemetrexed 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.
Doses of pemetrexed and/or cisplatin may be interrupted, delayed, reduced, or discontinued 
depending on how well the participant tolerates the treatment See the following sections for more
details: Section 7.4.1 (dose delays);, Section 7.4.2 (dose reductions); Section 7.4.3 (retreatment), 
and Section 8.1 (dose discontinuations).
All participants 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.
Participants who discontinue cisplatin alone may, at the investigator’s discretion, be switched to 
pemetrexed/carboplatin for the remainder of the platinum doublet cycles (up to 2 cycles in 
treatment arm or 4 cycles in control arm in total). Dosing for pemetrexed/carboplatin for such 
participants should follow the instructions in the pemetrexed/carboplatin with or without 
Pemetrexed Continuation Maintenance section below.
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7.1.1.2.3
Pemetrexed/Carboplatin
Pemetrexed dosing calculations should be based on the body surface area calculation. The dose 
may remain the same if the participant’s weight is within 10% weight used to calculate the previous 
dose.
Oral corticosteroid premed for pemetrexed should be given according to local standards at a dose 
equivalent to dexamethasone 4 mg BID on the day prior to, the day of, and the day after the 
administration of pemetrexed. Oral folic acid 350 to 1000 mcg daily should be given starting 
1 week prior to the first dose of pemetrexed, with at least 5 doses of folic acid administered in the 
7 days prior to the first dose. Oral folic acid should be continued daily throughout the treatment 
with pemetrexed and for 21 days after the last dose of pemetrexed. Intramuscular (IM) injection 
of vitamin B12 1000 mcg should be given approximately one week prior to the first dose of 
pemetrexed and repeated every 3 cycles thereafter during pemetrexed treatment. Subsequent 
injections of vitamin B12 may be given on the same day as pemetrexed. (Participant with non-
squamous histology may begin folic acid and vitamin B12 prior to randomization in anticipation 
of pemetrexed).
Participants will receive pemetrexed at a dose of 500 mg/m2 as a 10-minute IV infusion on Day 1, 
followed by carboplatin at a dose of AUC 5 or 6 as a 30-minute IV infusion, on Day 1 of a 3-week 
treatment cycle, for up to 4 cycles.
Pemetrexed dosing calculations should be based on the body surface area calculation. The dose 
may remain the same if the participant’s weight is within 10% weight used to calculate the previous 
dose.
The carboplatin dose will be calculated using the Calvert formula as follows:
•
Carboplatin dose (mg) = Target AUC x (CrCl [ml/min] + 25)
•
Creatinine clearance (CrCl) calculation is based on the Cockcroft-Gault formula (see Inclusion 
criterion in Section 6.1) and should include the most recent serum creatinine and most recent 
weight. NOTE: If calculation of the CrCl by the Cockcroft-Gault formula yields a result of 
> 125 mL/min, then a CrCl should be calculated by an alternative formula per institutional 
standards or capped at 125 mL/min. 
Doses of pemetrexed and/or carboplatin may be interrupted, delayed, reduced, or discontinued 
depending on how well the participant tolerates the treatment. All chemotherapy agents 
preparation, premedication, administration, monitoring, and management of complications are to 
follow local prescription guideline and regulation. The dose of chemotherapy may be capped per 
local standards.
7.1.1.3
Optional Continuation-Maintenance
After cycle 4 in control arm, participants with non-squamous histology who have stable disease or 
response after induction chemotherapy are permitted to receive pemetrexed 500 mg/m² alone as 
maintenance therapy until disease progression or unacceptable toxicity. 
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7.1.2
Treatment of Nivolumab or Ipilimumab Infusion Reactions
Since nivolumab and ipilimumab contain only human immunoglobulin protein sequences, they are 
unlikely to be immunogenic and induce infusion or hypersensitivity reactions. However, if such a 
reaction were to occur, it might manifest with fever, chills, rigors, headache, rash, pruritus, 
arthralgias, hypo- or hypertension, bronchospasm, or other symptoms. All Grade 3 or 4 infusion 
reactions should be reported within 24 hours to the BMS Medical Monitor and reported as an SAE 
if criteria are met. Infusion reactions should be graded according to NCI CTCAE (Version 4.0) 
guidelines.
Treatment recommendations are provided below and may be modified based on local treatment 
standards and guidelines, as appropriate:
For Grade 1 symptoms: (mild reaction; infusion interruption not indicated; intervention not 
indicated)
•
Remain at bedside and monitor participant until recovery from symptoms. The following 
prophylactic premedications are recommended for future infusions: diphenhydramine 50 mg 
(or equivalent) and/or acetaminophen/paracetamol 325 to 1000 mg at least 30 minutes before 
additional nivolumab or ipilimumab administrations.
For Grade 2 symptoms: (moderate reaction requires therapy or infusion interruption but 
responds promptly to symptomatic treatment [eg, antihistamines, non-steroidal 
anti-inflammatory 
drugs,
narcotics, 
corticosteroids, 
bronchodilators, 
IV 
fluids]; 
prophylactic medications indicated for ≤24 hours)
•
Stop the nivolumab or ipilimumab infusion, begin an IV infusion of normal saline, and treat 
the 
participant
with 
diphenhydramine 
50 
mg 
IV 
(or 
equivalent) 
and/or 
acetaminophen/paracetamol 325 to 1000 mg; remain at bedside and monitor participant until 
resolution of symptoms. Corticosteroid and/or bronchodilator therapy may also be 
administered as appropriate. If the infusion is interrupted, then restart the infusion at 50% of 
the original infusion rate when symptoms resolve; if no further complications ensue after 
30 minutes, the rate may be increased to 100% of the original infusion rate. Monitor participant
closely. If symptoms recur, then no further nivolumab or ipilimumab will be administered at 
that visit. Administer diphenhydramine 50 mg IV, and remain at bedside and monitor the 
participant until resolution of symptoms. The amount of study drug infused must be recorded 
on the electronic case report form (eCRF).
•
For future infusions, the following prophylactic premedications are recommended: 
diphenhydramine 50 mg (or equivalent) and/or 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 SoluCortef or equivalent) may be used.
For Grade 3 or 4 symptoms: (severe reaction, Grade 3: prolonged [ie, not rapidly responsive 
to symptomatic medication and/or brief interruption of infusion]; recurrence of symptoms 
following initial improvement; hospitalization indicated for other clinical sequelae [eg, renal 
impairment, pulmonary infiltrates]. Grade 4: Life threatening; pressor or ventilatory 
support indicated)
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•
Immediately discontinue infusion of nivolumab or ipilimumab. Begin an IV infusion of normal 
saline and treat the participant as follows: Recommend bronchodilators, epinephrine 0.2 to 1 
mg of a 1:1000 solution for subcutaneous administration or 0.1 to 0.25 mg of a 1:10,000 
solution injected slowly for IV administration, and/or diphenhydramine 50 mg IV with 
methylprednisolone 100 mg IV (or equivalent), as needed. Participant should be monitored 
until the investigator is comfortable that the symptoms will not recur. Nivolumab or 
ipilimumab will be permanently discontinued. Investigators should follow their institutional 
guidelines for the treatment of anaphylaxis. Remain at bedside and monitor participant until 
recovery of the symptoms.
In case of late-occurring hypersensitivity symptoms (eg, appearance of a localized or generalized 
pruritus within 1 week after treatment), symptomatic treatment may be given (eg, oral 
antihistamine or corticosteroids).
7.1.3
Treatment Beyond Disease Progression 
Accumulating evidence indicates a minority of participants treated with immunotherapy may 
derive clinical benefit despite initial evidence of PD.21
Participants will be permitted to continue on nivolumab + ipilimumab for treatment beyond initial 
RECIST 1.1 defined PD as long as they meet the following criteria:
•
Investigator-assessed clinical benefit and no rapid disease progression
•
Participant is tolerating study treatment
•
Stable performance status
•
Treatment beyond progression will not delay an imminent intervention to prevent serious 
complications of disease progression (eg, CNS metastases)
•
Participant provides written informed consent prior to receiving additional nivolumab and 
ipilimumab treatment, using an ICF describing any reasonably foreseeable risks or 
discomforts, or other alternative treatment options.
The decision to continue treatment beyond initial investigator-assessed progression should be 
discussed with the BMS Medical Monitor and documented in the study records. A follow-up scan 
should be performed within six (6) weeks ± 7 days of original PD to determine whether there has 
been a decrease in the tumor size, or continued progression of disease. Subsequent scans should 
be performed per protocol defined schedule ± 7 days until further progression is determined.
If the investigator feels that the participant continues to achieve clinical benefit by continuing 
treatment, the participant should remain on the trial and continue to receive monitoring according 
to the Time and Events Schedule in Section 2.
For the participants who continue study therapy beyond progression, further progression is defined 
as an additional 10% increase in tumor burden from time of initial PD. This includes an increase 
in the sum of diameters of all target lesions and/ or the diameters of new measurable lesions 
compared to the time of initial PD. Nivolumab and ipilimumab treatment should be discontinued 
permanently upon documentation of further progression.
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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.
7.2
Method of Treatment Assignment
After the participant’s initial eligibility is established and informed consent has been obtained, the 
participant must be enrolled into the study by calling an interactive web response system (IWRS) 
to obtain the participant number. Every participant that signs the informed consent form must be 
assigned a participant number in IWRS. Specific instructions for using IWRS will be provided to 
the investigational site in a separate document. The investigator or designee will register the 
participant for enrollment by following the enrollment procedures established by BMS. The 
following information is required for enrollment:
•
Date that informed consent was obtained
•
Participant number
•
Date of birth
Participants enrolled will be grouped according to PD-L1 status (positive, negative, or not 
quantifiable, using membranous staining in ≥1% tumor cells vs membranous staining in < 1% 
tumor cells). PD-L1 expression data will be transferred directly from analyzing lab to IWRS. 
IWRS will be used to track the enrollment number.
Once enrolled in IWRS, enrolled participants that have met all eligibility criteria will be
randomized through IWRS. The following information is required for participant randomization:
•
Participant number
•
Date of birth
•
Gender
•
Histology (squamous or non-squamous). 
−
Participants with mixed histology should be classified according to the predominant 
histology. 
−
Participants with adenosquamous histology should be classified as non-squamous 
histology.
•
PD-L1 status
•
Will participant be treated with cisplatin, if eligible?
Participants meeting all eligibility criteria will be stratified by tumor histology (squamous vs 
non-squamous), gender (male vs female), and PD-L1 level (< 1% vs ≥ 1% expression levels) 
Participants will be randomized in a 1:1 ratio to treatment and control arms.
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Note: participants whose PD-L1 status is not quantifiable will be classified as PD-L1 < 1%. The 
total number of participants with not quantifiable PD-L1 status should not exceed 10% of total 
randomized participants for Part 2.
Enrollment will end after approximately 420 participants are randomized.
The exact procedures for using the IWRS will be detailed in the IWRS manual.
7.3
Blinding
Not applicable. This is an open-label study, blinding procedures are not applicable.
7.4
Dosage Modification
Immuno-oncology (I-O) agents are associated with AEs that can differ in severity and duration 
than AEs caused by other therapeutic classes. Nivolumab and ipilimumab are considered immuno-
oncology agents in this protocol. Early recognition and management of AEs associated with 
immuno-oncology agents may mitigate severe toxicity. Management Algorithms have been 
developed to assist investigators in assessing and managing the following groups of AEs:
•
Gastrointestinal
•
Renal
•
Pulmonary
•
Hepatic
•
Endocrinopathy
•
Skin
•
Neurological
The above algorithms are found in both the nivolumab and ipilimumab Investigator Brochures, as 
well as in Appendix 6.
7.4.1
Dose Delay Criteria
7.4.1.1
Dose Delay Criteria for Nivolumab and Ipilimumab
Tumor assessments for all participants should continue as per protocol even if dosing is delayed.
Nivolumab and ipilimumab administration should be delayed for the following:
•
Any Grade ≥2 non-skin, drug-related adverse event, except for fatigue and laboratory 
abnormalities
•
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 or asymptomatic amylase or lipase:
−
Grade 3 lymphopenia does not require a dose delay
−
If a participant has a baseline AST, ALT, or total bilirubin that is within normal limits, 
delay dosing for drug-related Grade 2 toxicity
−
If a participant has baseline AST, ALT, or total bilirubin within the Grade 1 toxicity range, 
delay dosing for drug-related Grade ≥3 toxicity
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−
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 inter-current illness which, in the judgment of the 
investigator, warrants delaying the dose of study medication.
Participants receiving ipilimumab in combination with nivolumab that 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.)
Participants who require delay should be re-evaluated weekly or more frequently if clinically
indicated. Participants should resume dosing when re-treatment criteria are met.
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. 
•
A dose delay of ipilimumab which results in no ipilimumab dosing for > 12 weeks requires 
ipilimumab discontinuation, with exceptions as noted in Section 8.1.
•
Treatment arm: if any adverse event meeting the dose delay criteria for chemotherapy is felt to 
be related to only one particular agent in the platinum doublet chemotherapy regimen, then 
that chemotherapy agent alone may be omitted for that cycle while the other agents (nivolumab 
and one themotherapy agent) are given. Dosing of nivolumab and both chemotherapy agents 
should be delayed if any criteria for nivolumab or “both platinum-doublet chemotherapy
agents” are met.
7.4.1.2
Dose Delay Criteria for Chemotherapy
Chemotherapy drugs should be delayed for any of the following on the Day 1 of each cycle:
•
Absolute neutrophil count (ANC) < 1500/μL
•
Platelets < 100,000/mm3
•
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
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•
Any Grade ≥3 drug-related laboratory abnormality, with the following exceptions for 
lymphopenia, AST, ALT, or total bilirubin:
•
Grade 3 lymphopenia does not require dose delay.
•
If a participant has a baseline AST, ALT or total bilirubin that is within normal limits, delay 
dosing for drug-related Grade ≥2 toxicity. 
•
If a participant 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 participant for 
additional guidance on dose delays.
•
Participants receiving cisplatin with pemetrexed must discontinue cisplatin if the calculated 
creatinine clearance decreases to < 50 mL/min (based on the Cockroft Gault formula). The 
other drug (pemetrexed) may be continued, and the platinum agent may, at the investigator’s 
discretion, be switched to carboplatin for the rest of cycles when the participant meets 
retreatment criteria. Note that pemetrexed can only be administered if CrCl is ≥ 45 ml/min 
(calculated per Cockroft-Gault formula)
•
In addition, if participants receiving carboplatin with paclitaxel and must discontinue 
carboplatin, the paclitaxel may be continued at the investigator’s discretion. 
•
If any non-hematologic adverse event meeting the dose delay criteria above is felt to be related 
to only one particular agent in the platinum doublet chemotherapy 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 7.4.2.2 to determine if dose reduction of the resumed agent is required.
•
If both drugs in the platinum doublet chemotherapy regimen are delayed, then the participant
should be re-evaluated weekly or more frequently if clinically indicated until re-treatment 
criteria are met (as per Section 7.4.3.3).
•
Treatment arm: Dosing of nivolumab and both chemotherapy agents should be delayed if any 
criteria for nivolumab or “both platinum-doublet chemotherapy agents” are met.
7.4.2
Dose Reductions
7.4.2.1
Dose Reduction for Nivolumab or Ipilimumab 
There will be no dose reductions for nivolumab or ipilimumab.
7.4.2.2
Dose Reduction for Chemotherapy 
Dose reductions of chemotherapy may be required, and will be performed according to Table 
7.4.2.2-1. Chemotherapy dose reductions are permanent; once the dose of any chemotherapy agent 
is reduced, it may not be re-escalated in subsequent cycles, except as noted when starting 
pemetrexed maintenance therapy. The dose reductions for each agent in the platinum doublet 
chemotherapy regimen are not linked and may be adjusted independently as summarized below.
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Table 7.4.2.2-1:
Dose Modifications of Chemotherapeutic Agents
Dose Level
Carboplatin
Pemetrexed
Paclitaxel
Cisplatin
Starting dose
AUC 6 or AUC 5
500 mg/m²
200 mg/m²
75 mg/m²
First dose 
reduction
AUC 5 (if starting dose is 
AUC 6) or AUC 4 (if 
starting dose is AUC of 5)
375 mg/m²
150 mg/m²
56 mg/m²
Second dose 
reduction
AUC 4 (if starting dose is 
AUC 6) or AUC 3 (if 
starting dose is AUC 5)
250 mg/m²
100 mg/m²
38 mg/m²
Third dose 
reduction
Discontinue
Discontinue
Discontinue
Discontinue
Any participants with two prior dose reductions for one agent who experiences a toxicity that 
would cause a third dose reduction must be discontinued from that agent.
7.4.2.3
Dose Reductions for Hematologic Toxicity 
Dose modifications for hematologic toxicities (according to CTCAE version 4) are summarized in 
Table 7.4.2.3-1. Dose adjustments are based on nadir blood counts (assessed as per local standards) 
since the preceding drug administration. Dose level adjustments for platinum doublet 
chemotherapy are relative to that of the preceding administration. Generally, both chemotherapy 
agents in the platinum doublet chemotherapy regimen should be dose reduced together for 
hematologic toxicity. After the first cycle, growth factors 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 7.4.2.3-1:
Dose Modifications for Hematologic Toxicity (Based on Nadir 
Counts)
Toxicity
Carboplatin
Paclitaxel
Pemetrexed
Cisplatin
Neutrophil Count Decreased
Grade 4 
(< 500/mm3 or < 0.5 x 109/L)
Reduce one 
dose level
Reduce one 
dose level
Reduce one 
dose level
Reduce one 
dose level
Platelet Count Decreased
Grade 3
(25,000 - < 50,000/mm3; 25.0 -< 50.0 x 109/L)
Reduce one 
dose level
Reduce one 
dose level
Reduce one 
dose level
Reduce one 
dose level
Grade 4 
(< 25,000/mm3; < 25.0 x 109/L)
Reduce one 
dose level
Reduce one 
dose level
Reduce one 
dose level
Reduce one 
dose level
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7.4.2.4
Chemotherapy - Dose Reductions for Non-Hematologic Toxicities 
Dose adjustments for chemotherapy for non-hematologic toxicities during treatment are described 
in Section 7.4.2.2. All dose reductions should be made based on the worst grade toxicity. 
Participants experiencing any of the toxicities during the previous cycle should have their 
chemotherapy delayed until retreatment criteria are met and then reduced for all subsequent cycles 
by 1 dose level or discontinued as appropriate. Dose levels for the two drugs in the 
platinum-doublet chemotherapy regimen are not linked and may be reduced independently, as 
summarized in Table 7.4.2.4-1.
Table 7.4.2.4-1:
Dose Modifications for Non-hematologic Toxicity
Toxicity
Paclitaxel
Carboplatin
Pemetrexed
Cisplatin
Febrile Neutropenia
Grade ≥3
Reduce one dose 
level
Reduce one dose 
level
Reduce one 
dose level
Reduce one 
dose level
Diarrhea 
Grade ≥3
Reduce one dose 
level
No change
Reduce one 
dose level
No change
Allergic reactiona
Grade ≥3
Discontinue
Discontinue
Discontinue
Discontinue
Neuropathy
Grade 2
Reduce one dose 
level
No change
No change
Reduce one 
dose level
Neuropathy
Grade ≥3
Discontinue
Discontinue
Discontinue
Discontinue
Calculated creatinine clearance
< 50 mL/min
No change
Discontinue if 
creatinine clearance 
< 20 ml/min
No change
Discontinue
Other Grade ≥3 toxicity 
(except for fatigue and transient 
arthralgia and myalgia)
Adjust as 
medically 
indicated
Adjust as medically 
indicated
Adjust as 
medically 
indicated
Adjust as 
medically 
indicated
a Only the drug(s) causing the hypersensitivity reaction or acute infusion reaction (≥Grade 3) require(s) 
discontinuation. All other drugs may be continued.
7.4.3
Criteria to Resume Dosing
7.4.3.1
Criteria to Resume Nivolumab Dosing
Participants may resume treatment with nivolumab when the drug-related AE(s) resolve(s) to 
Grade ≤1 or baseline, with the following exceptions:
•
Participants may resume treatment in the presence of Grade 2 fatigue.
•
Participants who have not experienced a Grade 3 drug-related skin AE may resume treatment 
in the presence of Grade 2 skin toxicity.
•
Participants 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.
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•
Participants with combined Grade 2 AST/ALT and total bilirubin values meeting 
discontinuation parameters (Section 8.1) should have treatment permanently discontinued.
•
Drug-related pulmonary toxicity, diarrhea, or colitis must have resolved to baseline before 
treatment is resumed. Participants with persistent Grade 1 pneumonitis after completion of a 
steroid taper over at least 1 month may be eligible for retreatment if discussed with and 
approved by the BMS Medical Monitor.
•
Participants who received systemic corticosteroids for management of any drug-related 
toxicity must be off corticosteroids or have tapered down to an equivalent dose of prednisone
≤10 mg/day.
•
Drug-related endocrinopathies adequately controlled with only physiologic hormone 
replacement may resume treatment.
•
Dose delay of nivolumab which results in treatment interruption of > 6 weeks requires 
treatment discontinuation, with exceptions as noted in Section 8.1.
•
Participants who delay study treatment due to any Grade 3 amylase or lipase abnormality that 
is not associated with symptoms or clinical manifestations of pancreatitis, which is assessed 
by the investigator to be related to ipilimumab and not to nivolumab, may resume nivolumab 
when the amylase or lipase abnormality has resolved to Grade < 3. The BMS Medical Monitor 
should be consulted prior to resuming nivolumab in such participants. 
7.4.3.2
Criteria to Resume Ipilimumab Dosing
Participants may resume treatment with nivolumab and ipilimumab when drug-related AE(s) 
resolve(s) to Grade 1 or baseline value, with the following exceptions: 
•
Participants may resume treatment in the presence of Grade 2 fatigue.
•
Participants who have not experienced a Grade 3 drug-related skin AE may resume treatment 
in the presence of Grade 2 skin toxicity.
•
Participants 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.
•
Participants with combined Grade 2 AST/ALT and total bilirubin values meeting 
discontinuation parameters (Section 8.1) should have treatment permanently discontinued.
•
Drug-related pulmonary toxicity, diarrhea, or colitis must have resolved to baseline before 
treatment is resumed.
•
Participants who received systemic corticosteroids for management of any drug-related 
toxicity must be off corticosteroids or have tapered down to an equivalent dose of prednisone 
≤10 mg/day.
•
Drug-related endocrinopathies adequately controlled with only physiologic hormone 
replacement may resume treatment after consultation with the BMS Medical Monitor.
•
Dose delay of ipilimumab which results in no ipilimumab dosing for > 12 weeks requires 
ipilimumab discontinuation, with exceptions as noted in Section 8.1.
•
Ipilimumab may not be resumed sooner than 6 weeks (± 5days) after the prior ipilimumab 
dose.
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•
In general, participants who meet criteria to resume ipilimumab will also have met criteria to 
resume nivolumab, so it should be feasible to synchronize dosing of both drugs when resuming 
ipilimumab. In order to facilitate this, 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.
•
NOTE: One exception occurs when ipilimumab and nivolumab doses are delayed due to 
drug-related Grade 3 amylase or lipase abnormalities not associated with symptoms or clinical 
manifestations of pancreatitis. If the investigator assesses the Grade 3 amylase or lipase 
abnormality is related to ipilimumab and not related to nivolumab, nivolumab may be resumed 
when the amylase or lipase abnormality resolves to Grade < 3 but ipilimumab may only resume
when the amylase or lipase abnormality resolves to Grade 1 or baseline. Investigator attribution 
of this toxicity to the ipilimumab dosing must be clearly noted in the participant's medical 
chart. The BMS Medical Monitor should be consulted prior to resuming ipilimumab in the
participant. 
7.4.3.3
Criteria to Resume Treatment with Chemotherapy 
•
Participants may resume treatment with chemotherapy when the ANC returns to 1500/μl. l, the 
platelet count returns to 100,000/mm3, and all other drug-related toxicities have returned to 
baseline or Grade 1 (or Grade 2 for alopecia and fatigue).
•
If a participant fails to meet criteria for re-treatment, then re-treatment should be delayed, and 
the participant should be re-evaluated weekly or more frequently as clinically indicated. Any 
participant who fails to recover from toxicity attributable to chemotherapy to baseline or Grade 
1 (except Grade 2 alopecia and fatigue) within 6 weeks from the last dose given should 
discontinue the drug(s) that caused the delay.
•
When resuming chemotherapy treatment, please follow the dose reduction recommendations 
in Section 7.4.2.2.
7.5
Preparation/Handling/Storage/Accountability
For nivolumab and ipilimumab, please refer to the current version of the Investigator Brochures 
and/or pharmacy manual for complete storage, handling, dispensing, and infusion information. 
The investigational product should be stored in a secure area according to local regulations. It is 
the responsibility of the investigator to ensure that investigational product is only dispensed to 
study Participants. The investigational product must be dispensed only from official study sites by 
authorized personnel according to local regulations.
The product storage manager should ensure that the study treatment is stored in accordance with 
the environmental conditions (temperature, light, and humidity) as determined by BMS. If 
concerns regarding the quality or appearance of the study treatment arise, the study treatment
should not be dispensed and contact BMS immediately.
Study treatment not supplied by BMS will be stored in accordance with the package insert.
Investigational product documentation (whether supplied by BMS or not) must be maintained that 
includes all processes required to ensure drug is accurately administered. This includes 
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7.7.2.1
Permitted Therapy
Participants are permitted the use of topical, ocular, intra-articular, intranasal, and inhalational 
corticosteroids (with minimal systemic absorption). Adrenal replacement steroid doses > 10 mg 
daily prednisone are permitted. A brief (less than 3 weeks) course of corticosteroids for 
prophylaxis (eg, contrast dye allergy) or for treatment of non-autoimmune conditions 
(eg, delayed-type hypersensitivity reaction caused by a contact allergen) is permitted.
Regular concomitant use of bisphosphonates and RANK-L inhibitors for prevention or reduction 
of skeletal-related events in patients with bone metastases is allowed if initiated prior to first dose 
of study therapy. Prior palliative radiotherapy must have been completed at least 2 weeks prior to 
treatment.
7.7.2.2
Palliative Local Therapy
Palliative local therapy, including palliative radiation therapy- and palliative surgical resection, to 
symptomatic non-target bone lesions, skin lesions, or CNS lesions is permitted prior to 
discontinuation of study treatment for participants who do not have evidence of overall clinical or 
radiographic progression per RECIST 1.1. Palliative local therapy to lesions causing hemoptysis 
may also be permitted prior to discontinuation of study treatment in participants who do not have 
evidence of overall clinical or radiographic progression per RECIST 1.1, provided that the lesions 
undergoing palliative local therapy are not the only sites of measurable disease and the case is 
discussed with and approved by the BMS Medical Monitor.
Participants requiring palliative local therapy should be evaluated for objective evidence of disease 
progression prior to the initiation of such therapy, particularly if the most recent tumor assessment 
was more than 4 weeks prior to the start of local therapy. If progression per RECIST 1.1 is 
identified on any tumor assessments prior to the initiation of palliative local therapy, then 
participants must either discontinue study drug treatment or they must meet criteria to continue 
treatment beyond progression (Section 7.1.3) in order to resume immunotherapy after palliative 
local therapy. If radiographic progression per RECIST 1.1 is identified prior to the initiation of 
palliative local therapy, sites must request a BICR from the third party radiology vendor
(Section 5.1.1.2). However, the initiation of palliative local therapy need not be delayed to await 
the assessment by the BICR.
The potential for overlapping toxicities with radiotherapy and nivolumab/ipilimumab currently is 
not known; however, anecdotal data suggests that it is tolerable. As concurrent radiotherapy and 
nivolumab/ipilimumab have not been formally evaluated, in cases where palliative radiotherapy is 
required for a tumor lesion, then nivolumab/ipilimumab should be withheld for at least 1 week 
before, during, and 1 week after radiation. Participants should be closely monitored for any 
potential toxicity during and after receiving radiotherapy, and AEs should resolve to Grade 
≤1 prior to resuming nivolumab or nivolumab plus ipilimumab.
7.7.2.3
Imaging Restriction and Precautions
It is the local imaging facility’s responsibility to determine, based on participant attributes 
(eg, allergy history, diabetic history and renal status), the appropriate imaging modality and 
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contrast regimen for each participant. Imaging contraindications and contrast risks should be 
considered in this assessment. Participants with renal insufficiency should be assessed as to 
whether or not they should receive contrast and if so, what type and dose of contrast is appropriate. 
Should a participant have a contraindication for CT IV contrast, a non-contrast CT of the chest and 
a contrast enhanced MRI of the abdomen and pelvis may be obtained.
Specific to MRI, participants with severe renal insufficiency (ie, estimated glomerular filtration 
rate (eGFR) < 30 mL/min/1.73 m2) are at increased risk of nephrogenic systemic fibrosis. MRI 
contrast should not be given to this participant population. In addition, participants are excluded 
from MRI if they have tattoos, metallic implants, pacemakers, etc. The ultimate decision to 
perform MRI in an individual participant in this study rests with the site radiologist, the 
investigator and the standard set by the local Ethics Committee.
7.8
Treatment After the End of the Study
At the end of the study, BMS will not continue to provide BMS supplied study treatment to 
participants/investigators unless BMS chooses to extend the study. The investigator should ensure 
that the participant receives appropriate standard of care to treat the condition under study.
BMS reserves the right to terminate access to BMS supplied study treatment if any of the following 
occur: a) the study is terminated due to safety concerns; b)the development of the nivolumab or 
ipilimumab is terminated for other reasons, including but not limited to lack of efficacy and/or not 
meeting the study objectives; c) the participant can obtain medication from a government 
sponsored or private health program. In all cases BMS will follow local regulations
8
DISCONTINUATION CRITERIA
8.1
Discontinuation from Study Treatment
For all participants, global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be reported as ‘symptomatic 
deterioration’ in the source data and in the case report form. Tumor assessments for participants 
who discontinue study treatment without radiographic progression, confirmed by BICR
(Section 5.1.1.2), should continue as per protocol until radiographic progression is determined by 
blinded independent central review.
If participant is intolerant of nivolumab treatment during the chemotherapy cycles, participant
should be withdrawn from the treatment phase of the study.
Chemotherapy dose reduction is allowed on study. Any participant with two prior dose reductions 
to one agent who experiences a toxicity that would cause a third dose reduction must be 
discontinued from that agent. A participant in treatment arm who is discontinued from the 
chemotherapy treatment will remain on the study and receive nivolumab and ipilimumab therapy 
with option of pemetrexed maintenance (non-squamous histology only).
If the investigator assesses the drug-related AE to be related to ipilimumab only and not related to 
nivolumab, ipilimumab dosing alone may be discontinued while nivolumab dosing is delayed until 
the participant meets criteria to resume nivolumab treatment.
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8.1.1
Nivolumab Dose Discontinuation
Treatment with nivolumab should be permanently discontinued for any of the following:
•
Any Grade ≥2 drug-related uveitis or eye pain or blurred vision that does not respond to topical 
therapy and does not improve to Grade 1 severity within the re-treatment period OR requires 
systemic treatment
•
Any Grade ≥2 drug-related pneumonitis or interstitial lung disease that does not resolve to 
dose delay and systemic steroids (also see Pulmonary Adverse Event Management Algorithm);
•
Any Grade 3 drug-related bronchospasm, hypersensitivity reaction, or infusion reaction, 
regardless of duration;
•
Any Grade 3 non-skin, drug-related adverse event lasting > 7 days, with the following 
exceptions for uveitis, pneumonitis, bronchospasm, diarrhea, colitis, neurologic toxicity, 
hypersensitivity reactions, infusion reactions, endocrinopathies, and laboratory abnormalities:
•
Grade 3 drug-related uveitis, pneumonitis, bronchospasm, diarrhea, colitis, neurologic toxicity, 
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 (also see Hepatic Adverse Event Management Algorithm):
•
Any drug related liver function test (LFT) abnormality that meets the following criteria require 
discontinuation 
−
Grade ≥3 drug-related AST, ALT or Total Bilirubin requires discontinuation*
* In most cases of Grade 3 AST or ALT elevation, study drugs(s) will be permanently 
discontinued. If the investigator determines a possible favorable benefit/risk ratio that 
warrants continuation of study drugs(s), a discussion between the investigator and the BMS 
medical monitor or designee must occur.
−
Concurrent AST or ALT > 3 x ULN and total bilirubin > 2x ULN
−
Any Grade 4 drug-related adverse event or laboratory abnormality, except for the following 
events, which do not require discontinuation:
♦Grade 4 neutropenia ≤7 days
♦Grade 4 lymphopenia or leukopenia
♦Isolated Grade 4 amylase or lipase abnormalities that are not associated with symptoms 
or clinical manifestations of pancreatitis and decrease to < Grade 4 within 1 week of 
onset. The BMS Medical Monitor should be consulted for Grade 4 amylase or lipase
abnormalities.
♦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
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♦Grade 4 drug-related endocrinopathy adverse events such as adrenal insufficiency, 
ACTH deficiency, hyper- or hypothyroidism, or glucose intolerance, which resolve or 
are adequately controlled with physiologic hormone replacement (corticosteroids, 
thyroid hormones) or glucose controlling agents, respectively, may not require 
discontinuation after discussion with and approval from the BMS Medical Monitor.
−
Dosing delays lasting > 6 weeks from the previous dose that occur for non-drug-related 
reasons may be allowed if approved by the BMS medical monitor. Prior to re-initiating 
treatment in a participant with a dosing delay lasting > 6 weeks, the BMS medical monitor 
must be consulted. Tumor assessments should continue as per protocol even if dosing is 
delayed. Periodic study visits to assess safety and laboratory studies should also continue 
every 6 weeks or more frequently if clinically indicated during such dosing delays.
−
Any adverse event, laboratory abnormality, or intercurrent illness which, in the judgment 
of the Investigator, presents a substantial clinical risk to the participant with continued 
nivolumab dosing.
The assessment for discontinuation of nivolumab should be made separately from the assessment 
made for discontinuation of ipilimumab. 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. 
If a participant meets criteria for discontinuation and investigator is unable to determine whether 
the event is related to nivolumab, ipilimumab or chemotherapy (if chemotherapy is part of the 
treatment regimen), the participant should discontinue all treatment: nivolumab, ipilimumab and 
chemotherapy (if chemotherapy is part of the treatment regimen), and be taken off the treatment 
phase of the study. Continuation of ipilimumab after discontinuation of nivolumab is not allowed 
on study. The assessment for discontinuation of nivolumab and ipilimumab should be made 
separately from the assessment made for discontinuation of chemotherapy doublet. If criteria for 
discontinuation for nivolumab and ipilimumab are met before the nivolumab and ipilimumab plus 
platinum doublet chemotherapy cycles have been completed, platinum doublet chemotherapy may 
continue until 2 cycles have been completed. 
8.1.2
Ipilimumab Dose Discontinuation
Ipilimumab should be permanently discontinued if any of the following criteria are met:
•
Any Grade ≥2 drug-related uveitis or eye pain or blurred vision that does not respond to topical 
therapy and does not improve to Grade 1 severity within 2 weeks OR requires systemic 
treatment;
•
Any Grade ≥3 bronchospasm or other hypersensitivity reaction;
•
Any other Grade 3 non-skin, drug-related adverse with the following exceptions for laboratory 
abnormalities, grade 3 nausea and vomiting, grade 3 neutropenia and thrombocytopenia, and 
symptomatic endocrinopathies which resolved (with or without hormone substitution);
•
Any drug-related liver function test (LFT) abnormality that meets the following criteria require 
discontinuation:
−
Grade ≥3 drug related AST, ALT or Total Bilirubin required discontinuation
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♦* In most cases of Grade 3 AST, ALT evaluation study drug(s) will be permanently 
discontinued. If the investigator determines a possible favorable benefit/risk ratio that 
warrants continuation of study drug(s), a discussion between the investigator and the 
BMS medical monitor or designee must occur.
−
Concurrent AST or ALT > 3 x ULN and total bilirubin > 2X ULN
•
Any Grade 4 drug-related adverse event or laboratory abnormality, except for the following 
events, which do not require discontinuation:
−
Grade 4 neutropenia ≤7 days
−
Grade 4 lymphopenia or leukopenia
−
Isolated Grade 4 amylase or lipase abnormalities which are not associated with symptoms 
or clinical manifestations of pancreatitis. 
−
Isolated Grade 4 electrolyte imbalances/abnormalities that are not associated with clinical 
sequelae and are corrected with supplementation/appropriate management within 72 hours 
of their onset
−
Grade 4 drug-related endocrinopathy adverse events such as adrenal insufficiency, ACTH 
deficiency, hyper- or hypothyroidism, or glucose intolerance, which resolve or are 
adequately controlled with physiologic hormone replacement (corticosteroids, thyroid 
hormones) or glucose controlling agents, respectively, may not require discontinuation 
after discussion with and approval from the BMS Medical Monitor.
•
Any treatment delay resulting in no ipilimumab dosing for > 12 weeks with the following 
exceptions: Dosing delays to manage drug-related adverse events, such as prolonged steroid 
tapers, are allowed. Prior to re-initiating treatment in a participant with a dosing delay lasting 
> 12 weeks, the BMS medical monitor must be consulted. Tumor assessments should continue 
as per protocol even if dosing is delayed.
•
Dosing delays resulting in no ipilimumab dosing for > 12 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 participant with a dosing delay lasting > 12 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 participant with continued 
ipilimumab 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.
If a participant meets criteria for discontinuation and investigator is unable to determine whether 
the event is related to nivolumab, ipilimumab or chemotherapy (if chemotherapy is part of the 
treatment regimen), the participant should discontinue nivolumab, ipilimumab or chemotherapy 
(if chemotherapy is part of the treatment regimen) and be taken off the treatment phase of the 
study. The assessment for discontinuation of nivolumab and ipilimumab should be made separately 
from the assessment made for discontinuation of chemotherapy doublet. If criteria for 
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discontinuation for nivolumab and ipilimumab are met before the nivolumab and ipilimumab plus 
platinum doublet chemotherapy cycles have been completed, platinum doublet chemotherapy may 
continue until 2 cycles have been completed. 
8.1.3
Chemotherapy Dose Discontinuation 
Except where specified below, chemotherapy drugs in the platinum doublet chemotherapy regimen 
or pemetrexed should be discontinued for any of the following:
•
Any Grade ≥3 peripheral neuropathy
•
Grade ≥3 drug-related thrombocytopenia associated with clinically significant bleeding
•
Any drug-related liver function test (LFT) abnormality that meets the following criteria 
requires discontinuation:
−
AST or ALT > 5-10x ULN for > 2 weeks
−
AST or ALT > 10x ULN
−
Total bilirubin > 5 x ULN
−
Concurrent AST or ALT > 3 x ULN and total bilirubin > 2 x ULN
•
Any drug-related adverse event which recurs after two prior dose reductions for the same 
drug-related adverse event 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 Grade 4 drug-related adverse event which the investigator deems is inappropriate to be 
managed by dose reduction(s) requires discontinuation of the drug(s) felt to be causing the 
event. The drug not felt to be related to the event may be continued.
•
Any event that leads to delay in dosing of any study drug(s) for > 6 weeks from the previous 
dose requires discontinuation of that drug(s) with the following exception:
−
Dosing delays lasting > 6 weeks from the previous dose that occur for non-drug-related 
reasons may be allowed if approved by the BMS medical monitor. Prior to re-initiating 
treatment in a participant with a dosing delay lasting > 6 weeks, the BMS medical monitor 
must be consulted. Periodic study visits to assess safety and laboratory studies should also 
continue every 6 weeks or more frequently if clinically indicated during such dosing 
delays.
•
Any adverse event, laboratory abnormality, or intercurrent illness which, in the judgment of 
the Investigator, presents a substantial clinical risk to the participant with continued platinum 
doublet chemotherapy dosing. Investigators should consult local labeling for the chemotherapy 
drugs being administered to any given participant for additional guidance on dose 
discontinuation.
•
For participants in control arm for whom it was indicated that maintenance pemetrexed therapy 
would be administered, 4 cycles of chemotherapy should be given prior to starting the 
maintenance treatment. However, participants who experience grade 4 treatment-related 
hematologic toxicity, or grade 3 treatment-related non-hematologic toxicity, may start 
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maintenance therapy after 3 cycles of chemotherapy. The nature and grade of the toxicity must 
be clearly noted, and the medical monitor must be notified.
•
In addition, participants receiving cisplatin with pemetrexed must discontinue cisplatin if the 
calculated creatinine clearance decreases to < 50 mL/min based on the Cockcroft Gault 
formula) The other drug (pemetrexed) may be continued, and the platinum agent may, at the 
investigator’s discretion, be switched to carboplatin for the remainder of the platinum doublet 
cycles when the participant meets retreatment criteria.
Note: For participants in treatment arm, if the investigator is unable to determine whether an 
adverse event is due to nivolumab or ipilimumab or platinum doublet chemotherapy, then all drugs 
must be discontinued. The assessment for discontinuation of nivolumab and ipilimumab should be 
made separately from the assessment made for discontinuation of chemotherapy doublet. If criteria 
for discontinuation for nivolumab and ipilimumab are met before the nivolumab and ipilimumab 
plus platinum doublet chemotherapy cycles have been completed, platinum doublet chemotherapy 
may continue until 2 cycles have been completed. 
A participant in treatment arm who is discontinued from the chemotherapy treatment due to 
toxicities related to chemotherapy only, will remain on the study and receive nivolumab and 
ipilimumab therapy.
8.2
Discontinuation from Study 
Participants who request to discontinue study treatment will remain in the study and must continue 
to be followed for protocol specified follow-up procedures. The only exception to this is when a 
participant specifically withdraws consent for any further contact with him/her or persons 
previously authorized by participant to provide this information. 
•
Participants should notify the investigator of the decision to withdraw consent from future 
follow-up in writing, whenever possible.
•
The withdrawal of consent should be explained in detail in the medical records by the 
investigator, as to whether the withdrawal is from further treatment with study treatment only 
or also from study procedures and/or post treatment study follow-up, and entered on the 
appropriate CRF page.
•
In the event that vital status (whether the participant is alive or dead) is being measured, 
publicly available information should be used to determine vital status only as appropriately 
directed in accordance with local law.
•
If the participant withdraws consent for disclosure of future information, the sponsor may 
retain and continue to use any data collected before such a withdrawal of consent.
In the case of pregnancy, the investigator must immediately notify the BMS Medical 
Monitor/designee of this event. In the event a normal healthy female participant becomes pregnant 
during a clinical trial, the study treatment must be discontinued immediately. In most cases, the 
study treatment will be permanently discontinued in an appropriate manner (eg, dose tapering if 
necessary for participant safety). Please call the BMS Medical Monitor within 24 hours of 
awareness of the pregnancy. If the investigator determines a possible favorable benefit/risk ratio 
that warrants continuation of study treatment, a discussion between the investigator and the BMS 
Medical Monitor/designee must occur.
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All participants who discontinue study treatment should comply with protocol specified follow-up 
procedures as outlined in Section 2. The only exception to this requirement is when a participant
withdraws consent for all study procedures including post-treatment study follow-up or loses the 
ability to consent freely (ie, is imprisoned or involuntarily incarcerated for the treatment of either 
a psychiatric or physical illness).
If study treatment is discontinued prior to the participant’s completion of the study, the reason for 
the discontinuation must be documented in the participant’s medical records and entered on the 
appropriate case report form (CRF) page.
8.2.1
Post Study Treatment Study Follow-up
In this study, OS is a key endpoint of the study. Post study follow-up is of critical importance and 
is essential to preserving participant safety and the integrity of the study. Participants who 
discontinue study treatment must continue to be followed for collection of outcome and/or survival 
follow-up data as required and in line with Section 5 until death or the conclusion of the study.
8.3
Lost to Follow-Up
•
All reasonable efforts must be made to locate participants to determine and report their ongoing 
status. This includes follow-up with persons authorized by the participant.
•
Lost to follow-up is defined by the inability to reach the participant after a minimum of three
documented phone calls, faxes, or emails as well as lack of response by participant to one 
registered mail letter. All attempts should be documented in the participant’s medical records.
•
If it is determined that the participant has died, the site will use permissible local methods to 
obtain date and cause of death.
•
If investigator’s use of third party representative to assist in the follow-up portion of the study 
has been included in the participant’s informed consent, then the investigator may use a 
Sponsor retained third party representative to assist site staff with obtaining participant’s 
contact information or other public vital status data necessary to complete the follow-up 
portion of the study. 
•
The site staff and representative will consult publicly available sources, such as public health 
registries and databases, in order to obtain updated contact information.
•
If after all attempts, the participant remains lost to follow-up, then the last known alive date as 
determined by the investigator should be reported and documented in the participant’s medical 
records.
9
STUDY ASSESSMENTS AND PROCEDURES
•
Study procedures and timing are summarized in the Schedule of Activities. 
•
Protocol waivers or exemptions are not allowed.
•
All immediate safety concerns must be discussed with the Sponsor immediately upon
occurrence or awareness to determine if the participant should continue or discontinue 
treatment.
•
Adherence to the study design requirements, including those specified in the Schedule of 
Activities, is essential and required for study conduct.
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•
All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria before randomization. The investigator will maintain a 
screening log to record details of all participants screened and to confirm eligibility or record 
reasons for screening failure, as applicable.
•
Procedures conducted as part of the participant’s routine clinical management (eg, blood count) 
and obtained before signing of informed consent may be utilized for screening or baseline 
purposes provided the procedure meets the protocol-defined criteria and has been performed 
within the timeframe defined in the Schedule of Activities.
9.1
Efficacy Assessments
Study evaluations will take place in accordance with the Schedule of Activities in Section 2.
Images will be submitted to an imaging core lab. Sites should be trained prior to scanning the first 
study participant. Image acquisition guidelines and submission process will be outlined in the 
CA2099LA Imaging Charter to be provided by the core lab. 
9.1.1
Methods of Measurements
The following imaging assessments should be performed at pre-specified intervals: CT of the 
chest, CT or MRI of the abdomen, pelvis, and other known sites of disease.
•
Baseline assessment must occur prior to dosing
•
CT scans should be acquired with slice thickness of 5 mm or less with no intervening gap 
(continuous) 
•
Should a participant have a contraindication for CT IV contrast, a non-contrast CT of the chest 
and a contrast enhanced MRI of the abdomen and pelvis and other sites of disease may be 
obtained. MRIs should be acquired with slice thickness of 5 mm or less with no gap 
(continuous).
•
Every attempt should be made to image each participant using an identical acquisition protocol 
on the same scanner for all imaging time points. 
NOTE: Use of CT component of a PET/CT scanner: Combined modality scanning, such as with 
FDG-PET/CT, is increasingly used in clinical care and is a modality/technology that is in rapid 
evolution; therefore, the recommendations outlined here may change rather quickly with time. If 
a site can document that the CT performed as part of a FDG-PET/CT is of identical diagnostic 
quality to a diagnostic CT (with IV contrast), then the CT portion of the FDG-PET/CT can be used 
for RECIST 1.1 measurements. Note, however, that the FDG-PET portion of the scan introduces 
additional data which may bias an investigator if it is not routinely or serially performed. 
MRI of brain is required at screening in order to rule out active metastatic disease. 
Bone scan or PET scan is not adequate for assessment of RECIST 1.1 response in target lesions. 
In selected circumstances where such modalities are the sole modality used to assess certain non -
target organs, those non-target organs may be evaluated less frequently. For example, bone scans 
may need to be repeated only when complete response is identified in target disease or when 
progression in bone is suspected.
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9.1.2
Imaging and Clinical Assessment 
Screening baseline tumor assessments must be performed within 28 days prior to randomization. 
In addition to the chest, abdomen, pelvis, and brain (to rule out brain metastases), all known sites 
of disease should be assessed at baseline. Subsequent assessments should include chest, abdomen, 
pelvis, and all known sites of disease using the same imaging method and technique as was used 
at baseline. 
Radiographic tumor response will be assessed at week 6 (± 7 days) from first dose date, then every 
6 weeks (± 7 days) for the first 12 months (until Week 48) and every 12 weeks (± 7 days) thereafter, 
until disease progression is documented or treatment is discontinued (whichever occurs later). 
Participants with a history of brain metastasis may have surveillance MRI approximately every 12 
weeks (± 7 days) from the date of first dose, or sooner if clinically indicated.
Tumor assessments for each participant 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 participant and determine if RECIST 1.1 criteria for progression 
have been met. The independent assessment of whether or not the given participant met RECIST 
1.1 criteria for progression will be provided to the site. Participants whose disease progression is 
not confirmed centrally will be required to continue tumor assessments (if clinically feasible) 
according to the protocol-specified schedule. 
The BICR will also review tumor images in all treated participants to determine RECIST 1.1 
response for the analyses of ORR and PFS. Details of the BICR responsibilities and procedures 
will be specified in the BICR charter.
9.1.2.1
Assessment of Baseline Tumor Assessment
Screening/baseline imaging (ie, CT of the chest, CT or MRI of the abdomen, pelvis, and other 
known sites of disease) should be submitted to the imaging core lab. MRI preferred or CT scan of 
the brain should be performed within 28 days of randomization and submitted to the imaging core 
lab. 
9.1.2.2
BICR Assessment of Progression
Sites should submit all scans to BICR on a rolling basis, preferably within 7 days of scan 
acquisition, throughout the duration of the study. BICR will review scans on a rolling basis and 
remain blinded to treatment arm and investigator assessment of submitted scans. When progression 
is diagnosed by the investigator, the site will inform the imaging core lab, so that the BICR 
assessment of progression can be performed. 
Participants whose progression is not confirmed by the BICR will be required to continue tumor 
assessments (if clinically feasible) according to the protocol-specified schedule or sooner if 
clinically indicated until the BICR confirms progression on a subsequent tumor assessment. Also, 
if participants discontinue treatment without radiographic progression, tumor assessments will 
continue according to the protocol specified schedule, as noted in Section 2, until progression has 
been confirmed by BICR.
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9.1.3
Study Outcomes Research Assessments
The evaluation of health related quality of life is an increasingly important aspect of a clinical 
efficacy. Such data provides an understanding of the impact of treatment from the participants’ 
perspective and offers insights into the patient experience that may not be captured through 
physician reporting. Generic health related quality of life scales additionally provide data 
necessary in calculating utility values for health economic models. In this study, the EQ-5D (EQ-
5D-3L) will be collected in order to assess the impact of study treatment on generic health related 
quality of life, which will also be used in populating health economic models most notably, cost 
effectiveness analysis. The Lung Cancer Symptom Scale (LCSS) will be collected to assess the 
impact of study treatment on patient reported disease-related symptoms.
The EQ-5D is a standardized instrument for use as a measure of self-reported health status. The 
EQ-5D includes a 5-dimension descriptive system as well as a visual analog rating scale (VAS). 
The EQ-5D descriptive system is comprised of the following 5-dimensions: mobility, self-care, 
usual activities, pain/discomfort, and anxiety/depression. Utility data generated from the EQ-5D
3L are recommended for use in cost effectiveness analysis. The EQ-5D VAS records the 
participant’s self-rated health status on a 100-point vertical visual analogue scale (0=worst 
imaginable health state, 100 = best imaginable health state).
The LCSS is a validated instrument designed to assess the impact of treatment on disease-related 
symptoms. It consists of 6 symptom-specific questions related to dyspnea, cough, fatigue, pain, 
hemoptysis and anorexia plus 3 summary items: symptom distress, interference with activity, and 
global health related quality of life (HRQoL). The questionnaire uses a 24-hour recall period. For 
the six individual symptom measures, the degree of impairment is recorded on a 100 mm visual 
analogue scale with scores from 0 to 100 with zero representing the best score. The LCSS average 
symptom burden index (ASBI) can be derived as the average of scores for the six symptom-related 
items. A clinically meaningful change in ASBI score has been defined as 10 points.
9.2
Adverse Events
The definitions of an AE or serious adverse event (SAE) can be found in Appendix 3.
AEs will be reported by the participant (or, when appropriate, by a caregiver, surrogate, or the 
participant's legally authorized representative). 
The investigator and any designees are responsible for detecting, documenting, and reporting 
events that meet the definition of an AE or SAE and remain responsible for following up AEs that 
are serious, considered related to the study treatment or the study, or that caused the participant to 
discontinue before completing the study. 
Contacts for SAE reporting specified in Appendix 3
9.2.1
Time Period and Frequency for Collecting AE and SAE Information
The collection of nonserious AE information should begin at initiation of study treatment and 
within 100 days of discontinuation of dosing at the timepoints specified in the Schedule of 
Activities (Section 2). 
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Sections 5.6.1 and 5.6.2 in the Investigator Brochure (IB) represent the Reference Safety 
Information to determine expectedness of serious adverse events for expedited reporting. 
Following the participant’s written consent to participate in the study, all SAEs, whether related 
or not related to study drug, must be collected, including those thought to be associated with 
protocol-specified procedures.
All SAEs must be collected that occur during the screening period (after signing the consent) and 
within 100 days of discontinuation of dosing. For participants randomized to treatment and never 
treated with study drug, SAEs should be collected for 30 days from the date of randomization. If 
applicable, SAEs must be collected that relate to any later protocol-specified procedure (eg, a 
follow-up skin biopsy).
The investigator must report any SAE that occurs after these time periods and that is believed to 
be related to study drug or protocol-specified procedure.
•
Medical occurrences that begin before the start of study treatment but after obtaining informed 
consent will be recorded on the appropriate section of the eCRF section.
•
All SAEs will be recorded and reported to Sponsor or designee within 24 hours, as indicated 
in Appendix 3. 
•
The investigator will submit any updated SAE data to the sponsor within 24 hours of this being 
available.
Investigators are not obligated to actively seek AEs or SAEs in former study participants. 
However, if the investigator learns of any SAE, including a death, at any time after a participant 
has been discharged from the study, and he/she considers the event reasonably related to the study 
treatment or study participation, the investigator must promptly notify the sponsor.
The method of evaluating, and assessing causality of AEs and SAEs and the procedures for 
completing and reporting/transmitting SAE reports are provided in Appendix 3.
9.2.2
Method of Detecting AEs and SAEs
Adverse events can be spontaneously reported or elicited during open-ended questioning, 
examination, or evaluation of a participant. (In order to prevent reporting bias, participants should 
not be questioned regarding the specific occurrence of one or more AEs.)
9.2.3
Follow-up of AEs and SAEs
•
Nonserious AEs should be followed to resolution or stabilization, or reported as SAEs if they 
become serious (see Section Appendix 3).
•
Follow-up is also required for nonserious AEs that cause interruption or discontinuation of 
study treatment and for those present at the end of study treatment as appropriate.
•
All identified nonserious AEs must be recorded and described on the nonserious AE page of 
the CRF (paper or electronic). Completion of supplemental CRFs may be requested for AEs 
and/or laboratory abnormalities that are reported/identified during the course of the study.
After the initial AE/SAE report, the investigator is required to proactively follow each participant 
at subsequent visits/contacts. All SAEs, and non-serious AEs of special interest (as defined in 
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Section 9.2.6 will be followed until resolution, until the condition stabilizes, until the event is 
otherwise explained, or until the participant is lost to follow-up (as defined in Section 8.3).
Further information on follow-up procedures is given in Appendix 3.
9.2.4
Regulatory Reporting Requirements for SAEs
•
Prompt notification by the investigator to the Sponsor of SAEs is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of a 
product under clinical investigation are met.
•
An investigator who receives an investigator safety report describing SAEs or other specific 
safety information (eg, summary or listing of SAEs) from the Sponsor will file it along with 
the Investigator’s Brochure and will notify the IRB/IEC, if appropriate according to local 
requirements.
Sponsor or designee will be reporting adverse events to regulatory authorities and ethics 
committees according to local applicable laws including European Directive 2001/20/EC and FDA 
Code of Federal Regulations 21 CFR Parts 312 and 320. A SUSAR (Suspected, Unexpected 
Serious Adverse Reaction) is a subset of SAEs and will be reported to the appropriate regulatory 
authorities and investigators following local and global guidelines and requirements.
9.2.5
Pregnancy
If, following initiation of the study treatment, it is subsequently discovered that a participant is 
pregnant or may have been pregnant at the time of study exposure, including during at least 
5 half-lives after product administration, the investigator must immediately notify the BMS 
Medical Monitor/designee of this event and complete and forward a Pregnancy Surveillance Form 
to BMS Designee within 24 hours of awareness of the event and in accordance with SAE reporting 
procedures described in Appendix 3
In most cases, the study treatment will be permanently discontinued in an appropriate manner (eg, 
dose tapering if necessary for participant safety). Please call the BMS Medical Monitor within 
24 hours of awareness of the pregnancy.
Protocol-required procedures for study discontinuation and follow-up must be performed on the
particpant.
Follow-up information regarding the course of the pregnancy, including perinatal and neonatal 
outcome and, where applicable, offspring information must be reported on the Pregnancy 
Surveillance Form.
Any pregnancy that occurs in a female partner of a male study participant should be reported to 
Sponsor or designee. In order for Sponsor or designee to collect any pregnancy surveillance 
information from the female partner, the female partner must sign an informed consent form for 
disclosure of this information. Information on this pregnancy will be collected on the Pregnancy 
Surveillance Form.
9.2.6
Adverse Events of Special Interest
Definition of Immune-mediated Adverse Events (IMAEs)
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Immune-mediated AEs are specific events that include pneumonitis, diarrhea/colitis, hepatitis, 
nephritis/renal 
dysfunction, 
rash, 
and 
endocrine 
(adrenal 
insufficiency, 
hypothyroidism/thyroiditis, hyperthyroidism, diabetes mellitus, and hypophysitis) for which 
participants received immunosuppressive medication for treatment of the event, with the exception 
of endocrine events (hypothyroidism/thyroiditis, hyperthyroidism, hypophysitis, diabetes mellitus, 
adrenal insufficiency), which are included regardless of treatment since these events are often 
managed without immunosuppression.
IMAEs include events, regardless of causality, occurring within 100 days of the last dose. This list 
is subject to change based on Health Authority feedback or change of MedDRA version. The final 
list used will be described in the CSR.
Table 9.2.6-1 below provides a summary of the IMAEs category and their respective preferred 
terms. This list is subject to change based on Health Authority feedback or change of MedDRA 
version. The final list used will be described in the CSR.
Table 9.2.6-1:
Preferred Terms Included in Analysis of IMAEs to Support 
Warnings and Precautions
IMAE Category
PTs included under IMAE Category
Pneumonitis
Pneumonitis, Interstitial lung disease
Diarrhea/Colitis
Diarrhea, Colitis, Enterocolitis
Hepatitis
Hepatotoxicity, Hepatitis, Hepatitis acute, Autoimmune hepatitis, AST increased, 
ALT increased, Bilirubin increased, ALP increased
Adrenal insufficiency
Adrenal insufficiency
Hypothyroidism/Thyroiditi
s
Hypothyroidism, Thyroiditis
Thyroiditis acute (collapsed with thyroiditis for frequency), Autoimmune 
thyroiditis (collapsed with thyroiditis for frequency)
Hyperthyroidism
Hyperthyroidism
Hypophysitis
Hypophysitis
Diabetes mellitus
Diabetes mellitus, Diabetic ketoacidosis
Nephritis and renal 
dysfunction
Nephritis, Nephritis allergic, Tubulointerstitial nephritis, Acute renal failure, Renal 
failure, Increased creatinine
Rash
Rash, Rash maculopapular
9.2.7
Laboratory Test Result Abnormalities
The following laboratory test result abnormalities should be captured on the nonserious AE CRF 
page or SAE Report Form electronic, as appropriate. Paper forms are only intended as a back-up 
option when the electronic system is not functioning.
•
Any laboratory test result that is clinically significant or meets the definition of an SAE 
•
Any laboratory test result abnormality that required the participant to have study treatment
discontinued or interrupted
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Any laboratory test result abnormality that required the participant to receive specific 
corrective therapy
It is expected that wherever possible, the clinical rather than laboratory term would be used by the 
reporting investigator (eg, anemia versus low hemoglobin value).
9.2.8
Potential Drug Induced Liver Injury (DILI)
Wherever possible, timely confirmation of initial liver-related laboratory abnormalities should 
occur prior to the reporting of a potential DILI event. All occurrences of potential DILIs, meeting 
the defined criteria, must be reported as SAEs (see Section 9.2 and Appendix 3 for reporting 
details).
Potential drug induced liver injury is defined as: 
1.
AT (ALT or AST) elevation > 3 times upper limit of normal (ULN)
AND
2) Total bilirubin > 2 times ULN, without initial findings of cholestasis (elevated serum alkaline 
phosphatase),
AND
3) No other immediately apparent possible causes of AT elevation and hyperbilirubinemia, 
including, but not limited to, viral hepatitis, pre-existing chronic or acute liver disease, or the 
administration of other drug(s) known to be hepatotoxic.
9.2.9
Other Safety Considerations
Any significant worsening noted during interim or final physical examinations, electrocardiogram, 
x-ray filming, any other potential safety assessment required or not required by protocol should 
also be recorded as a nonserious or serious AE, as appropriate, and reported accordingly.
9.3
Overdose
An overdose is defined as the accidental or intentional administration of any dose of a product that 
is considered both excessive and medically important. All occurrences of overdose must be 
reported as an SAE (see Section 9.2).
9.4
Safety
Planned time points for all safety assessments are listed in the Schedule of Activities.
9.4.1
Physical Examinations
See Section 2 Schedule of Activities.
9.4.2
Vital signs
See Section 2 Schedule of Activities.
9.4.3
Clinical Safety Laboratory Assessments
•
Investigators must document their review of each laboratory safety report.
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Hematology (CBC)
Hemoglobin
Hematocrit
Total leukocyte count, including differential
Platelet count
Chemistry
Aspartate aminotransferase (AST)
Alanine aminotransferase (ALT)
Total bilirubin
Alkaline phosphatase
Lactate dehydrogenase (LDH)
Creatinine
Blood Urea Nitrogen (BUN)
Glucose
Albumin
Sodium
Potassium
Chloride
Calcium, Corrected calcium
Phosphorus
Magnesium
Amylase
Lipase
Serology
Serum for hepatitis C antibody or HCV RNA, hepatitis B surface antigen (screening only)
HIV testing (if mandated locally)
Other Analyses
TSH with reflexive fT3 and fT4 if TSH is abnormal
Pregnancy test (WOCBP only: screening and during study)
9.4.4
Imaging Safety Assessment
Any incidental findings of potential clinical relevance that are not directly associated with the 
objectives of the protocol should be evaluated and handled by the Study Investigator as per 
standard medical/clinical judgment. 
9.4.5
Electrocardiogram (ECG)
All subjects who have met the eligibility criteria are required to have a 12-lead ECG performed
during Screening. If clinically indicated, additional ECGs may be obtained during the study
 
 
 
 
 
 
 
 
 
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Population
Description
Enrolled 
All participants who sign informed consent and were registered 
into the IWRS
Randomized
All participants who were randomized to either treatment arm. 
This is the primary dataset for analyses of demography, protocol 
deviations, baseline characteristics, efficacy,
and outcome 
research.
Treated
All participants who received at least one dose of any study 
medication. This is the primary dataset for dosing and safety 
analysis.
The efficacy analysis for secondary endpoints will be performed by treatment group as randomized
for all randomized participants.
10.3
Statistical Analyses
The statistical analysis plan will be developed and finalized before database lock and will describe 
the selection of participants to be included in the analyses, and procedures for accounting for 
missing, unused, and spurious data. Below is a summary of planned statistical analyses of the 
primary and secondary endpoints.
10.3.1
Efficacy Analyses
Endpoint
Statistical Analysis Methods
Primary
Primary endpoint is OS with nivolumab and ipilimumab plus chemotherapy vs. 
chemotherapy alone. OS is defined as the time between the date of the 
randomization date and the date of death due to any cause. OS will be censored 
on the last date a participant was known to be alive.
Secondary
•
BICR assessed PFS with nivolumab and ipilimumab plus chemotherapy vs. 
chemotherapy alone
•
BICR ORR with nivolumab and ipilimumab plus chemotherapy vs. 
chemotherapy alone
•
ORR, PFS, and OS in nivolumab and ipilimumab plus chemotherapy vs. 
chemotherapy in subgroups with different PD-L1 expression levels
•
Tumor cell total somatic mutations and their association with ORR, PFS, 
and OS
PFS is defined as the time from the randomization date to the date of the first 
documented tumor progression as determined by the BICR (per RECIST 1.1), 
or death due to any cause. Participants who die without a reported prior 
progression will be considered to have progressed on the date of their death. 
Participants who did not progress or die will be censored on the date of their 
last evaluable tumor assessment. Participants who did not have any on study 
tumor assessments will be censored on the randomization date. Participants
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Endpoint
Statistical Analysis Methods
who started any palliative local therapy or subsequent anti-cancer therapy 
without a prior reported progression will be censored at the last evaluable tumor 
assessment prior to initiation of the palliative local therapy or subsequent anti-
cancer therapy, whichever procedure occurred first.
ORR is defined as the number of participants with a best overall response 
(BOR) of confirmed CR or PR divided by the number of treated participants. 
BOR is defined as the best response designation, as determined by the BICR, 
recorded between baseline and the date of objectively documented progression 
per RECIST 1.1 or the date of initiation of palliative local therapy or the date 
of initiation of subsequent anti-cancer therapy, whichever occurs first. For 
participants without documented progression or palliative local therapy or 
subsequent anti-cancer therapy, all available response designations will 
contribute to the BOR determination. For participants 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. Complete or partial responses may be claimed only if the criteria 
for each are met at a subsequent time point of ≥4 weeks later. Further 
characterization of the response will include time to OR (time from first dosing 
date to first CR or PR) and depth of response (maximum tumor shrinkage in 
target lesions).
10.3.1.1
Methods for Primary Endpoints
The efficacy analysis will be performed by treatment group as randomized. For the primary 
endpoint, the distribution of OS will be compared in two randomized arms at the two interim and 
final analysis via a two-sided, log-rank test stratified by PD-L1, histology and gender with an 
overall significance level of 0.05. A group sequential testing procedure will be applied to OS to 
control the overall type I error for interim and final analyses. Hazard ratios and corresponding 
two-sided 95% confidence intervals (CI) will be estimated using a Cox proportional hazard model, 
with treatment group as a single covariate, stratified by above factors. OS curves OS medians with 
95% CIs, and OS rates at 6, 12, 18, 24, 36, and 48 months with 95% CIs will be estimated using 
Kaplan-Meier methodology if follow-up requirement is met.
10.3.1.2
Methods for Secondary Endpoints
The efficacy analysis for secondary endpoints will be performed by treatment group as randomized
for all randomized participants. PFS comparison will be conducted. The comparison will be based 
on a two-sided stratified log-rank test, stratified by PD-L1, histology and gender at a two-sided 
alpha of 0.05 level. Hazard ratios and corresponding two-sided 95% confidence intervals (CI) will 
be estimated using a Cox proportional hazard model, with treatment group as a single covariate, 
stratified by above factors. PFS curves, PFS medians with 95% CIs, and PFS rates at 6, 12, 18, 24, 
36, and 48 months with 95% CIs will be estimated using Kaplan-Meier methodology if follow-up 
requirement is met. 
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The comparison of ORR as per BICR assessment will be conducted using a two-sided Cochran-
Mantel-Haenszel (CMH) test stratified by PD-L1, histology and gender to compare the treatment 
group to the control group. An estimate of the difference in ORRs and their corresponding 95% 
exact CI will also be calculated. The number and percentage of participants in each category of 
best overall response per BICR (confirmed complete response [CR], confirmed partial response 
[PR], stable disease [SD], progressive disease [PD], or unable to determine [UD]) according to the 
BICR will be presented, by treatment group. An estimate of the response rate and an associated 
exact two-sided 95% CI (Clopper and Pearson) will be presented, by treatment group.
ORR, PFS and OS will also be assessed by treatment groups within subgroups of PD-L1 
expression levels: PD-L1 positive, PD-L1 negative, PD-L1 not quantifiable. The pre-specified 
TMB thresholds will be used to categorize participants in subgroups. ORR, PFS and OS will be 
assess by TMB subgroups.
10.3.2
Safety Analyses
Safety analysis will be performed in all treated participants. Analysis on randomization phase will 
be based on treatment groups. Descriptive statistics of safety will be presented using National 
Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. 
All on-study AEs, drug related AEs, SAEs and drug-related SAEs, AEs and drug-related AEs 
leading to drug discontinuation will be tabulated using worst grade per NCI CTCAE v 4.0 criteria 
by system organ class and preferred term, based on MedDRA terminology. On-study lab 
parameters including hematology, coagulation, chemistry, liver function and renal function will 
be summarized using worst grade per NCI CTCAE v 4.0 criteria.
A tabular summary of the incidence of overall IMAEs (by preferred term) and serious IMAEs will 
be performed. Frequency, management and resolution of IMAEs will be analyzed and a descriptive 
analysis of IMAEs including time-to-onset, severity, duration, action taken with the study drug, 
dosing delays of the study drug, corticosteroid details, re-challenge information and outcome of 
the AE will be individually characterized by IMAE category (see Section 9.2.6).
Endpoint
Statistical Analysis Methods
Exploratory
Safety and tolerability objectives will be measured by the incidence of adverse 
events, serious events, deaths, and laboratory abnormalities. 
 
 
 
 
 
 
Date: 10-May-2017
88
1.0
Approved
930114362
1.0
v

Clinical Protocol
CA2099LA
BMS-936558
nivolumab
 
 
 
 
 
 
 
 
 
 
10.3.6
Interim Analyses 
Two formal interim analysis for the OS are planned after 163 and 198 deaths have been observed 
respectively, which are expected to occur approximately 18 and 21 months after study initiation. 
At the time of the interim analysis, the DMC will review efficacy and safety data as specified in 
the DMC charter. This formal comparison of OS will allow for early stopping for superiority. Lan-
DeMets alpha 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. 
In addition to the formal planned interim analyses for OS, the DMC will have access to periodic 
unblinded interim reports of efficacy and safety to allow a risk/benefit assessment. The Statistical 
Analysis Plan will further describe the planned interim analyses.
Date: 10-May-2017
89
1.0
Approved
930114362
1.0
v

Clinical Protocol
CA2099LA
BMS-936558
nivolumab
Date: 10-May-2017
93
1.0
Approved
930114362
1.0
v