A Study of Nivolumab in Combination With Ipilimumab (Part 1); and Nivolumab Plus Ipilimumab in Combination With Chemotherapy (Part 2) as First Line Therapy in Stage IV Non-Small Cell Lung Cancer (NSCLC)
Phase: PHASE2
Conditions: Non-Small-Cell Lung Cancer
Sponsor: Bristol-Myers Squibb



Clinical Protocol
CA209568
BMS-936558
nivolumab
Revised Protocol No: 06
Date: 11-Jan-2018
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be added to this document is also confidential and proprietary to BMS and must be kept in 
confidence in the same manner as the contents of this document. Any person who receives 
this document without due authorization from BMS is requested to return it to BMS or 
promptly destroy it. All other rights reserved. References to BMS in this protocol may apply 
to partners to which BMS has transferred obligations, eg, a Contract Research Organization 
(CRO).
Replace all previous version(s) of the protocol with this revised protocol and please provide a copy 
of this revised protocol to all study personnel under your supervision, and archive the previous 
versions.
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Revised Protocol No: 06
Date: 11-Jan-2018
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Document
Date of Issue
Summary of Change
Administrative 
Letter 01
14-Oct-2016
Section 4.5.4.1 Criteria to Resume Nivolumab Dosing.  Corrected a 
typographical error found in Revised Protocol v01 dated 21Sep2016, to 
the sixth bullet in regards to prednisone dosing. The ≥sign was 
inadvertently used in lieu of the ≤sign in front of the equivalent dose of 
prednisone 10mg/day.
Revised 
Protocol 01
21-Sep-2016
Incorporates Amendment 01
Amendment 01
21-Sep-2016
To increase sample size and some language adjustments on study 
objectives and stat analyses with added population of PD-L1>=50% and 
efficacy analyses in PD-L1 negative population.
Original 
Protocol
09-Dec-2015
Not applicable
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SUMMARY OF KEY CHANGES OF REVISED PROTOCOL 06
Section Number & Title
Description of Change
Section 3.3.2 Exclusion 
Criteria Other Exclusion 
Criteria 5 e)
Section 3.4.1 Prohibited 
and/or Restricted Treatments
Excluded/prohibited 
treatment with botanical 
preparations during study 
treatment
Section 4.5.1.1 Nivolumab 
and ipilimumab dosing
Sequence of study treatment 
administration updated. 
Additional language added to 
separate dosing for Part 1 
and Part 2
Section 4.5.4.2 Criteria to 
Resume Ipilimumab Dosing
Section 4.5.5.1 Nivolumab 
Dose Discontinuation
Adrenal insufficiency 
requires discontinuation 
regardless of control with 
hormone replacement.
Section 4.5.5.1 Nivolumab 
Dose Discontinuation 
Exceptions for Grade 3 non-
skin, drug-related adverse 
event lasting > 7 days 
updated
Section 5.3 Safety 
Assessments
Pulmonary toxicity 
evaluation added when 
pulmonary-related signs are 
present
Section 5.4 Efficacy 
Assessments
Added the collection of 
additional imaging that may 
demonstrate tumor response 
or progression
Section 5.6 Subheadings 
Table 5.6.2.6-1
Language added to 
subheadings to differentiate 
procedures for Part 1 and 
Part 2
Table reformatted to identify 
biomarker collection Part 1 
and Part 2
Section 7.1 Data Monitoring 
Committee
Removed DMC section
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SYNOPSIS
Clinical Protocol CA209568
Protocol Title: A Study of Nivolumab in Combination with Ipilimumab (Part 1); and Nivolumab plus 
Ipilimumab in Combination with Chemotherapy (Part 2) as First Line Therapy in Stage IV Non-Small Cell 
Lung Cancer (NSCLC)
Investigational Product(s), Dose and Mode of Administration, Duration of Treatment with Investigational 
Product(s): 
Part 1: Nivolumab administered IV over 30 minutes at 3 mg/kg every 2 weeks combined with ipilimumab 
administered IV over 30 minutes at 1 mg/kg every 6 weeks until progression, unacceptable toxicity, or other reasons 
specified in the protocol. Treatment with nivolumab and ipilimumab will be given for a maximum of 2 years from the 
start of study treatment in the absence of disease progression or unacceptable toxicity. 
Part 2: Nivolumab administered IV and ipilimumab administered IV together with 2 cycles of histology based 
platinum doublet chemotherapy as induction treatment, followed by nivolumab and ipilimumab until disease 
progression or unacceptable toxicity. Treatment with nivolumab and ipilimumab will be given for a maximum of 2 
years from the start of study treatment in the absence of disease progression or unacceptable toxicity. 
The 2 cycles of histology-based platinum doublet chemotherapy include: 
Histology-based platinum doublet chemotherapy:
•
Squamous histology: Carboplatin AUC6 + 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. 
Study Phase: 2 
Research Hypotheses:
Part 1: In subjects with PD-L1 positive (membranous staining in ≥1% tumor cells ) and negative (membranous 
staining in < 1% tumor cells) stage IV NSCLC, the administration of nivolumab in combination with ipilimumab as 
first line treatment will lead to clinical benefit as demonstrated by a clinically meaningful objective response rate 
(ORR) and duration of response. 
Part 2: Nivolumab and ipilimumab combined with 2 cycles of standard of care chemotherapy are tolerable 
Objectives: 
Part 1 
Primary Objectives (Part 1)
•
To determine the objective response rate (ORR) in all treated PD-L1 positive (≥1%) subjects by blinded 
independent central review per RECIST 1.1 in stage IV NSCLC subjects treated with nivolumab in combination 
with ipilimumab as first line therapy.
•
To determine the ORR in all treated PD-L1 negative (< 1%) subjects by blinded independent central review per 
RECIST 1.1 in stage IV NSCLC subjects treated with nivolumab in combination with ipilimumab as first line 
therapy. 
Secondary Objectives (Part 1) 
•
To assess ORR by blinded independent central review per RECIST 1.1 in all treated subjects treated with 
nivolumab in combination with ipilimumab as first line therapy.
•
To assess progression free survival (PFS) based on blinded independent central review assessment per RECIST 
1.1
•
To assess overall survival.
•
To assess ORR, PFS and OS by PD-L1 expression levels.
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Part 2 Schema for Safety Lead-in:
The safety lead-in phase will be conducted to evaluate safe dose level: approximately 28 subjects (in order to achieve 
at least 22 DLT evaluable subjects) will receive 2 cycles of induction chemotherapy and nivolumab plus ipilimumab. 
The starting dose of nivolumab is 360mg every 3 weeks and ipilimumab is 1 mg/kg every 6 weeks. 
‘Safe’ is defined as 25% evaluated subjects or less exhibit DLTs (ie, 5 or less subjects with such events out of 22 DLT 
evaluable subjects).
A safety assessment will be performed on the first 10 subjects after a minimum of 9 weeks of follow-up. If 20% or 
less of the first 10 subjects exhibit DLTs (ie, 2 or less subjects with such events), the regimen is determined safe and 
enrollment in subsequent studies using this combination may start while the safety lead in phase of CA209568 is 
ongoing. If more than 20% of the first 10 subjects exhibit DLTs, the full safety cohort will be evaluated prior to using 
this dose regimen in subsequent studies. If more than 25% of the overall DLT evaluable subjects exhibit DLTs, the 
protocol may be amended to evaluate different dose levels, depending on the toxicities observed.
After above 2 cycles of induction treatment, nivolumab and ipilimumab will continue until disease progression or 
unacceptable toxicity, withdrawal of consent, or for a maximum of 2 years from the start of study treatment in in the 
absence of disease progression or inacceptable toxicity. 
Study Population: Subjects must meet all eligibility criteria specified in Section 3.3 of the protocol, including the 
following:
Key inclusion criteria include:
•
Male and female subjects (≥18 years of age).
•
Subjects with histologically confirmed stage IV NSCLC (per the 7th International Association for the Study of 
Lung Cancer classification) squamous or non-squamous histology.
•
No prior systemic therapy for stage IV disease. Prior definitive chemoradiation for locally advanced disease is 
permitted as long as the last administration of chemotherapy or radiotherapy (which ever was given last) occurred 
at least 6 months prior to enrollment. Locally advanced disease with recurrence after concurrent chemoradiation 
therapy (stage IIIB, specifically refers to patients with no curative treatment options) is eligible to enroll. Prior 
adjuvant or neoadjuvant chemotherapy for early stage lung cancer is permitted if completed at least 6 months 
before initiating study treatment. 
•
EGFR/ALK wild type, and ECOG PS 0 or 1
•
Subjects are to have tumor tissue sample available at central lab for PD -L1 IHC testing during the screening 
period.
•
Measurable disease by CT or MRI per RECIST 1.1 criteria
Subjects in safety lead in phase may initiate therapy before the result of IHC testing once the central lab has confirmed 
receiving of samples.  
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Either a formalin-fixed, paraffin-embedded (FFPE) tissue block or unstained tumor tissue sections, with an associated 
pathology report, must be submitted for biomarker evaluation prior to treatment. The tumor tissue sample may be 
fresh or archival if obtained within 6 months prior to Part 1 enrollment (archival tissue is to be obtained within 
3 months prior to Part 2 enrollment), and there can have been no systemic therapy (eg. adjuvant or neoadjuvant 
chemotherapy) given after the sample was obtained. 
Tissue samples must be collected by 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. 
Key Exclusion Criteria
•
Subjects 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 subjects with 
non-squamous histology must have been tested for EGFR mutation status. EGFR test is to be done locally. Use 
of an FDA-approved or local Health Authority approved test is strongly encouraged. Tests other than PCR or next 
generation sequencing will be requested to repeat using PCR or next generation sequencing based method. 
Subjects with non-squamous histology with unknown or indeterminate EGFR status are excluded.
•
Subjects with known ALK translocations which are sensitive to available targeted inhibitor therapy are excluded. 
ALK tests are to be done at local lab and use of a FDA-approved test is strongly encouraged. Subjects with 
unknown or indeterminate ALK status may be enrolled.
•
Subjects with untreated CNS metastases are excluded.
Subjects are eligible if CNS metastases are adequately treated and subjects are neurologically returned to baseline 
(except for residual signs or symptoms related to the CNS treatment) for at least 2 weeks prior to first dose. In addition, 
subjects 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 dose.
•
Subjects with carcinomatous meningitis
•
Subjects with an active, known or suspected autoimmune disease. Subjects with type I diabetes mellitus, 
hypothyroidism only requiring hormone replacement, skin disorders (such as vitiligo, psoriasis, or alopecia) not 
requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are permitted 
to enroll.
•
Subjects with a condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone 
equivalent) or other immunosuppressive medications within 14 days of first treatment. Inhaled or topical steroids, 
and adrenal replacement steroid > 10 mg daily prednisone equivalent, are permitted in the absence of active 
autoimmune disease.
•
Subjects with history of screen failure to any anti-PD-L1 or anti-PD-L1 antibody clinical trial due to PD-L1-
negative status. 
Study Drug: includes both Investigational [Medicinal] Products (IP/IMP) and Non-investigational [Medicinal] 
Products (Non-IP/Non-IMP) as listed:
Study Drugs for CA209568
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
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Part 1:
•
The objective response rate (ORR) in all treated PD-L1 positive (≥1%) subjects by blinded independent central 
review per RECIST 1.1 in stage IV NSCLC subjects treated with nivolumab in combination with ipilimumab as 
first line therapy.
•
The ORR in all treated PD-L1 negative (< 1%) subjects by blinded independent central review per RECIST 1.1 
in stage IV NSCLC subjects treated with nivolumab in combination with ipilimumab as first line therapy. 
Objective response rate (ORR) is based on blinded independent central review assessment per RECIST 1.1 criteria. 
ORR is defined as the number of subjects with a best overall response (BOR) of confirmed CR or PR, divided by the 
number of treated subjects among PD-L1 positive or PD-L1 negative subjects or all treated subjects. BOR is defined 
as the best response designation 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 anticancer therapy, 
whichever occurs first.
Blinded independent central review determined PFS is defined as the time from the first dosing date for treated subjects
in Part 1) to the date of the first documented tumor progression as determined by blinded independent central review
(per RECIST 1.1), or death due to any cause. Subjects who did not progress or die will be censored on the date of their 
last evaluable tumor assessment. Subjects who did not have any on study tumor assessments will be censored at the
first dose date for subjects. Subjects who started any palliative local therapy or subsequent anti-cancer therapy without
a prior reported progression will be censored on the date of their last evaluable tumor assessment prior to the initiation
of the palliative local therapy or subsequent anti-cancer therapy, whichever procedure occurred first.
Part 2: 
•
To determine the incidence of DLT (dose limiting toxicity) during DLT evaluation period (within 9 
weeks after first dose)
•
To determine the safety and tolerability of nivolumab and ipilimumab combined with chemotherapy.
Secondary Endpoints:
Part 1:
•
ORR by blinded independent central review per RECIST 1.1 in all treated subjects treated with nivolumab in 
combination with ipilimumab as first line therapy
•
Progression free survival (PFS) based on blinded independent central review assessment per RECIST 1.1
•
Overall survival (OS)
•
ORR, PFS and OS by PD-L1 expression levels
•
Tumor cell total somatic mutations and their association with ORR, PFS, and OS
Part 2:
•
To evaluate ORR and PFS by investigator assessment using RECIST 1.1, and OS 
OS is defined as the time between the date of the first dosing date and the date of death due to any cause.
Analyses: Demographics and baseline laboratory results will be summarized using descriptive statistics for all treated 
subjects in Part 1 and all treated subjects in Part 2.
Among all treated subjects, the ORR and PFS will be determined by investigator assessment and will be summarized 
by binomial response rates and their corresponding two-sided 95% exact CIs using Clopper-Pearson method. In parts
1 and 2, separately, time to event distribution such as PFS and OS will be estimated using Kaplan Meier techniques. 
To further characterize the response, time to objective response, depth of response, and BOR by response category 
will be summarized using descriptive statistics. 
The safety analysis will be performed in all treated subjects. Descriptive statistics of safety will be presented using the 
National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. 
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APPENDIX 3 RECIST 1.1 GUIDELINES .................................................................. 
 
APPENDIX 4 REVISED PROTOCOL SUMMARY OF CHANGE HISTORY ........ 
 
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1.2
Research Hypothesis 
Part 1: In subjects with PD-L1positive (membranous staining in ≥1% tumor cells) and negative 
(membranous staining in < 1% tumor cells) stage IV NSCLC, the administration of nivolumab in 
combination with ipilimumab as first line treatment will lead to clinical benefit as demonstrated 
by a clinically meaningful objective response rate (ORR) and duration of response.
In individual patient data meta-analysis of 2968 patients suggests that cisplatin or carboplatin 
based chemotherapy has response rate of 30% (cisplatin based chemo) or 24% (carboplatin based 
chemo).25 Clinically meaningful objective response rate is defined as higher than 30% which is 
the ORR of cisplatin based standard of care chemotherapy, and/or considerably longer duration of 
response.
Part 2: nivolumab and ipilimumab combined with standard of care chemotherapy are tolerable in 
first line stage IV NSCLC unselected for PD-L1 expression.
1.3
Objectives(s)
1.3.1
Primary Objectives
Part 1:
•
To determine the objective response rate (ORR) in all treated PD-L1 positive (≥ 1%) subjects 
by blinded independent central review per RECIST 1.1 in stage IV NSCLC subjects treated 
with nivolumab in combination with ipilimumab as first line therapy.
•
To determine the ORR in all treated PD-L1 negative (< 1%) subjects by blinded independent 
central review per RECIST 1.1 in stage IV NSCLC subjects treated with nivolumab in 
combination with ipilimumab as first line therapy.
Part 2:
Primary Endpoints:
•
To determine the incidence of DLT (dose limiting toxicity) during DLT evaluation period 
(within 9 weeks after first dose)
•
To determine the safety and tolerability of nivolumab and ipilimumab combined with 
chemotherapy.
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The study will be conducted in compliance with the protocol. The protocol and any amendments 
and the subject informed consent will receive Institutional Review Board/Independent Ethics 
Committee (IRB/IEC) approval/favorable opinion prior to initiation of the study.
All potential serious breaches must be reported to BMS immediately. A serious breach is a breach 
of the conditions and principles of GCP in connection with the study or the protocol, which is 
likely to affect, to a significant degree, the safety or physical or mental integrity of the subjects of 
the study or the scientific value of the study.
Personnel involved in conducting this study will be qualified by education, training, and 
experience to perform their respective tasks.
This study will not use the services of study personnel where sanctions have been invoked or where 
there has been scientific misconduct or fraud (eg, loss of medical licensure, debarment). 
2.2
Institutional Review Board/Independent Ethics Committee 
Before study initiation, the investigator must have written and dated approval/favorable opinion 
from the IRB/IEC for the protocol, consent form, subject recruitment materials 
(eg, advertisements), and any other written information to be provided to subjects. The investigator 
or BMS should also provide the IRB/IEC with a copy of the Investigator Brochure or product 
labeling information to be provided to subjects and any updates. 
The investigator or BMS should provide the IRB/IEC with reports, updates and other information 
(eg, expedited safety reports, amendments, and administrative letters) according to regulatory 
requirements or institution procedures.
2.3
Informed Consent
Investigators must ensure that subjects are clearly and fully informed about the purpose, potential 
risks, and other critical issues regarding clinical studies in which they volunteer to participate. 
In situations where consent cannot be given to subjects, their legally acceptable representatives 
(as per country guidelines) are clearly and fully informed about the purpose, potential risks, and 
other critical issues regarding clinical studies in which the subject volunteers to participate. 
BMS will provide the investigator with an appropriate (ie, Global or Local) sample informed 
consent form which will include all elements required by ICH, GCP and applicable regulatory 
requirements. The sample informed consent form will adhere to the ethical principles that have 
their origin in the Declaration of Helsinki.
Investigators must:
A. Provide a copy of the consent form and written information about the study in the language in 
which the subject is most proficient prior to clinical study participation. The language must be 
non-technical and easily understood. 
B. Allow time necessary for subject or subject's legally acceptable representative to inquire about 
the details of the study.
C. Obtain an informed consent signed and personally dated by the subject or the subject's legally 
acceptable representative and by the person who conducted the informed consent discussion. 
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D. Obtain the IRB/IEC’s written approval/favorable opinion of the written informed consent form 
and any other information to be provided to the subjects, prior to the beginning of the study, 
and after any revisions are completed for new information.
E. If informed consent is initially given by a subject’s legally acceptable representative or legal 
guardian, and the subject subsequently becomes capable of making and communicating his or 
her informed consent during the study, consent must additionally be obtained from the subject.
F. Revise the informed consent whenever important new information becomes available that is 
relevant to the subject's consent. The investigator, or a person designated by the investigator, 
should fully inform the subject or the subject's legally acceptable representative or legal 
guardian, of all pertinent aspects of the study and of any new information relevant to the 
subject's willingness to continue participation in the study. This communication should be 
documented. 
The confidentiality of records that could identify subjects must be protected, respecting the privacy 
and confidentiality rules applicable to regulatory requirements, the subjects' signed ICF and, in the 
US, the subjects’ signed HIPAA Authorization.
The consent form must also include a statement that BMS and regulatory authorities have direct 
access to subject records. 
Subjects unable to give their written consent (eg, stroke or subjects with or severe dementia) may 
only be enrolled in the study with the consent of a legally acceptable representative. The subject 
must also be informed about the nature of the study to the extent compatible with his or her 
understanding, and should this subject become capable, he or she should personally sign and date 
the consent form as soon as possible. The explicit wish of a subject who is unable to give his or 
her written consent, but who is capable of forming an opinion and assessing information to refuse 
participation in, or to be withdrawn from, the clinical study at any time should be considered by 
the investigator.
The rights, safety, and well-being of the study subjects are the most important considerations and 
should prevail over interests of science and society.
3
INVESTIGATIONAL PLAN
3.1
Study Design and Duration
Adults (≥18 years) male and female subjects, with stage IV non-small cell lung cancer, previously 
untreated for advanced disease are eligible for enrollment, irrespectively of PD-L1 expression. 
Subjects will be assessed by PD-L1 expression, and categorized into 4 groups (PD-L1 positive, 
PD-L1 ≥50%, PD-L1 negative, and PD-L1 not quantifiable). PD-L1 status will be determined by 
Dako PD-L1 IHC 28-8 pharmDx test for immunohistochemical (IHC) staining of PD-L1 protein 
in the submitted tumor sample.
•
PD-L1 positive (≥1% tumor cell membrane staining in a minimum of a hundred evaluable 
tumor cells) 
•
PD-L1 ≥50% (≥50% tumor cell membrane staining in a minimum of a hundred evaluable 
tumor cells) and is a subset of all PD-L1 positive subjects.
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•
PD-L1 negative (< 1% tumor cell membrane staining in a minimum of a hundred evaluable 
tumor cells)
•
PD-L1 not quantifiable (subjects with tumor biopsy specimens without quantifiable PD-L1 
expression)
Throughout both parts of the study, subjects are to have tumor tissue sample available for PD-L1 
IHC testing performed by the central lab during the screening period. In part 1, subjects can initiate 
therapy before the result of IHC testing. PD-L1 test will be used to track PD-L1 positive and PD-L1 
negative treated subjects. Subjects in safety lead in phase may initiate therapy before IHC result. 
Part 1 enrollment will end after at least 120 PD-L1 positive and 100 PD-L1 negative subjects are 
treated, whichever comes later (Part 1 enrollment target was reached on Nov. 15 2016. Future 
enrollment will be in Part 2 study).
For the Part 2 safety lead in, only receipt of suitable tissue by the central lab is required for 
treatment. 
3.1.1
Study design
3.1.1.1
Part 1 study design
Nivolumab is administered IV over 30 minutes at 3 mg/kg every 2 weeks combined with 
ipilimumab administered IV over 30 minutes at 1 mg/kg every 6 weeks until progression, 
unacceptable toxicity, or other reasons specified in the protocol. In study CA209568, treatment 
with nivolumab with ipilimumab will be given for a maximum of 2 years from the start of study 
treatment in the absence of disease progression or unacceptable toxicity. 
Treatment beyond initial investigator-assessed RECIST 1.1 defined progression is permitted if the 
subject as specified in Section 4.5.6 has investigator assessed clinical benefit and is tolerating 
nivolumab and ipilimumab. 
On-study tumor assessments will begin 6 weeks post first dose date (+/-7 days) and be performed 
every 6 weeks (+/- 7 days) until week 48. After week 48, tumor assessments will be performed 
every 12 weeks (+/- 7 days) until blinded independent central review assessed progression. 
Subjects received nivolumab plus ipilimumab beyond investigator-assessed progression must also 
continue tumor assessments until further progression at subsequent tumor assessment as indicated 
in Section 4.5.6.
The study design schematic is presented in Figure 3.1.1.1-1.
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Figure 3.1.1.1-1:
Part 1 Study Design Schematic
Part 1:
3.1.1.2
Part 2 study design
Figure 3.1.1.2-1:
Part 2 Study Design Schematic 
Safety lead-in phase will be conducted to evaluate safe dose level for the Part 2 study. 
Approximately 28 subjects will receive 2 cycles of induction chemotherapy and nivolumab plus 
ipilimumab. The starting dose of nivolumab is 360mg every 3 weeks and ipilimumab is 1 mg/kg 
every 6 weeks. Nivolumab will be administered with ipilimumab, plus 2 cycles of histology based 
platinum doublet chemotherapy as follows:
•
Squamous histology: Carboplatin AUC6 + Paclitaxel 200mg/m2. 
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•
Non-squamous histology: Carboplatin AUC 5 or6 + pemetrexed 500mg/m2 or Cisplatin 
75mg/m2 + pemetrexed 500mg/m2.
After above 2 cycles of induction therapy, nivolumab is administered IV over 30 minutes 
combined with ipilimumab administered IV over 30 minutes until progression, unacceptable 
toxicity, or other reasons specified in the protocol. In study CA209568, treatment with nivolumab 
and ipilimumab will be given for a maximum of 2 years from the start of study treatment in the 
absence of disease progression or unacceptable toxicity. 
Treatment beyond initial investigator assessed RECIST 1.1 defined progression is permitted if the 
subject as specified in Section 4.5.6 has investigator assessed clinical benefit and is tolerating 
nivolumab and ipilimumab.
On-study tumor assessments will begin at week 6 post first dose date (+/- 7 days) and be performed 
every 6 weeks (+/- 7 days) until week 48. After week 48, tumor assessments will be performed 
every 12 weeks (+/- 7 days) until investigator assessed progression or treatment discontinuation 
(whichever occurs later). Subjects receiving nivolumab plus ipilimumab beyond investigator 
assessed progression must also continue tumor assessments until further progression at subsequent 
tumor assessment as indicated in Section 4.5.6.
3.1.2
Study Phase
3.1.2.1
Screening Phase
•
Begins by establishing the subject’s initial eligibility and signing of the informed consent 
(ICF).
•
Subject is enrolled using the Interactive Web Response System (IWRS).
•
Tumor tissue (archival or recent tumor biopsy) must be submitted by the site to a third party 
vendor for determination of PD-L1 status. An email/fax communication will be sent by the 
third party vendor to site for confirmation upon receiving tumor tissue.
•
Subject is assessed for study eligibility as described in Table 5.1-1. 
•
All screening assessments and procedures must be performed within 28 days prior to treatment.
Part 1:
Subjects can initiate therapy before the result of IHC testing.
Part 1 treatment
•
Nivolumab 3 mg/kg IV will be administered every 2 weeks.
•
Ipilimumab 1 mg/kg IV will be administered every 6 weeks following the administration of 
nivolumab.
•
On the day of infusion, nivolumab is to be administered first. The second infusion will always 
be ipilimumab (if ipilimumab is scheduled to be given), and will start at least 30 minutes after 
completion of the nivolumab infusion.
•
Nivolumab 3 mg/kg Q2 weeks and ipilimumab 1 mg/kg Q6 weeks will be continued until the 
progression of disease, discontinuation due to toxicity, withdrawal of consent, or study closure. 
In study CA209568, treatment with nivolumab with ipilimumab will be given for a maximum 
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of 2 years from the start of study treatment in the absence of disease progression or 
unacceptable toxicity. 
Part 2 
Safety lead-in phase will be conducted to evaluate safe dose level for the subsequent studies using 
same drug combination. Approximately 28 subjects will receive 2 cycles of induction 
chemotherapy and nivolumab plus ipilimumab. The starting dose of nivolumab is 360 mg every 3 
weeks and ipilimumab is 1 mg/kg every 6 weeks. Subjects can initiate therapy before PD-L1 
testing results.
Dose limiting toxicities are defined as any of the items listed below which occur during the first 
9 weeks.*
•
Any Grade 2 drug-related uveitis or eye pain 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 in 14 days (radiologic changes may take longer to resolve). The 
management algorithm for pneumonitis or pulmonary toxicity can be found in the appendix 
and in the current Investigator Brochure.22
•
Any Grade 3 non-skin drug-related adverse event with the exception of laboratory 
abnormalities that cannot be alleviated (defined as returning to grade 1, radiologic changes 
may take longer to resolve) or controlled by appropriate care within 14 days (appropriate care 
being defined as treatment outlined in AE management algorithms in the investigators 
brochure).
•
Any Grade 4 drug-related adverse event including laboratory abnormalities except Grade 4 
leukopenia or neutropenia lasting < 14 days and asymptomatic amylase/lipase elevation
•
Any of the following drug-related hepatic function laboratory abnormalities:
−
AST or ALT >5-10x ULN for > 2 weeks
−
AST or ALT > 10x ULN
−
Total bilirubin > 5 x ULN
−
Concurrent AST or ALT > 3x ULN and total bilirubin > 2x ULN
−
Grade 3 thrombocytopenia associated with bleeding
*During the first 9 weeks: subjects should discontinue treatment if they experience any adverse 
event, laboratory abnormality or intercurrent illness (regardless of causality) which, in the opinion 
of the investigator, presents a substantial clinical risk to the subject with continued nivolumab 
dosing. Such discontinuation, however, will not be considered a DLT unless it meets at least one 
of the DLT criteria defined above. Treatment delay, modification and discontinuation criteria are 
to be followed for management of safety lead in subjects as outlined in Sections 4.5.2, 4.5.3, and 
4.5.5.
Subjects in safety lead in will follow Part 2 study procedures, and will have on study tumor 
assessment as outlined in Table 5.1-3. Investigator assessed efficacy evaluation will be based on 
RECIST 1.1. Independent radiology central review is not required for safety lead in subjects. Upon 
completion of dosing, subjects will enter Follow-up phase Table 5.1-4.
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Nivolumab and ipilimumab will be continued until the progression of disease, discontinuation due 
to toxicity, withdrawal of consent, for a maximum of 2 years from the start of study treatment in 
the absence of disease progression, or unacceptable toxicity. 
3.1.3
Post-Treatment Follow-up
The post-treatment follow-up begins when the decision to discontinue a subject from all treatment 
is made.
•
Subjects who discontinue treatment for reasons other than disease progression will continue to 
have tumor assessments (if clinically feasible) according to the schedule in Table 5.1-4 until 
progression confirmed by blinded independent central review.
•
At the time of investigator-assessed radiographic progression per RECIST 1.1, sites must 
request a blinded independent central review from the third party radiology vendor for subjects 
in Part 1, as specified in Section 7.2.
•
Subjects will be followed for drug-related toxicities until these toxicities resolve, return to 
baseline or are deemed irreversible. All adverse events will be documented for a minimum of 
100 days after the last dose of study medication Section 6.
•
After completion of the first two follow-up visits, subjects will be followed every 3 months for 
survival. Survival Follow-up visits may be performed by phone contact or office visit 
(Section 5.1). BMS may request that survival data be collected on all treated subjects outside 
of the protocol defined window. At that time of this request, each subject will be contacted to 
determine their survival status unless the subject had withdrawn consent for all contact.
3.1.4
Duration of Study
Part 1:
The analysis of the primary endpoint ORR will be performed at least six month after last subject 
first treatment. Additional survival follow-up may continue for up to 5 years from the primary 
analysis. The study will end once survival follow-up has concluded.
Part 2:
The duration of the study is from the start of safety-lead in phase until the analyses of PFS and OS 
are complete, about 13.5 months after first subject in Part 2 is treated. Additional survival follow-
up may continue for up to 5 years from the primary analysis.
3.2
Post Study Access to Therapy
At the conclusion of the study, subjects who continue to demonstrate clinical benefit will be 
eligible to receive BMS supplied study drug. Study drug will be provided via an extension of the 
study, a rollover study requiring approval by responsible health authority and ethics committee or 
through another mechanism at the discretion of BMS. BMS reserves the right to terminate access 
to BMS supplied study drug if any of the following occur: a) the marketing application is rejected 
by responsible health authority; b) the study is terminated due to safety concerns; c) the subject 
can obtain medication from a government sponsored or private health program; or d) therapeutic 
alternatives become available in the local market.
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3.3
Study Population
For entry into the study, the following criteria MUST be met.
3.3.1
Inclusion Criteria
1. Signed Written Informed Consent
a) Subjects must have signed and dated an IRB/IEC approved written informed consent form 
in accordance with regulatory and institutional guidelines. This must be obtained before 
the performance of any protocol related procedures that are not part of normal subject care.
b) Subjects must be willing and able to comply with scheduled visits, treatment schedule, and 
laboratory testing.
2. Target Population
a) ECOG Performance Status of 0-1
b) Subjects with histologically confirmed stage IV NSCLC per the 7th International 
Association for the Study of Lung Cancer classification (IASLC)53 of squamous or 
nonsquamous histology, with no prior systemic anticancer therapy (including EGFR and 
ALK inhibitors) given as primary therapy for advanced or metastatic disease. Prior 
definitive chemoradiation for locally advanced disease is permitted as long as the last 
administration of chemotherapy or radiotherapy (which ever was given last) occurred at 
least 6 months prior to enrollment. Locally advanced disease with recurrence after 
chemoradiation therapy (stage IIIB disease, specifically refers to patients with no curative 
options), is eligible to enroll. Prior adjuvant or neoadjuvant chemotherapy for early stage 
lung cancer is permitted if completed at least 6 months prior to initiating study treatment.
c) Measurable disease by CT or MRI per RECIST 1.1 criteria (Appendix 3); radiographic 
tumor assessment performed within 28 days before treatment.
i)
Target lesions may be located in a previously irradiated field if there is documented 
(radiographic) disease progression in that site after the completion of radiation 
therapy.
d) Subjects are to have tumor tissue sample available at central lab for PD -L1 IHC testing 
during the screening period. Subjects can initiate therapy before the result of IHC testing 
for Part 1 subjects.
Part 2 subjects must have PD-L1 IHC testing performed by the central lab. If results are not 
available during screening period, participants can initiate treatment. Subjects in safety lead in 
phase may initiate therapy before the result of PD-L1 IHC testing.
Subjects in safety lead in phase may initiate therapy before the result of PD-L1 IHC testing.
Either a formalin-fixed, paraffin-embedded (FFPE) tissue block or unstained tumor tissue sections, 
with an associated pathology report, must be submitted for biomarker evaluation prior to treatment. 
The tumor tissue sample may be fresh or archival if obtained within 6 months prior to Part 1 
enrollment,(archival tissue is to be obtained within 3 months prior to Part 2 enrollment), and there 
can have been no systemic therapy (eg, adjuvant or neoadjuvant chemotherapy) given after the 
sample was obtained. 
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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.
e) 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.
f)
Screening laboratory values must meet the following criteria (using CTCAE v4):
i)
WBC ≥2000/μL
ii) Neutrophils ≥1500/μL
iii) Platelets ≥100 x 103/μL
iv) Hemoglobin ≥9.0 g/dL
v) Serum creatinine ≤1.5 x ULN or calculated creatinine clearance ≥50 mL/min (using 
the Cockcroft Gault formula)
Female CrCl = 
(140- age in years) x weight in kg x 0.85
72 x serum creatinine in mg/dL
Male CrCl = (140- age in years) x weight in kg x 1.00
72 x serum creatinine in mg/dL
vi) AST/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) WOCBP must also agree to follow instructions for method(s) of contraception from the 
time of enrollment for the duration of treatment with chemotherapy plus 5 half-lives of 
chemotherapy plus 30 days (duration of ovulatory cycle) for a total of 30 days post 
treatment completion or a duration specified by the local labels of the chemotherapy 
drugs received, whichever is longer (for Part 2 subjects).
f)
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}.
g) Males who are sexually active with WOCBP must agree to follow instructions for 
methods(s) of contraception for the duration of treatment with chemotherapy plus 5 half-
lives of chemotherapy plus 90 days (duration of sperm turnover) for a total of 90 days 
poste treatment completion or a duration specified by the local labels of the 
chemotherapy drugs received, whichever is longer (for Part 2 subjects).
h) 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 subjects who are sexually active with WOCBP on 
the importance of pregnancy prevention and the implications of an unexpected pregnancy.
Investigators shall advise WOCBP and male subjects who are sexually active with WOCBP on the 
use of highly effective methods of contraception. Highly effective methods of contraception have 
a failure rate of < 1% when used consistently and correctly.
Local Laws and Regulations may require use of alternative and/or additional contraception 
methods.
At a minimum, subjects must agree to use one highly effective method of contraception as listed 
below:
Highly Effective Contraceptive Methods That Are User Dependent 
Failure rate of <1% per year when used consistently and correctly.a
•
Combined (estrogen- and progestogen-containing) hormonal contraception associated with 
inhibition of ovulationb 
−
oral 
−
intravaginal 
−
transdermal 
•
Progestogen-only hormonal contraception associated with inhibition of ovulationb 
−
oral 
−
injectable 
Highly Effective Methods That Are User Independent
•
Implantable progestogen-only hormonal contraception associated with inhibition of 
ovulation b
•
Hormonal methods of contraception including oral contraceptive pills containing a 
combination of estrogen and progesterone, vaginal ring, injectables, implants and 
intrauterine hormone-releasing system (IUS)c
•
Intrauterine device (IUD)c
•
Bilateral tubal occlusion
•
Vasectomized partner 
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A vasectomized partner is a highly effective contraception method provided that the partner 
is the sole male sexual partner of the WOCBP and the absence of sperm has been confirmed. 
If not, an additional highly effective method of contraception should be used. 
•
Sexual abstinence
Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study drug. The 
reliability of sexual abstinence needs to be evaluated in relation to the duration of the study 
and the preferred and usual lifestyle of the participant.
•
It is not necessary to use any other method of contraception when complete abstinence is 
elected. 
•
WOCBP participants who choose complete abstinence must continue to have pregnancy 
tests, as specified in Section 2. 
•
Acceptable alternate methods of highly effective contraception must be discussed in the 
event that the WOCBP participants chooses to forego complete abstinence 
NOTES: 
a Typical use failure rates may differ from those when used consistently and correctly. Use should be consistent 
with local regulations regarding the use of contraceptive methods for participants participating in clinical studies. 
b Hormonal contraception may be susceptible to interaction with the study drug, which may reduce the efficacy 
of the contraceptive method.  Hormonal contraception is permissible only when there is sufficient evidence that 
the IMP and other study medications will not alter hormonal exposures such that contraception would be 
ineffective or result in increased exposures that could be potentially hazardous.  In this case, alternative methods 
of contraception should be utilized. 
c Intrauterine devices and intrauterine hormone releasing systems are acceptable methods of contraception in the 
absence of definitive drug interaction studies when hormone exposures from intrauterine devices do not alter 
contraception effectiveness
Unacceptable Methods of Contraception*
•
Male or female condom with or without spermicide.  Male and female condoms cannot be 
used simultaneously
•
Diaphragm with spermicide
•
Cervical cap with spermicide
•
Vaginal Sponge with spermicide
•
Progestogen-only oral hormonal contraception, where inhibition of ovulation is not the 
primary mechanism of action
•
Periodic abstinence (calendar, symptothermal, post-ovulation methods)
•
Withdrawal (coitus interruptus).
•
Spermicide only
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•
Lactation amenorrhea method (LAM)
Contraception Guidance for Male Participants with Partner(s) of Child Bearing Potential.
Male participants with female partners of childbearing potential are eligible to participate if they 
agree to the following during the treatment and until the end of relevant systemic exposure.
•
Inform any and all partner(s) of their participation in a clinical drug study and the need to 
comply with contraception instructions as directed by the investigator.
•
Male participants are required to use a condom for study duration and until end of relevant 
systemic exposure defined as 7 months after the end of study treatment.
•
Female partners of males participating in the study to consider use of effective methods of 
contraception until the end of relevant systemic exposure, defined as 7 months after the end of 
treatment in the male participant.
•
Male participants with a pregnant or breastfeeding partner must agree to remain abstinent from 
penile vaginal intercourse or use a male condom during each episode of penile penetration 
during the treatment and until 7 months after the end of study treatment. 
•
Refrain from donating sperm for the duration of the study treatment and until 7 months after 
the end of study treatment.
3.3.2
Exclusion Criteria
1. Target Disease Exceptions
a) Subjects 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 subjects 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 central lab. Use of an FDA-approved or local Health Authority approved test
is strongly encouraged. Subjects of non-squamous histology with unknown or 
indeterminate EGFR status are excluded.
b) Subjects 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. 
Subjects with unknown or indeterminate ALK status may be enrolled.
c) Subjects with untreated CNS metastases are excluded. Subjects are eligible if CNS 
metastases are adequately treated and subjects 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, subjects 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) Subjects with carcinomatous meningitis
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2. Medical History and Concurrent Diseases
a) Subjects must have recovered from the effects of major surgery or significant traumatic 
injury at least 14 days before first treatment.
b) Subjects 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.
c) Other active malignancy requiring concurrent intervention.
d) Subjects with an active, known or suspected autoimmune disease. Subjects with type I 
diabetes mellitus, hypothyroidism only requiring hormone replacement, skin disorders 
(such as vitiligo, psoriasis, or alopecia) not requiring systemic treatment, or conditions not 
expected to recur in the absence of an external trigger are permitted to enroll.
e) Subjects with a condition requiring systemic treatment with either corticosteroids (> 10 mg 
daily prednisone equivalent) or other immunosuppressive medications within 14 days of 
first treatment. Inhaled or topical steroids, and adrenal replacement steroid > 10 mg daily 
prednisone equivalent, are permitted in the absence of active autoimmune disease.
f)
Subjects with interstitial lung disease that is symptomatic or may interfere with the 
detection or management of suspected drug-related pulmonary toxicity. 
g) Known history of testing positive for human immunodeficiency virus (HIV) or known 
acquired immunodeficiency syndrome (AIDS). (Testing for HIV must be performed at 
sites mandated by local requirements.)
h) Known medical condition that, in the investigator’s opinion, would increase the risk 
associated with study participation or study drug administration or interfere with the 
interpretation of safety results.
i)
Prior treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CTLA-4 antibody, or any 
other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways
3. Physical and Laboratory Test Findings
a) Any positive test for hepatitis B virus or hepatitis C virus indicating acute or chronic 
infection
b) Subjects with ≥Grade 2 peripheral neuropathy
4. Allergies and Adverse Drug Reaction
a) History of allergy or hypersensitivity to study drug components
5. Other Exclusion Criteria
a) Prisoners or subjects who are involuntarily incarcerated. (Note: under certain specific 
circumstances a person who has been imprisoned may be included or permitted to continue 
as a subject. Strict conditions apply and Bristol-Myers Squibb approval is required.
b) Subjects who are compulsorily detained for treatment of either a psychiatric or physical 
(eg, infectious disease) illness
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3.5
Discontinuation of Subjects following any Treatment with Study Drug 
Subjects MUST discontinue investigational product (and non-investigational product at the 
discretion of the investigator) for any of the following reasons:
•
Subject’s request to stop study treatment
•
Any clinical adverse event (AE), laboratory abnormality or intercurrent illness which, in the 
opinion of the investigator, indicates that continued participation in the study is not in the best 
interest of the subject
•
Termination of the study by Bristol-Myers Squibb (BMS)
•
Loss of ability to freely provide consent through imprisonment or involuntarily incarceration 
for treatment of either a psychiatric or physical (e.g., infectious disease) illness
•
Pregnancy*
*In the case of pregnancy, the investigator must immediately notify the BMS Medical 
Monitor/designee of this event. In most cases, the study drug will be permanently discontinued in 
an appropriate manner. If the investigator determines a possible favorable benefit/risk ratio that 
warrants continuation of study drug, a discussion between the investigator and the BMS Medical 
Monitor/designee must occur, if local regulations allow.
All subjects who discontinue study drug should comply with protocol specified follow-up 
procedures as outlined in Section 5. The only exception to this requirement is when a subject 
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withdraws consent for all study procedures including post-treatment study follow-up or loses the 
ability to consent freely (ie, is imprisoned or involuntarily incarcerated for the treatment of either 
a psychiatric or physical illness).
If study drug is discontinued prior to the subject’s completion of the study, the reason for the 
discontinuation must be documented in the subject’s medical records and entered on the 
appropriate case report form (CRF) page.
3.6
Post Study Drug Study Follow up
Subjects who discontinue study drug must continue to be followed for collection of outcome and/or 
survival follow-up data as required and in line with Section 5 until death or the conclusion of the 
study.
Follow-Up Visit 1 to occur 35 days from the last dose (+/- 7 days) or coinciding with the date of 
discontinuation of study drug (+/- 7 days) if the date of discontinuation is greater than 42 days 
from the last dose. Follow-Up Visit 2 to occur 115 days from Follow-Up Visit 1 (+/- 7 days). 
Survival Follow-Up Visits to occur approximately every 3 months from Follow-Up Visit 2. 
Survival Follow-up visits may be performed by phone contact or office visit.
BMS may request that survival data be collected on all subjects outside of the protocol defined 
window. At the time of this request, each subject will be contacted to determine their survival 
status unless the subject has withdrawn consent for all contact.
3.6.1
Withdrawal of Consent
Subjects who request to discontinue study drug will remain in the study and must continue to be 
followed for protocol specified follow-up procedures. The only exception to this is when a subject 
specifically withdraws consent for any further contact with him/her or persons previously 
authorized by subject to provide this information. Subjects should notify the investigator of the 
decision to withdraw consent from future follow-up in writing, whenever possible. The 
withdrawal of consent should be explained in detail in the medical records by the investigator, as 
to whether the withdrawal is from further treatment with study drug only or also from study 
procedures and/or post treatment study follow-up, and entered on the appropriate CRF page. In the 
event that vital status (whether the subject is alive or dead) is being measured, publicly available 
information should be used to determine vital status only as appropriately directed in accordance 
with local law.
3.6.2
Lost to Follow-Up
All reasonable efforts must be made to locate subjects to determine and report their ongoing status. 
This includes follow-up with persons authorized by the subject as noted above. Lost to follow-up 
is defined by the inability to reach the subject after a minimum of three documented phone calls, 
faxes, or emails as well as lack of response by subject to one registered mail letter. All attempts 
should be documented in the subject’s medical records. If it is determined that the subject has died, 
the site will use permissible local methods to obtain the date and cause of death.
If investigator’s use of third party representative to assist in the follow-up portion of the study has 
been included in the subject’s informed consent, then the investigator may use a Sponsor-retained 
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third party representative to assist site staff with obtaining subject’s contact information or other 
public vital status data necessary to complete the follow-up portion of the study. The site staff and 
representative will consult publicly available sources, such as public health registries and 
databases, in order to obtain updated contact information. If after all attempts, the subject remains 
lost to follow-up, then the last known alive date as determined by the investigator should be 
reported and documented in the subject’s medical records.
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4
STUDY DRUG
Study drug includes both Investigational [Medicinal] Product (IP/IMP) and Non-investigational [Medicinal] Product (Non-IP/Non-IMP) 
and can consist of the following:
Table 4-1:
Product Description - Treatment Phase
Product Description 
and Dosage Form
Potency
Primary Packaging 
(Volume)/Label Type
Secondary Packaging 
(Qty)/Label Type
Appearance
Storage Conditions 
(per label)
BMS-936558-01 
nivolumab Solution for 
Injectiona
100 mg 
(10 mg/mL)
10 mL per vial/
Open-label
5 or 10 vials per carton/ 
Open-label
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)
40 mL vial/Open-label
4 vials per
carton/Open-label
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)
45 mL per vial/
Open label
4 vials per
carton/Open-label
Clear, colorless or slightly 
yellow solution
Store at or below 25° C 
Protect from light
Paclitaxel Solution for 
Injectionb
100 mg/vialb
(6 mg/mL)
16.7 mL vial/
Open-label
4 vials per
carton/Open-label
Clear, colorless or
slightly yellow viscous solution
Store at 15°C-30°C.
Protect from light.
Pemetrexed Powder for 
Concentrate for 
Solution for Infusionb
500 mg/vial
500 mg per vial/
Open label
1 vial per carton/ Open-
label
White to either light yellow or 
green-yellow lyophilised 
powder
Store at 25° C. 
Excursions permitted 
(15-30° C)
Cisplatin Solution for 
Infusionb
100 mg/vial 
(1 mg/mL)
100 mL per vial/
Open-label
4 vials per carton
Open-label
Clear, colorless solution
Do not store above 25°
C. Do not refrigerate or 
freeze. Store in original 
container.
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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4.1
Investigational Product
An investigational product, also known as investigational medicinal product in some regions, is
defined a pharmaceutical form of an active substance or placebo being tested or used as a reference 
in a clinical study, including products already with a marketing authorization but used or 
assembled (formulated or packaged) differently than the authorized form, or used for an 
unauthorized indication, or when used to gain further information about the authorized form.
The investigational product should be stored in a secure area according to local regulations. It is 
the responsibility of the investigator to ensure that investigational product is only dispensed to 
study subjects. The investigational product must be dispensed only from official study sites by 
authorized personnel according to local regulations. 
In this protocol, investigational product(s) is/are:
•
Nivolumab
•
Ipilimumab
•
Carboplatin
•
Pemetrexed
•
Paclitaxel
•
Cisplatin
4.2
Non-Investigational Product
Other medications used as support or escape medication for preventative, diagnostic, or therapeutic 
reasons, as components of the standard of care for a given diagnosis, may be considered as 
non-investigational products. 
In this protocol, non-investigational product(s) is/are: any medications used to treat 
nivolumab/ipilimumab or chemotherapy infusion-related reactions (eg, steroids). These non-
investigational products should be sourced by the investigator sites if available and permitted by 
local regulations.
4.3
Storage and Dispensing
The product storage manager should ensure that the study drug is stored in accordance with the 
environmental conditions (temperature, light, and humidity) as determined by BMS. If concerns 
regarding the quality or appearance of the study drug arise, the study drug should not be dispensed 
and contact BMS immediately.
Study drug not supplied by BMS will be stored in accordance with the package insert.
Investigational product documentation (whether supplied by BMS or not) must be maintained that 
includes all processes required to ensure drug is accurately administered. This includes 
documentation of drug storage, administration and, as applicable, storage temperatures, 
reconstitution, and use of required processes (eg, required diluents, administration sets).
Infusion-related supplies (eg, IV bags, in-line filters, 0.9% NaCl solution) will not be supplied by 
the sponsor and should be purchased locally if permitted by local regulations.
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For nivolumab and ipilimumab, please refer to the current version of the Investigator Brochures 
and/or pharmacy reference sheets for complete storage, handling, dispensing, and infusion 
information.
Nivolumab is to be administered as an approximately 30-minute IV infusion. At the end of the 
infusion, flush the line with a sufficient quantity of normal saline or dextrose solution. Ipilimumab 
is to be administered as an approximately 30-minute IV infusion. At the end of the infusion, flush 
the line with a sufficient quantity of normal saline or 5% dextrose solution. When both study drugs 
are to be administered on the same day, separate infusion bags and filters must be used for each 
infusion. Nivolumab is to be administered first. The nivolumab infusion must be promptly 
followed by a saline flush to clear the line of nivolumab before starting the infusion. The second 
infusion will always be ipilimumab, and will start at least 30 minutes after completion of the 
nivolumab infusion.
4.4
Method of Assigning Subject Identification
After the subject’s initial eligibility is established and informed consent has been obtained, the 
subject must be enrolled into the study by calling an interactive web response system (IWRS) to 
obtain the subject number. Every subject that signs the informed consent form must be assigned a 
subject number in IWRS. Specific instructions for using IWRS will be provided to the 
investigational site in a separate document. The investigator or designee will register the subject 
for enrollment by following the enrollment procedures established by BMS. The following 
information is required for enrollment:
•
Date that informed consent was obtained
•
Subject number
•
Date of birth
Subjects 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.
Part 1:
Enrollment will end after the last 120 PD-L1 positive and 100 PD-L1 negative subjects are treated, 
whichever comes later (part 1 enrollment target was reached on Nov. 15, 2016. Future enrollment 
will be in Part 2 only). The exact procedures for using the IWRS will be detailed in the IWRS 
manual.
Part 2: 
The exact procedures for using the IWRS will be detailed in the IWRS manual.
4.5
Selection and Timing of Dose for Each Subject
All subjects 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 4.5.2, 4.5.3, 4.5.4 and 4.5.5.
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Table 4.5-1:
Part 1 Dosing Schedule*
Week 1
Day 1
± 3 Days
Week 
2
Week 3
Day 1
± 3 Days
Week 4
Week 5
Day 1
± 3 Days
Week 
6
Part 1 Nivolumab 3 mg/kg q 2 weeks
+ Ipilimumab 1 mg/kg q 6 weeksa
Day 1
Nivolumab
+
Ipilimumab
Day 1
Nivolumab
Day 1
Nivolumab
a continues until disease progression, discontinuation due to unacceptable toxicity, withdrawal of consent, or study 
closure, for a maximum of 2 years from the start of study treatment in the absence of disease progression or 
unacceptable toxicity. 
* Both nivolumab and ipilimumab should be administered as 30 minute infusions. Nivolumab is to be administered 
first. The second infusion will be ipilimumab, and will start at least 30 minutes after completion of the nivolumab 
infusion
Table 4.5-2:
Part 2 Dosing Schedule*
Week 1
Day 1
± 3 Days
Wk 2
Wk 3
Week 4
Day 1
+/- 3 days
Wk 
5
Wk 
6
Week 7
Day 1 
± 3 Days
Safety lead in phase
Part 2 Safety Lead-in
Nivolumab + ipilimumab 
+
Platinum-doublet 
chemotherapy q 3wk x 2 
cycles
followed by nivolumab 
(360 mg q 3wks) + 
ipilimumab 1mg/kg q 
6wksa
Cycle 1
Nivolumab
+
Ipilimumab
+
Histology based 
chemotherapy
Cycle 2
Nivolumab
+
Histology based 
chemotherapy
Cycle 3
Nivolumab
+
Ipilimumab
* Both nivolumab and ipilimumab should be administered as 30 minute infusions. Nivolumab is to be administered 
first. The second infusion will be ipilimumab, and will start 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).
a Continues until disease progression, discontinuation due to unacceptable toxicity, withdrawal of consent, or study 
closure. A maximum of 2 years from the start of study treatment in the absence of disease progression or 
unacceptable toxicity. 
4.5.1
Dosing
4.5.1.1
Nivolumab and ipilimumab dosing
For Part 1, subjects will receive treatment with nivolumab as a 30 minute infusion 3 mg/kg every 
2 weeks and ipilimumab as a 30 minute infusion 1 mg/kg every 6 weeks, starting on Day 1, until 
progression, unacceptable toxicity, withdrawal of consent, or the study ends, whichever occurs 
first. Nivolumab and ipilimumab will be continued until the progression of disease, discontinuation 
due to toxicity, withdrawal of consent, or study closure. In study CA209568, treatment with 
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nivolumab with ipilimumab will be given for a maximum of 2 years from the start of study 
treatment in the absence of disease progression or unacceptable toxicity. Participants should begin 
study treatment within 3 calendar days of treatment assignment.
For Part 1 and Part 2: When study treatments (nivolumab and ipilimumab) are to be administered 
on the same day, nivolumab is to be administered first. Nivolumab infusion must be promptly 
followed by a flush of diluent to clear the line of nivolumab before starting the ipilimumab 
infusion. The second infusion will always be the ipilimumab study treatment and will start after 
the infusion line has been flushed, filters changed and patient has been observed to ensure no 
infusion reaction has occurred. Nivolumab and ipilimumab may be diluted in 0.9% Sodium 
Chloride Solution or 5% Dextrose solution. 
Dosing calculations should be based on the body weight. If the subject’s weight on the day of 
dosing differs by > 10% from the weight used to calculate the prior dose, the dose must be 
recalculated. All doses should be rounded to the nearest milligram. There will be no dose 
modifications allowed.
Subjects may be dosed with nivolumab no less than 12 days from the previous dose. There are no 
premedications recommended.
Subjects should be carefully monitored for infusion reactions. If an acute infusion reaction is noted, 
subjects should be managed according to Section 4.5.8.
Doses of nivolumab and/or ipilimumab may be interrupted, delayed, or discontinued depending 
on how well the subject tolerates the treatment. Dosing visits are not skipped, only delayed. For 
more details, see Sections 4.5.2 (dose delays), 4.5.4 (resuming treatment), and 4.5.5
(discontinuation).
For Part 2 only: On cycle 1 day 1, subjects will receive nivolumab by 30 minute infusion, then 
followed by ipilimumab by 30 minute infusion, followed by histology-based chemotherapy. One 
cycle is every 3 weeks. On cycle 2 day 1, subjects will receive 30 minute nivolumab infusion, 
followed by histology based chemotherapy. In safety lead-in phase, nivolumab dose during 
induction is 360 mg, and ipilimumab dose is 1 mg/kg. Participants should begin study treatment 
within 3 calendar days of treatment assignment.
At the time of completion of 2 cycles of therapy, subjects 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. Treatment will continue 
until progression, unacceptable toxicity, withdrawal of consent, for a maximum of 2 years from
the start of study treatment in the absence of disease progression or unacceptable toxicity. The 
maximum 2 years of treatment also applies to treatment beyond progression. Dosing calculations 
should be on the body surface area calculation and maybe capped per local standards. The dose 
may remain the same if the subject’s weight is within 10% of the baseline weight or prior dose 
weight.
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4.5.1.2
Part 2-Chemotherapy Dosing for Safety Lead-in 
Histology based chemotherapy:
Squamous histology: Carboplatin AUC6 + 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
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. 
Dosing calculations should be on the body surface area calculation and maybe capped per local 
standards. The dose may remain the same if the subject’s weight is within 10% of the baseline 
weight or prior dose weight
4.5.1.2.1
Paclitaxel 
Subjects may 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 is to 
be administered before carboplatin. 
Paclitaxel dosing calculations should be based on the body surface area calculation. The dose may 
remain the same if the subject’s weight is within 10% of the baseline weight or prior dose weight.
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 subject tolerates the treatment. 
4.5.1.2.2
Pemetrexed 
Pemetrexed dosing calculations should be based on the body surface area calculation. The dose 
may remain the same if the subject’s weight is within 10% weight used to calculate the previous 
dose.
Premedication for use with pemetrexed: 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 
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injections of vitamin B12 may be given on the same day as pemetrexed. (Subjects with non-
squamous histology may begin folic acid and vitamin B12 prior to treatment in anticipation of 
pemetrexed). 
Doses of pemetrexed may be interrupted, delayed, reduced, or discontinued depending on how 
well the subject tolerates the treatment.
4.5.1.2.3
Cisplatin 
Cisplatin 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 subject’s weight is within 10% 
of the baseline weight or prior dose weight.
Cisplatin will be administered to subjects 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 cisplatin may be interrupted, delayed, reduced, or discontinued depending on how well 
the subject tolerates the treatment See the following sections for more details: 4.5.2 (dose delays), 
4.5.3.1, 4.5.3.2, 4.5.3.3, and 4.5.3.4 (dose reductions); 4.5.4 (retreatment), and 4.5.5 (dose 
discontinuations).
All subjects who will be receiving cisplatin should have audiometric testing performed prior to 
initiation of therapy and prior to subsequent doses of cisplatin, or as per local standards of care.
Subjects who discontinue cisplatin alone may, at the investigator’s discretion, be switched to 
pemetrexed/carboplatin for the remainder of the platinum doublet cycles.
4.5.1.2.4
Carboplatin 
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 2f in Section 3.3.1) 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. 
•
The dose of carboplatin may be capped per local standards.
Premedications for use with carboplatin: may be employed at the discretion of the Investigator.
Carboplatin is to be administered after paclitaxel. 
Doses of carboplatin may be interrupted, delayed, reduced, or discontinued depending on how well 
the subject tolerates the treatment.
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4.5.2
Dose Delay Criteria
4.5.2.1
Dose Delay Criteria for Nivolumab and Ipilimumab
Tumor assessments for all subjects 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 subject has a baseline AST, ALT, or total bilirubin that is within normal limits, delay 
dosing for drug-related Grade 2 toxicity
−
If a subject has baseline AST, ALT, or total bilirubin within the Grade 1 toxicity range, 
delay dosing for drug-related Grade ≥3 toxicity
−
Any Grade ≥3 drug-related amylase or lipase abnormality that is not associated with 
symptoms or clinical manifestations of pancreatitis does not require dose delay. The BMS 
Medical Monitor should be consulted for such Grade ≥3 amylase or lipase abnormalities.
−
Any AE, laboratory abnormality or inter-current illness which, in the judgment of the 
investigator, warrants delaying the dose of study medication.
•
Subjects 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.)
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 4.5.5.
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4.5.2.2
Dose Delay Criteria for Chemotherapy
In Part 2, 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
•
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 subject has a baseline AST, ALT or total bilirubin that is within normal limits, delay dosing 
for drug-related Grade ≥2 toxicity. 
•
If a subject has baseline AST, ALT, or total bilirubin within the Grade 1 toxicity range, delay 
dosing for drug-related Grade ≥3 toxicity. 
•
Any adverse event, laboratory abnormality, or intercurrent illness which, in the judgment of 
the investigator, warrants delaying the dose of study medication. Investigators should consult 
local labeling for the chemotherapy drugs being administered to any given subject for 
additional guidance on dose delays.
In addition, if subjects 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 4.5.3.2 to determine if dose reduction of the resumed agent 
is required.
If both drugs in the platinum doublet chemotherapy regimen are delayed, then the subject should 
be re-evaluated weekly or more frequently if clinically indicated until re-treatment criteria are met 
(as per Section 4.5.4.3).
Part 2 safety lead in: 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 chemotherapy agent) are given. Dosing of nivolumab and both chemotherapy agents should 
be delayed if criteria for nivolumab or “both platinum-doublet chemotherapy agents” are met. 
Therefore nivolumab and chemotherapy can be given as combination.
4.5.3
Dose Reductions
4.5.3.1
Dose Reduction for Nivolumab or Ipilimumab in both Part 1 and Part 2
There will be no dose reductions for nivolumab or ipilimumab.
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4.5.3.2
Dose Reduction for Chemotherapy in Part 2
Dose reductions of chemotherapy may be required, and will be performed according to Table
4.5.3.2-1. 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.
Table 4.5.3.2-1:
Dose Modifications of Chemotherapeutic Agents
Dose Level
Carboplatin
Pemetrexed
Paclitaxel
Cisplatin
Starting dose
AUC 6 or AUC 5 
depending on 
regimen
500 mg/m²
200 mg/m²
75 mg/m²
First dose reduction
AUC 5 if starting 
dose is AUC 6
AUC 4 if starting 
dose is AUC 5
375 mg/m²
150 mg/m²
56 mg/m²
Second dose 
reduction
AUC 4 if starting 
dose is AUC 6
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 subjects 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.
4.5.3.3
Dose Reductions for Hematologic Toxicity 
Dose modifications for hematologic toxicities (according to CTCAE version 4) are summarized in 
Table 4.5.3.3-1. 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.
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Table 4.5.3.3-1:
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
4.5.3.4
Chemotherapy - Dose Reductions for Non-Hematologic Toxicities 
Dose adjustments for chemotherapy for non-hematologic toxicities during treatment are described 
in Table 4.5.3.4-1. All dose reductions should be made based on the worst grade toxicity. Subjects 
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 the 
Table 4.5.3.4-1 below
Table 4.5.3.4-1:
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
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Table 4.5.3.4-1:
Dose Modifications for Non-hematologic Toxicity
Toxicity
Paclitaxel
Carboplatin
Pemetrexed
Cisplatin
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.
4.5.4
Criteria to Resume Dosing
4.5.4.1
Criteria to Resume Nivolumab Dosing
Subjects may resume treatment with nivolumab when the drug-related AE(s) resolve(s) to 
Grade ≤1 or baseline, with the following exceptions:
•
Subjects may resume treatment in the presence of Grade 2 fatigue.
•
Subjects who have not experienced a Grade 3 drug-related skin AE may resume treatment in 
the presence of Grade 2 skin toxicity.
•
Subjects with baseline Grade 1 AST/ALT or total bilirubin who require dose delays for reasons 
other than a 2-grade shift in AST/ALT or total bilirubin may resume treatment in the presence 
of Grade 2 AST/ALT OR total bilirubin.
•
Subjects with combined Grade 2 AST/ALT and total bilirubin values meeting discontinuation 
parameters (Section 4.5.5) should have treatment permanently discontinued.
•
Drug-related pulmonary toxicity, diarrhea, or colitis must have resolved to baseline before 
treatment is resumed. Subjects with persistent Grade 1 pneumonitis after completion of a 
steroid taper over at least 1 month may be eligible for retreatment if discussed with and 
approved by the BMS Medical Monitor.
•
Subjects 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.
•
Subjects who delay study treatment due to any Grade ≥3 amylase or lipase abnormality that is 
not associated with symptoms or clinical manifestations of pancreatitis, and that 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 subjects.
•
Dose delay of nivolumab which results in treatment interruption of > 6 weeks requires 
treatment discontinuation, with exceptions as noted in Section 4.5.5.
4.5.4.2
Criteria to Resume Ipilimumab Dosing
Subjects may resume treatment with nivolumab and ipilimumab when drug-related AE(s) 
resolve(s) to Grade 1 or baseline value, with the following exceptions: 
•
Subjects may resume treatment in the presence of Grade 2 fatigue.
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•
Subjects who have not experienced a Grade 3 drug-related skin AE may resume treatment in 
the presence of Grade 2 skin toxicity.
•
Subjects with baseline Grade 1 AST/ALT or total bilirubin who require dose delays for reasons 
other than a 2-grade shift in AST/ALT or total bilirubin may resume treatment in the presence 
of Grade 2 AST/ALT or total bilirubin.
•
Subjects with combined Grade 2 AST/ALT and total bilirubin values meeting discontinuation 
parameters (Section 4.5.5) should have treatment permanently discontinued.
•
Drug-related pulmonary toxicity, diarrhea, or colitis must have resolved to baseline before 
treatment is resumed.
•
Subjects 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. Adrenal 
insufficiency requires discontinuation regardless of control with hormone replacement.
•
Dose delay of ipilimumab which results in no ipilimumab dosing for > 12 weeks requires 
ipilimumab discontinuation, with exceptions as noted in Section 4.5.5.
•
Ipilimumab may not be resumed sooner than 6 weeks (+/- 5days) after the prior ipilimumab 
dose.
•
In general, subjects 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.
•
One exception to note is 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 to be 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 be resumed 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 
subject’s medical chart. The BMS Medical Monitor should be consulted prior to resuming 
nivolumab in such subjects.
4.5.4.3
Criteria to Resume Treatment with Chemotherapy 
•
Subjects may resume treatment with chemotherapy when the ANC returns to 1500/μl, 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 subject fails to meet criteria for re-treatment, then re-treatment should be delayed, and the 
subject should be re-evaluated weekly or more frequently as clinically indicated. Any subject 
who fails to recover from toxicity attributable to 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.
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•
When resuming chemotherapy treatment, please follow the dose reduction recommendations 
in Section 4.5.3.2.
4.5.5
Treatment Discontinuation Criteria
For all subjects, 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 subjects who 
discontinue study treatment without radiographic progression, confirmed by independent 
radiology review (Section 7.2), should continue as per protocol until radiographic progression is 
determined by blinded independent central review.
Part 2: If a subject is intolerant of nivolumab treatment during the chemotherapy cycles, the 
subject should be withdrawn from the study.
Chemotherapy dose reduction is allowed on study. Any subject 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 subject 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 subject meets criteria to resume nivolumab treatment.
4.5.5.1
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 drug-related 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, 
myocarditis, hypersensitivity reaction, or infusion reaction of any duration requires 
discontinuation.
•
Grade 3 drug-related endocrinopathies adequately controlled with only physiologic hormone 
replacement do not require discontinuation. Adrenal insufficiency requires discontinuation 
regardless of control with hormone replacement
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•
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
•
Grade 4 drug-related endocrinopathy adverse events, such as hyper- or hypothyroidism, 
or glucose intolerance, which resolve or are adequately controlled with physiologic 
hormone replacement (corticosteroids, thyroid hormones) or glucose controlling 
agents, respectively, may not require discontinuation after discussion with and approval 
from the BMS Medical Monitor.
−
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 subject 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 subject 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. 
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If a subject 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 subject should discontinue 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 given in Part 2 study. 
4.5.5.2
Definition of DLTs in safety-lead in of Part 2
Dose limiting toxicities are defined as any of the items listed below which occur during the first 9 
weeks.
•
Any Grade 2 drug-related uveitis or eye pain 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 in 14 days (radiologic changes may take longer to resolve). The 
management algorithm for pneumonitis or pulmonary toxicity can be found in the appendix 
and in the current Investigator Brochure.22
•
Any Grade 3 non-skin drug-related adverse event with the exception of laboratory 
abnormalities, that cannot be alleviated (defined as returning to grade 1, radiologic changes 
may take longer to resolve) or controlled by appropriate care within 14 days (appropriate care 
being defined as treatment outlined in AE management algorithms in the investigators 
brochure).
•
Any Grade 4 drug-related adverse event including laboratory abnormalities except Grade 4 
leukopenia or neutropenia lasting < 14 days and asymptomatic amylase/lipase evaluation.
•
Any of the following drug-related hepatic function laboratory abnormalities:
−
AST or ALT > 5-10x ULN for > 2 weeks
−
AST or ALT >10 x ULN
−
Total bilirubin > 5 x ULN
−
Concurrent AST or ALT > 3 x ULN and total bilirubin > 2 x ULN
−
Grade 3 thrombocytopenia associated with bleeding
Safety lead in subjects should discontinue treatment if they experience any adverse event, 
laboratory abnormality or intercurrent illness (regardless of causality) which, in the opinion of 
the investigator, presents a substantial clinical risk to the subject with continued nivolumab 
dosing. Such discontinuation, however, will not be considered a DLT unless it meets at least 
one of the DLT criteria defined above. Treatment delay, modification, and discontinuation 
criteria are to be followed for management of safety lead in subjects as outlined in 
Sections 4.5.2, 4.5.3, 4.5.5.
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4.5.5.3
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
•
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 subject 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 subject 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.
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•
Any adverse event, laboratory abnormality, or intercurrent illness which, in the judgment of 
the Investigator, presents a substantial clinical risk to the subject with continued 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 subject 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 subject 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 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 given in Part 2 study. 
4.5.5.4
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 
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treatment in a subject 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 subject with continued platinum 
doublet chemotherapy dosing. Investigators should consult local labeling for the chemotherapy 
drugs being administered to any given subject for additional guidance on dose discontinuation.
•
In addition, subjects 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 subject meets retreatment criteria.
Note: 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 given in Part 2 study. 
A subject 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.
4.5.6
Treatment Beyond Disease Progression for Part 1 and Part 2 
Accumulating evidence indicates a minority of subjects treated with immunotherapy may derive 
clinical benefit despite initial evidence of PD.21
Subjects will be permitted to continue on nivolumab + ipilimumab for treatment beyond initial 
RECIST 1.1 defined PD, assessed by the investigator, for a maximum of 2 years from the start of 
study treatment as long as they meet the following criteria:
•
Investigator-assessed clinical benefit and no rapid disease progression
•
Subject 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)
•
Subject 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 ± 5 days of original PD to determine whether there has 
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been a decrease in the tumor size, or continued progression of disease. Subsequent scans should 
be performed per protocol defined schedule ± 5 days until further progression is determined.
If the investigator feels that the subject continues to achieve clinical benefit by continuing 
treatment, the subject should remain on the trial and continue to receive monitoring according to 
the Time and Events Schedule on Table 5.1-2 and Table 5.1-3.
For the subjects who continue study therapy beyond progression, further progression is defined as 
an additional 10% increase in tumor burden with a minimum of 5 mm absolute increase from time 
of initial PD. This includes an increase in the sum of diameters of all target lesions and/ or the 
diameters of new measurable lesions compared to the time of initial PD. Nivolumab and 
ipilimumab treatment should be discontinued permanently upon documentation of further 
progression.
New lesions are considered measureable at the time of initial progression if the longest diameter 
is at least 10 mm (except for pathological lymph nodes which must have a short axis of at least 
15 mm). Any new lesion considered non-measureable at the time of initial progression may 
become measureable and therefore included in the tumor burden if the longest diameter increases 
to at least 10 mm (except for pathological lymph nodes which must have a short axis of at least 
15 mm). In situations where the relative increase in total tumor burden by 10% is solely due to 
inclusion of new lesions which become measurable, these new lesions must demonstrate an 
absolute increase of at least 5 mm.
4.5.7
Management Algorithms for Immuno-Oncology Agents
Immuno-oncology (I-O) agents are associated with AEs that can differ in severity and duration 
than AEs caused by other therapeutic classes. Nivolumab and ipilimumab 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
 
4.5.8
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 
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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 subject until recovery from symptoms. The following 
prophylactic premedications are recommended for future infusions: diphenhydramine 50 mg 
(or equivalent) and/or acetaminophen/paracetamol 325 to 1000 mg at least 30 minutes before 
additional nivolumab or ipilimumab administrations.
For Grade 2 symptoms: (moderate reaction 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 subject with diphenhydramine 50 mg IV (or equivalent) and/or acetaminophen/paracetamol 
325 to 1000 mg; remain at bedside and monitor subject until resolution of symptoms. 
Corticosteroid and/or bronchodilator therapy may also be administered as appropriate. If the 
infusion is interrupted, then restart the infusion at 50% of the original infusion rate when 
symptoms resolve; if no further complications ensue after 30 minutes, the rate may be 
increased to 100% of the original infusion rate. Monitor subject closely. If symptoms recur, 
then no further nivolumab or ipilimumab will be administered at that visit. Administer 
diphenhydramine 50 mg IV, and remain at bedside and monitor the subject until resolution of 
symptoms. The amount of study drug infused must be recorded on the electronic case report 
form (eCRF).
•
For future infusions, the following prophylactic premedications are recommended: 
diphenhydramine 50 mg (or equivalent) and/or 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)
•
Immediately discontinue infusion of nivolumab or ipilimumab. Begin an IV infusion of normal 
saline and treat the subject as follows: Recommend bronchodilators, epinephrine 0.2 to 1 mg 
of a 1:1000 solution for subcutaneous administration or 0.1 to 0.25 mg of a 1:10,000 solution 
injected slowly for IV administration, and/or diphenhydramine 50 mg IV with 
methylprednisolone 100 mg IV (or equivalent), as needed. Subject should be monitored until 
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the investigator is comfortable that the symptoms will not recur. Nivolumab or ipilimumab 
will be permanently discontinued. Investigators should follow their institutional guidelines for 
the treatment of anaphylaxis. Remain at bedside and monitor subject until recovery of the 
symptoms.
In case of late-occurring hypersensitivity symptoms (eg, appearance of a localized or generalized 
pruritus within 1 week after treatment), symptomatic treatment may be given (eg, oral 
antihistamine or corticosteroids).
4.6
Blinding/Unblinding
Not applicable.
4.7
Treatment Compliance
Treatment compliance will be monitored by drug accountability as well as the subject’s medical 
record and eCRF.
4.8
Destruction of Study Drug
For this study, study drugs (those supplied by BMS or sourced by the investigator) such as partially 
used study drug containers, vials and syringes may be destroyed on site. 
Any unused study drugs can only be destroyed after being inspected and reconciled by the 
responsible Study Monitor unless study drug containers must be immediately destroyed as required 
for safety, or to meet local regulations (eg, cytotoxics or biologics). 
On-site destruction is allowed provided the following minimal standards are met:
•
On-site disposal practices must not expose humans to risks from the drug.
•
On-site disposal practices and procedures are in agreement with applicable laws and 
regulations, including any special requirements for controlled or hazardous substances.
•
Written procedures for on-site disposal are available and followed. The procedures must be 
filed with the site’s SOPs and a copy provided to BMS upon request.
•
Records are maintained that allow for traceability of each container, including the date 
disposed of, quantity disposed, and identification of the person disposing the containers. The 
method of disposal, ie, incinerator, licensed sanitary landfill, or licensed waste disposal vendor 
must be documented.
•
Accountability and disposal records are complete, up-to-date, and available for the Monitor to 
review throughout the clinical trial period.
If conditions for destruction cannot be met the responsible Study Monitor will make arrangements 
for return of study drug.
It is the investigator’s responsibility to arrange for disposal of all empty containers, provided that 
procedures for proper disposal have been established according to applicable federal, state, local, 
and institutional guidelines and procedures, and provided that appropriate records of disposal are 
kept.
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4.9
Return of Study Drug
If study drug will not be destroyed upon completion or termination of the study, all unused and/or 
partially used study drug that was supplied by BMS must be returned to BMS. The return of study 
drug will be arranged by the responsible Study Monitor. 
It is the investigator’s responsibility to arrange for disposal of all empty containers, provided that 
procedures for proper disposal have been established according to applicable federal, state, local, 
and institutional guidelines and procedures, and provided that appropriate records of disposal are 
kept. 
Arrangements for the return of study drug will be made by the responsible Study Monitor.
4.10
Retained Samples for Bioavailability / Bioequivalence
Not Applicable. 
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5
STUDY ASSESSMENTS AND PROCEDURES
5.1
Flow Chart/Time and Events Schedule 
Table 5.1-1:
Screening Assessments and Procedures (CA209568) - All Subjects
Procedure
Screening
Visit
Notes
Eligibility Assessments
Informed Consent
X
Section 2.3
Inclusion/Exclusion Criteria
X
Section 3.3. 
All inclusion/exclusion criteria should be assessed prior to first dose
Medical History
X
Section 3.3 and 5.3
Safety Assessments
Physical Measurements/Physical 
Examination
X
Section 5.3. Include Height and Weight Within 28 days prior to first dose
ECOG Performance Status
X
Section 5.3.1 and Appendix 1
Vital Signs and Oxygen Saturation
X
Section 5.3
Including BP, HR, & temperature. Obtain at the screening visit and within 72 hours prior to first 
dose
Assessment of Baseline Signs and 
Symptoms
X
Section 5.3
Within 14 days prior to first dose
Concomitant Medication Collection
X
Section 3.4
Within 14 days prior to first dose through the study treatment period 
Pregnancy Test (WOCBP only) 
X
Section 5.3.2
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). 
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Table 5.1-1:
Screening Assessments and Procedures (CA209568) - All Subjects
Procedure
Screening
Visit
Notes
Laboratory Tests
X
Section 5.3
CBC w/differential, Chemistry panel including: LDH, AST, ALT, ALP, T. bili, BUN or serum 
urea level, creatinine, albumin, Ca, Mg, Na, K, Cl, phosphate, glucose, amylase, lipase, TSH, 
Free T4, Free T3, within 14 days prior to first dose.
Hep B/C (HBV sAg, HCV antibody or HCV RNA), within 28 days prior to first dose.
ECG (12-lead) 
X
Section 5.3.4
Obtained only for subjects who have met all eligibility criteria
Efficacy Assessments
Radiographic Tumor Assessments(chest, 
abdomen, pelvis, brain)
X
Section 5.4
Performed within 28 days prior to first dose. CT of chest, abdomen and pelvis, and MRI of brain 
(to rule out brain metastases) & all known or suspected sites of disease should be assessed at 
baseline 
Biomarker Assessments
Archived Tumor Tissue or Recent Tumor 
Biopsy
X
Section 3.3.1
Recent sample or archival, obtained within 6 months of Part 1 enrollment (archival tissue is to be 
obtained within 3 month prior to Part 2 enrollment).
One (1) formalin-fixed paraffin embedded tumor tissue block or a minimum of 10 unstained 
tumor tissue sections are acceptable.
Submission of fewer than 10 unstained slides may be acceptable in some circumstances 
following discussion with the BMS Medical Monitor.
Specimens must be tested by third party lab to determine PD-L1 status. An email or fax 
communication will be sent to site by third party lab for confirmation upon receiving tumor 
tissue. Subjects in Part 1can initiate therapy before the result of IHC testing. Subjects in safety 
lead in phase can initiate therapy before the result of IHC test.
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Table 5.1-1:
Screening Assessments and Procedures (CA209568) - All Subjects
Procedure
Screening
Visit
Notes
EGFR Mutation ALK Translocation Status
X
Section 3.3.2 To be performed prior to first dose for all non-squamous subjects. EGFR and ALK 
tests are to be done locally (not by central lab). EGFR test is mandatory for subjects with non-
squamous histology, and to be performed using PCR based assay or next generation sequencing 
from tumor tissue. Tests other than PCR or next generation sequencing will be requested to 
repeat using PCR or next generation sequencing based methods.
IWRS /Clinical Drug Supplies
IWRS
X
Section 4.4
For subject number assignment at the time informed consent is obtained
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Table 5.1-2:
On Study Assessments Treatment Phase (CA209568)
Part 1 (2 weeks/cycle)
Part 1 Procedurea
Cycle 1 
Day 1
Each 
Subsequent 
Cycle
Day1
(± 3 Days)
Every 2 Cycles
Day 1
(± 3 Days)
Every 3 Cycles
Day 1
(± 3 Days)
Notes
For purposes of this table, a cycle refers to 
the nivolumab every 2 weeks regimen.
Safety Assessments
Physical Measurements & ECOG 
Performance Status
X
X
Section 5.3, 5.3.1 & Appendix 1
Vital Signs and Oxygen Saturation
X
X
Section 5.3
Adverse Event Assessments
Continuously during the study
Section 6. SAEs should be approved in Trial 
Access Online (TAO) within 5 days from entry. 
Beyond 100 days from the last dose of study 
drug, subjects will be followed for ongoing 
drug-related adverse events until resolved,
return to baseline or deemed irreversible, or 
until lost to follow-up, withdrawal of study 
consent, or start of subsequent therapy
Laboratory Tests
X
X
X (TSH)
Section 5.3
Within 72 hrs. prior to dosing to include CBC 
w/ differential, AST, ALT, ALP, T. bili, BUN 
or serum urea level, creatinine, albumin, Ca, 
Mg, Na, K, Cl, LDH, phosphate, glucose, 
amylase, lipase, TSH (with reflexive Free T4 
and Free T3).
Thyroid Function Testing to be evaluated every 
6 weeks
Note: C1D1 labs do not need to be repeated if 
they were performed within 14 days of dosing.
Pregnancy Test (WOCBP only) 
X
X
Sections 5.3.2 To be evaluated at least every 
4 weeks
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Table 5.1-3:
On Study Assessments Treatment Phase-
Part 2 - Nivolumab+ ipilimumab+ platinum-doublet chemotherapy combination (3 weeks/cycle)
Part 2 Procedure
Cycle 1 
Day 1
Each 
Subsequent 
Cycle
Day1
(± 3 Days)
Every 2 
Cycles
Day 1
(± 3 Days)
Every 3 
Cycles
Day 1
(± 3 Days)
Notes
For the purposes of this table, a cycle refers to the 
nivolumab +ipilimumab+ platinum-doublet 
chemotherapy every 3 weeks x2 cycles regimen 
Safety Assessments
Physical Measurements & ECOG 
Performance Status
X
X
Sections 5.3, 5.3.1 Appendix 1
Vital Signs and Oxygen Saturation
X
Section 5.3
Adverse Event Assessments
Continuously during the study
Section 6. SAEs should be approved in Trial
Access Online (TAO) within 5 days from entry.
Laboratory Tests
X
X
X(TSH)
Section 5.3
Within 72 hrs. prior to dosing to include CBC w/ 
differential, AST, ALT, ALP, T. bili, BUN or serum 
urea level, creatinine, albumin, Ca, Mg, Na, K, Cl, 
LDH, phosphate, glucose, amylase, lipase, TSH (with 
reflexive Free T4 and Free T3).
Thyroid Function Testing to be evaluated every 6 
weeks 
Note:  C1D1 labs do not need to be repeated if they 
were performed within 14 days of dosing.
Pregnancy Test (WOCBP only) 
X
X
Sections 5.3.2 To be evaluated at least every 3 weeks 
for cycles 1- 4 and a minimum of every 4 weeks after 
cycle 4 dose, to align with clinic visits.
Efficacy Assessments
Radiographic Tumor Assessment 
(CT/MRI chest, abdomen, pelvis)
Section 5.4. 
FIRST tumor assessment should first be performed at 6 weeks (± 7 days) from first dose date.
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Table 5.1-3:
On Study Assessments Treatment Phase-
Part 2 - Nivolumab+ ipilimumab+ platinum-doublet chemotherapy combination (3 weeks/cycle)
Part 2 Procedure
Cycle 1 
Day 1
Each 
Subsequent 
Cycle
Day1
(± 3 Days)
Every 2 
Cycles
Day 1
(± 3 Days)
Every 3 
Cycles
Day 1
(± 3 Days)
Notes
For the purposes of this table, a cycle refers to the 
nivolumab +ipilimumab+ platinum-doublet 
chemotherapy every 3 weeks x2 cycles regimen 
Clinical Drug Supplies
IWRS Vial Assignment
X
X
Section 4.4. 
Within 3 business days prior to first dosing
Nivolumab + ipilimumab + platinum-
doublet chemotherapy q 3w x2 cycles
X
X
Section 4.5 & Table 4.5-2
Note: 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
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5.1.1
Retesting During Screening or Lead-in Period
Retesting of laboratory parameters and/or other assessments during the Screening period will not 
be permitted (this does not include parameters that require a confirmatory result).
Any new result will override the previous result (ie, the most current result prior to first dose) and 
is the value by which study inclusion will be assessed, as it represents the subject’s most current, 
clinical state.
5.2
Study Materials
•
NCI CTCAE version 4
•
Nivolumab Investigator Brochure
•
Ipilimumab Investigator Brochure
•
Pharmacy Binder
•
Laboratory manuals for collection and handling of blood (including PK, biomarker and 
immunogenicity) and tissue specimens
•
Site manual for operation of Interactive Web Response System (IWRS), including enrollment 
worksheets
•
Manual for entry of local laboratory data
•
Pregnancy Surveillance Forms
•
RECIST 1.1 pocket guide
•
CA209568 study Imaging Manual
•
Blinded Independent Central Review manual
•
5.3
Safety Assessments
At baseline, a medical history will be obtained to capture relevant underlying conditions. The 
baseline examinations should include weight, height, ECOG Performance Status, blood pressure 
(BP), heart rate (HR), and temperature at rest, and should be performed within 28 days prior to 
first dose. Baseline signs and symptoms are those that are assessed within 14 days prior to first 
dose. Concomitant medications will be collected from within 14 days prior to the first dose through 
the study treatment period (see Section 5.1).
Baseline local laboratory assessments should be done within 14 days prior to first dose and are to 
include: CBC w/differential, LFTs (ALT, AST, total bilirubin, alkaline phosphatase), BUN or 
serum urea level, creatinine, albumin, Ca, Mg, Na, K, Cl, phosphate, LDH, glucose, amylase, 
lipase, Thyroid function tests includes TSH, free T4, and free T3.
The following baseline local laboratory assessments should be done within 28 days prior to first 
treatment: Hepatitis B and C testing (HBV sAg and HCV Ab or HCV RNA).
Pregnancy testing for WOCBP (done locally) must be performed within 24 hours prior to the Day 1 
at baseline and then every 4 weeks (2 cycles) ± 3 days. Pregnancy testing must be within 24 hours 
prior to Day 1 of each treatment cycle (prior to dosing).
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While on-study the following local laboratory assessments are to be done within 3 days prior to 
each dose: CBC with differential, LFTs (ALT, AST, total bilirubin, alkaline phosphatase), BUN 
or serum urea level, creatinine, albumin, Ca, Mg, Na, K, Cl, phosphate, LDH, glucose, amylase, 
and lipase. Thyroid function testing is to be done every 6 weeks.
Subjects will be evaluated for safety if they have received any study drug. Toxicity assessments 
will be continuous during the treatment phase. During the safety follow-up phase (Table 5.1-3) 
toxicity assessments should be done in person. Once subjects reach the survival follow-up phase 
either in person or documented telephone calls to assess the subject’s status are acceptable. 
Adverse events and laboratory values will be graded according to the NCI-CTCAE version 4.0.
On-study weight, ECOG performance status, and vital signs should be assessed at each on-study 
visit prior to dosing. Vital signs should also be taken as per institutional standard of care prior to, 
during and after infusions. The start and stop time of the study therapy infusions should be 
documented.
Physical examinations are to be performed as clinically indicated. If there are any new or 
worsening clinically significant changes since the last exam, report changes on the appropriate 
non-serious or serious adverse event page.
On treatment local laboratory assessments are to be completed within 72 hours prior to dosing.
Additional measures, including non-study required laboratory tests, should be performed as 
clinically indicated or to comply with local regulations. Laboratory toxicities (eg, suspected drug 
induced liver enzyme evaluations) will be monitored during the follow-up phase via on site/local 
labs until all study drug related toxicities resolve, return to baseline, or are deemed irreversible.
If a participant shows pulmonary-related signs (hypoxia, fever) or symptoms (eg. dyspnea, cough, 
fever) consistent with possible pulmonary adverse events, the participant should be immediately 
evaluated to rule out pulmonary toxicity, according to the suspected pulmonary toxicity 
management algorithm in the BMS-936558 (nivolumab) Investigator Brochure.
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.
5.3.1
ECOG Performance Status 
Eastern Cooperative Oncology Group (ECOG) Performance Status will be evaluated and 
documented at Screening and within 72 hours prior to each dosing visit as outlined in Section 5.1. 
See Appendix 1 for description of ECOG status.
5.3.2
Pregnancy Testing
WOCBP are required to have pregnancy tests performed. WOCBP must exhibit a negative serum 
or urine pregnancy (minimum sensitivity 25 IU/L or equivalent units of HCG within 24 hours prior 
to Day 1 of each treatment period and safety follow-up visits. Pregnancy testing will be done 
locally and as outlined in Section 5.1. An extension up to 72 hours prior to start of study drug may 
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be permissible in situations where results cannot be obtained within the standard 24 hour window. 
This is subject to medical monitor/MST Chair approval.
5.3.3
Thyroid Function Testing
Thyroid function testing will be performed as outlined in Section 5.1
At Screening, thyroid function testing is to include TSH, free T3 and free T4. At subsequent time 
points, thyroid function testing consists of TSH only. However, if the TSH is abnormal, reflexive 
testing of free T3 and free T4 are to be performed. 
Management algorithms for suspected endocrinopathy adverse events (including abnormal thyroid 
function) can be found in the nivolumab investigator brochure and Appendix 2 of the protocol.
5.3.4
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.
5.4
Efficacy Assessments
Images will be submitted to an imaging third party radiology vendor for central review (for 
subjects participating in Part 1). Any additional imaging that may demonstrate tumor response or 
progression (including scans performed at unscheduled timepoints and/or at an outside institution) 
should be collected for RECIST 1.1 tumor assessment and submitted to the BICR. Sites will be 
trained prior to scanning the first study subject. Image acquisition guidelines and submission 
process will be outlined in the study Imaging Manual to be provided by the radiology vendor. 
Tumor assessments should be submitted to the third party radiology vendor as they are performed 
on an ongoing basis. At the time of investigator-assessed disease progression, the site must request 
a Blinded Independent Central Review from the third party radiology vendor for confirmation of 
progression, as specified in Section 7.2. 
Contrast enhanced CT with PO/IV contrast or contrast enhanced MRI are the preferred imaging 
modalities for assessing radiographic tumor response. If a subject has a known allergy to contrast 
material, local prophylaxis standards may be used to obtain the assessment with contrast if at all 
possible, or use the alternate modality. In cases where contrast is strictly contraindicated, a 
non-contrast scan will suffice. Should a subject have a contraindication for CT IV contrast, a non-
contrast CT of the chest and a contrast enhanced MRI of the abdomen and pelvis may be obtained. 
Every attempt should be made to image each subject using an identical acquisition protocol on the 
same scanner for all imaging time points. (Applies to both Part 1 and Part 2 Safety Lead in).
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. At 
present, low dose or attenuation correction CT portions of a combined FDG-PET/CT are of limited 
use in anatomically based efficacy assessments and it is therefore suggested that they should not 
be substituted for dedicated diagnostic contrast enhanced CT scans for anatomically based 
RECIST measurements. However, 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 and oral contrast) then 
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the CT portion of the FDG-PET/CT can be used for RECIST 1.1measurements. Note, however, 
that the FDG-PET portion of the CT 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.
Screening assessments are to be performed within 28 days prior to first dose. 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). 
Subjects with a history of brain metastasis may have surveillance MRI approximately every 
12 weeks from the date of first dose, or sooner if clinically indicated.
Tumor measurements should be made by the same investigator or radiologist for each assessment 
whenever possible. Change in tumor measurements and tumor response will be assessed by the 
Investigator using the RECIST 1.1 criteria Appendix 3.
Tumor assessments should be submitted to the third party radiology vendor as they are performed 
on an ongoing basis, with the exception of safety lead in subjects. At the time of investigator-
assessed disease progression, the site must request a Blinded Independent Central Review from 
the third party radiology vendor, as specified in Section 7.2. 
Subjects whose disease progression is not confirmed by the blinded, independent radiologist 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 review by the blinded, independent radiologists and may be discontinued when the 
investigator and independent radiologists both assess the subject to have met RECIST 1.1 criteria 
for progression.
In addition, subjects receiving nivolumab and ipilimumab +/- chemotherapy treatment beyond 
progression must continue tumor assessments until such treatment has been discontinued.
If clinically acceptable, subsequent therapy should begin only after RECIST 1.1 progression has 
been assessed by Blinded Independent Central Review. Subjects who start palliative local therapy 
or subsequent therapy without prior assessment of RECIST 1.1 progression by central review, the 
Blinded Independent Central Review must continue tumor assessments (if clinically feasible) 
according to the protocol-specified schedule and submit them to the third party radiology vendor. 
When RECIST 1.1 progression is assessed by the investigator (whether assessed before or after 
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the start of palliative local therapy or subsequent therapy), the Blinded Independent Central 
Review must be requested. Tumor assessments may be discontinued when the independent 
radiologist assesses the subject to have met RECIST 1.1 criteria for progression.
5.4.1
Primary Efficacy Assessment
Part 1: The primary endpoint is objective response rate (ORR) based on blinded independent 
central review assessment in all treated PD-L1 positive (≥1%) subjects and ORR in all treated 
PD-L1 negative (< 1%) subjects. All treated subjects will be monitored by radiographic assessment 
every 6 weeks (± 7 days) until week 48 and every 12 weeks (± 7 days) thereafter [beginning from 
the first on-study assessment on week 6 (± 7 days)], to determine changes in tumor size. RECIST 
1.1 criteria will be used for the assessment. 
Part 2: 
Primary Endpoints will be descriptive.
•
The incidence of DLT (dose limiting toxicity) during DLT evaluation period (within 9 weeks 
after first dose)
•
The safety and tolerability of nivolumab and ipilimumab combined with chemotherapy.
5.4.2
Secondary Efficacy Assessment
Part 1: Objective response rate (ORR) based on blinded independent central review assessment in 
all treated subjects. Progression free survival (PFS) based on blinded independent central review 
assessment, overall survival and ORR, PFS and OS by PD-L1 expression levels. 
Part 2: 
•
ORR, PFS by investigator assessment, and OS 
 
 
 
 
 
 
 
 
 
 
 
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6
ADVERSE EVENTS
An Adverse Event (AE) is defined as any new untoward medical occurrence or worsening of a 
preexisting medical condition in a clinical investigation subject administered study drug and that 
does not necessarily have a causal relationship with this treatment. An AE can therefore be any 
unfavorable and unintended sign (such as an abnormal laboratory finding), symptom, or disease 
temporally associated with the use of study drug, whether or not considered related to the study 
drug.
The causal relationship to study drug is determined by a physician and should be used to assess all 
adverse events (AE). The causal relationship can be one of the following:
Related: There is a reasonable causal relationship between study drug administration and 
the AE.
Not related: There is not a reasonable causal relationship between study drug 
administration and the AE. 
The term "reasonable causal relationship" means there is evidence to suggest a causal relationship. 
Adverse events can be spontaneously reported or elicited during open-ended questioning, 
examination, or evaluation of a subject. (In order to prevent reporting bias, subjects should not be 
questioned regarding the specific occurrence of one or more AEs.)
BMS will be reporting adverse events to regulatory authorities and ethics committees according to 
local applicable laws including European Directive 2001/20/EC and FDA Code of Federal 
Regulations 21 CFR Parts 312 and 320.
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6.1
Serious Adverse Events
A Serious Adverse Event (SAE) is any untoward medical occurrence that at any dose: 
•
results in death
•
is life-threatening (defined as an event in which the subject was at risk of death at the time of 
the event; it does not refer to an event which hypothetically might have caused death if it were 
more severe)
•
requires inpatient hospitalization or causes prolongation of existing hospitalization (see NOTE
below)
•
results in persistent or significant disability/incapacity
•
is a congenital anomaly/birth defect 
•
is an important medical event (defined as a medical event(s) that may not be immediately 
life-threatening or result in death or hospitalization but, based upon appropriate medical and 
scientific judgment, may jeopardize the subject or may require intervention [eg, medical, 
surgical] to prevent one of the other serious outcomes listed in the definition above.) Examples 
of such events include, but are not limited to, intensive treatment in an emergency room or at 
home for allergic bronchospasm; blood dyscrasias or convulsions that do not result in 
hospitalization.) Potential drug induced liver injury (DILI) is also considered an important 
medical event. (See Section 6.6 for the definition of potential DILI.)
Suspected transmission of an infectious agent (eg, pathogenic or nonpathogenic) via the study drug 
is an SAE. 
Although pregnancy, overdose, cancer, and potential drug induced liver injury (DILI) are not 
always serious by regulatory definition, these events must be handled as SAEs. (See Section 6.1.1
for reporting pregnancies).
Any component of a study endpoint that is considered related to study therapy (eg, death is an 
endpoint, if death occurred due to anaphylaxis, anaphylaxis must be reported) should be reported 
as SAE (see Section 6.1.1 for reporting details).
NOTE: 
The following hospitalizations are not considered SAEs in BMS clinical studies: 
−
a visit to the emergency room or other hospital department < 24 hours, that does not result 
in admission (unless considered an important medical or life-threatening event)
−
elective surgery, planned prior to signing consent
−
admissions as per protocol for a planned medical/surgical procedure
−
routine health assessment requiring admission for baseline/trending of health status 
(eg, routine colonoscopy)
−
medical/surgical admission other than to remedy ill health and planned prior to entry into 
the study. Appropriate documentation is required in these cases
−
admission encountered for another life circumstance that carries no bearing on health status 
and requires no medical/surgical intervention (eg, lack of housing, economic inadequacy, 
caregiver respite, family circumstances, administrative reason)
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−
Admission for administration of anticancer therapy in the absence of any other SAEs 
(applies to oncology protocols)
6.1.1
Serious Adverse Event Collection and Reporting
Sections 5.6.1 and 5.6.2 in the Investigator Brochure (IB) represent the Reference Safety 
Information to determine expectedness of serious adverse events for expedited reporting. 
Following the subject’s written consent to participate in the study, all SAEs, whether related or not 
related to study drug, must be collected, including those thought to be associated with protocol-
specified procedures. All SAEs must be collected that occur during the screening period and within 
100 days of discontinuation of dosing. For subjects randomized to treatment and never treated with 
study drug, SAEs should be collected for 30 days from the date of treatment. If applicable, SAEs 
must be collected that relate to any later protocol-specified procedure (eg, a follow-up skin biopsy). 
The investigator must report any SAE that occurs after these time periods and that is believed to 
be related to study drug or protocol-specified procedure. 
An SAE report must be completed for any event where doubt exists regarding its seriousness. 
If the investigator believes that an SAE is not related to study drug, but is potentially related to the 
conditions of the study (such as withdrawal of previous therapy or a complication of a study 
procedure), the relationship must be specified in the narrative section of the SAE Report Form.
SAEs, whether related or not related to study drug, and pregnancies must be reported to BMS 
(or designee) within 24 hours of awareness of the event. SAEs must be recorded on the SAE Report 
Form; pregnancies on a Pregnancy Surveillance Form (electronic or paper forms). The preferred 
method for SAE data reporting collection is through the eCRF. The paper SAE/pregnancy 
surveillance forms are only intended as a back-up option when the eCRF system is not functioning. 
In this case, the paper forms are to be transmitted via email or confirmed facsimile (fax) 
transmission to:
SAE Email Address: Refer to Contact Information list.
SAE Facsimile Number: Refer to Contact Information list.
For studies capturing SAEs through electronic data capture (EDC), electronic submission is the 
required method for reporting. In the event the electronic system is unavailable for transmission, 
paper forms must be used and submitted immediately. When paper forms are used, the original 
paper forms are to remain on site.
SAE Telephone Contact (required for SAE and pregnancy reporting): Refer to Contact 
Information list.
If only limited information is initially available, follow-up reports are required. (Note: Follow-up 
SAE reports must include the same investigator term(s) initially reported.) 
If an ongoing SAE changes in its intensity or relationship to study drug or if new information 
becomes available, the SAE report must be updated and submitted within 24 hours to BMS 
(or designee) using the same procedure used for transmitting the initial SAE report.
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All SAEs must be followed to resolution or stabilization.
6.2
Nonserious Adverse Events
A nonserious adverse event is an AE not classified as serious.
6.2.1
Nonserious Adverse Event Collection and Reporting
The collection of nonserious AE information should begin at initiation of study drug. All 
nonserious adverse events (not only those deemed treatment-related) are to be collected 
continuously during the treatment period and for a minimum of 100 days following the last dose 
of study treatment.
Nonserious AEs should be followed to resolution or stabilization, or reported as SAEs if they 
become serious (see Section 6.1.1). Follow-up is also required for nonserious AEs that cause 
interruption or discontinuation of study drug and for those present at the end of study treatment as 
appropriate. All identified nonserious AEs must be recorded and described on the nonserious AE 
page of the CRF (paper or electronic). 
Completion of supplemental CRFs may be requested for AEs and/or laboratory abnormalities that 
are reported/identified during the course of the study.
6.3
Laboratory Test Result Abnormalities
The following laboratory test result abnormalities should be captured on the nonserious AE CRF 
page or SAE Report Form electronic) as appropriate. Paper forms are only intended as a back-up 
option when the electronic system is not functioning.
•
Any laboratory test result that is clinically significant or meets the definition of an SAE 
•
Any laboratory test result abnormality that required the subject to have study drug discontinued 
or interrupted
•
Any laboratory test result abnormality that required the subject to receive specific corrective 
therapy. It is expected that wherever possible, the clinical rather than laboratory term would 
be used by the reporting investigator (eg, anemia versus low hemoglobin value).
6.4
Pregnancy
If, following initiation of the study drug, it is subsequently discovered that a study subject is 
pregnant or may have been pregnant at the time of study exposure, including during at least 
5 half-lives after product administration, the investigator must immediately notify the 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 Section 6.1.1.
In most cases, the study drug will be permanently discontinued in an appropriate manner (eg, dose 
tapering if necessary for subject safety). Please call the BMS Medical Monitor within 24 hours of 
awareness of the pregnancy.
In the rare event that the benefit of continuing study drug is thought to outweigh the risk, after 
consultation with BMS, the pregnant subject may continue study drug after a thorough discussion 
of benefits and risk with the subject, if allowed by local regulations.
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Protocol-required procedures for study discontinuation and follow-up must be performed on the 
subject unless contraindicated by pregnancy (eg, x-ray studies). Other appropriate pregnancy 
follow-up procedures should be considered if indicated.
The investigator must immediately notify the BMS (or designee) Medical Monitor of this event 
and complete and forward a Pregnancy Surveillance Form to BMS (or designee) within 24 hours 
of awareness of the event and in accordance with SAE reporting procedures described in 
Section 6.1.1. 
Follow-up information regarding the course of the pregnancy, including perinatal and neonatal 
outcome and, where applicable, offspring information must be reported on the Pregnancy 
Surveillance Form.
Any pregnancy that occurs in a female partner of a male study participant should be reported to 
BMS. Information on this pregnancy will be collected on the Pregnancy Surveillance Form.
6.5
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 6.1.1 for reporting details.).
6.6
Potential Drug Induced Liver Injury (DILI)
Wherever possible, timely confirmation of initial liver-related laboratory abnormalities should 
occur prior to the reporting of a potential DILI event. All occurrences of potential DILIs, meeting 
the defined criteria, must be reported as SAEs (see Section 6.1.1 for reporting details).
Potential drug induced liver injury is defined as: 
1. AT (ALT or AST) elevation > 3 times upper limit of normal (ULN)
AND
2. Total bilirubin > 2 times ULN, without initial findings of cholestasis (elevated serum alkaline 
phosphatase),
AND
3. No other immediately apparent possible causes of AT elevation and hyperbilirubinemia, 
including, but not limited to, viral hepatitis, pre-existing chronic or acute liver disease, or the 
administration of other drug(s) known to be hepatotoxic.
6.7
Other Safety Considerations
Any significant worsening noted during interim or final physical examinations, electrocardiogram, 
x-ray filming, any other potential safety assessment required or not required by protocol should 
also be recorded as a nonserious or serious AE, as appropriate, and reported accordingly.
6.7.1
Adverse Events of 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 
subjects 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 6.7.1-1 below provides a summary of the IMAEs category and their respective PTs. 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 6.7.1-1:
Preferred Terms Included in Analysis of IMAEs to Support 
Warnings and Precautions
IMAE Category
PTs included under IMAE Category
Pneumonitis
Pneumonitis, Interstitial lung disease
Diarrhea/Colitis
Diarrhea, Colitis, Enterocolitis
Hepatitis
Hepatotoxicity, Hepatitis, Hepatitis acute, Autoimmune 
hepatitis, AST increased, ALT increased, Bilirubin 
increased, ALP increased
Adrenal insufficiency
Adrenal insufficiency
Hypothyroidism/Thyroiditis
Hypothyroidism, Thyroiditis
Thyroiditis acute (collapsed with thyroiditis for 
frequency), Autoimmune thyroiditis (collapsed with 
thyroiditis for frequency)
Hyperthyroidism
Hyperthyroidism
Hypophysitis
Hypophysitis
Diabetes mellitus
Diabetes mellitus, Diabetic ketoacidosis
Nephritis and renal dysfunction
Nephritis, Nephritis allergic, Tubulointerstitial 
nephritis, Acute renal failure, Renal failure, Increased 
creatinine
Rash
Rash, Rash maculopapular
7
DATA MONITORING COMMITTEE AND OTHER EXTERNAL 
COMMITTEES
When required, adjudicated events will be submitted to Health Authorities for review on a 
specified timeframe in accordance with the adjudication documentation.
7.1
Data Monitoring Committee (DMC)
Not applicable.
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7.2
Blinded Independent Radiology Central Review 
At the time of investigator-assessed initial radiographic progression per RECIST 1.1 in any given 
subject, the site must request the Independent Central Review from the third party radiology 
vendor for confirmation of progression for Part 1.
Tumor assessments for each subject should be submitted to the radiology vendor as they are 
performed on an ongoing basis. The blinded, independent radiologists will review all available 
tumor assessments for that given subject and determine if RECIST 1.1 criteria for progression have 
been met. The independent assessment of whether or not the given subject met RECIST 1.1 criteria 
for progression will be provided to the site. Subjects whose disease progression is not confirmed 
centrally will be required to continue tumor assessments (if clinically feasible) according to the 
protocol-specified schedule. Subsequent tumor assessments must be submitted to the third party 
radiology vendor for subsequent review and may be discontinued when the investigator and 
independent radiologists both assess the subject to have met RECIST 1.1 criteria for progression.
The Blinded Independent Central Review will also review tumor images in all treated subjects
(Part 1) to determine RECIST 1.1 response for the analyses of ORR or PFS. Details of the Blinded 
Independent Central Review responsibilities and procedures will be specified in the Blinded 
Independent Central Review charter.
At time of analysis of ORR or PFS, Independent Radiology Review Committee will review tumor 
assessments in all treated subjects to determine RECIST 1.1 progression and response for the 
analyses of PFS and ORR. Details of the IRRC responsibilities and procedures will be specified 
in the IRRC charter.
8
STATISTICAL CONSIDERATIONS
8.1
Sample Size Determination
The reported objective response rate for the investigational treatment based on 77 treated subjects 
treated with nivolumab plus ipilimumab in phase I study CA209012 was 43% in August 2015-
database lock. The reported objective response rate based on 23 PD-L1 positive subjects was 48%. 
However, given the small sample size in that cohort, the observed ORR in CA209568 might be 
lower.
Table 8.1-1 summarizes the 95% exact CI for some scenarios of observed ORRs and 95% 
confidence intervals. The part 1 sample size of at least 120 PD-L1 positive subjects, can provide 
95% confidence that the observed ORR can be estimated to within 9.5% of the estimates. With an 
observed ORR of 48%, the lower bound of the observed ORR is not less than 39%. In addition, 
the 95% exact CI for the target ORRs for a sample size of 60 PD-L1 ≥50% population and 
100 PD-L1 negative subjects are summarized. The sample sizes of approximately 300 all treated 
subjects, 60 PD-L1 ≥50% subjects and 100 PD-L1 negative subjects, can provide 95% confidence 
that the observed ORR can be estimated to within 5.8%, 13.5% and 10.5% of the estimates. 
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Table 8.1-1:
Observed ORR with Exact 95% CI
ORR
# Responders
95% Exact CI
N=300 All Treated
30%
90
[24.9, 35.5]
40%
120
[34.4, 45.8]
50%
150
[44.2, 55.8]
N=120 PD-L1 positive
40%
48
[31.2; 49.3]
44%
53
[35.1; 53.5]
48%
58
[39.1; 57.6]
57.5%
69
[48.1, 66.5]
N=60 PD-L1 ≥50%
60%
36
[46.5; 72.4]
65%
39
[51.6; 76.9]
70%
42
[56.8; 81.2]
N=100 PD-L1 negative
10%
10
[4.9, 17.6]
20%
20
[12.7, 29.2]
30%
30
[21.2, 40.0]
40%
40
[30.3, 50.3]
95% CI based on Clopper-Pearson method
Assuming 35% screening failure rate and 50% of all tested tissue samples are PD-L1 positive, it 
is estimated that approximately 440 subjects will be enrolled in order to achieve approximately 
300 subjects treated which including at least 120 PD-L1 positive and 100 PD-L1 negative treated.
For Part 2 lead-in phase, there are 22 DLT evaluable subjects within 28 subjects who initiate 
treatment assuming 20% of subjects do not complete the 9 week DLT evaluation period for reasons 
other than dose limiting toxicities. With a sample size of 22 DLT evaluable subjects with a safety 
event incident rate as 10%, there is above 90% probability to observe 1 or more cases of this safety 
event in this group. The goal is to identify safe regimens for future development, and safe is defined 
as 25% evaluated subjects or less exhibit DLTs (ie, 5 or less subjects with such events out of 
22 subjects). With 22 evaluable subjects, the false rejection rate is 10% if the true toxicity rate is 
15%, the false acceptance rate is 16% if the true toxicity rate is 35%. The false rejection and false 
acceptance rates are deemed acceptable.
8.2
Populations for Analyses
Part 1:
•
All enrolled subjects: all subjects who signed an informed consent form and were registered 
into the IWRS
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•
All treated subjects: all subjects who received at least one dose of any study medication.
•
All treated PD-L1 positive subjects: all treated subjects with PD-L1 membranous staining in 
≥1% tumor cells.
•
All treated PD-L1 negative subjects: all treated subjects with PD-L1 membranous staining in 
< 1% tumor cells. 
•
All Treated PD-L1 ≥50% subjects: all treated subjects with PD-L1 membranous staining in 
≥50% tumor cells). This is a subject set of subjects in all treated PD-L1 positive subjects.
Part 2:
•
All enrolled subjects: all subjects who signed an informed consent form and were registered 
into the IWRS
•
All treated subjects: all subjects who received at least one dose of any study medication. This 
is the primary dataset for dosing and safety analysis.
Safety lead in subjects will be described separately on safety and efficacy (ie overall response rate 
and DLT incidence).
Additional specific populations will be described in the statistical analysis plan
8.3
Endpoints
8.3.1
Primary Endpoint(s)
Part 1:
•
ORR in all treated PD-L1 positive (≥1%) subjects by blinded independent central review per 
RECIST 1.1 in stage IV NSCLC subjects with nivolumab in combination with ipilimumab as 
first line therapy. 
•
ORR in all treated PD-L1 negative (< 1%) subjects by blinded independent central review per 
RECIST 1.1 in stage IV NSCLC subjects treated with nivolumab in combination with 
ipilimumab as first line therapy. 
ORR is defined as the number of subjects with a best overall response (BOR) of confirmed CR or 
PR divided by the number of treated subjects. BOR is defined as the best response designation, as 
determined by the blinded independent central review, 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 anticancer therapy, whichever occurs first. For 
subjects without documented progression or palliative local therapy or subsequent anti-cancer 
therapy, all available response designations will contribute to the BOR determination. For subjects 
who continue treatment beyond progression, the BOR will be determined based on response 
designations recorded up to the time of the initial RECIST 1.1-defined progression.
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 objective response (time from first 
dosing date to first CR or PR) and depth of response (maximum tumor shrinkage in target lesions).
The analysis of the primary endpoint ORR will be performed at least six month after last subject 
first treatment.
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8.5
Interim Analyses
Not applicable
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9
STUDY MANAGEMENT
9.1
Compliance
9.1.1
Compliance with the Protocol and Protocol Revisions
The study shall be conducted as described in this approved protocol. All revisions to the protocol 
must be discussed with, and be prepared by, BMS. The investigator should not implement any 
deviation or change to the protocol without prior review and documented approval/favorable 
opinion from the IRB/IEC of an amendment, except where necessary to eliminate an immediate 
hazard(s) to study subjects. 
If a deviation or change to a protocol is implemented to eliminate an immediate hazard(s) prior to 
obtaining IRB/IEC approval/favorable opinion, as soon as possible the deviation or change will be 
submitted to:
•
IRB/IEC for review and approval/favorable opinion
•
BMS
•
Regulatory Authority(ies), if required by local regulations
Documentation of approval signed by the chairperson or designee of the IRB(s)/IEC(s) must be 
sent to BMS.
If an amendment substantially alters the study design or increases the potential risk to the subject: 
(1) the consent form must be revised and submitted to the IRB(s)/IEC(s) for review and 
approval/favorable opinion; (2) the revised form must be used to obtain consent from subjects 
currently enrolled in the study if they are affected by the amendment; and (3) the new form must 
be used to obtain consent from new subjects prior to enrollment.
If the revision is done via an administrative letter, investigators must inform their IRB(s)/IEC(s).
9.1.2
Monitoring
BMS representatives will review data centrally to identify potential issues to determine a schedule 
of on-site visits for targeted review of study records. 
Representatives of BMS must be allowed to visit all study site locations periodically to assess the 
data quality and study integrity. On site they will review study records and directly compare them 
with source documents, discuss the conduct of the study with the investigator, and verify that the 
facilities remain acceptable. 
In addition, the study may be evaluated by BMS internal auditors and government inspectors who 
must be allowed access to CRFs, source documents, other study files, and study facilities. BMS 
audit reports will be kept confidential.
The investigator must notify BMS promptly of any inspections scheduled by regulatory authorities, 
and promptly forward copies of inspection reports to BMS. 
9.1.2.1
Source Documentation
The Investigator is responsible for ensuring that the source data are accurate, legible, 
contemporaneous, original and attributable, whether the data are hand-written on paper or entered 
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electronically. If source data are created (first entered), modified, maintained, archived, retrieved, 
or transmitted electronically via computerized systems (and/or any other kind of electronic 
devices) as part of regulated clinical trial activities, such systems must be compliant with all 
applicable laws and regulations governing use of electronic records and/or electronic signatures. 
Such systems may include, but are not limited to, electronic medical/health records (EMRs/EHRs), 
adverse event tracking/reporting, protocol required assessments, and/or drug accountability 
records).
When paper records from such systems are used in place of electronic format to perform regulated 
activities, such paper records should be certified copies. A certified copy consists of a copy of 
original information that has been verified, as indicated by a dated signature, as an exact copy 
having all of the same attributes and information as the original. 
9.1.3
Investigational Site Training
Bristol-Myers Squibb will provide quality investigational staff training prior to study initiation. 
Training topics will include but are not limited to: GCP, AE reporting, study details and procedure, 
electronic CRFs, study documentation, informed consent, and enrollment of WOCBP.
9.2
Records
9.2.1
Records Retention
The investigator must retain all study records and source documents for the maximum period 
required by applicable regulations and guidelines, or institution procedures, or for the period 
specified by BMS, whichever is longer. The investigator must contact BMS prior to destroying 
any records associated with the study.
BMS will notify the investigator when the study records are no longer needed.
If the investigator withdraws from the study (eg, relocation, retirement), the records shall be 
transferred to a mutually agreed upon designee (eg, another investigator, IRB). Notice of such 
transfer will be given in writing to BMS.
9.2.2
Study Drug Records 
It is the responsibility of the investigator to ensure that a current disposition record of study drug 
(inventoried and dispensed) is maintained at the study site to include investigational product and 
the following non-investigational product(s) Records or logs must comply with applicable 
regulations and guidelines and should include:
•
amount received and placed in storage area
•
amount currently in storage area
•
label identification number or batch number 
•
amount dispensed to and returned by each subject, including unique subject identifiers
•
amount transferred to another area/site for dispensing or storage
•
nonstudy disposition (eg, lost, wasted) 
•
amount destroyed at study site, if applicable
•
amount returned to BMS
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•
retain samples for bioavailability/bioequivalence, if applicable 
•
dates and initials of person responsible for Investigational Product dispensing/accountability, 
as per the Delegation of Authority Form.
BMS will provide forms to facilitate inventory control if the investigational site does not have an 
established system that meets these requirements.
9.2.3
Case Report Forms
An investigator is required to prepare and maintain adequate and accurate case histories designed 
to record all observations and other data pertinent to the investigation on each individual treated 
or entered as a control in the investigation. Data that are derived from source documents and 
reported on the CRF must be consistent with the source documents or the discrepancies must be 
explained. Additional clinical information may be collected and analyzed in an effort to enhance 
understanding of product safety. CRFs may be requested for AEs and/or laboratory abnormalities 
that are reported or identified during the course of the study.
For sites using the BMS electronic data capture tool, electronic CRFs will be prepared for all data 
collection fields except for fields specific to SAEs and pregnancy, which will be reported on the 
electronic SAE form and Pregnancy Surveillance form, respectively. If electronic SAE form is not 
available, a paper SAE form can be used. 
The confidentiality of records that could identify subjects must be protected, respecting the privacy
and confidentiality rules in accordance with the applicable regulatory requirement(s).
The investigator will maintain a signature sheet to document signatures and initials of all persons 
authorized to make entries and/or corrections on CRFs. 
The completed CRF, SAE/pregnancy CRFs, must be promptly reviewed, signed, and dated by the 
investigator or qualified physician who is a subinvestigator and who is delegated this task on the 
Delegation of Authority Form. For electronic CRFs, review and approval/signature is completed 
electronically through the BMS electronic data capture tool. The investigator must retain a copy 
of the CRFs including records of the changes and corrections.
Each individual electronically signing electronic CRFs must meet BMS training requirements and 
must only access the BMS electronic data capture tool using the unique user account provided by 
BMS. User accounts are not to be shared or reassigned to other individuals.
9.3
Clinical Study Report and Publications
A Signatory Investigator must be selected to sign the clinical study report. 
For this protocol, the Signatory Investigator will be selected as appropriate based on the following 
criteria:
•
Subject recruitment (eg, among the top quartile of enrollers)
•
Involvement in trial design
•
Other criteria (as determined by the study team)
The data collected during this study are confidential and proprietary to BMS. Any publications or 
abstracts arising from this study must adhere to the publication requirements set forth in the clinical 
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trial agreement (CTA) governing [Study site or Investigator] participation in the study. These 
requirements include, but are not limited to, submitting proposed publications to BMS at the 
earliest practicable time prior to submission or presentation and otherwise within the time period 
set forth in the CTA.
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10
GLOSSARY OF TERMS
Term
Definition
Complete Abstinence
Complete Abstinence is defined as complete avoidance of heterosexual 
intercourse and is an acceptable form of contraception for all study drugs. 
This also means that abstinence is the preferred and usual lifestyle of the 
patient. This does not mean periodic abstinence (eg, calendar, ovulation, 
symptothermal, profession of abstinence for entry into a clinical trial, 
post-ovulation methods) and withdrawal, which are not acceptable 
methods of contraception. Women must continue to have pregnancy tests. 
Acceptable alternate methods of highly or less effective contraception’s 
must be discussed in the event that the subject chooses to forego complete 
abstinence.
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11
LIST OF ABBREVIATIONS
Term
Definition
AE
adverse event
ACLS
advanced cardiac life support
AI
accumulation index
AI_AUC
AUC Accumulation Index; ratio of AUC(TAU) at steady state to 
AUC(TAU) after the first dose
AI_Cmax
Cmax Accumulation Index; ratio of Cmax at steady state to Cmax after 
the first dose
AI_Ctau
Ctau Accumulation Index; ratio of Ctau at steady state to Ctau after the 
first dose
ALT
alanine aminotransferase
ANC
absolute neutrophil count
ANOVA
analysis of variance
aPTT
activated partial thromboplastin time
AST
aspartate aminotransferase
AT
aminotransaminases
AUC
area under the concentration-time curve
AUC(INF)
area under the concentration-time curve from time zero extrapolated to 
infinite time
AUC(0-T)
area under the concentration-time curve from time zero to the time of the 
last quantifiable concentration
AUC(TAU)
area under the concentration-time curve in one dosing interval
A-V
atrioventricular
β-HCG
beta-human chorionic gonadotrophin
BA/BE
bioavailability/bioequivalence
%BE
percent biliary excretion
BID, bid
bis in die, twice daily
BLQ
below limit of quantification 
BMI
body mass index
BMS
Bristol-Myers Squibb
BP
blood pressure
BRt
Total amount recovered in bile
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Term
Definition
%BRt
Total percent of administered dose recovered in bile
BUN
blood urea nitrogen
C
Celsius
C12
concentration at 12 hours
C24
concentration at 24 hours
Ca++
calcium
Cavg
average concentration
CBC
complete blood count
Cexpected-tau
expected concentration in a dosing interval
CFR
Code of Federal Regulations 
CI
confidence interval
C1-
chloride
CLcr
creatinine clearance
CLD
Dialysate clearance of drug from plasma/serum
CLNR
nonrenal clearance
CLR
renal clearance
CLT
total body clearance
CLT/F (or CLT)
apparent total body clearance
CLT/F/fu or 
CLT/fu
Apparent clearance of free drug or clearance of free if (if IV)
cm
centimeter
Cmax, CMAX
maximum observed concentration
Cmin, CMIN
trough observed concentration
CNS
Central nervous system
CRC
Clinical Research Center
CRF
Case Report Form, paper or electronic
Ct
Expected concentration at a certain time, usually at the end of an 
expected future dosing interval (eg, concentration at 24 hours, 
concentration at 12 hours, etc.)
Ctau
Concentration in a dosing interval (eg, concentration at 24 hours, 
concentration at 12 hours, etc.)
Ctrough
Trough observed plasma concentration
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Term
Definition
CV
coefficient of variation
CYP
cytochrome p-450
D/C
discontinue
dL
deciliter
DRt
Total amount recovered in dialysate
%DRt
Total percent of administered dose recovered in dialysate
DSM IV
Diagnostic and Statistical Manual of Mental Disorders (4th Edition)
EA
extent of absorption
ECG
electrocardiogram
eCRF
Electronic Case Report Form
EDC
Electronic Data Capture
EEG
electroencephalogram
eg
exempli gratia (for example)
ESR
Expedited Safety Report
F
bioavailability
Fb
fraction of bound drug
FDA
Food and Drug Administration
FI
fluctuation Index ([Cmax-Ctau)/Cavg])
FRt
total amount recovered in feces
%FRt
total percent of administered dose recovered in feces
FSH
follicle stimulating hormone
%FE
percent fecal excretion
fu
fraction of unbound drug
g
gram
GC
gas chromatography
GCP
Good Clinical Practice
G criteria
adjusted R2 value of terminal elimination phase
GGT
gamma-glutamyl transferase
GFR
glomerular filtration rate
h
hour
HBsAg
hepatitis B surface antigen
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Term
Definition
HBV
hepatitis B virus
HCV
hepatitis C virus
HCO3-
bicarbonate
HIV
Human Immunodeficiency Virus
HR
heart rate
HRT
hormone replacement therapy
ICD
International Classification of Diseases
ICH
International Conference on Harmonisation 
ie
id est (that is)
IEC
Independent Ethics Committee
IMP
investigational medicinal products
IND
Investigational New Drug Exemption
IRB
Institutional Review Board
IU
International Unit
IV
intravenous
K
slope of the terminal phase of the log concentration-time curve
K3EDTA
potassium ethylenediaminetetraacetic acid
K+
potassium
kg
kilogram
λz
terminal disposition rate constant
L
liter
LAM
Lactation amenorrhea method
LC
liquid chromatography
LDH
lactate dehydrogenase
ln
natural logarithm
Lz_Start
The time point starting the log-linear elimination phase defining the 
terminal half life
Lz_End
The time point ending the log-linear elimination phase defining the
terminal half life
Lz_N
Number of time points in the log-linear elimination phase defining the 
terminal half life
mg
milligram
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Term
Definition
Mg++
magnesium
MIC
minimum inhibitory concentration
min
minute
mL
milliliter
mmHg
millimeters of mercury
MR_AUC(0-T)
Ratio of metabolite AUC(0-T) to parent AUC(0-T), corrected for 
molecular weight
MR_AUC(INF)
Ratio of metabolite AUC(INF) to parent AUC(INF), corrected for 
molecular weight
MR_AUC(TAU)
Ratio of metabolite AUC(TAU) to parent AUC(TAU), corrected for 
molecular weight
MR_Cmax
Ratio of metabolite Cmax to parent Cmax, corrected for molecular 
weight
MR_Ctau
Ratio of metabolite Ctau to parent Ctau, corrected for molecular weight
MRT
mean residence time
MS
mass spectrometry
MTD
maximum tolerated dose
μg
microgram
N
number of subjects or observations
Na+
sodium
N/A
not applicable
ng
nanogram
NIMP
non-investigational medicinal products 
NSAID
nonsteroidal anti-inflammatory drug
pAUCe
Extrapolated partial AUC from last quantifiable concentration to infinity
Pb
percent of bound drug
PD
pharmacodynamics
PK
pharmacokinetics
PO
per os (by mouth route of administration)
PT
prothrombin time
PTT
partial thromboplastin time
Pu
percent of unbound drug
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Term
Definition
QC
quality control
QD, qd
quaque die, once daily
R2
coefficient of determination
RBC
red blood cell
SAE
serious adverse event
SD
standard deviation
SOP
Standard Operating Procedures
sp.
species
Subj
subject
t
temperature
T
time
TAO
Trial Access Online, the BMS implementation of an EDC capability
T-HALF
Half life
T-HALFeff_AUC
Effective elimination half life that explains the degree of AUC 
accumulation observed
T-HALFeff_Cmax
Effective elimination half life that explains the degree of Cmax 
accumulation observed)
TID, tid
ter in die, three times a day
Tmax, TMAX
time of maximum observed concentration
TR_AUC(0-T)
AUC(0-T) treatment ratio
TR_AUC(INF)
AUC(INF) treatment ratio
TR_Cmax
Cmax treatment ratio
UR
urinary recovery
%UR
percent urinary recovery
URt
total amount recovered in urine
%URt
total percent of administered dose recovered in urine
UV
ultraviolet
Vss/F (or Vss)
apparent volume of distribution at steady state
Vz
Volume of distribution of terminal phase (if IV and if multi-exponential 
decline)
W
washout
WBC
white blood cell
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Term
Definition
WHO
World Health Organization
WOCBP
women of childbearing potential
x g
times gravity
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APPENDIX 1
ECOG PERFORMANCE STATUS 
ECOG PERFORMANCE STATUS a
0
Fully active, able to carry on all pre-disease performance without restriction
1
Restricted in physically strenuous activity but ambulatory and able to carry out work of a 
light or sedentary nature, eg, light house work, office work
2
Ambulatory and capable of all selfcare but unable to carry out any work activities. Up and 
about more than 50% of waking hours
3
Capable of only limited selfcare, confined to bed or chair more than 50% of waking hours
4
Completely disabled. Cannot carry on any selfcare. Totally confined to bed or chair
5
Dead
 
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APPENDIX 3
RECIST 1.1 GUIDELINES
1
EVALUATION OF LESIONS
At baseline, tumor lesions/lymph nodes will be categorized measurable or non-measurable as 
follows:
1.1
Measurable
Tumor lesions: Must be accurately measured in at least one dimension (longest diameter in the 
plane of measurement is to be recorded) with a minimum size of:
1. 10 mm by CT scan (CT scan slice thickness no greater than 5 mm)
2. 10 mm caliper measurement by clinical exam (lesions which cannot be accurately measured 
with calipers should be recorded as non-measurable)
3. 20 mm by chest x-ray
Malignant lymph nodes: To be considered pathologically enlarged and measurable, a lymph 
node must be ≥15 mm in short axis when assessed by CT scan (CT scan slice thickness 
recommended to be no greater than 5 mm).
Lymph nodes merit special mention since they are normal anatomical structures which may be 
visible by imaging even if not involved by tumor. Pathological nodes which are defined as 
measurable and may be identified as target lesions must meet the criterion of a short axis of 
≥15 mm by CT scan. Only the short axis of these nodes will contribute to the baseline sum. The 
short axis of the node is the diameter normally used by radiologists to judge if a node is involved 
by solid tumor. Nodal size is normally reported as two dimensions in the plane in which the 
image is obtained (for CT scan this is almost always the axial plane; for MRI the plane of 
acquisition may be axial, saggital or coronal). The smaller of these measures is the short axis. 
For example, an abdominal node which is reported as being 20 mm x 30 mm has a short axis of 
20 mm and qualifies as a malignant, measurable node. In this example, 20 mm should be 
recorded as the node measurement. All other pathological nodes (those with short axis ≥10 mm 
but < 15 mm) should be considered non-target lesions. Nodes that have a short axis < 10 mm are 
considered non-pathological and should not be recorded or followed.
1.2
Non-Measurable
All other lesions are considered non-measurable, including small lesions (longest diameter 
< 10mm or pathological lymph nodes with ≥10 to < 15 mm short axis) as well as truly 
non-measurable lesions. Lesions considered truly non-measurable include: leptomeningeal 
disease, ascites, pleural or pericardial effusion, inflammatory breast disease, lymphangitic 
involvement of skin or lung, abdominal masses/abdominal organomegaly identified by physical 
exam that is not measurable by reproducible imaging techniques.
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2
BASELINE DOCUMENTATION OF ‘TARGET’ AND ‘NON-TARGET’ 
LESIONS
When more than one measurable lesion is present at baseline all lesions up to a maximum of five 
lesions total (and a maximum of two lesions per organ) representative of all involved organs 
should be identified as target lesions and will be recorded and measured at baseline (this means 
in instances where patients have only one or two organ sites involved a maximum of two and 
four lesions respectively will be recorded).
Target lesions should be selected on the basis of their size (lesions with the longest diameter), be 
representative of all involved organs, but in addition should be those that lend themselves to 
reproducible repeated measurements. It may be the case that, on occasion, the largest lesion does 
not lend itself to reproducible measurement in which circumstance the next largest lesion which 
can be measured reproducibly should be selected.
A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target 
lesions will be calculated and reported as the baseline sum diameters. If lymph nodes are to be 
included in the sum, then as noted above, only the short axis is added into the sum. The baseline 
sum diameters will be used as reference to further characterize any objective tumor regression in 
the measurable dimension of the disease.
All other lesions (or sites of disease) including pathological lymph nodes should be identified as 
non-target lesions and should also be recorded at baseline. Measurements are not required and 
these lesions should be followed as ‘present’, ‘absent’, or in rare cases ‘unequivocal progression’ 
(more details to follow). In addition, it is possible to record multiple nontarget lesions involving 
the same organ as a single item on the case record form (eg, ‘multiple enlarged pelvic lymph 
nodes’ or ‘multiple liver metastases’).
3
RESPONSE CRITERIA
3.1
Evaluation of Target Lesions
Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes 
(whether target or non-target) must have reduction in short axis to < 10 mm.
Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, taking 
as reference the baseline sum diameters.
Progressive Disease (PD): At least a 20% increase in the sum of diameters of target lesions, 
taking as reference the smallest sum on study (this includes the baseline sum if that 
is the smallest on study). In addition to the relative increase of 20%, the sum must 
also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of 
one or more new lesions is also considered progression).
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest sum diameters while on study.
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3.1.1
Special Notes on the Assessment of Target Lesions
3.1.1.1
Lymph nodes
Lymph nodes identified as target lesions should always have the actual short axis measurement 
recorded (measured in the same anatomical plane as the baseline examination), even if the nodes 
regress to below 10 mm on study. This means that when lymph nodes are included as target 
lesions, the ‘sum’ of lesions may not be zero even if complete response criteria are met, since a 
normal lymph node is defined as having a short axis of < 10 mm. Case report forms or other data 
collection methods may therefore be designed to have target nodal lesions recorded in a separate 
section where, in order to qualify for CR, each node must achieve a short axis < 10 mm. For PR, 
SD and PD, the actual short axis measurement of the nodes is to be included in the sum of target 
lesions.
3.1.1.2
Target lesions that become ‘too small to measure’
While on study, all lesions (nodal and non-nodal) recorded at baseline should have their actual 
measurements recorded at each subsequent evaluation, even when very small (eg, 2 mm). 
However, sometimes lesions or lymph nodes which are recorded as target lesions at baseline 
become so faint on CT scan that the radiologist may not feel comfortable assigning an exact 
measure and may report them as being ‘too small to measure’. When this occurs it is important 
that a value be recorded on the case report form. If it is the opinion of the radiologist that the 
lesion has likely disappeared, the measurement should be recorded as 0 mm. If the lesion is 
believed to be present and is faintly seen but too small to measure, a default value of 5 mm 
should be assigned (Note: It is less likely that this rule will be used for lymph nodes since they 
usually have a definable size when normal and are frequently surrounded by fat such as in the 
retroperitoneum; however, if a lymph node is believed to be present and is faintly seen but too 
small to measure, a default value of 5 mm should be assigned in this circumstance as well). This 
default value is derived from the 5 mm CT slice thickness (but should not be changed with 
varying CT slice thickness). The measurement of these lesions is potentially non-reproducible, 
therefore providing this default value will prevent false responses or progressions based upon 
measurement error. To reiterate, however, if the radiologist is able to provide an actual measure, 
that should be recorded, even if it is below 5 mm.
3.1.1.3
Lesions that split or coalesce on treatment
When non-nodal lesions ‘fragment’, the longest diameters of the fragmented portions should be 
added together to calculate the target lesion sum. Similarly, as lesions coalesce, a plane between 
them may be maintained that would aid in obtaining maximal diameter measurements of each 
individual lesion. If the lesions have truly coalesced such that they are no longer separable, the 
vector of the longest diameter in this instance should be the maximal longest diameter for the 
‘coalesced lesion’.
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3.2
Evaluation of Non-Target Lesions
This section provides the definitions of the criteria used to determine the tumor response for the 
group of non-target lesions. While some non-target lesions may actually be measurable, they 
need not be measured and instead should be assessed only qualitatively at the time points 
specified in the protocol.
Complete Response (CR): Disappearance of all non-target lesions and normalization of tumor 
marker level. All lymph nodes must be non-pathological in size (< 10mm short 
axis). 
Non-CR/Non-PD: Persistence of one or more non-target lesion(s) and/or maintenance of tumor 
marker level above the normal limits.
Progressive Disease (PD): Unequivocal progression (see comments below) of existing non-
target lesions. (Note: the appearance of one or more new lesions is also considered 
progression).
3.2.1
Special Notes on Assessment of Progression of Non-Target Disease
The concept of progression of non-target disease requires additional explanation as follows:
3.2.1.1
When the patient also has measurable disease
In this setting, to achieve ‘unequivocal progression’ on the basis of the non-target disease, there 
must be an overall level of substantial worsening in non-target disease such that, even in 
presence of SD or PR in target disease, the overall tumor burden has increased sufficiently to 
merit discontinuation of therapy (see examples in Appendix 2 and further details below). A 
modest ‘increase’ in the size of one or more non-target lesions is usually not sufficient to qualify 
for unequivocal progression status. The designation of overall progression solely on the basis of 
change in non-target disease in the face of SD or PR of target disease will therefore be extremely 
rare.
3.2.1.2
When the patient has only non-measurable disease
This circumstance arises in some trials when it is not a criterion of study entry to have 
measurable disease. The same general concepts apply here as noted above, however, in this 
instance there is no measurable disease assessment to factor into the interpretation of an increase 
in non-measurable disease burden. Because worsening in non-target disease cannot be easily 
quantified (by definition: if all lesions are truly non-measurable) a useful test that can be applied 
when assessing patients for unequivocal progression is to consider if the increase in overall 
disease burden based on the change in non-measurable disease is comparable in magnitude to the 
increase that would be required to declare PD for measurable disease: ie, an increase in tumor 
burden representing an additional 73% increase in ‘volume’ (which is equivalent to a 20% 
increase diameter in a measurable lesion). Examples include an increase in a pleural effusion 
from ‘trace’ to ‘large’, an increase in lymphangitic disease from localized to widespread, or may 
be described in protocols as ‘sufficient to require a change in therapy’. If ‘unequivocal 
progression’ is seen, the patient should be considered to have had overall PD at that point. While 
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it would be ideal to have objective criteria to apply to non-measurable disease, the very nature of 
that disease makes it impossible to do so; therefore the increase must be substantial.
3.2.2
New Lesions
The appearance of new malignant lesions denotes disease progression; therefore, some 
comments on detection of new lesions are important. There are no specific criteria for the 
identification of new radiographic lesions; however, the finding of a new lesion should be 
unequivocal: ie, not attributable to differences in scanning technique, change in imaging 
modality or findings thought to represent something other than tumor (for example, some ‘new’ 
bone lesions may be simply healing or flare of pre-existing lesions). This is particularly 
important when the patient’s baseline lesions show partial or complete response. For example, 
necrosis of a liver lesion may be reported on a CT scan report as a ‘new’ cystic lesion, which it is 
not.
A lesion identified on a follow-up study in an anatomical location that was not scanned at 
baseline is considered a new lesion and will indicate disease progression. An example of this is 
the patient who has visceral disease at baseline and while on study has a CT or MRI brain 
ordered which reveals metastases. The patient’s brain metastases are considered to be evidence 
of PD even if he/she did not have brain imaging at baseline.
If a new lesion is equivocal, for example because of its small size, continued therapy and 
follow-up evaluation will clarify if it represents truly new disease. If repeat scans confirm there 
is definitely a new lesion, then progression should be declared using the date of the initial scan. 
While FDG-PET response assessments need additional study, it is sometimes reasonable to 
incorporate the use of FDG-PET scanning to complement CT scanning in assessment of 
progression (particularly possible ‘new’ disease). New lesions on the basis of FDG-PET imaging 
can be identified according to the following algorithm:
1. Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of PD based 
on a new lesion.
2. No FDG-PET at baseline and a positive FDG-PET at follow-up: If the positive FDG-PET at 
follow-up corresponds to a new site of disease confirmed by CT, this is PD. If the positive 
FDG-PET at follow-up is not confirmed as a new site of disease on CT, additional follow-up 
CT scans are needed to determine if there is truly progression occurring at that site (if so, the 
date of PD will be the date of the initial abnormal FDG-PET scan). If the positive FDG-PET 
at follow-up corresponds to a pre-existing site of disease on CT that is not progressing on the 
basis of the anatomic images, this is not PD.
3.3
Response Assessment
3.3.1
Evaluation of Best Overall Response
The best overall response is the best response recorded from the start of the study treatment until 
the end of treatment taking into account any requirement for confirmation. The patient’s best 
overall response assignment will depend on the findings of both target and non-target disease and 
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will also take into consideration the appearance of new lesions. Furthermore, depending on the 
nature of the study and the protocol requirements, it may also require confirmatory measurement.
3.3.2
Time Point Response
It is assumed that at each protocol specified time point, a response assessment occurs. Table 
3.3.2-1 provides a summary of the overall response status calculation at each time point for 
patients who have measurable disease at baseline. When patients have non-measurable (therefore 
non-target) disease only, Table 3.3.2-2 is to be used. 
Table 3.3.2-1:
Time Point Response: Patients With Target (+/- Non-Target) 
Disease
Target Lesions
Non-Target Lesions
New Lesions
Overall Response
CR
CR
No
CR
CR
Non-CR/non-PD
No
PR
CR
Not evaluated
No
PR
PR
Non-PD or not all 
evaluated
No
PR
SD
Non-PD or not all 
evaluated
No
SD
Not all evaluated
Non-PD
No
NE
PD
Any
Yes or No
PD
Any
PD
Yes or No
PD
Any
Any
Yes
PD
CR = complete response, PR = partial response, SD = stable disease, PD = progressive disease and NE = inevaluable
Table 3.3.2-2:
Time Point Response: Patients with Non-target Disease Only
Non-Target Lesions
New Lesions
Overall Response
CR
No
CR
Non-CR/non-PD
No
Non-CR/non-PDa
Not all evaluated
No
NE
Unequivocal PD
Yes or No
PD
Any
Yes
PD
CR = complete response, PD = progressive disease and NE = inevaluable
a Non-CR/non-PD is preferred over SD for non-target disease since SD is increasingly used as endpoint for 
assessment of efficacy in some trials so to assign this category when no lesions can be measured is not advised.
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3.3.3
Best Overall Response 
Best response determination of complete or partial response requires confirmation: Complete or 
partial responses may be claimed only if the criteria for each are met at a subsequent time point 
of ≥4 weeks later. In this circumstance, the best overall response can be interpreted as in Table 
3.3.3-1.
Special note on response assessment: When nodal disease is included in the sum of target 
lesions and the nodes decrease to ‘normal’ size (< 10 mm), they may still have a measurement 
reported on scans. This measurement should be recorded even though the nodes are normal in 
order not to overstate progression should it be based on increase in size of the nodes. As noted 
earlier, this means that patients with CR may not have a total sum of ‘zero’ on the case report 
form (CRF).
Table 3.3.3-1:
Best Overall Response (Confirmation of CR&PR Required)
Overall Response 
First Time Point
Overall Response 
Subsequent Time Point
BEST Overall Response
CR
CR
CR
CR
PR
SD, PD or PRa
CR
SD
SD provided minimum criteria for SD durationb met, 
otherwise, PD
CR
PD
SD provided minimum criteria for SD durationb met, 
otherwise, PD
CR
NE
SD provided minimum criteria for SD durationb met, 
otherwise, NE
PR
CR
PR
PR
PR
PR
PR
SD
SD
PR
PD
SD provided minimum criteria for SD durationb met, 
otherwise, PD
PR
NE
SD provided minimum criteria for SD duration bmet, 
otherwise, NE
NE
NE
NE
CR = complete response, PR = partial response, SD = stable disease, PD = progressive disease, and 
NE = unevaluable
a If a CR is truly met at first time point, then any disease seen at a subsequent time point, even disease meeting PR 
criteria relative to baseline, makes the disease PD at that point (since disease must have reappeared after CR). 
Best response would depend on whether minimum duration for SD was met. However, sometimes ‘CR’ may be 
claimed when subsequent scans suggest small lesions were likely still present and in fact the patient had PR, not 
CR at the first time point. Under these circumstances, the original CR should be changed to PR and the best 
response is PR.
b Minimum duration for SD is 6 weeks.
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3.3.4
Confirmation Scans
Verification of Response: To be assigned a status of CR or PR, changes in tumor measurements 
must be confirmed by consecutive repeat assessments that should be performed no less than 
28 days after the criteria for response are first met. For this study, the next scheduled tumor 
assessment can meet this requirement.
Verification of Progression: Progression of disease should be verified in cases where progression 
is equivocal. If repeat scans confirm PD, then progression should be declared using the date of 
the initial scan. If repeat scans do not confirm PD, then the subject is considered to not have 
progressive disease.
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