An Exploratory Study of the Biologic Effects of Nivolumab and Ipilimumab Monotherapy and Nivolumab in Combination With Ipilimumab Treatment in Subjects With Advanced Melanoma (Unresectable or Metastatic)
Phase: PHASE1
Conditions: Advanced Melanoma, Metastatic Melanoma
Sponsor: Bristol-Myers Squibb



Clinical Protocol
CA209038
BMS-936558
nivolumab
Revised Protocol No.: 07
2
Date: 25-Oct-2016
who receives this document without due authorization from BMS is requested to return it 
to BMS or promptly destroy it. All other rights reserved.
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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.

Clinical Protocol
CA209038
BMS-936558
nivolumab
Subsequent to a durationof 2 years of active treatmentor following the last dose of treatment in the Extension 
Period, each patient will continue follow-up consisting of office visits, lab work and tumor assessments for a 
maximum period of up to 100 days;follow-up office visits 1 and 2 (40-60 days and 101-120 days after the stop of 
study therapy). Completion of subsequent follow-up office visits will depend on the status of the subject at the end 
of the treatment period.  
All patients who have not completed 2 years of treatment will be followed for overall survival assessment by 
telephone contact every 3 months from the last follow-up office visit for the remainder of time left to complete 
2years from the first dose of treatment.Patients that enter the Extension Period will be followed for overall survival
assessments up toa maximum of 100 days after the last treatment dose.
Figure 1:
Study Schema 
*At the completion of two years of therapy, those subjects who are benefiting and meet criteria may
 continue after 
discussion and agreement between the Investigator and Medical Monitor and will enter the Extension Period (See 
Section 4.3.7).
**Subjects may be treated beyond PD, refer to Section 4.3.8
***In Parts 3 and 4, infusion times for nivolumab and ipilimumab will be as follows:
nivolumab(3 mg/kg) monotherapy will be infused over 30 minutes 
for the combination, nivolumab (1 mg/kg) will be infused over 30 minutes and after a 30-minute break, 
ipilimumab (3 mg/kg) will be infused over 30 minutes, then nivolumab (3 mg/kg) will be infused over 30 
minutes
Duration of Study: The study is expected to accrue over a period of approximately 2 years. 
maximum 28 days of screening
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Statistical Considerations:
Sample size:
The primary objective of this study is to assess the pharmacodynamicactivity of immunomodulatory biomarkers 
following treatment with nivolumab and nivolumab in combination with ipilimumab. It is of interest to ensure 
precision of the estimate of the ratio of on-treatment biomarker assessments to baseline levels in part 1 cohort 1 and 
2. Assuming that a biomarker is measured as a continuous variable, 40 subjects per cohort will provide the following 
confidence that the estimate of the ratio of on-treatment to baseline values will be within 20% of the true value:
Table 1:
Probability that estimated ratio of on-treatment to baseline value is within 20% of 
true value
Intra-subject Standard deviation 
(log-scale)
0.20
0.30
0.40
0.50
0.60
0.70
0.80
Probability
100%
100%
97%
93%
86%
80%
74%
For example, for a biomarker with an intra-subject standard deviation of 0.5, if the true ratio of post-baseline to 
baseline geometric means is 1.2 (increase from baseline is 20%), there is 93% probability that the estimated ratio 
would be within 0.96 and 1.44 (or a percent change between -4% and 44%). If the true increase from baseline is 
60%, for a biomarker with the same variability, then there is 93% probability that the estimated percent change 
would be between 28% and 92%.  
More specifically, preliminary data analysis of activated and memory CD4 and CD8 T cells in CA209-003 project 
an intra-subject standard deviation on the log scale between 0.5 and 0.6. Assuming this variability estimate is 
applicable to this study, there is 86%-93% probability that the geometric mean ratio of on-treatment to baseline T 
cell subset levels will be within 20% of their true value.
It is of interest to ensure precision of the estimate of the proportion of subjects with increased activatedT cells on-
treatment (at optimal window for biopsy) in part 2 and 3 Arms Aand B. With a total of 30 subjects (from part 2 and 
part 3) treated in Arm A (with biopsy collected at optimal on-treatment window), the maximum width of the exact 
2-sided 95% confidence interval (CI) is 37% when the proportion of subjects with increased activated T cells is 
expected to be in the 20% to 60% range. The 95% exact CIs are presented in Table 2. 
Table 2:
95% Exact CI for Proportion of Subjects with Increased Activated T Cell On-
treatment
Proportion
20%
30%
40%
50%
60%
95% Exact CI
(7.7%, 38.6%) (14.7%, 49.4%) (22.7%, 59.4%) (31.3%, 68.7%) (40.6%, 77.3%)
With a total of 10 subjects treated in Arm B (with biopsy collected at optimal on-treatment window), the maximum 
width of the exact 2-sided 95% confidence interval (CI) is 59% when the proportion of subjects with increased 
activated T cells is expected to be in the 20% to 30% range. The 95% exact CIs are presented in Table 3.
Table 3:
95% Exact CI for Proportion of Subjects with Increase Activated T Cell on-
Treatment
Proportion
20%
30%
95% Exact CI
(2.5%, 55.6%)
(6.7%, 65.3%)
For example, if the observed proportion of subjects with increased activated T cells is 20% (data from CA184-004 
indicate that ~25% of metastatic melanoma patients have an increase in intratumoral, activated  T cells with 
ipilimumab alone), there is 95% probability that the exact CI (2.5, 55.6%) will cover the true proportion. 
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3.4.1 Prohibited and/or Restricted Treatments................................................. 
3.4.2 Other Restrictions and Precautions 
......................................................... 
3.4.3 Permitted Therapy ................................................................................... 
3.5 Discontinuation of Subjects From Treatment 
................................................... 
3.5.1 Permanent Discontinuation Criteria of Subjects from Treatment 
........... 
3.6 Post Treatment Study Follow-up 
...................................................................... 
3.6.1 Withdrawal of Consent ............................................................................ 
3.6.2 Lost to Follow-Up 
.................................................................................... 
4 TREATMENTS 
......................................................................................................... 
4.1 Study Treatments 
.............................................................................................. 
4.1.1 Investigational Product 
............................................................................ 
4.1.2 Non-investigational Product 
.................................................................... 
4.1.3 Handling and Dispensing ........................................................................ 
4.1.4 Nivolumab Vial Storage 
........................................................................... 
4.1.5 Ipilimumab Vial Storage 
.......................................................................... 
4.1.6 Study Drug Administration 
...................................................................... 
4.2 Method of Assigning Subject Identification 
..................................................... 
4.3 Selection and Timing of Dose for Each Subject 
............................................... 
4.3.1 Dose Modifications 
.................................................................................. 
4.3.2 Intrasubject Dose Escalation 
................................................................... 
4.3.3 Dose Reductions....................................................................................... 
4.3.4 Dose Delay Criteria 
................................................................................. 
4.3.5 Study Drug Discontinuation Criteria due to Adverse Event(s) ............... 
4.3.6 Criteria to Resume Treatment with Study Drug ...................................... 
4.3.7 Criteria to Enter Extension Period 
.......................................................... 
4.3.8 Treatment Beyond Progression of Disease 
.............................................. 
4.3.9 Infusion Delays and Missed Doses 
.......................................................... 
4.3.10 Discontinuation Due to Confirmed Complete Response ....................... 
4.3.11 Stopping Rules for Clinical Deterioration 
............................................. 
4.3.12 Prophylactic and Acute Management of Infusion Reactions 
................. 
4.3.13 Guidelines for Management of Gastrointestinal, Pulmonary and 
Endocrine Adverse Events .......................................................................... 
4.4 Blinding/Unblinding 
......................................................................................... 
4.5 Treatment Compliance 
...................................................................................... 
4.6 Destruction and Return of Study Drug 
............................................................. 
4.6.1 Destruction of Study Drug 
....................................................................... 
4.6.2 Return of Study Drug 
............................................................................... 
4.7 Retained Samples for Bioavailability / Bioequivalence ................................... 
5 STUDY ASSESSMENTS AND PROCEDURES 
..................................................... 
5.1 Flow Chart/Time and Events Schedule 
............................................................. 
5.2 Study Materials 
................................................................................................. 
5.3 Safety Assessments 
........................................................................................... 
5.3.1 Laboratory Test Assessments 
................................................................... 
5.3.2 ECG Evaluation 
....................................................................................... 
5.4 Efficacy Assessments 
........................................................................................ 
5.5 Pharmacokinetic Assessments 
.......................................................................... 
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1.2
Research Hypothesis 
It is hypothesized that nivolumab (an anti-Programmed Cell Death-1 (PD-1) monoclonal 
antibody) and nivolumab in combination with ipilimumab will produce pharmacodynamic 
changes in the peripheral blood and tumor tissue of subjects with advanced melanoma 
(unresectable or metastatic).
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2
ETHICAL CONSIDERATIONS
2.1
Good Clinical Practice
This study will beconducted in accordance with Good Clinical Practice (GCP), as defined by the 
International Conference on Harmonisation (ICH) and in accordance with the ethical principles 
underlying European Union Directive 2001/20/EC and the United States Code of Federal
Regulations, Title 21, Part 50 (21CFR50).
The study will be conducted in compliance with the protocol. The protocol and any amendments 
and the subject informed consent will receive Institutional Review Board/Independent Ethics 
Committee (IRB/IEC) approval/favorable opinion prior to initiation of the study.
All potential serious breaches must be reported to BMS immediately. A serious breach is a 
breach of the conditions and principles of GCP in connection with the study or the protocol, 
which is likely to affect, to a significant degree, the safety or physical or mental integrity of the 
subjects of the study or the scientific value of the study
.
Study personnel involved in conducting this study will be qualified by education, training, and 
experience to perform their respective task(s).
This study will not use the services of study personnel where sanctions have been invoked or 
where there has been scientific misconduct or fraud (e.g., loss of medical licensure, debarment). 
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2.2
Institutional Review Board/Independent Ethics Committee 
Before study initiation, the investigator must have a writtenand dated approval/favorable 
opinion from the IRB/IEC for the protocol, consent form, subject recruitment materials/process 
(e.g., advertisements), and any other written information to be provided to subjects. The 
investigator or Sponsor 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 Sponsor should provide the IRB/IEC with reports, updates and other 
information (e.g., 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
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 (i.e., 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:
1. 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. 
2. Allow time necessary for subject or subject
's legally acceptable representative to inquire 
about the details of the study
3. Obtain an informed consent signed and personally dated by the subject or the subject
's 
legally acceptable representative and by the person who conducted theinformed consent 
discussion. 
4. 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 completedfor new information.
5. 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 their 
informed consent during the study, then consent must additionally be obtained from the 
subject.
6. 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. 
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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. 
For minors, according to local legislation, one or both parents or a legally acceptable 
representative must be informed of the study procedures and must sign the informed consent 
form approved for the study prior to clinical study participation. The explicit wish of a minor, 
who is capable of forming an opinion and assessing this information to refuse participation in, or 
to be withdrawn from, the clinical study at any time should be considered by the investigator. 
Minors who are judged to be of an age of reason must also give their written assent.
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
Study Design: This is an exploratory, open-label, multicenter study of nivolumaband nivolumab 
in combination with ipilimumab.
Approximately 150 subjects with advanced melanoma (unresectable or metastatic) will be 
treated in this study in four (4) parts. Part 1 of this study will have two (2) cohorts consisting of 
approximately 40 patients each: cohort 1 will consist of anti-CTLA4 therapy-naivepatients and 
cohort 2 will consist of patients who have progressed on an anti-CTLA-4 regimen. Cohorts 1 and 
2 will be administered nivolumab at 3 mg/kg dose level every 2 weeks. Subjects will go through 
a screening periodof no longer than 28 days and eligible subjects will start the treatment 
periodfor a durationof 2 years depending on their response. Nivol
umab will be administered by 
IV infusion every 14 days in 56 day cycles (on days 1, 15, 29 and 43 of each cycle).Response 
assessments will be performed on days 49-56. The response assessment must be completed 
before the first dose in the next cycle.
In Part 2, approximately 20 anti-CTLA4 therapy-naive patients will be administered nivolumab 
at 1 mg/kg and ipilimumabat 3 mg/kg every 3 weeks for 4 doses, followed by nivolumab 
3mg/kg alone every 2 weeks (Arm A). This part of the study is aimed at defining the optimal 
window for on-treatment biopsy with concurrent nivolumab and ipilimumab therapy. All 
subjects will be required to undergo a pre-treatment biopsy and consent to on-treatment biopsy. 
Two (2) groups of approximately 10 patients each will be enrolled sequentially with the first 
group assigned to an on-treatment biopsy between Days 8 and 15 (weeks 2 and 3) after the start 
of therapy and the second group assigned to an on-treatment biopsy between Days 22 and 
29(subsequent to the second dose of therapy between weeks 4 and 5) after the start of therapy. 
Optimal biopsy timing will be defined as the biopsy window with the greatest pharmacodynamic 
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increase in intratumoral activated T cells compared to the pre-treatment biopsy. The defined 
optimal on-treatment biopsy window will be used in the third part of this study.
In Part 3, approximately 30 anti-CTLA4 therapy-naive patients will be randomized 2:1and 
treated with one of the following:
Arm A: nivolumab 1 mg/kg IV combined with ipilimumab 3 mg/kg IV Q3W for 
4doses then nivolumab 3 mg/kg IV Q2W 
Arm B: nivolumab 3 mg/kg IV Q2W
In Part 4, approximately 20 anti-CTLA4therapy-naive patients with brain metastases will be 
randomized 1:1 and treated with one of the following:
Arm D: nivolumab 1 mg/kg IV combined with ipilimumab 3 mg/kg IV Q3W for 
4doses then nivolumab 3 mg/kg IV Q2W 
Arm E: nivolumab 3 mg/kg IV Q2W
In Parts 2, 3 and 4 of this study, patients will also go through a screening period of no longer 
than 28 days. In Parts 2 and 3, pre-treatment samples will be centrally assessed for tumor content 
and subjects who have samples with insufficient tumor content (<100 tumor cells in a 4 micron 
tissue section) will require re-biopsy or will not be treated. In Part 4, tumor biopsy collection is 
optional, but strongly encouraged if clinically safe. Eligible subjects will then start the treatment 
period for a maximum of two years of therapy. Subjects randomized to Arm C in Part 3 of this 
study prior to the closure of this Arm have the option to receive nivolumab monotherapy upon 
consultation with the medical monitor.
Response assessments will be performed approximately every 8 weeks (may differ by several 
weeks depending on treatment arm). The response assessment must be completed before the first 
dose in the next treatment visit.
A study schema is presented below in Figure 3.1.
At the completion of 2 years of therapy, those subjects who are benefiting and still meet study 
criteria may continue after discussion and agreement between the investigator and Medical 
Monitor and will enter the Extension Period (See Section 4.3.7).Treatment in the Extension 
Periodwill continue until progression ofdisease or unacceptable toxicity.
Subsequent to a durationof 2 years of activetreatmentor following the last dose of treatment in 
the Extension Period, each patient will continue follow-upconsisting of office visits, lab work 
and tumor assessments for a maximum period of up to 100 days;follow-up office visits 1 and 2 
(40-60 daysand 101-120 days after the stop of study therapy). Completion of subsequent follow-
up office visits will depend on the status of the subject at the end of the treatment period. 
Patients with confirmed disease progression as described in Sections 1.1.9and 4.3.8will 
complete follow-up office visits 1 and 2 and will then continue follow-up by telephone 
assessmentevery 3 months for the remainder of time left to complete 2 years from the first dose 
of treatment.
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All patients will be followed for overall survival assessment by telephone contact every 3 months 
from the last follow-up office visit for the remainder of time left to complete 2 years from the 
first dose of therapy.Patients that enter the Extension Period will be followed for overall survival 
assessments up toa maximum of 100 days after the last treatment dose.
Figure 3.1:
Study schema 
*At the completion of two years of therapy, those subjects who are benefiting and meet criteria 
may continue after discussion and agreement between the Investigator and Medical Monitor 
and will enter the Extension Period (See Section 4.3.7).
**Subjects may be treated beyond PD, refer to Section 4.3.8***In Parts 3 and 4: 
nivolumab (3 mg/kg) as monotherapy will be infused over 30 minutes 
for the combination, nivolumab (1 mg/kg) will be infused over 30 minutes and after a 30-minute break, 
ipilimumab (3 mg/kg) will be infused over 30 minutes, then nivolumab (3mg/kg) will be infused over 30 
minutes
Number of Subjects:  approximately 150 subjects treated 
Duration of Study: The study is expected to accrue over a period of approximately 2 years. 
maximum 28 days of screening 
At the completion of 2 years of therapy, those subjects who are benefiting and still meet 
study criteria may continue after discussion and agreement between the investigator and 
Medical Monitor and will enter the Extension Period (See Section 4.3.7)
approximately 3 months follow-up office visits (including tumor assessments) 
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2 year overall survival assessment (by telephone contact) from first therapy dose for time 
remaining from last follow up office visitor for those patients that enter the Extension 
Period, overall survival assessments will be continued for 100 days following the last 
treatment dose.
3.2
Post Study Access to Therapy
Not applicable for this study
3.3
Study Population
Eligibility criteria for this study have been carefully considered to ensure the safety of the study 
subjects and to ensure that the results of the study can be used. It is imperative that subjects fully 
meet all eligibility criteria. No exceptions will be granted.
For entry into the study, the following criteria MUST be met.
3.3.1
Inclusion Criteria
1) Informed Consent:
a) Signed, written Informed Consent must be obtained prior to the performance of any 
study related procedures that are not considered part of standard of care
2) Target Population:
a) Subjects with advanced melanoma (unresectable or metastatic) who have receivedand 
either progressed or discontinued on no more than 3 prior treatment regimens or have 
refused standard therapy for treatment of metastatic melanoma. 
i.
Subjects may have been treated or offered treatments for melanoma (e.g., 
chemotherapy, biological therapy, targeted therapy, vaccine therapy or cytokine 
therapy). 
ii.
Subjects who have never received any treatment for metastatic disease, ie. 
newly diagnosed subjects, may be allowed on study if they have been offered 
and have refused standard therapy or are deemed to be inappropriate candidates 
for standard therapy by the investigator.
iii.
Subjects enrolled to Cohort 1 and Arms A, B, D and E (see Figure 3.1) must 
never have received anti-CTLA4 therapy (anti-CTLA4 naive).
iv.
Subjects enrolled to cohort 2 (see Figure 3.1) must have had anti-CTLA4 
monoclonal antibody (mAb) based therapy as 1 of the prior regimens 
(anti-CTLA4 progressors). If anti-CTLA4mAb therapy was the last treatment 
regimen prior to study entry, the last dose of anti-CLTA4 mAb must have been 
administered at least 6 weeks prior to initiation of study therapy.Relapse 
during or within 6 month of last dose of anti-CTLA4 mAb adjuvant treatment 
for completely resected melanoma alone will also fulfill this criterion. 
v.
Subjects enrolled to Arms D and E
(1)Must have at least one measurable index brain metastases > 0.5 cm and not 
larger than 3 cm that has not been previously irradiated
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(2)Index brain lesions must not have sequela of prior therapy that would 
confound attribution of tumor response including edema or hemorrhage
(3)Must not have neurologic symptoms secondary to metastatic lesions
(4)Must not have received systemic corticosteroids within 14 days prior to 
initiation of study therapy. 
b) Subjects must have histologic confirmation of advanced melanoma. Confirmation of 
diagnosis must be obtained fromthepre-treatment biopsy if it is not available from a 
prior diagnostic procedure. 
c) Subjects must consent to allow the acquisition of existing (archival) formalin-fixed 
paraffin-embedded (FFPE) material (block or a minimum of 10 unstained slides) for 
performance of correlative studies. 
d)Subjects must have at least onemeasurable lesion atbaseline by CT or MRI as per 
RECIST 1.1criteria (see Appendix 2).
i.
Tumor sites used to satisfy this criterion must not have received any prior 
radiation therapy.
ii.
Sites for biopsy must be distinct from target lesions used for efficacy 
assessment.
e) Subjects must have at least 1 tumor site that can be biopsied at acceptable clinical risk, 
as judged by the Investigator, and must consent to pre-treatment and on-treatment 
tumor biopsies. For Part 4, pre-treatment and on-treatment biopsies are optional, but 
strongly encouraged.
i. Lesions should not have received prior radiation therapy
ii. These sites must be designated for biopsy prior to the first treatment, to avoid 
selection bias that may affect study endpoints.
iii. In Part 1, pathologic confirmation of viable tumor cells (touch imprint 
cytopathology) from collected tissue samples is strongly recommended to 
permit consideration of repeat biopsy if deemed of acceptable clinical risk. 
Subjects for whom pre-treatment adequate tissue biopsy (demonstration of 
tumor cells on touch prep) cannot be achieved may still remain on study and 
continue to receive study therapy and undergo other sample collections. 
However, that subject will then be replaced.
iv.
In Parts 2 and 3, pre-treatment tumor samples must contain sufficient tumor 
content (≤100 tumor cells/4-micron tissue section) upon central assessment. If 
sample contains insufficient tumor content, a re-biopsy will be required to 
obtain a sample with sufficient tumor content prior to treatment.
v.
The site of biopsy should not include lymph nodes in Parts 2, 3 and 4.
f) Subjects must have ECOG performance status≤1 (See Appendix 1).
g) Subjects must have the ability to comply with treatment, PK, biomarker sample 
collection, and required study follow-up.
h) Organ and marrow function as follows(blood product transfusion is not permitted in 
the 4 weeks prior to achieve entry criteria):
i.
White blood cell count ≥ 2,000 cells/mm3
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ii.
Neutrophils ≥ 1500/μL (stable, off any growth factor for at least 4 weeks prior 
to study drug administration)
iii.
Platelet count ≥ 100,000/mm3
iv.
Hemoglobin ≥ 9.0 g/dL 
v.
Total bilirubin ≤ 1.5x the institutional upper limit of normal (IULN)
vi.
Subjects with Gilbert’s syndrome are eligible if their total bilirubin is less than 
3.0 mg/dl
vii.
ALT (alanine aminotransferase) and AST (aspartate aminotransferase) 
<3xIULN
viii.
Estimated GFR (eGFR) calculated via MDRD or Cockcroft-Gault equations 
≥40 mL/min
i) Known BRAF V600 mutation status (Parts 2, 3 and 4). Subjects with either V600 
wild-type or V600 mutation-positive status, are eligible.
3) Age and Reproductive Status:
a) Males and females≥ 16 years of age.
b) Women of childbearing potential:
i.
Women of childbearing potential (WOCBP) must use method(s) of 
contraception based on the tables in Appendix 3. A highly effective method(s) 
of contraception(failure rate of less than 1% per year) is required. The 
individual methods of contraception should be determined in consultation with
the investigator. WOCBP must follow instructions for birth control when the 
half life of the investigational drug is greater than 24 hours, contraception 
should be continued for a period of 30 days plus the time required for the 
investigational drug to undergo five half lives (total of 23 weeks after the last 
dose of investigational product). 
ii.
Women must have a negative serum or urine pregnancy test (minimum 
sensitivity 25 IU/L or equivalent units of HCG) within 24 hoursprior to the 
start of investigational product.
iii.
Women must not be breastfeeding.
c) Menwho are sexually active with WOCBP must use any contraceptive method with a 
failure rate of less than 1% per year. Men that are sexually active with WOCBP must 
follow instructions for birth control when the half life of the investigational drug is 
greater than 24 hours, contraception should be continued for a period of 90 days plus 
the time required for the investigational drug to undergo five half lives (total of 
31weeks after the last dose of investigational product).
d) Women who are not of childbearing potential (ie, who are postmenopausal or surgically 
sterile; see Section 3.3.3for the definition of WOCBP) and azoospermic men do not 
require contraception. 
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3.3.2
Exclusion Criteria
1. Target Disease Exceptions 
a) Cohort 1 and 2, Arms A and B: Active CNS metastases (including evidence of 
cerebral edema by CT scan or MRI, progression from prior imaging study, any 
requirement for steroids or clinical symptoms of/from CNS metastases) within 
28days of study enrollment.
b) Cohort 1 and 2, Arms Aand B: Subjects with known metastases must have a repeat 
imaging brain scan within 28 days of randomization/registration. If progression in 
prior lesion(s) or new lesion(s) is/are detected on repeat brain scan, patients are 
excluded from study. 
c) Arms D and E: History of carcinomatous meningitis (lumbar puncture is not 
required).
d) Arms D and E: Radiation within 14 days prior to initiation of study therapy, and the 
radiation field cannot have included the index brain lesion.
2) Medical History and Concurrent Diseases 
a) Participation in a blinded trial or study which has not yet completed final database 
lock and has not been unblinded for primary endpoint analysis
b) Subjects with other concomitant malignancies, except basal cell or squamous cell skin 
cancers, superficial bladder cancer, or carcinoma in situ of the cervix or breast, are 
excluded unless a complete remission was achieved at least 2 years prior to study entry 
and no additional therapy is required or anticipated to be required during the study 
period
c) Subjects with active autoimmune disease, a history of known or suspected 
autoimmune disease or a history of a syndrome requiring systemic corticosteroids 
(>10 mg daily prednisone equivalent), cytotoxic therapy or immunosuppressive 
medications with the exception of:
i.
Isolated vitiligo
ii.
Resolved childhood atopy
iii.
The history of positive ANA titer without associated symptoms or history of 
symptoms of an autoimmune disorder
iv.
Controlled thyroid disorders
d) Positive tests for human immunodeficiency virus (HIV 1/2) antibody (may obtain 
additional testing or substitute testing per institutional guidelines to rule out infection), 
or known acquired immunodeficiency syndrome (AIDS)
e) History of any chronic hepatitis including alcoholic, non-alcoholic steatohepatitis
(NASH), drug related, autoimmune, chronicviral
i.
Positive tests for hepatitis B virus surface antigen (HBsAg) or 
ii.
hepatitis C antibody (may obtain additional testing or substitute testing per 
institutional guidelines to rule out infections)
f) Evidence of active infection ≤ 7 days prior to initiation of study drug therapy.
g) Prior organ allograft or allogenic bone marrow transplantation.
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nivolumab
h) Uncontrolled or significant cardiovascular disease including, but not limited to, any of 
the following:
i.
Myocardial infarction within the past 6 months
ii.
Uncontrolled angina within the past 3 months
iii.
History (family or personal) of congenital long QT syndrome 
iv.
Any history of clinically significant arrhythmias (such as ventricular 
tachycardia, ventricular fibrillation or Torsades de pointes)
v.
Controlled atrial fibrillation by itself is not an exclusion criterion
vi.
History of other clinically significant heart disease (i.e. cardiomyopathy, 
NYHA functional classification III-IV)
vii.
Requirement for daily supplemental oxygen therapy
i) Known or underlying medical condition (e.g., a condition associated with diarrhea, 
diverticulitis, neuropathy or atopy ) that, in the Investigator’s opinion, would make the 
administration of study drug hazardous to the subjects or obscure the interpretation of 
toxicity determination or adverse events
j) Subjects with evidence of bleeding disorderdeemed unsafe by the Investigator to 
undergo biopsies
k) Subjects who are unable to undergo venipuncture and/or to tolerate venous access.
l) Subjects who have undergoneany major surgery within 4 weeks of study drug 
administration
m) Subjects with psychiatric illness or social situations that would preclude study 
compliance or the ability to tolerate study procedures and or study therapy.
n) Subjects with the presence of underlying medical condition that in the opinion of the 
Investigator or Sponsor could adversely affect the ability of the subject to comply with 
or tolerate study procedures and/or study therapy
3) Allergies and Adverse Drug Reaction
a) History of allergy to components of the study drug or known allergy to antibody 
therapies
b) Subjects with a known history of the following anti-CTLA4 therapy related adverse 
reactions based on the CTCAE v4.0 criteria:
i.
Any ≥ grade 3 anti-CTLA4 mAb related dose-limiting adverse reaction
ii.
Any anti-CTLA4 mAb related event requiring permanent discontinuation of 
therapy regardless of grade 
iii.
Any adverse reaction that did not resolve with steroids alone (i.e. required 
infliximab, mycophenolate or cyclophosphamide)
iv.
Any Grade 3 non-laboratory anti-CTLA4 therapy related adverse reaction 
except for: 
(a)Endocrinopathies where clinical symptoms were controlled with 
appropriate hormone replacement therapy
(b)Nausea
(c)Fatigue
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BMS-936558
nivolumab
v.
Any Grade ≥3 laboratory abnormalities except for:
(a)Any Grade ≥3 lymphopenia
(b)Any transient Grade ≥3 electrolyte abnormalities that occurred while on 
anti-CTLA4 therapy that were not associated with clinical symptoms 
and responded with 72 hours
(c)Any AST, ALT or T. bilirubin such that:
(i)AST or ALT > 10 x ULN
(ii)Total bilirubin > 5 x ULN
vi.
Any Grade 2 eye pain or reduction of visual acuity that did not respond to 
topical therapy and did not improve to Grade 1 severity within 2 weeks of 
starting topical therapy or required systemic treatment.
vii.
History of Grade 3 neurologic toxicity
4) Sex and Reproductive Status
a) WOCBP who are unwilling or unable to use an acceptable method to minimize the 
risk of pregnancy for the entire study period and for at least 23 weeks after the last 
dose of investigational product.
b) Women who are pregnant or breastfeeding.
c) Women with a positive pregnancy test on enrollment or prior to investigational 
product administration.
d) Sexually active fertile men not using effective birth control when their partners are 
WOCBP for at least 31 weeks afterthe last dose of investigational product.
5) Prohibited Prior Treatments and/or Therapies
a) Subjects who have received prior treatment with T cell coregulatory protein targeted 
therapies including but not limited to,  anti-PD-1, anti-PD-L1, anti-PD-L2, 
anti-CD137, anti-OX-40, anti-CD40 in the adjuvant or metastatic setting are ineligible 
to participate in the study. Prior anti-CTLA4 monoclonal antibody therapy is permitted 
for cohort 2. 
i.
Prior cytokine therapy is allowed (e.g. interferon or interleukin-2).
b) Exposure to any other investigational drug within 4 weeks of study drug 
administration 
c) Any anti-cancer therapy (e.g., chemotherapy, biologics, vaccines, radiotherapy, or 
hormonal treatment) within 5 half lives or within a maximum of 4 weeksof study drug 
administration (if 5 half-lives is longer than 4 weeks)
d) Use of non-oncology vaccines (live, attenuated, or inactivated) against infectious 
diseases (for example, MMR, polio, Pneumovax®, Zostavax®. Flumist® ) within 
4weeks (28 days) of initiation of study therapy 
i.
Use of the seasonal killed influenza vaccine is allowed without restriction.
e) Use of growth factors, including, but not limited to, granulocyte-colony stimulating 
factor (G-CSF), granulocyte macrophage-colony stimulating factor (GM-CSF) or 
erythropoietin within 4 weeks of study drug therapy
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nivolumab
f) Use of pRBC or platelet transfusion 4 weeks prior to study drugtherapy
g) Systemic corticosteroids must be <10 mg daily prednisone equivalents 4 weeks before 
the first dose of study therapy. Subjects requiring long term immunosuppression are 
not eligible.
h) Use of anti-RANKL therapy (i.e. denosumab as Xgeva® or Prolia®) within 140 days 
(5 half-lives) prior to study drug administration
i) Use of oral or intravenous bisphosphonate therapy (e.g. zolendronic acid, alendronate
or risedronate) less than 5 half-lives prior to study drug administration
j) Use of herbal over-the-counter (OTC) supplements is not permitted. Concerns 
regarding specific OTC therapies may be discussed with the medical monitor.
6) Other Exclusion Criteria
a) Prisoners or subjects who are involuntarily incarcerated
b) Subjects who are compulsorily detained for treatment of either a psychiatric or 
physical (e.g. infectious disease) illness
Eligibility criteria for this study have been carefully considered to ensure the safety of the study 
subjects and to ensure that the results of the study can be used. It is imperative that subjects fully 
meet all eligibility criteria.
No exceptions to these criteria will be granted by the Sponsor.
3.3.3
Women of Childbearing Potential
AWoman of Childbearing Potential (WOCBP) is defined as any female who has experienced 
menarche and who has not undergone surgical sterilization (hysterectomy or bilateral 
oophorectomy) and is notpostmenopausal. Menopause is defined as 12 months of amenorrhea in 
a woman over age 45 years in the absence of other biological or physiological causes. In 
addition, females under the age of 55 must have a serum follicle stimulating hormone, (FSH) 
level > 40mIU/mL to confirm menopause. 
*Females treated with hormone replacement therapy, (HRT) are likely to have artificially 
suppressed FSH levels and may require a washout period in order to obtain a physiologic FSH 
level. The duration of the washout period is a function of the type of HRT used. The duration of 
the washout period below are suggested guidelines and the investigators should use their 
judgment in checking serum FSH levels. If the serum FSH level is > 40 mIU/ml at any time 
during the washout period, the woman can be considered postmenopausal:
1 week minimum for vaginal hormonal products, (rings, creams, gels)
4 week minimum for transdermal products
8 week minimum for oral products
Other parenteral products may require as long as 6 months.
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BMS-936558
nivolumab
3.4
Concomitant Treatments
All medications taken within 28 days before the administration of study drug and all concomitant 
therapy administered during the study will be recorded on the relevant CRF, along with the 
reasons for and details of therapy use.
3.4.1
Prohibited and/or Restricted Treatments 
1) Concurrent chemotherapy, hormonal therapy, immunotherapy regimens, or radiation 
therapy, standard or investigational. Exceptions include:
a) Palliative or supportive care may be offered to all subjects.
b) Palliative/therapeutic therapies (e.g., focal radiotherapy for pain or bone 
metastases, thoracocentesis or paracentesis for comfort) may be administered after 
consultation with the Medical Monitor. 
c) Palliative radiation therapy for bone metastases is permitted, but subjects should 
not receive study treatment during radiation and must meet re-treatment criteria 
prior to resuming treatment. 
d) Treatment of isolated symptomatic lesions by local surgery is permitted for 
palliative or potentially curative management at any time. All interventions 
should be discussed in advance with the BMS MedicalMonitor. All tumor tissue 
that is not required for clinical pathology will be sent to BMS.
e) A new biopsy will not be required for resuming re-treatment in the setting of 
interrupted active treatment for local palliative therapies, although it is 
encouraged, if considered safe by the investigator. All tumor tissue that is not 
required for clinical pathology will be sent to BMS.
2) Use of growth factors including, but not limited to, granulocyte colony stimulating 
factor (G-CSF), granulocytemacrophage colony stimulating factor (GM-CSF), or 
erythropoietin stimulating agents are not permitted, unless deemed necessary by 
investigator and discussed with medical monitor.
3) Use of systemic corticosteroids at > 10 mg daily prednisone equivalent, unless 
requiredfor the treatment of infusion reactions, other adverse events, or for palliation 
as determined by the investigator.
4) Use of RANKL therapy unless required for management of osteolytic bone lesions, 
other adverse events or for palliation and after a discussion between the investigator 
and the medical monitor. Since RANKL therapy is a recognized immune modulator, 
discussion must occur before starting any patient on RANKL therapy.
5) Use of bisphosphate therapy, unless required for management of osteolytic bone 
lesions, adverse events or for palliation and after a discussion between the investigator 
and the medical monitor. Since bisphonates are recognized as immune modulators, 
discussion must occur before starting any patient on bisphosphonate therapy.
6) Steroids must not be given as prophylactic anti-emetic therapy.
7) Use of herbal remedies is not permitted
Use of prescription and over-the-counter medications (except medications from categories 
outlined above) is permitted at the discretion of the Investigator and must be recorded on CRF.
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nivolumab
3.4.2
Other Restrictions and Precautions
None
3.4.3
Permitted Therapy
Subjects are permitted the use of topical, ocular, intranasal, intra-articular, and inhalational 
corticosteroids (with minimal systemic absorption). Immunosuppressive doses (e.g., prednisone 
> 10 mg/day or equivalent) and/or physiologic replacement dosesof systemic corticosteroids 
(e.g., prednisone 10 mg/day) are permitted in the context of treating adverse events. A brief 
course of corticosteroids for prophylaxis (e.g., contrast dye allergy) or for treatment of 
non-autoimmune conditions (e.g., delayed-type hypersensitivity reaction caused by a contact 
allergen) is permitted.
Prophylactic anti-emetics, with the exception of steroids, may be administered at the discretion 
of the treating physician before any doses of study drug.
Use of the seasonal killed influenza vaccine during therapy is permitted without restriction. 
However, influenza vaccines containing live attenuated virus (Flumist ®) or other clinically 
indicated vaccinations for infectious diseases (killed or attenuated, e.g., Pneumovax ®, varicella, 
MMR, etc) may be permitted, but must be discussed with the Sponsor’s Medical Monitor and 
may require a study drug washout period prior to and after administration of the vaccine.
3.5
Discontinuation of Subjects From Treatment
3.5.1
Permanent Discontinuation Criteria of Subjects from Treatment
Subjects MUST PERMANENTLY discontinue investigational product (and non-investigational 
product at the discretion of the investigator) for any of the following reasons:
Withdrawal of informed consent (subject’s decision to withdraw for any reason)
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 as per Section 4.3.5
Pregnancy
Termination of the study by Bristol-Myers Squibb (BMS)
Loss of ability to freely provide consent through imprisonment or involuntary 
incarceration for treatment of either a psychiatric or physical (e.g., infectious disease) 
illness
Subjects should discontinue study therapy upon evidence of further disease progression, 
defined as an additional 10% or greater increase in tumor burden volume from the time of 
initial progression (including all target lesions and new measurable lesions), as per 
Section 4.3.8
Clinical deterioration while receiving activestudy therapy.
Inability to comply with the protocol
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All subjects who discontinue should comply with protocol specified follow-up procedures as 
outlined in Section 3.1. Theonly exception to this requirement is when a subject withdraws 
consent for all study procedures or loses the ability to consent freely (i.e., is imprisoned or 
involuntarily incarcerated for the treatment of either a psychiatric or physical illness).
If study treatment 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 Treatment Study Follow-up 
Subjects who discontinue study treatment may continue to be followed. Please refer to Section 
3.1and Tables in Section 5.1for details. 
3.6.1
Withdrawal of Consent 
Subjects who request to discontinue study treatment will remain in the study and must continue 
to be followed for protocol specified follow-up procedures. The only exception to this is when a 
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 
BMS-retained third-party representative to assist site staff with obtaining subject’s contact 
information or other public vital status data necessary to complete the follow-up portion of the 
study. If after all attempts, the subject remains lost to follow-up, then the last known alive date as 
determined by the investigator should be reported and documented in the subject’s medical 
records.
4
TREATMENTS
All protocol-specified investigational and non-investigational products are considered study 
drug. 
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nivolumab
4.1
Study Treatments
Treatment administration for nivolumab and ipilimumab (a ±2-day window will be allowed):
Table 4.1-1:
Treatment Administration
Cohort/Arm
Dose
Infusion Time
1 and 2
3 mg/kg nivolumab every 2 weeks
60 minutes 
A
1 mg/kg nivolumab + 3 mg/kg ipilimumab every 
3 weeks x 4 doses
and then 3 mg/kg nivolumab every 2 weeks 
Part 2: nivolumab 60 minutes
             + 30 minutes break
            ipilimumab 90 minutes
            and then nivolumab 60 minutes 
Part 3: nivolumab 30 minutes 
            + 30 minutes break
            ipilimumab 30 minutes 
            and then nivolumab 30 minutes
B
3 mg/kg nivolumab every 2 weeks
30 minutes 
D
1 mg/kg nivolumab + 3 mg/kg ipilimumab every 
3 weeks x 4 doses
and then 3 mg/kg nivolumab every 2 weeks 
nivolumab 30 minutes 
+ 30 minutes break
ipilimumab 30 minutes
and then nivolumab 30 minutes
E
3 mg/kg nivolumab every 2 weeks
30 minutes 
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nivolumab
Table 4.1-2:
Product Description
Product Description 
and Dosage Form
Potency
PrimaryPackaging
(Volume)/ Label Type
Secondary Packaging
(Qty) /Label Type
Appearance
Storage Conditions
(per label)
BMS-936558-01 
Solution for Injection 
100 mg (10mg/mL)
10 mL/ 
open label
10 vials per box/ open 
labels
Colorless to pale 
yellow, clear to 
opalescent solution; 
may contain particles
Store Refrigerated, 
2-8° C (36-46 F)
Protect from light and 
freezing.
Ipilimumab Solution for 
Injection
200 mg (5 mg/mL)
40 mL per vial/Open-
label
4 vials per 
carton/Open-label
Clear, colorless to pale 
yellowliquid. May 
contain particles
2 to 8°C. Protect from 
light and freezing.
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4.1.1
Investigational Product
An investigational product, also known as investigational medicinal product in some regions, is 
defined as follows:
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) in a way different from the authorized form, or used for an 
unauthorized indication, or when used to gain further information about the authorized form.
The investigational product should be stored in a secure area according to local regulations.It is 
the responsibility of the investigator to ensure that investigational product is only dispensed to 
study subjects. The investigational product must be dispensed only from official study sites by 
authorized personnel according to local regulations. 
In this protocol, the investigational products are: nivolumab and ipilimumab 
The sites will be responsible to procure IV bags, diluents, and micron in-line filters (ie 
0.2/0.22micron; see current nivolumab and ipilimumab Investigator Brochure for required filter 
details)
4.1.2
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) are not applicable.
4.1.3
Handling 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 the Sponsor. If 
concerns regarding the quality or appearance of the study drug arise, do not dispense the study 
drug and contact the Sponsor immediately.
4.1.4
Nivolumab Vial Storage  
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 the sponsor. If 
concerns regarding the quality or appearance of the study drug arise, donot dispense the study 
drug. Contact the sponsor immediately. Nivolumab vials must be stored in the refrigerator at 
2-8°C, protected from light and freezing. If stored in a glass front refrigerator, vials should be 
stored in the carton. Recommended safety measures for preparation and handling of nivolumab 
include laboratory coats and gloves.
After nivolumab has been prepared for administration, the total storage time (combination of 
refrigeration and room temperature exposure) is not to exceed 24 hours. For details on prepared 
drug storage and use time under room temperature/light and refrigeration, please refer to the 
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current nivolumab Investigator Brochure.48Care must be taken to assure sterility of the prepared 
solution as the product does not contain any anti-microbial preservative or bacteriostatic agent. 
4.1.5
Ipilimumab Vial Storage  
For ipilimumab storage and administration instructions, please refer to the ipilimumab IB.
4.1.6
Study Drug Administration
Nivolumab is to be administered as an approximate 60 minute IV infusion in Parts 1 and 2, using 
a volumetric pump with a 0.2/0.22 micron in-line filter at the protocol-specified doses. It is not to 
be administered as an IV push or bolus injection. At the end of the infusion, flush the line with a 
sufficient quantity of normal saline (per institutional standard of care). Details regarding the 
mixing and concentrations of the dose(preparation) and administration will be found in the 
current Investigator Brochure for nivolumab.
48
Ipilimumab is to be administered as an approximate 90-minute IV infusion in Parts 1 and 2, 
using a volumetric pump with a 0.2to 1.2 micron in-line filter at the protocol-specified dose. 
Care must be taken to assure sterility of the prepared solutions, since the drug product does not 
contain any antimicrobial preservatives or bacteriostatic agents. Please refer to the ipilimumab 
IB for further details regarding preparation/administration.
In Parts 3 and 4 of the study, the infusion times for nivolumab and ipilimumab will be shortened 
to 30 minutes each. 
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 ipilimumab infusion. The second infusion will always be the 
ipilimumabstudy drug, and will start no sooner than 30 minutes after completion of the 
nivolumab infusion and after thepost-nivolumab pharmacokinetic blood sample is drawn.
4.2
Method of Assigning Subject Identification
CA209038 is an open-label study. All enrolled subjects will be assigned a subject number, 
starting with 00001 and increasing sequentially with each additional enrolled subject. The 
subject number will be assigned by the Sponsor via IVRS once the subject signs the informed 
consent form. Each subject will then be identified by a distinct patient identification number 
(PID) which is comprised of the site number and the subject number. The Investigator or 
designee will register the subject following the enrollment procedures established by BMS. The 
following information is required for registration:
Date of birth
Gender
Diagnosis
Date of Informed Consent
Planned date of 1st dose
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Subjects will undergo screening evaluations to determine eligibility within 28 days prior to 
dosing. The investigative site will contact the Sponsor via IVRS for treatment assignment once a 
subject is determined to be eligible for enrollment. Enrolled subjects meeting all eligibility 
criteria will be assigned to Cohort 1 or 2 depending on prior anti-CTLA4 therapy status. After 
Amendment 04, enrolled subjects meeting all eligibility criteria will be assigned to Arm A for 
Part 2. After the optimal timing of the biopsy has been determined in Part 2 then, enrolled 
subjects meeting all eligibility criteria will be randomly assigned to Arms Aor Bin a 2:1ratio in 
Part 3. In parallel, enrolled subjects meeting all eligibility criteria will be randomly assigned to 
Arms D or E in a 1:1 ratio in Part 4.
Subjects who do not have both pre-treatment and on-treatment biopsy will be replaced. Subjects 
in Arms D and E may undergo optional biopsies, especially if they have lesions in locations 
otherthan the brain. Subjects in Arms D and E will not be replaced. Replacement subjects will 
receive the same treatment but will be assigned a new subject number.
Specific instructions regarding enrollment and randomization will be provided to the 
investigational sites in their training materials. 
4.3
Selection and Timing of Dose for Each Subject
As described in Section 4.2, subjects will be assigned to a cohort/arm in the order they enter the 
study. The subjects enrolled prior to Amendment 04 will be assigned a patient identification 
number (PID) by IVRS and placed into 1 of 2 dose cohorts based on whether they have had prior 
anti-CTLA4 treatment. Subjects enrolled after Amendment 04 will be assigned a patient 
identification number (PID) by IVRS and placed into Arms A, B,D or E.
4.3.1
Dose Modifications
There will be no actual dose adjustments allowed for nivolumab or ipilimumab except for weight 
changes (an increase or decrease of ≥ 10% in weight) at the beginning of each cycle. 
4.3.2
Intrasubject Dose Escalation
No intrasubject dose escalation will be allowed
4.3.3
Dose Reductions
Nivolumab and ipilimumab dose reductions are not permitted in this study.
4.3.4
Dose Delay Criteria 
Study drug administration should be interrupted and increased monitoring of subjects should 
ensue if any of the following drug related adverse event(s) occurs:
Any persistent grade ≥2 non laboratory non-skin drug related adverse event except for 
fatigue and weakness
Any grade ≥2 endocrine drug-related adverse event
Any grade ≥ 3 skin drug related adverse event
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Any Grade ≥ 3 drug-related laboratory abnormality (except lymphopenia, asymptomatic 
lipase or amylase increases, or any electrolyte abnormality without any clinical sequelae 
that is either spontaneously reversible or resolves with clinical management to grade 2 or 
less within 72 hours)
ALT or AST > 3X ULN (treatment may resume when the AE resolves to Grade 1)
Patients with pre-existing neurologic or opthalmologic anti-CTLA4 related adverse event 
who develop clinical symptoms leading to a 1 grade drug related shift (i.e. grade 1 to 
grade 2)
Any AE, laboratory abnormality or inter-current illness which, in the judgment of the
investigator, warrants skipping the dose of study medication
If dose delay is necessary, both nivolumab and ipilimumab must be delayed until treatment can 
resume. If a delay prevents subsequent infusion of ipilimumab, the dose of ipilimumab should be 
replaced as soon as possible. At least 19 days must elapse between the replacement dose of 
ipilimumab and the administration of the next dose of the combination.
The occurrenceof clinically meaningful drug related AEs requires early recognition and prompt 
intervention. Management algorithms are available for suspected pulmonary, gastrointestinal, 
hepatic, renal, endocrine, neurological and skin toxicities. The recommendation isto follow the 
nivolumab IB adverse event algorithm. The algorithms can also be found on Appendix 4.
4.3.5
Study Drug Discontinuation Criteria due to Adverse Event(s)
Study drug administration must be discontinued if at least one of the following drug related
adverse event(s) occurs:
Any ≥ Grade 2 eye pain or reduction of visual acuity that does not respond to topical 
therapy and does not improve to Grade 1 severity within 2 weeks of starting therapy OR 
requires systemic treatment;
Any ≥ Grade 3 non laboratory drug-related adverse event with the exception of fatigue, 
and endocrine drug related AEs which are stable with  hormone replacement therapy
Any ≥ Grade 3 bronchospasm, hypersensitivity reaction, or infusion reaction;
Any patient that experiences any grade allergic/infusion reaction while receiving study 
drug at a slower infusion rate and/or with premedication due to a prior allergic/infusion 
reaction
Any drug-related Grade 4 laboratory abnormalities, (except lymphopenia, asymptomatic 
lipase or amylase increases, or any electrolyte abnormality without any clinical sequelae 
that is either spontaneously reversible or resolves with clinical management to grade 2 or 
less within 72 hours)
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Hepatoxicity as evidenced by any of the following:
• AST or ALT > 5 -10x ULN for >2 weeks
• AST or ALT > 10 ULN
• Total bilirubin > 5 x ULN
• Concurrent AST or ALT > 3 x ULN and total bilirubin > 2 ULN (potential Hy’s 
Law case)
Any adverse event, laboratory abnormality or intercurrent illness, which in the judgment 
of the Investigator, presents a substantial clinical risk to the subject 
All adverse events that meet discontinuation criteria, as well as any Grade 3 or 4 infusion 
reactions must be reported to BMS, within 24 hours using the rapid notification 
procedures described in Section 6.1.1.
Subjects who experience AEs that require discontinuation while receiving both nivolumab and 
ipilimumab may be allowed to continue therapy with nivolumab only if deemed in their best 
interest by both the PI and the BMS medical monitor. This will be decided on a case by case 
basis and will require convincing evidence that the benefit outweighs the risk.
4.3.6
Criteria to Resume Treatment with Study Drug
Subjects may resume treatment with study drug when the drug-related AE(s) resolve(s) to Grade 
1 or baseline value. Subjects must be re-treated within 6 weeks from the previous dose. For 
selected patients who are assessed to be deriving clinical benefit from treatment or for patients 
where resumption of therapy is delayed, re-initiation of therapy may be delayed even further on a 
case-by-case basis in consultation with the Sponsor. 
In the case of endocrine-related AEs, hormone replacement therapy may be utilized to restore 
physiologic function and to permit retreatment with nivolumab. If this is not possible, the subject 
must be discontinued from study therapy. 
4.3.7
Criteria to Enter Extension Period
At the completion of two years of therapy, those subjects that meet the following criteria may 
continue to receive nivolumab at the dose of 3mg/kg every 2 weeks (14 days):
Subject demonstrates investigator-assessed clinical benefit as defined by stable 
disease, partial response, or complete response
Subjects who demonstrate a complete response can only receive treatment until 
confirmation of CR or for an additional 2 doses (whichever is longer) and then enter 
the follow up period.
Subject is tolerating nivolumab therapy
All decisions to continue treatment in the Extension Period must be discussed with and approved 
by the BMS Medical Monitor and documented in the study records.
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4.3.8
Treatment Beyond Progression of Disease 
As described in Section 1.1.9, accumulating evidence indicates a minority of subjects treated 
with immunotherapy may derive clinical benefit despite initial evidence of PD.
76
Subjects will be permitted to continue study drug beyond initial RECIST1.1 defined PD as long 
as they meet the following criteria:
Continue to meet all other study protocol eligibility criteria 
Obtaining Investigator assessed clinical benefit and without rapid disease progression or 
clinical deterioration
Stable performance status
Tolerance of study drug
Treatment beyond progression will not delay an imminent intervention to prevent serious 
complications of disease progression (eg, CNS metastases)
A follow up scan should be performed at the next assessment or earlier to determine whether 
there has been a decrease in the tumor size, or continued PD. The assessment of clinical benefit 
should be balanced by clinical judgment as to whether the subject is clinically deteriorating and 
unlikely to receive any benefit from continued treatment with study drug. If the investigator feels 
that the subject continues to achieve clinical benefit by continuing treatment, the subjects should 
remain on trial and continue to receive monitoring according to the Time and Events Schedule 
on Tables in Section 5.1. The decision to continue treatment should be discussed with the BMS 
Medical Monitor and documented in the study records.
For the subjects who continue study therapy beyond progression, further progression is defined 
as an additional 10% increase in tumor burden volume from time of initial PD. This includes an 
increase in all target lesions and/or the development of new measurable lesions. 
New lesions are considered measurable 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 
15mm). Any new lesion considered non-measurable at the time of initial progression may 
become measurable and therefore included in the tumor burden volume if the longest diameter 
increases to at least 10 mm (except for pathological lymph nodes, which must have a short axis 
of at least 15 mm).
For statistical analyses that include the investigator-assessed progression date subjects who 
continue treatment beyond initial investigator-assessed RECIST 1.1 defined progression will be 
considered to have investigator-assessed progressive disease at the time of the initial progression 
event.
4.3.9
Infusion Delays and Missed Doses
In the case that an infusion cannot be administered at a scheduled visit, it should be administered 
as soon as possible. If the delay is between 1 and 7 days, the procedures at the original scheduled 
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visit should be performed. If the delay is more than 7 days, the infusion at the original scheduled 
visit will be considered a missed dose, and the procedures at the next visit should be performed. 
Response assessments must never be omitted. Subsequent visits will follow accordingly from the 
actual date of last study drug administration. Subjects with infusion delays ≥ 8 weeks should 
normally discontinue treatment and enter the follow-up period with the exception of delays as 
described in Section 4.3.6and after specific consultation and agreement between the investigator 
and BMS Medical Monitor in settings where benefit/risk may justify continued study therapy.
4.3.10
Discontinuation Due to Confirmed Complete Response
Subjects with a CR may continue to receive study therapy until response confirmation or for an 
additional 2 cycles (whichever is longer) and then enter the follow-up period. 
4.3.11
Stopping Rules for Clinical Deterioration
Accumulating evidence indicates that the emergence of objective responses to agents that 
activate anti-tumor immune responses may follow delayed kinetics of weeks or months, and can 
be preceded by initial apparent radiological progression or appearance of new lesions or some 
enlarging lesions while certain target lesions are regressing (“mixed response”). It is thus 
reasonable to allow for these possibilities and continue to treat the subject until progression is 
confirmed and found to be advancing and continuing at the next imaging assessment. These 
considerations should be balanced by clinical judgment as to whether the subject is clinically 
deteriorating and unlikely to receive any benefit from continued treatment. Such deterioration 
will be assessed to have occurred after a clinical event that, in the Investigator’s opinion, is 
attributable to disease progression, is unlikely to reverse with continued study treatment and 
therefore indicates that the subject is not benefiting from study treatment and cannot be managed 
by the addition of supportive care (such as bone directed radiotherapy, thoracentesis or 
paracentesis of accumulating effusions). The decision to continue or stop treatment should be 
discussed with the BMS Medical Monitor and will be documented in the study records.
4.3.12
Prophylactic and Acute Management of Infusion Reactions
Infusion reactions should be graded according to CTCAE Version 4.0 allergic 
reaction/hypersensitivity. These reactions may manifest with signs and symptoms that may 
include, but are not limited to fever, chills, headache, rash, pruritus, arthralgias, hypo-or 
hypertension, bronchospasm or other symptoms. Severe infusion reactions require the immediate 
interruption of study drug therapy and permanent discontinuation from further treatment. 
Appropriate medical therapy including epinephrine, corticosteroids, intravenous antihistamines, 
bronchodilators, and oxygen should be available for use in the treatment of such reactions. 
Subjects should be carefully observed until the complete resolution of all signs and symptoms. 
Following an infusion reaction, subjects should be premedicated with acetaminophen and 
diphenhydramine for future treatments.
Nivolumab and ipilimumab contain only human immunoglobulin protein sequences. 
Nevertheless, infusion reactions have been observed, although they are rare. Ifsuch a reaction 
were to occur, it might manifest with fever, chills, rigors, headache, rash, pruritis, arthralgias, 
hypotension or hypertension, bronchospasm, or other symptoms. All Grade 3 or 4 infusion 
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reactions should be reported within 24hours to theBMS Medical Monitor and reported as a 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)
The following prophylactic premedications are recommended for future infusions: 
diphenhydramine 50 mg (or equivalent) and/or paracetamol 325 to 1000 mg (acetaminophen) at 
least 30 minutes before additional study drug administrations.
For Grade 2 symptoms:(Moderate reaction requires therapy or infusion interruption but 
responds promptly to symptomatic treatment [eg, antihistamines, non-steroidal 
anti-inflammatorydrugs, narcotics, corticosteroids, iv fluids]; prophylactic medications indicated 
for 24 hours)
Stop the study drug infusion, begin an IV infusion of normal saline, and treat the subject with 
diphenhydramine 50 mg IV (or equivalent) and/or paracetamol 325 to 1000mg (acetaminophen); 
remain at bedside and monitor subject until resolution of symptoms. Corticosteroid 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. Monitor subject closely. If symptoms 
recur then no further study drug will be administered at that visit. Subsequent infusions should be 
administered over 2 hours. The amount of study drug infused must be recorded on the case report 
form (CRF). The following prophylactic premedications are recommended for future infusions: 
diphenhydramine 50 mg (or equivalent) and/or paracetamol 325 to 1000mg (acetaminophen) 
should be administered at least 30 minutes before additional study drug administrations. If 
necessary, corticosteroids (recommended dose: up to 25mg of SoluCortef or equivalent) may be 
used.
For Grade 3 or Grade 4 symptoms:(Severe reaction, Grade 3: prolonged [ie, not rapidly 
responsive to symptomatic medication and/or brief interruption of infusion]; recurrence of 
symptoms following initial improvement; hospitalization indicated for other clinical sequelae 
[eg, renal impairment, pulmonary infiltrates]. Grade 4: life-threatening; pressor or ventilatory 
support indicated). Immediately discontinue infusion of study drug. Begin an IV infusion of 
normal saline, and treat the subject as follows: recommend bronchodilators, epinephrine 0.2 to 
1mg of a 1:1,000 solution for subcutaneous administration or 0.1 to 0.25 mg of a 
1:10,000solution injected slowly for IV administration, and/or diphenhydramine 50 mg IV with 
methylprednisolone 100 mg IV (or equivalent), as needed. Subject should be monitored until the 
investigator is comfortable that the symptoms will not recur. Study drug will be permanently 
discontinued. Investigators should follow their institutional guidelines for the treatment of 
anaphylaxis. Remain at bedside and monitor subject until recovery from symptoms. In the case 
of late-occurring hypersensitivity symptoms (eg, appearance of a localized or generalized 
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pruritus within 1 week after treatment), symptomatic treatment may be given (eg, oral 
antihistamine, or corticosteroids).
4.3.13
Guidelines for Management of Gastrointestinal, Pulmonary and 
Endocrine Adverse Events
All subjects who receive treatment on this study should be closely monitored for any signs 
related to gastrointestinal, pulmonary or endocrine systems and aggressively managed at the first 
onset of clinical symptoms. A high index of suspicion for colitis, endocrinopathy (e.g. 
hypothyroidism or adrenal insufficiency) or pneumonitis should be maintained in all subjects 
who present with any symptoms referable to these events, including but not limited to diarrhea, 
abdominal symptoms, fatigue, lethargy, weakness, dehydration or shortness of breath. Prompt 
initiation of appropriate diagnosis and therapy, including early administration of steroids, should 
be instituted. Guidance is provided in the appendix of the Nivolumab Investigator Brochure48   
and Appendix 4. 
4.4
Blinding/Unblinding
Not applicable for this study.
4.5
Treatment Compliance
Treatment compliance will be monitored by drug accountability as well as the subject’s medical 
record and eCRF 
4.6
Destruction and Return of Study Drug
4.6.1
Destruction ofStudy Drug
For this study, study drugs (those supplied by BMS or sourced by the investigator) such as 
partially used study drug containers, vials and sy
ringes may be destroyed on site. 
Any unused study drugs can only be destroyed after being inspected and reconciled by the 
responsible BMS 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 
disposalvendor must be documented.
Accountability and disposal records are complete, up-to-date, and available for the 
Monitor to review throughout the clinical trial period.
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If conditions for destruction cannot be met, the responsible BMS 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 provi
ded that appropriate records of disposal are 
kept.
4.6.2
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 BMS 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 provi
ded that appropriate records of disposal are 
kept.
4.7
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 5.1A:
CA209038 Screening Procedural Outline 
Procedure
Screening
Visit
Visit 1
Day -3 
to Day 
1
Notes
Eligibility 
Assessments
Informed Consent
X
A subject is considered enrolled only when a protocol-specific informed consent is signed
Inclusion/Exclusion 
Criteria
X
All inclusion/exclusion criteria should be assessed prior to study assignment
Medical History
X
Include all previous treatments, any toxicities or allergy related to previous treatments, history of tobacco use 
(how many packs for how many years) and other pulmonary history (e.g. asthma or toxic exposures)
BRAF mutation 
status
X
Ahard copy of BRAFmutation status must be made available to the investigator and the Sponsor. 
For Part 1 only: If BRAF status is not known, then subjects
' archival tumor tissue will be sent for centralized 
testing at a Sponsor-selected lab. Fresh tumor tissue should be used for BRAF mutation status only ifthe 
BRAF status is unknown, no archival tumor tissue is available and if there is adequate tumor tissue for all other 
tumor tissue assays.
Tumor tissue 
samples
X
For Part 1, must have lesions from which a minimum of 2 core biopsies for FFPE and RNA extraction can be 
taken.
For Part 2 and 3, excisional/incisional biopsies preferred from non-lymph node lesion and tumor tissue samples 
will be centrally assessed for sufficient tumor content (≥100 tumor cells/4-micon section); subjects with 
samples that have insufficient tumor content will require re-biopsy prior to treatment.
In Part 4, pre-treatment and on-treatment biopsies are optional; although strongly recommended if clinically 
safe.
For Parts 1-4, archival tissue (FFPE block or a minimum of 10 unstained slides) should be obtained if 
available. 
See Section 5.6for detail.
Blood Samples for 
Biomarkers
X
See Table 5.5Aor Table 5.5Band Laboratory Manual for more details 
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Table 5.1A:
CA209038 Screening Procedural Outline 
Procedure
Screening
Visit
Visit 1
Day -3 
to Day 
1
Notes
Disease 
Assessments
X
CT chest, CT or MRI abdomen and pelvis, as well as MRI of brain should be performed if not performed 
within 28 days of anticipated drug administration. 
Safety 
Assessments
Assessment of 
Signs and 
Symptoms
X
Within 2 weeks prior to treatment; 
Record all medications taken within the prior 28 days as per Section 3.4
Concomitant Med 
Collection
X
Within 2 weeks prior to treatment;
Record all medications taken within the prior 28 days as per Section 3.4
Physical 
Examination
X
To include height, weight
Vital Signs  
(including ECOG 
Performance 
Status)
X 
X
Includes body temperature, respiratory rate, seated blood pressure and heart rate. Blood pressure and heart rate 
should be measured after the subject has been seated quietly for at least 5 minutes
Pulse oximetry
X
Collected at rest for at least 5 minutes. Oxygen levels will be used in combination with clinical signs and
symptoms and radiographic images to evaluate pulmonary/respiratory status. Changes in O2levels will not 
used in isolation to document or diagnosis pulmonary toxicity
ECG
X
Single 12 lead measurement should be recorded after the subject has been supine for at least 5 minutes
Chest Radiograph
X
Unless performed within 30 days of anticipated first dose
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Table 5.1A:
CA209038 Screening Procedural Outline 
Procedure
Screening
Visit
Visit 1
Day -3 
to Day 
1
Notes
Laboratory Tests 
(perform between 
day -14 to day -3)
X
To include CBC with differential, Complete Metabolic Panel (Na, K, Cl, CO2, BUN or serum urea level, Cr, 
eGFR, AST, ALT, Alk Phos, Albumin, Total Bilirubin, Total Protein, Calcium, glucose), direct bilirubin, 
amylase, lipase, magnesium, phosphorous, LDH, TSH (with reflex to free T3 and free T4 if abnormal), 
adenocorticotropic hormone (ACTH) collected in the morning (with reflex to cortisol if abnormal), Hep B 
surface Ag, Hep C antibody, HIV 1/2 antibody (may obtain additional testing or substitute testing per 
institutional guidelines to rule out infections), and urinalysis(dipstick); Subjects with suspected autoimmune 
thyroid disorders will also be tested for thyroid peroxidase antibodies and thyroid stimulating immunoglobulin
Serum or Urine 
Pregnancy Test 
X
For WOCBP within 24 hours of  Study Drug Administration
Follicle Stimulating 
Hormone (FSH) 
test (perform 
between day -14 to 
day -3)
X
Only required in certain instances in post-menopausal women. See Section 3.3.3for criteria
Adverse Event 
Reporting
Monitor for Serious 
Adverse Events
X
X
All SAEs must be collected from the date of the subject’s written consent until 100 days post discontinuation 
of dosing or subject’s participation in the study if the last scheduled visit occurs at a later time
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Table 5.1B:
CA209038 Treatment Procedural Outline, Part 1 (Cohorts 1 and 2) 
Procedure
Treatment Cycle = IV infusion q 2 weeks for 8 
weeks
End of 
Treatment
Visit
Notes
Day 1
Day 15 
Day 29 
Day 43
Safety Assessments
Physical Examination
X 
X
X
X
X
Done weekly in Cycle 1; to include body weight
Vital Signs  (including 
ECOG Performance 
status)
X 
X 
X
X
X
Measured before and after study drug administration. Includes 
body temperature, respiratory rate, seated blood pressure and 
heart rate. Blood pressure andheart rate should be measured 
after the subject has been seated quietly for at least 5 minutes.
Done weekly in Cycle 1 only.
Pulse oximetry
X 
X
X
X
X
Collected at rest for at least 5 minutes, before each study drug 
administration. Oxygen levels will be used in combination 
with clinical signs and symptoms and radiographic images to 
evaluate pulmonary/respiratory status. Changes in O2levels 
will not be used in isolation to document or diagnosis 
pulmonary toxicity.
Monitor for Adverse 
Events 
X 
X
X
X
X
All Non-Serious Adverse Eventswill be collected from 
Day1 until the subject’s 100 days post discontinuation of 
dosing or subject’s participation in the study if the last 
scheduled visit occurs at a later time
All Serious Adverse Eventsmust be collected from the date 
of the subject’s written consent until 100 days post 
discontinuation of dosing or subject’s participation in the 
study if the last scheduled visit occurs at a later time
Review Concomitant 
medications
X 
X
X
X
X
Laboratory Tests
X 
X
X
X
X
To include CBC with differential, Complete Metabolic Panel 
(Na, K, Cl, CO2, BUN, Cr, eGFR, AST, ALT, Alk Phos, 
Albumin, Total Bilirubin, Total Protein, Calcium, glucose), 
direct bilirubin, lipase, LDH, magnesium, phosphorus
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Table 5.1B:
CA209038 Treatment Procedural Outline, Part 1 (Cohorts 1 and 2) 
Procedure
Treatment Cycle = IV infusion q 2 weeks for 8 
weeks
End of 
Treatment
Visit
Notes
Day 1
Day 15 
Day 29 
Day 43
ECG
X
X
Single 12-lead ECGs will be collected at screening and prior 
to dosing on Day 1 of every other treatment cycle starting 
with Cycle 1. On Day 1 of Cycles 1, 2, and 4, an End of 
Infusion (EOI) ECG will be collected, as well. 
Electrocardiogram recording should be obtained just 
prior to as the serial PK samples as indicated in Table 
5.5A.
Chest radiograph
As clinicallyindicated
Serum or Urine 
Pregnancy Test
X
X
X
Starting with Day 1 and then every other dose or every 28 
days. For WOCBP within 24 hours of  Study Drug 
Administration
Serum TSH
X
On Day 1 of each cycle
Exploratory 
Blood samples for PK, 
ADA, Biomarkers 
See Table 5.5Afor timing of 
samples
Efficacy Response 
Assessments
Disease assessment, 
Tumor Imaging 
(CT or MRI of 
Chest/Abdomen/Pelvis;
MRI brain if clinically 
indicated
X (between 
days 49-56)
X
Tumor assessments should be done every 8 wks (+/-1 wk) 
until confirmed disease progression is documented or follow-
up is completed. Methods used at baseline should be 
continued throughout study.
MRI of brain are only required if clinically indicated
Clinical Drug
Dispense Study 
Drug/Treatment
X 
X
X
X
Nivolumab will be administered as an IV infusion on Days 1, 
15, 29, 43 of each 56 day treatment cycle (8 weeks/cycle)
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Table 5.1C:
CA209038 Follow-up Visits -Part 1 (Cohorts 1 and 2)
Procedure
Follow-up Visit 1 
(40-60 days) and 
Visit 2 (101-120 days)
Notes
Safety 
Assessments
Physical 
Examination
X
Vital Signs  
(including 
ECOG)
X
Includes body temperature, respiratory rate, pulse oximetry, seated blood pressure and heart rate. Blood 
pressure, pulse oximetry and heart rate should be measured after the subject has been seated quietly for at 
least 5 minutes
Adverse 
Events 
Assessment
X
For study related adverse events only
Review 
Concomitant 
Medications
X
Laboratory 
Tests
X
To include CBC with differential, Complete Metabolic Panel (Na, K, Cl, CO2, BUN, Cr, eGFR, AST, ALT, Alk 
Phos, Albumin, Total Bilirubin, Total Protein, Calcium, glucose), direct bilirubin, lipase, LDH, magnesium, 
phosphorus, TSH
Serum or 
Urine 
Pregnancy
Test
X
ECG
X
12 Lead; for the first two follow-up visits only. Measurement should be recorded after the subject has been 
supine for at least 5 minutes
Tumor biopsy
X
(encouraged, not 
mandated)
Upon confirmed progression
May be done at either Follow-up visit 1 or Follow-up visit 2
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Table 5.1C:
CA209038 Follow-up Visits -Part 1 (Cohorts 1 and 2)
Procedure
Follow-up Visit 1 
(40-60 days) and 
Visit 2 (101-120 days)
Notes
Efficacy 
Assessments
Disease 
assessment 
(CT/MRI)
X
Done after 12 weeks from the last on-study scan during Follow-up Visit 1 OR 2 then Q12wks by methods used 
at baseline
Not required for subjects entering follow-up period for confirmed disease progression
Exploratory
Blood samples 
for PK, ADA 
X
As per Table 5.5A
Survival 
Status
x
Survival status should be continued every 3 months for the time remaining after the last office follow-up visit 
until 2 years from the first dose of BMS-936558 or until subject death, subject withdraws consent, subject is lost-
to follow-up or the study is completed. This may be accomplished by visit or phone contact. 
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Table 5.1D:
On Treatment Procedural Outline (CA209038) -Part 2, Part 3 and Part 4: Arms A and D
[Procedure Window 2 days]
Procedure
Wk1
Day 1
Wk4
Day 1
Wk7
Day 1
Wk10
Day1
Wk 13
Day 1
and every 
2 weeks 
thereafter
End of 
Therapy
Follow-
Up Visits 
1 and 2a
Notes
Safety Assessments
Targeted Physical Examination
X 
X 
X 
X 
X 
X 
X
To be performed only as clinically indicated 
Vital Signs and Oxygen Saturation
X 
X 
X 
X 
X 
X 
X
Including BP, HR, temperature and oxygen 
saturation by pulse oximetry. Pulse oximetry at rest 
and after exertion within 72 hours prior to dosing 
Physical Measurements (including 
performance status)
X 
X 
X 
X 
X 
X 
X
Weight and ECOG performance status 
Adverse Events Assessment
X 
X 
X 
X 
X 
X 
X
Continuously throughout the study
Review of Concomitant Medications
X 
X 
X 
X 
X 
X 
X
12 Lead ECG
X*
*To be performed pre-dose at Week 13, Week 23 
and then every 16 weeks thereafter
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BMS-936558
nivolumab
Table 5.1D:
On Treatment Procedural Outline (CA209038) -Part 2, Part 3 and Part 4: Arms A and D
[Procedure Window 2 days]
Procedure
Wk1
Day 1
Wk4
Day 1
Wk7
Day 1
Wk10
Day1
Wk 13
Day 1
and every 
2 weeks 
thereafter
End of 
Therapy
Follow-
Up Visits 
1 and 2a
Notes
Laboratory Tests
Serum Chemistry
X 
X 
X 
X 
X
X 
X
Within 72 hours  prior to re-dosing to 
include:, Aspartate aminotransferase 
(AST), Alanine aminotransferase (ALT), 
total bilirubin, alkaline phosphatase, 
lactate dehydrogenase, creatinine, blood 
urea nitrogen (BUN) or serum urea level, 
amylase, lipase, glucose, sodium, 
potassium, chloride, CO2calcium, 
magnesium, TSH (if TSH is abnormal 
then obtain free T3 and free T4), ACTH 
collected in the morning as clinically 
indicated.
Hematology
X 
X 
X 
X 
X
X 
X
Within 72 hours prior to re-dosing to 
include CBC with differential
NOTE: Additionally required for the 
PBMC sample collection at the following 
timepoints: 
Week 1 Day 4; Week 2 Day 1; Week 3 
Day 1;
and Week 5 Day 1
Pregnancy Test (WOCBP only)
X 
X 
X 
X 
X 
X 
X 
X
Serum or urine within 24 hours prior to 
administration of study drug 
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CA209038
BMS-936558
nivolumab
Table 5.1D:
On Treatment Procedural Outline (CA209038) -Part 2, Part 3 and Part 4: Arms A and D
[Procedure Window 2 days]
Procedure
Wk1
Day 1
Wk4
Day 1
Wk7
Day 1
Wk10
Day1
Wk 13
Day 1
and every 
2 weeks 
thereafter
End of 
Therapy
Follow-
Up Visits 
1 and 2a
Notes
Pharmacokinetic Samples
PK samples
See Table 5.5C or Table 5.5E for 
schedule of samples
Other Samples
Immunogenicity blood sample (ADA)
See Table 5.5C or Table 5.5E for 
schedule of samples
Biomarker Samples
See Table 5.5Bfor schedule of samples
Efficacy Assessment 
Tumor Assessment
X
X
Subsequent assessments at week 23, then every 8 
weeks thereafter.
May be obtained up to 7 days prior to the required 
visit.
CT Chest and CT or MRI abdomen, pelvis and all 
known sites of disease. Use same imaging method 
used at screening. 
Arm D only, MRI brain also (subjects in other arms 
who have stable brain metastases should have 
surveillance brain MRI approximately every 16 
weeks and as clinically indicated).
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CA209038
BMS-936558
nivolumab
Table 5.1D:
On Treatment Procedural Outline (CA209038) -Part 2, Part 3 and Part 4: Arms A and D
[Procedure Window 2 days]
Procedure
Wk1
Day 1
Wk4
Day 1
Wk7
Day 1
Wk10
Day1
Wk 13
Day 1
and every 
2 weeks 
thereafter
End of 
Therapy
Follow-
Up Visits 
1 and 2a
Notes
Survival Data Collection
X
Survival status should be continued every 3 months 
for the time remaining after the last office follow-up 
visit until 2 years from the first dose of study drug or 
until subject death, subject withdraws consent, 
subject is lost-to follow-up or the study is completed. 
This may be accomplished by visit or phone contact.
Clinical Drug Supplies
IVRS drug vial assignment 
X 
X 
X 
X 
X
Nivolumab Infusiontreatment
X 
X 
X 
X 
X
Ipilimumab Infusion treatment
X 
X 
X 
X
a Follow up Visit 1 and 2 will occur at 40-60 days and 101-120 days after the stop of study therapy, respectively. Efficacy is required at Follow up visit 2 only.
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CA209038
BMS-936558
nivolumab
Table 5.1E:
On Treatment Procedural Outline (CA209038) -Part 3 and Part 4: Arms B and Ea
[Procedure Window 2 days]
Procedure
Wk1
Day 1
and every 2 weeks thereafter
End of 
Therapy
Follow-
Up 
Visits 1 
and 2b
Notes
Safety Assessments
Targeted Physical Examination
X
X 
X
To be performed only as clinically indicated 
Vital Signs and Oxygen Saturation
X
X 
X
Including BP, HR, temperature and oxygen saturation by pulse 
oximetry. Pulse oximetry at rest and after exertion within 72 hours 
prior to dosing 
Physical Measurements (including 
performance status)
X
X 
X
Weight and ECOG performance status 
Adverse Events Assessment
X
X 
X
Continuously throughout the study
Review of Concomitant Medications
X
X 
X
12 Lead ECG
See note
To be performedpre-doseat week 13, week 23 and then every 16 
weeks thereafter
Laboratory Tests
Serum Chemistry
X
X 
X
Within 72 hours  prior to re-dosing to include:, Aspartate 
aminotransferase (AST), Alanine aminotransferase (ALT), total 
bilirubin, alkaline phosphatase, lactate dehydrogenase, creatinine, 
blood urea nitrogen (BUN) or serum urea level, amylase, lipase, 
glucose, sodium, potassium, chloride, CO2, calcium, magnesium, 
TSH (if TSH is abnormal then obtain free T3 and free T4), ACTH 
collected in the morning as clinically indicated.
Hematology
X
X 
X
Within 72 hours prior to re-dosing to include CBC with 
differential
NOTE: Additionally required for the PBMC sample collection at 
the following timepoints: 
Week 1 Day 4; Week 2 Day 1; and Week 4 Day 1 
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CA209038
BMS-936558
nivolumab
Table 5.1E:
On Treatment Procedural Outline (CA209038) -Part 3 and Part 4: Arms B and Ea
[Procedure Window 2 days]
Procedure
Wk1
Day 1
and every 2 weeks thereafter
End of 
Therapy
Follow-
Up 
Visits 1 
and 2b
Notes
Pregnancy Test (WOCBP only)
X
X 
X
Serum or urine within 24 hours prior to administration of study 
drug 
Pharmacokinetic Samples
PK samples
See Table 5.5Dfor schedule of samples
Other Samples
Immunogenicity blood sample (ADA)
See Table 5.5Dfor schedule of samples
Biomarker Samples
See Table 5.5Bfor schedule of samples
Efficacy Assessment 
Tumor Assessment 
See Note 
Assessments at week 7, 13, 23 and then every 8 weeks thereafter.
May be obtained up to 7 days prior tothe required visit.
CT Chest and CT or MRI abdomen, pelvis and all known sites of 
disease. Use same imaging method used at screening. 
Arm E only, MRI brain also (subjects in other arms who have 
stable brain metastases should have surveillance brain MRI 
approximately every 16 weeks and as clinically indicated).
Survival Data Collection
X
Survival status should be continued every 3 months for the time 
remaining after the last office follow-up visit until 2 years from the 
first dose of study drug or untilsubject death, subject withdraws 
consent, subject is lost-to follow-up or the study is completed. 
This may be accomplished by visit or phone contact.
Clinical Drug Supplies
IVRS drug vial assignment 
X
Nivolumab Infusion treatment
X
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nivolumab
a Treatment Procedural Outline for subjects who progressed on Arm C.
b Follow up Visit 1 and 2 will occur at 40-60 days and 101-120 days after the stop of study therapy, respectively. Efficacy is required at Follow up visit 2 only.
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BMS-936558
nivolumab
Table 5.1F:
On Treatment Procedural Outline (CA209038) -Part 2, Part 3 and Part 4: Arms A, B, D, and E 
[Procedure Window 2 days]
Procedure
Extension PeriodStarting at 
2 years 
Every 2 weeks +/-2 days
End of 
Therapy
Follow-
Up 
Visits 1 
and 2a
Notes
Safety Assessments
Targeted Physical Examination
X
X 
X
To be performed only as clinically indicated 
Vital Signs and Oxygen Saturation
X
X 
X
Including BP, HR, temperatureand oxygen saturation by pulse 
oximetry. Pulse oximetry at rest and after exertion within 72 hours 
prior to dosing 
Physical Measurements (including 
performance status)
X
X 
X
Weight and ECOG performance status 
Adverse Events Assessment
X
X 
X
Continuously throughout the study
Review of Concomitant Medications
X
X 
X
Continuously throughout the study
12 Lead ECG
See note
To be performed every 16 weeks thereafter
Laboratory Tests
Serum Chemistry
X
X 
X
Within 72 hours  prior to re-dosing to include:, Aspartate 
aminotransferase (AST), Alanine aminotransferase (ALT), total 
bilirubin, alkaline phosphatase, lactate dehydrogenase, creatinine, 
blood urea nitrogen (BUN) or serum urea level, amylase, lipase, 
glucose, sodium, potassium, chloride, CO2, calcium, magnesium, 
TSH (if TSH is abnormal then obtain free T3 and free T4), ACTH 
collected in the morning as clinically indicated.
Hematology
X
X 
X
Within 72 hours prior to re-dosing to include CBC with 
differential 
Pregnancy Test (WOCBP only)
X
X 
X
Serum or urine within 24 hours prior to administration of study 
drug 
Efficacy Assessment 
Tumor Assessment 
X
X 
X
Subsequent assessments at week 23, then every 8 weeks thereafter.
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Clinical Protocol
CA209038
BMS-936558
nivolumab
Table 5.1F:
On Treatment Procedural Outline (CA209038) -Part 2, Part 3 and Part 4: Arms A, B, D, and E 
[Procedure Window 2 days]
Procedure
Extension PeriodStarting at 
2 years 
Every 2 weeks +/-2 days
End of 
Therapy
Follow-
Up 
Visits 1 
and 2a
Notes
May be obtained up to 7 days prior to the required visit.
CT Chest and CT or MRI abdomen, pelvis and all known sites of 
disease. Use same imaging method used at screening. 
Arms D and E only, MRI brain also (subjects in other arms who 
have stable brain metastases should have surveillance brain MRI 
approximately every 16 weeks and as clinically indicated).
Survival Data Collection
X
Patients that enter the Extension Period will be followed for 
overall survival assessments up to a maximum of 100 days after 
the last treatment dose.
Clinical Drug Supplies
IVRS drug vial assignment 
X
Nivolumab Infusion treatment
X
a Follow up Visit 1 and 2 will occur at 40-60 days and 101-120 days after the stop of study therapy, respectively. Efficacy is required at Follow up visit 2 only.
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5.2
Study Materials
The following materials will be provided at study start:
Protocol and appendices;
NCI CTCAE version 4.0;
Nivolumab Investigator Brochure;
IpilimumabInvestigator Brochure;
Laboratory kits, shipping materials;
Laboratory manuals for collection and handling of blood (including PKs, biomarker and 
immunogenicity) and tissue specimens;
Enrollment/randomization worksheets;
Pregnancy Surveillance Forms;
SAE reporting instructions and forms.
5.3
Safety Assessments
At baseline, a medical history will be obtained to capture relevant underlying conditions. 
Baseline signs and symptoms are those that are assessed within 2 weeks prior to treatment arm 
assignment. The baseline physical examination should include: weight, height, ECOG 
performance status, blood pressure, heart rate, electrocardiogram, O
2saturation (pulse oximetry) 
and temperature; it should be performed within 28 days of treatment arm assignment. 
Concomitant medications will be collected from within 2 weeks prior to treatment arm 
assignment through the study treatment period (see Table 5.1A, Table 5.1B, Table 5.1C, Table 
5.1D,andTable 5.1E).
Subjects will be considered evaluable for safety if they have received any study drug. 
Toxicity assessments will be continuous during the treatment phase and follow-up phases.
Performance status and body weight should be assessed at each on study visit. Vital signs should 
also be taken as per institutional standard of care prior to, during and after the infusions with 
investigational products. Pulse oximetry should be done prior to each infusion as well. The start 
and stop time of the study drug infusion should be documented. If there are any new or 
worsening clinically significantchanges since the last exam, report changes on the appropriate 
non-serious or serious adverse event page.
Additional measures including non-study required laboratory tests should be performed as 
clinically indicated.
Safety assessments will be based on the medical review of adverse event reports, results of vital 
sign measurements, Eastern Cooperative Oncology Group (ECOG) performance status, physical 
examinations, clinical laboratory results, ECGs, and imaging tests. 
The incidence of observed adverse events will be categorized using the most current version of 
MedDRA and reviewed for potential significance and clinical importance. Adverse events will 
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nivolumab
be evaluated according to the National Cancer Institute Common Terminology Criteria for 
Adverse Events (NCI CTCAE) version 4.0. 
5.3.1
Laboratory Test Assessments
Clinical laboratories will be assessed (see Table 5.1A, Table 5.1B, Table 5.1C, Table 5.1D, and 
Table 5.1E). Sites should collect screening samples between -14 to -3 days from assignment to 
insure that results required for eligibility purposes are verified prior to the assignment to study. 
Estimated GFR will be calculated by either Cockroft-Gault, CKD-EPI, or MDRD, formulas from 
the supplied serum creatinine value supplied by the site. Pregnancy testing must be performed 
within 24 hoursprior to the initial administration of investigational product at baseline and then 
within 24 hours of each study drug administration. CBC plus differential and serum chemistry 
panel should be drawn within 72 hours prior to each subsequent scheduled treatment. On study 
labs will be done on site/locally. Laboratory tests may be done more frequently if indicated. 
Additional laboratory tests should be performed as per standard of care. 
Laboratory toxicities (eg, suspected drug induced liver enzyme elevations) will be monitored 
during the follow-up phase via on site/local labs until all study drug related toxicities resolve, 
return to baseline or are deemed irreversible.
The following clinical laboratory tests will be performed:
Hematology
WBC
Hemoglobin
Hematocrit
MCV
RDW
Differential Count
Platelet count
Serum Chemistry
Sodium
Potassium
Chloride
CO2
Blood Urea Nitrogen (BUN) or serum urea level
Creatinine
Estimated GFR
Glucose
Calcium
Magnesium
Phosphorus
Aspartate Transaminase
Alanine  Transaminase
Alkaline Phosphatase
Total Bilirubin
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Direct Bilirubin
Albumin
Total Protein
Amylase
Lipase
Lactate Dehydrogenase
Serology (screening only)
Human immunodeficiency virus 1/2 antibody
Hepatitis B virus surface antigen
Hepatitis C antibody
Note: May obtainadditional testing or substitute testing per institutional guidelines to 
rule out infection
Urine Studies (screening only)
Urinalysis (dipstick)
Other Assays
TSH (if TSH is abnormal then obtain free T3 and free T4)
Anti-thyroid antibodies (stimulating and anti-thyroperoxidase (TPO) at screening 
only)
Adenocorticotropic hormone collected in the morning at screening, then as clinically 
indicated (if ACTH is abnormal then obtain cortisol)
Other Analyses
Pregnancy test (WOCBP only at screening and 24hrs prior study drug administration
FSH (if needed to document post-menopausal status as defined in Section 3.3.3)
At the investigator’s discretion, laboratory tests may be repeated if clinically significant.
Results of all laboratory tests required by this protocol must be provided to BMS, either recorded 
on the laboratory pages of the CRF or by another mechanism as agreed upon between the 
investigator and BMS (eg, provided electronically). If the units of a test result differ from those 
printed on the CRF, the recorded laboratory values must specify the correct units. Any abnormal 
laboratory test result considered clinically significant by the investigator must be recorded on the 
appropriate AE page of the CRF (see Section6.2Laboratory Test Abnormalities).
5.3.2
ECG Evaluation
Single 12-lead ECGs will be collected at screening and on study.
5.4
Efficacy Assessments
Disease evaluation with computed tomography (CT) and/or magnetic resonance imaging (MRI) 
of chest, abdomen, and pelvis, as appropriate, will be performed at baseline, and then 
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approximately every 8 weeks until confirmed disease progression as described in Section 4.3.8
and/or completion of follow-up. Brain MRI will be performed at screening, approximately every 
16 weeks thereafter, and ifclinically indicated. Brain MRI will be performed approximately 
every 8 weeks for subjects in Arms D and E.
In the Extension Period, tumor assessmentswill be performed every 8 weeks (prior to dosing). 
CT Chest and CT or MRI abdomen, pelvis and all known sites of diseaseshould be performed 
using thesame imaging method used at screening.For ArmsD and E only, MRI brain will also 
be performed (subjects in other arms who have stable brain metastases should have surveillance 
brain MRI approximately every 16weeks and as clinically indicated).
Tumor response will be determined for all subjects as defined by RECIST 1.1. Individual 
patients will be treated according to principles that allow treatment beyond initial radiographic 
progression (outlined in Section 4.3.8). 
At the sponsor’s discretion, scans and measurements may be reviewed by independent 
radiologists using RECIST 1.1 criteria at alater date or any time during the study. In the absence 
of clinical deterioration, any initial assessment of progressive disease (PD) will be confirmed by 
a repeat evaluation at the next tumor assessment time point, but no sooner than 4 weeks later.
5.5
Pharmacokinetic Assessments
Table 5.5A, Table 5.5C, Table 5.5Dand Table 5.5Elist the sampling schedule to be followed for 
the assessment of pharmacokinetics. Blood samples should be drawn from a site other than the 
infusion site (ie, contralateral arm) on days of infusion. All samples collected pre-dose should be 
taken just prior to the administration, and end-of-infusion (EOI) samples should be taken as close 
to EOI as possible (preferably 2 minutes prior to EOI) on the contralateral arm (ie, the arm not 
for the infusion). All other on-treatment timepoints are relative to the start of study drug 
administration; when both nivolumab and ipilimumab are administered on the same day, 
samples should be collected relative to the start of nivolumab infusion. If the infusion was 
interrupted, the reason for interruption should also be documented on the CRF. Blood samples 
will be processed to collect serum. PK samples willbe analyzed for nivolumab or ipilimumab by 
validated immunoassays. Additional exploratory analysis may be conducted; exploratory results 
will not be reported.Further details of blood collection, labeling, processing, storage and 
shipping will be providedto the site in the laboratory manual.
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Table 5.5A:
CA209038 Pharmacokinetic (PK), Pharmacodynamic, and Biomarker Sampling Schedule (Part 1, 
Cohorts 1 and 2)
Study 
Day
Time 
(Event)
Time 
(Relative to 
Start of 
Infusion) 
Hours:Min
PK 
Serum 
Sample
ADA
SNP&
HLA/
KIR 
typing
Tumor Ag 
specific
T-cells
with a 
CBC and 
differential
PB Gene 
Expression 
Profiling
PBMC 
Flow 
Cytometry
with a 
CBC  and 
differential
Soluble 
Factors 
(Serum)
Anti-
Tumor 
Antibodies
PBMC 
Functional 
Assays
with a 
CBC and 
differential
Tumor 
Biopsy
Screening 
(day -7 to 
day1 pre-
dose)
X 
X 
X 
X 
X 
X 
X
X (once 
eligibility 
determined)
Cycle1 
Day 1
0 
(predose)
00:00
X 
X
X
Cycle1 
Day 1
1 (EOI)
01:00 
X
Cycle1  
Day 1
3 
03:00
X
X
Cycle1  
Day 1
7 
07:00
X
X
Cycle 1
Day 2
0
24:00
X
X
X
Cycle 1
Day 3
0
48:00   
X
Cycle 1
Day 4
0
72:00
X
Xa
Cycle 1
Day 8
0
168:00
X
X
Xa
Xa
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nivolumab
Table 5.5A:
CA209038 Pharmacokinetic (PK), Pharmacodynamic, and Biomarker Sampling Schedule (Part 1, 
Cohorts 1 and 2)
Study 
Day
Time 
(Event)
Time 
(Relative to 
Start of 
Infusion) 
Hours:Min
PK 
Serum 
Sample
ADA
SNP&
HLA/
KIR 
typing
Tumor Ag 
specific
T-cells
with a 
CBC and 
differential
PB Gene 
Expression 
Profiling
PBMC 
Flow 
Cytometry
with a 
CBC  and 
differential
Soluble 
Factors 
(Serum)
Anti-
Tumor 
Antibodies
PBMC 
Functional 
Assays
with a 
CBC and 
differential
Tumor 
Biopsy
Cycle1 
Day 15
0 
(predose)
00:00
X 
X
X 
X
X
Cycle 1
Day 29
0 
(predose)
00:00
X
X 
X 
X 
X 
X 
X
X
(day 23 to 
day 29)
Cycle 1
Day 43 
0 
(predose)
00:00
X 
X
X
Cycle 1
Day 43
1 (EOI)
01:00
X
Cycle2 
Day1 
0 
(predose)
00:00
X 
X
X 
X 
X
X 
X
Cycle 2
Day 29
0 
(predose)
00:00
X
Cycle 3 
Day 15
0 
(predose)
00:00
X 
X
Cycle 3 
Day 15
1 (EOI)
01:00
X
Cycle 5 
Day 1
(Every 16 
weeks 
after 
Cycle 3)
0 
(predose)
00:00
X 
X
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BMS-936558
nivolumab
Table 5.5A:
CA209038 Pharmacokinetic (PK), Pharmacodynamic, and Biomarker Sampling Schedule (Part 1, 
Cohorts 1 and 2)
Study 
Day
Time 
(Event)
Time 
(Relative to 
Start of 
Infusion) 
Hours:Min
PK 
Serum 
Sample
ADA
SNP&
HLA/
KIR 
typing
Tumor Ag 
specific
T-cells
with a 
CBC and 
differential
PB Gene 
Expression 
Profiling
PBMC 
Flow 
Cytometry
with a 
CBC  and 
differential
Soluble 
Factors 
(Serum)
Anti-
Tumor 
Antibodies
PBMC 
Functional 
Assays
with a 
CBC and 
differential
Tumor 
Biopsy
Follow-up 
Visit 1
(40-60 
days after 
last 
treatment
X 
X
Follow-up 
Visit 2
(101-120 
days since 
last 
treatment)
X 
X
a CBCs required will be done locally and not by central lab
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Table 5.5B:
CA209038 Pharmacodynamic and Biomarker Sampling Schedule (Parts 2, 3 and 4, Arms A, B, D and E)
Study Day
Time 
(Event)
Time 
(Relative to 
Start of 
Infusion) 
Hours:Min
SNP&
HLA/
KIR 
typing
Tumor Ag 
specific
T-cells
with a 
CBC and 
differential
MDSCs
PB Gene 
Expression 
Profiling
PBMC Flow 
Cytometry
with a CBC  
and 
differential
Soluble 
Factors 
(Serum)
Anti-
Tumor 
Antibodies
PBMC 
Functional 
Assays
with a CBC 
and 
differential
Tumor 
Biopsy
Screening 
X
Xa
X 
X
Xa
X 
X
Xa
Xb,c
Week 1 
Day 1
0 (predose)
00:00
X
Week 1  
Day 1
3 h
03:00
X
Week 1  
Day 1
7 h
07:00
X
Week 1
Day 2
0
24:00
X
X
Week 1
Day 3
0
48:00   
X
Week 1
Day 4
0
72:00
Xa
X
Week 2
Day 1
0
168:00
X
Xa
X
Xa
X (+7 
days)c
,d
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Table 5.5B:
CA209038 Pharmacodynamic and Biomarker Sampling Schedule (Parts 2, 3 and 4, Arms A, B, D and E)
Study Day
Time 
(Event)
Time 
(Relative to 
Start of 
Infusion) 
Hours:Min
SNP&
HLA/
KIR 
typing
Tumor Ag 
specific
T-cells
with a 
CBC and 
differential
MDSCs
PB Gene 
Expression 
Profiling
PBMC Flow 
Cytometry
with a CBC  
and 
differential
Soluble 
Factors 
(Serum)
Anti-
Tumor 
Antibodies
PBMC 
Functional 
Assays
with a CBC 
and 
differential
Tumor 
Biopsy
Week 3 
Day 1
0 (predose)
00:00
X
Xa
X
Xa
Week 4
Day 1
0 (predose)
X
Xa
X
Xa
X (+7 
days 
after 2nd 
dose)c
,e
Week 5
Day 1
0 (predose)
00:00
Xa
X
Xa
X
Xa
Week 7 
Day 1
0 (predose)
00:00
X 
X
Xa
X 
X
Xa
Week 13 
Day 1
0 (predose)
00:00
Xa
Xa
X
Xa
Follow-up 
Visit 1
(40-60 days 
after last 
treatment
X -
obtain 
upon 
progressi
onf
Follow-up 
Visit 2
(101-120 days 
after last 
treatment)
X -
obtain 
upon 
progressi
on f
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Table 5.5B:
CA209038 Pharmacodynamic and Biomarker Sampling Schedule (Parts 2, 3 and 4, Arms A, B, D and E)
Study Day
Time 
(Event)
Time 
(Relative to 
Start of 
Infusion) 
Hours:Min
SNP&
HLA/
KIR 
typing
Tumor Ag 
specific
T-cells
with a 
CBC and 
differential
MDSCs
PB Gene 
Expression 
Profiling
PBMC Flow 
Cytometry
with a CBC  
and 
differential
Soluble 
Factors 
(Serum)
Anti-
Tumor 
Antibodies
PBMC 
Functional 
Assays
with a CBC 
and 
differential
Tumor 
Biopsy
Upon 
occurrence of 
≥ Grade 3/4 
drug-related 
AE
X
Local surgery 
of isolated 
symptomatic 
lesions (see 
Section 3.4.1)
Xf
Re-treatment 
after 
interrupted 
active 
treatment
Xf
a CBCs required will be done locally and not by central lab
b Must contain sufficient tumor content (≥100 tumor cells in a 4 micron section) upon central pathology assessment; 
c Biopsy is strongly encouraged but not mandatory in Part 4
d On-treatment biopsy window for Part 2, group 1 biopsy is Week 2, Day 1+7 days; potential on-treatment biopsy window for Parts 3 and 4, if determined to be 
optimal biopsy window. 
e On-treatment biopsy window for Part 2, group 2 is Week 4, Day 1+7 days; potential on-treatment biopsy window for Parts 3 and 4, if determined to be optimal 
biopsy window. 
fBiopsy is strongly encouraged but not mandatory. May be done at either Follow-up visit 1 or Follow-up visit 2
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Table 5.5C:
PK and ADA Sampling Schedule -Part 2 Arm A 
Study 
Day
Time 
(Event)
Time 
(Relative to 
Start of 
Nivolumab 
Infusion) 
Hours Mina
PK Serum 
Sample 
Nivolumab
Immuogenicity 
Sample 
Nivolumab
PK Serum 
Sample
Ipilimumab
Immunogenicity 
Sample 
Ipilimumab
Week 1
Day 1
0 (predose)
00:00
X
X
X
X
Week 1
Day 1
1 h (EOI-
Nivo)
01:00
X
Week 1
Day 1
3 h (EOI-
Ipi)
03:00
X
X
Week 1
Day 1
07:00
X
X
Week 1
Day 2
24:00
X
X
Week 1
Day 3
48:00
X
X
Week 1
Day 4
72:00
X
X
Week 2
Day 1
168:00
X
X
Week 4
Day 1
0 (predose)
00:00
X
X
X
X
Week 7
Day 1
0 (predose)
00:00
X
X
X
X
Week 7
Day 1
1 h (EOI-
Nivo)
01:00
X
Week 7
Day 1
3 h (EOI-
Ipi)
03:00
X
Week 10
Day 1
0 (predose)
00:00
X
X
X
X
Week 13
Day 1
0 (predose)
00:00
X
X
X
Week13 
Day 1
1 h (EOI-
Nivo)
01:00
X
Week 25
Day 1
0 (predose)
00:00
X
X
X
X
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Table 5.5C:
PK and ADA Sampling Schedule -Part 2 Arm A 
Study 
Day
Time 
(Event)
Time 
(Relative to 
Start of 
Nivolumab 
Infusion) 
Hours Mina
PK Serum 
Sample 
Nivolumab
Immuogenicity 
Sample 
Nivolumab
PK Serum 
Sample
Ipilimumab
Immunogenicity 
Sample 
Ipilimumab
Week 53
Day 1
0 (predose)
00:00
X
X
X
X
Week 79
Day 1
0 (predose)
00:00
X
X
Week 95
Day 1
0 (predose)
00:00
X
X
Follow-
up
Visit 1
(40-60 
days after 
last 
treatment)
X
X
Xb
Xb
Follow-
up Visit 2
(101-120 
days 
since last 
treatment)
X
X
Xb
Xb
a All samples should be timed relative to the start ofnivolumabinfusion, except for the ipilimumab end of 
infusion (EOI) samples which are to be taken just prior to the end of the ipilimumab infusion.
b Ipilimumab Follow up PK and immunogenicity samples collected only if subject discontinues treatment before 
Week 25.
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Table 5.5D:
PK and ADA Sampling Schedule Part 3 and Part 4, Arm B and E
Study Day
Time (Event)
Time (Relative to 
Start of Infusion) 
Hours:Min
PK Serum Sample
Nivolumab
Immunogenicity 
Sample Nivolumab
Week 1
Day 1
0 (predose)
00:00
X
X
Week 1
Day 1
0.5 (EOI)
00:30
X
Week 1
Day 1
03:00
X
Week 1
Day 1
07:00
X
Week 1
Day 2
24:00
X
Week 1
Day 3
48:00
X
Week 1
Day 4
72:00
X
Week 2
Day 1
168:00
X
Week 3
Day 1
0 (predose)
00:00
X
X
Week 5
Day 1
0 (predose)
00:00
X
Week 7
Day 1
0 (predose)
00:00
X
X
Week 7
Day 1
0.5 h (EOI)
00:30
X
Week 13
Day 1
0 (predose)
00:00
X
X
Week 13
Day 1
0.5 h (EOI)
00:30
X
Week 25
Day 1
0 (predose)
00:00
X
X
Week 53
Day 1
0 (predose)
00:00
X
X
Week 79
Day 1
0 (predose)
00:00
X
X
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Table 5.5D:
PK and ADA Sampling Schedule Part 3 and Part 4, Arm B and E
Study Day
Time (Event)
Time (Relative to 
Start of Infusion) 
Hours:Min
PK Serum Sample
Nivolumab
Immunogenicity 
Sample Nivolumab
Week 95 
Day 1
0 (predose)
00:00
X
X
Follow-up Visit 1
(40-60 days after 
last treatment)
X
X
Follow-up Visit 2
(101-120 days since 
last treatment)
X
X
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Table 5.5E: 
PK and ADA Sampling Schedule -Parts 3 and 4 Arm A and D 
Study 
Day
Time 
(Event)
Time 
(Relative to 
Start of 
Nivolumab 
Infusion) 
Hours Mina
PK Serum 
Sample 
Nivolumab
Immuogenicity 
Sample 
Nivolumab
PK Serum 
Sample
Ipilimumab
Immunogenicity 
Sample 
Ipilimumab
Week 1
Day 1
0 (predose)
00:00
X
X
X
X
Week 1
Day 1
0.5 h (EOI-
Nivo)
00:30
X
Week 1
Day 1
1.5 h (EOI-
Ipi)
01:30
X
X
Week 1
Day 1
07:00
X
X
Week 1
Day 2
24:00
X
X
Week 1
Day 3
48:00
X
X
Week 1
Day 4
72:00
X
X
Week 2
Day 1
168:00
X
X
Week 4
Day 1
0 (predose)
00:00
X
X
X
X
Week 7
Day 1
0 (predose)
00:00
X
X
X
X
Week 7
Day 1
0.5 h (EOI-
Nivo)
00:30
X
Week 7
Day 1
1.5 h (EOI-
Ipi)
01:30
X
Week 10
Day 1
0 (predose)
00:00
X
X
X
X
Week 13
Day1
0 (predose)
00:00
X
X
X
Week13 
Day 1
0.5 h (EOI-
Nivo)
00:30
X
Week 25
Day 1
0 (predose)
00:00
X
X
X
X
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Table 5.5E: 
PK and ADA Sampling Schedule -Parts 3 and 4 Arm A and D 
Study 
Day
Time 
(Event)
Time 
(Relative to 
Start of 
Nivolumab 
Infusion) 
Hours Mina
PK Serum 
Sample 
Nivolumab
Immuogenicity 
Sample 
Nivolumab
PK Serum 
Sample
Ipilimumab
Immunogenicity 
Sample 
Ipilimumab
Week 53
Day 1
0 (predose)
00:00
X
X
X
X
Week 79
Day 1
0 (predose)
00:00
X
X
Week 95
Day1
0 (predose)
00:00
X
X
Follow-
up
Visit 1
(40-60 
days after 
last 
treatment)
X
X
Xb
Xb
Follow-
up Visit 2
(101-120 
days 
since last 
treatment)
X
X
Xb
Xb
a All samples should be timed relative to the start ofnivolumabinfusion, except for the ipilimumab end of 
infusion (EOI) samples which are to be taken just prior to the end of the ipilimumab infusion.
b Ipilimumab Follow up PK and immunogenicity samples collected only if subject discontinues treatment before 
Week 25.
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5.8
Outcomes Research Assessments
Not applicable for this study
 
 
 
 
 
 
 
 
 
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 an investigational 
(medicinal) product 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 investigational product, 
whether or not considered related to the investigational product.
The causal relationship to study drug is determined by a physician and should be used to assess 
all adverse events (AE). The casual 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.)
An algorithm for the suggested management of drug-related immune events is included in 
Appendix of the Nivolumab Investigator Brochure.
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6.1
Serious Adverse Events
A serious AE (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 whichhypothetically might have caused 
death if it were more severe)
requires inpatient hospitalization or causes prolongation of existing hospitalization (see 
NOTEbelow)
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 [e.g., 
medical, surgical] to prevent one of the other serious outcomes listed in the definition 
above.) Examples of such events include, but are not limited to, intensive treatment in an 
emergency room or at home for allergic bronchospasm; blood dyscrasias or convulsions 
that do not result in hospitalization.) Potential drug induced liver injury (DILI) is also 
considered an important medical event. (See Section 6.6for the definition of potential 
DILI).
Suspected transmission of an infectious agent (e.g., any organism, virus or infectious particle, 
pathogenic or non-pathogenic) 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 6.4
for reporting pregnancies).
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 "important medical event" or event life 
threatening)
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 (e.g., 
routine colonoscopy)
medical/surgical admission for purpose other than remedying ill health state and was 
planned prior to entry into the study. Appropriate documentation is required in these 
cases
admission encounteredfor another life circumstance that carries no bearing on health 
status and requires no medical/surgical intervention (e.g., lack of housing, economic 
inadequacy, care-giver respite, family circumstances, administrative).
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6.1.1
Serious Adverse Event Collection and 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, of any causality, must be collected that occur during 
the screening period and within 100 days of discontinuation of dosing for those subjects that 
receive study therapy(within 30 days of last visit for enrollment failures). If applicable, SAEs 
must be collected thatrelate to any later protocol-specified procedure (e.g., a follow-up skin 
biopsy). 
The investigator should report any SAE occurring after these time periods that is believed to be 
related to study drug or protocol-specified procedure. 
An SAE report should be completed for any event where doubt exists regarding its status of 
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 should 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. SAEs must be recorded on the SAE Report Form; pregnancies on a 
Pregnancy Surveillance Form (electronic or paper forms). When using paper forms, the reports 
are to be transmitted via email or confirmed facsimile (fax) transmission to:
SAE Email Address: See Contact Information list.
SAE Facsimile Number: See Contact Information list.
For studies capturing SAEs/pregnancies through electronic data capture (EDC), electronic 
submission is the required method for reporting. The paper forms should be used and submitted 
immediately, only in the event the electronic system is unavailable for transmission. When paper 
forms are used, the original paper forms are to remain on site.
SAE Telephone Contact(required for SAE and pregnancy reporting): See Contact Information 
list.
If only limited information is initially available, follow-up reports are required. (Note: Follow-up 
SAE reports should 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, a follow-up SAE report should be sent within 24 hours to the BMS (or 
designee) using the same procedure used for transmitting the initial SAE report. 
All SAEs should be followed to resolution or stabilization.
6.2
Nonserious Adverse Events
Anonserious adverse eventis an AE not classified as serious.
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6.2.1
Nonserious Adverse Event Collection and Reporting
The collection of nonserious AE information should begin at initiation of study drug. Nonserious 
AE information should also be collected from the start of a placebo lead-in period or other 
observational period intended to establish a baseline status for the subjects. 
In the event that a subject has a late emerging (after 100 days from last dose of study drug) non-
laboratory, study drug related toxicity, it should be reported as an adverse event. 
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, or those that are 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 courseof the study.
6.3
Laboratory Test  Result Abnormalities
The following laboratory abnormalities should be captured on the nonserious AE CRF page or 
SAE Report Form (paper or electronic) as appropriate:
Any laboratory test result that is clinically significant or meets the definition of an SAE 
Any laboratory abnormality that required the subject to have study drug discontinued or 
interrupted
Any laboratory abnormality that required the subject to receive specific corrective 
therapy.
It is expected that wherever possible, the clinical, rather than the laboratory term would be used 
by the reporting investigator (e.g., anemia versus low hemoglobin value).
6.4
Pregnancy
If, following initiation of the investigational product, it is subsequently discovered that astudy 
subject is pregnant or may have been pregnant at thetime of studyexposure, including during at 
least 5half 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 and in accordance with SAE reporting procedures 
described in Section6.1.1.
Inmost cases, the study drug will be permanently discontinued in an appropriate manner (eg, 
dose tapering if necessary for subject safety).
In the rare event that the benefit of continuing study drug is thought to outweigh the risk, after 
consultation with BMS, the pregnant subject may continue study drug after a thorough 
discussion of benefits and risk with the subject.
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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.
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 
the Sponsor. 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 6.1.1for reporting details.).
6.6
Potential Drug Induced Liver Injury (DILI)
Whenever 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:
ALT or AST elevation > 3 times upper limit of normal (ULN)
AND
Total bilirubin > 2 times ULN, without initial findings of cholestasis (elevated serum alkaline 
phosphatase),
AND
No other immediately apparent possible causes of aminotransferase 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, 
electrocardiograms, x-rays, and any other potential safety assessments, whether or not these 
procedures are required by the protocol, should also be recorded as a nonserious or serious AE, 
as appropriate, and reported accordingly. 
7
DATA MONITORING COMMITTEE AND OTHER EXTERNAL 
COMMITTEES
Not applicable for this study.
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8
STATISTICAL CONSIDERATIONS
8.1
Sample Size Determination
The primary objective of this study is to assess the pharmacodynamic activity of 
immunomodulatory biomarkers following treatment with nivolumab and nivolumab in 
combination with ipilimumab. It is of interest to ensure precision of the estimate of the ratio of 
on-treatment biomarker assessments to baseline levels in Part 1 cohorts 1 and 2. Assuming that a 
biomarker is measured as a continuous variable, 40 subjects per cohort will provide the 
following confidence that the estimate of the ratio of on-treatment to baseline values will be 
within 20% of the true value:
Table 8.1A:
Probability that estimated ratio of on-treatment to baseline value is 
within 20% of true value
Intra-subject Standard deviation 
(log-scale)
0.20
0.30
0.40
0.50
0.60
0.70
0.80
Probability
100%
100%
97%
93%
86%
80%
74%
For example, for a biomarker with an intra-subject standard deviation of 0.5, if the true ratio of 
post-baseline to baseline geometric means is 1.2 (increase from baseline is 20%), there is 
93%probability that the estimatedratio would be within 0.96 and 1.44 (or a percent change 
between -4% and 44%). If the true increase from baseline is 60%, for a biomarker with the same 
variability, then there is 93% probability that the estimated percent change would be between 
28% and 92%.
More specifically, preliminary data analysis of activated and memory CD4 and CD8 T cells in 
CA209003 project an intra-subject standard deviation on the log scale between 0.5 and 0.6. 
Assuming this variability estimate is applicable to this study, thereis 86%-93% probability that 
the geometric mean ratio of on-treatment to baseline T cell subset levels will be within 20% of 
their true value.
It is of interest to ensure precision of the estimate of the proportion of subjects with increased 
activated T cellson-treatment (at optimal window for biopsy) in part 2 and part 3 Arms Aand B. 
With a total of 30 subjects (from part 2 andpart3) treated in Arm A (with biopsy collected at 
optimal on-treatment window), the maximum width of the exact 2-sided 95% confidence interval 
(CI) is 37% when the proportion of subjects with increased activated T cells is expected to be in 
the 20% to 60% range. The 95% exact CIs are presented in Table 8.1B.
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Table 8.1B:
95% Exact CI for Proportion of Subjects with Increased Activated T 
cell On-treatment
Proportion
20%
30%
40%
50%
60%
95% Exact CI
(7.7%, 
38.6%)
(14.7%, 
49.4%)
(22.7%, 
59.4%)
(31.3%, 
68.7%)
(40.6%, 
77.3%)
With a total of 10 subjects treated in Arm B (with biopsy collected at optimal on-treatment 
window), the maximum width of the exact 2-sided 95% confidence interval (CI) is 59% when 
the proportion of subjects with increased activated T cells is expected to be in the 20% to 30% 
range. The 95% exact CIs are presented in Table 8.1C.
Table 8.1C:
95% Exact CI for Proportion of Subjects with Increased Activated T 
cell On-treatment
Proportion
20%
30%
95% Exact CI
(2.5%, 55.6%)
(6.7%, 65.3%)
For example, if the observed proportion of subjects with increased activated T cell is 20% (data 
from CA184-004 indicate that ~25% of metastatic melanoma patients have an intratumoral, 
activated T cells with ipilimumab alone), there is 95% probability that the exact CI (2.5%, 
55.6%) will cover the true proportion.
Approximately 10 subjects will be treated in Arm D and 10 subjects in Arm E to provide 
additional information regarding pharmacodynamic activity of immunomodulatory biomarkers 
following treatment with nivolumab and nivolumab in combination with ipilimumab. 
Administration of nivolumab andnivolumab in combination with ipilimumab to 10 subjects per 
arm provides 90% probability of observing at least one occurrence of any adverse event (or one 
response) that would occur with a 21% incidence in the population from which the sample is 
drawn. 
8.2
Populations for Analyses
All Enrolled Subjects: All subjects who sign an informed consent formand were 
registered into the IVRS.
All Treated Subjects: All subjects who receive at least one dose of study medication.
Pharmacokinetic Subjects: All subjects who receive at least once dose of study 
medication and have available serum concentration data.
Response-Evaluable Subjects: All treated subjects with measureable disease at baseline 
and one of the following: 1) at least one on-treatment tumor assessment, 2) clinical 
progression, or 3) death, ifdeath occurred within 100 days after last administration of 
study medication
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Immunogenicity Subjects: All treated subjects who have baseline and at least one post 
baseline immunogenicity assessment
Biomarker Subjects: All subjects who receive at least onedose of study medication and 
have available biomarker data 
8.3
Endpoint Definitions
8.3.1
Primary Endpoints
The primary objective relating to the pharmacodynamic activity of biomarkers will be measured 
by changes from baseline in activated and memory T cells, interferon, interferon inducible 
factors, and CD4 and CD8 T cell infiltration. Time points for collection are specified in Table 
5.5Aand Table 5.5B.
8.3.2
Secondary Endpoint(s)
8.3.2.1
Safety
The secondary objective relates to safety and tolerability of nivolumab and nivolumab in 
combination of ipilimumab in subjects with advanced melanoma. These will be measured by the 
following endpoints:
Incidence rate of adverse events, serious adverse events, and deaths: all non-serious adverse 
eventswill be collected from Day 1 until 100 days after the subjects last dose of therapy or until 
they discontinue the study as per Section 3.1. All serious adverse events must be collected from 
the date of the subjects’ written consent until 100 days after discontinuation of dosing or until 
they discontinue the study as per Section 3.1.
Occurrence of clinical laboratory test abnormalities including hematology and serum chemistry 
abnormalities assessed at specified timepoints as designated in the Time and Events Section 
(Section 5.1). Safety labs are listed in Section 5.3.1.
Vital signs: Changes in vital signs relative to baseline including blood pressure and heart rate 
measurements. These will be measured at time points designated in the Time and Events Section 
(Section 5.1).
8.3.2.2
Efficacy
The secondary objective relating to efficacy is to describe the anti-tumor activity of nivolumab 
and nivolumab in combination with ipilimumab in subjects with advanced melanoma. This 
objective will be measured by the following endpoints based on RECIST 1.1 criteria 
(Appendix2). Disease evaluation will be performed at baseline, and then approximately every 
8weeks until disease progressionor treatment discontinuation, whichever happens later. 
The best overall response (BOR), computed for all treated subjects, is defined as the best 
response designation over the study as a whole, recorded between the dates of first dose until the 
last tumor assessment prior to subsequent therapy. CR or PR determinations included in the BOR 
assessment must be confirmed by a second scan performed no less than 4 weeks after the criteria 
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for response are first met. For those subjects who have surgical resection, only pre-surgical 
tumor assessments will be considered in the determination of BOR.
The objective response rate (ORR) is defined as the proportion of subjects with a BOR of CR or 
PR divided by the number of treated subjects (or response-evaluable subjects).
The Progression Free Survival Rate (PFSR) is defined as the probability of a subject remaining 
progression free or survival to time t, where t=24 weeks. This probability will be calculated by 
the product limit method (Kaplan-Meier estimates) which takes into account censored data.
The duration of response, computed for all treated subjects with a BOR of CR or PR, is defined 
as the time between the date of first response and the date of disease progression or death, 
whichever occurs first. For those subjects who remain alive and have not progressed or received 
subsequent therapy, duration of response will be censored on the date of last tumor assessment. 
For subjects who receive subsequent therapy prior to documented progression, duration of 
response willbe censored on the date of subsequent therapy.
Progression free survival (PFS), computed for all treated subjects, is defined as the time between 
date of first dose of study therapy and date of progression or death, whichever occurs first.
 
 
 
 
 
8.4
Analyses
Subjects who were randomized to Arm C (ipilimumab monotherapy) prior to Amendment 06 
maynot be included in the analysis, but will be listed separately.
8.4.1
Demographics and Baseline Characteristics
Frequency distributions of gender, race, age category, race, ethnicity, and ECOG status, will be 
tabulated by cohort/arm. Summary statistics for age, body weight, height, body mass index 
(BMI) will be provided by cohort/arm.
8.4.2
Efficacy Analyses
All available tumor measurement data will be listed. Individual best overall response (BOR) will 
be listed and tabulated by cohort. The objective response rate (ORR), and corresponding 
90%confidence intervals will be reported by cohort/arm. 
Medians and corresponding two-sided 95% confidence intervals will be reported for duration of 
response, PFS, and OS by cohort and analyzed using Kaplan-Meier methods. Estimated PFSR at 
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24 weeks (by Kaplan-Meier methods) and 90% confidence intervals (based on Greenwood’s 
formula) will be reported.
Cohort 1 and Arm B (nivolumab monotherapy with CTLA4 naive patient) will be combined for 
efficacy analyses. 
Efficacy analyses will be performed separately for the populations of all treated subjects and 
response-evaluable subjects. 
8.4.3
Safety Analyses
All recorded adverse events will be listed and tabulated by system organ class, preferred term, 
and cohort/arm and coded according to the most current version of MedDRA. The incidence of 
adverse events will be reviewed for potential significance and clinical importance. Vital signs 
and clinical laboratory test results will be listed and summarized by cohort/arm. Any significant 
physical examination findings and results of clinical laboratory tests will be listed. The incidence 
of infusion reactions will be reviewed to assess the safety and tolerability of reduced infusion 
times for nivolumab and nivolumab in combinationwith ipilimumab.
ECG readings will be evaluated by the investigator and abnormalities, if present, will be listed. 
8.4.4
Pharmacokinetic Analyses
The following pharmacokinetic parameters of nivolumab and ipilimumab derived from serum 
concentration time profiles of subjects will be included for PK analyses:
Cmax -Maximum observed serum concentration
Tmax -Time of maximum observed serum concentration
AUC(0-T) -Area under the plasma concentration-time curve from time zero to the last time of 
the last quantifiable concentration
Cmin -Serum concentration achieved at the end of dosing interval (trough concentration)
Ceoinf -Serum concentration achieved at the end of the infusion
Summary statistics for serum nivolumab and ipilimumab concentrations (including Cmin and 
Ceoinf) will be tabulated by cohort/arm, study day, and time. Summary statistics will be 
provided for pharmacokinetic parameters for nivolumab and ipilimumab (Cmax, AUC(0-T) and 
Tmax) by cohort/arm. Geometric means and coefficients of variation will be presented for Cmax, 
and AUC (0-T). Medians, minima, and maxima values will be presented for Tmax. Part 1 Cohort 
1 and Part 3 Arm B(nivolumab monotherapy with CTLA4 naive subjects) may be combined for 
PK analyses if appropriate.Part 2 Arm A and Part 3 Arm A (combination therapy with 
CTLA4naive subjects) may also be combined for PK analyses if appropriate. 
In addition, pharmacokinetic data from this study may be combined with data from other studies 
for a population PK model, which may be presented in a separate report. 
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8.4.8
Outcomes Research Analyses
Not applicable to this study.
 
 
 
 
 
 
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8.5
Interim Analyses
Administrative interim analyses may be performed at several times prior to completion of the 
study in order to facilitate program decisions and to support presentations or publications.
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
Bristol-Myers Squibb
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 an administrative letter, investigators must inform their IRB(s)/IEC(s).
9.1.2
Monitoring
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. 
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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, studydocumentation, informed consent, and enrollment of WOCBP.
9.2
Records
9.2.1
Records Retention
The investigator must retain all study recordsand source documents for the maximum period 
required by applicable regulations and guidelines, or institution procedures, or for the period 
specified by the Sponsor, 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 (e.g., relocation, retirement), the records shall be 
transferred to a mutually agreed upon designee (e.g, 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 
investigational product (those supplied by the sponsor)is maintained at each study site where 
study drug is inventoried and dispensed. 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 ID number or batch number 
amount dispensed to and returned by each subject, including unique subject identifiers
amount transferred to another area/sitefor dispensing or storage
non-study disposition (e.g., lost, wasted) 
amount destroyed at study site, if applicable
amount returned to the Sponsor
retain samples for bioavailability/bioequivalence, if applicable 
dates and initials of person responsible for Investigational Product (IP) 
dispensing/accountability, as per the Delegation of Authority Form.
The Sponsor 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 
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or entered as a control in the investigation. Datareported on the CRF that are derived from 
source documents must be consistent with the source documents or the discrepancies must be 
explained. 
For sites using the BMS electronic data capture tool, electronic CRFs will be prepared for all 
data collectionfields except for fields specific to SAEs and pregnancy, which will be reported on 
the paper or electronic SAE form and Pregnancy Surveillance form, respectively. Spaces may be 
left blank only in those circumstances permitted by study-specific CRF completion guidelines 
provided by the Sponsor. 
The confidentiality of records that could identify subjects must be protected, respecting the 
privacy and confidentiality rules in accordance with the applicable regulatory requirement(s).
The investigator will maintain a signature sheet to document signatures and initials of all persons 
authorized to make entries and/or corrections on CRFs. 
The completed CRF, including any paper or electronic SAE/pregnancy CRFs, must be promptly 
reviewed, signed, and dated by a qualified physician who is an investigator or sub investigator. 
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 the Sponsor. 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 considering the following criteria:
Subject recruitment (e.g., among the top quartile of enrollers)
Involvement in trial design
Regional representation (e.g., among top quartile of enrollers from a specified region or 
country)
Other criteria (as determined bythe study team)
The data collected during this study are confidential and proprietary to the Sponsor. Any 
publications or abstracts arising from this study require approval by the Sponsor prior to 
publication or presentation and must adhere to the Sponsor’s publication requirements as set 
forth in the approved clinical trial agreement (CTA). All draft publications, including abstracts or 
detailed summaries of any proposed presentations, must be submitted to the Sponsor at the 
earliest practicable time forreview, but at any event not less than 30 days before submission or 
presentation unless otherwise set forth in the CTA. Sponsor shall have the right to delete any 
confidential or proprietary information contained in any proposed presentation or abstract and 
may delay publication for up to 60 days for purposes of filing a patent application.
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10
GLOSSARY OF TERMS
Term
Definition
Adverse Reaction
An adverse event that is considered by either the 
investigator or the Sponsor as related to the 
investigational product
Unexpected Adverse 
Reaction
An adverse reaction, the nature or severity of which is 
not consistent with the applicable product information 
(e.g., Investigator Brochure for an unapproved 
investigational product)
Serious Adverse Event 
Serious adverseevent defined as 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 havecaused 
death if it were more severe), requires inpatient 
hospitalization or causes prolongation of existing 
hospitalization; 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.). For reporting purposes 
only, BMS also considers the occurrence of pregnancy, 
overdose (regardless of association with an AE), and 
cancer as important medical events.
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11
LIST OF ABBREVIATIONS
Abbreviation
Term
ALT
alanine aminotransferase
AIDS
acquired immunodeficiency syndrome
APC
Antigen-presenting cells
AST
Aspartate aminotransferase
BOR
Best overall response 
BORR
Best overall response rate
BP
Blood pressure
CI
Confidence interval
CR
Complete response
CRF
Casereport form
CT
Computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
CTLA-4
Cytotoxic T lymphocyte-associated antigen 4
DC
Dendritic cells
DCF
Data clarification form
DLT
Dose-limiting toxicity
DNA
Deoxyribonucleic acid
DTIC
Dacarbazine
ECG
Electrocardiogram
EDC
Electronic data capture
FDA
Food and Drug Administration
FFPE
Formalin fixed paraffin embedded
FSH
Follicle stimulating hormone
GCP
Good clinical practices
GMP
Good manufacturing practices
GCSF
Granulocyte colony stimulating factor
GI
Gastrointestinal
GM-CSF
Granulocyte macrophage colony stimulating factor
HBV SAg
Hepatitis B virus surface antigen
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Abbreviation
Term
HCV RNA
hepatitis C virus ribonucleic acid
HIPAA
Health Information Portability and Accountability Act
HIV
human immunodeficiency virus
ICF
Informed consent form
ICH
International Conference on Harmonisation
IEC
Independent Ethics Committee
IFN
Interferon
IL-2
Interleukin-2
IULN
Institutional upper limit of normal
IP
Investigational product
IRB
Institutional Review Board
IV
Intravenous
LFTs
Liver function tests
mAb
Monoclonal antibody
MedDRA
Medical Dictionary for Regulatory Activities
MEL
Metastatic melanoma
MLR
Mixed lymphocyte reaction
MRI
Magnetic resonance imaging
ORR
Objective response rate
PBMC
Peripheral blood mononuclear cell
PD
Progressive disease
PD-1
Programmed cell death 1
PD-L1
Programmed cell death ligand 1
PD-L2
Programmed cell death ligand 2
PR
Partial response
PVG
Pharmacovigilance
RECIST
Response EvaluationCriteria in Solid Tumors
RNA
Ribonucleic acid
RT
Radiation therapy
SAE
Serious adverse event
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Abbreviation
Term
SD
Stable disease
SLD
Sum of longest diameters 
SNP
Single nucleotide polymorphism
SOP
Standard operating procedures
SUV
Standardized uptake value
TCR
T-cell receptor(s)
TSH
Thyroid stimulating hormone
ULN
Upper limit of normal
WBC
White blood cell
WOCBP
Women of child bearing potential
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APPENDIX 2
RECIST 1.1
1
ASSESSMENT OF OVERALL TUMOR BURDEN AND MEASURABLE 
DISEASE
To assess objective response or future progression, it is necessary to estimate the overalltumor
burdenatbaselineand use this as a comparator for subsequent measurements. Measurable 
disease is defined by the presence of at least one measurable tumor lesion. When CT scans have 
slice thickness greater than 5mm, the minimum size for a measurable lesion should be twicethe 
slice thickness.
At baseline, tumor lesions/lymph nodes will be categorized measurable or non-measurable as 
follows:
1.1
Measurable lesions
Measurable lesions mustbe accurately measured in at least one dimension(longest diameter in 
the plane of the measurement to be recorded) with a minimum size of:
10 mm byCT/MRIscan-(CT/MRI scan slice thickness no greater than 5 mm)
10 mm caliper measurement by clinical exam (lesions which cannot be accurately 
measured with calipers should be recorded as non-measurable)
20 mm by chest x-ray
Malignant lymph nodes: To be considered pathologically enlarged andmeasurable, a 
lymph node must be 15mm in shortaxis when assessed by CT scan (CT scan slice 
thickness recommended to be no greater than 5mm). At baseline and in follow-up, only the 
shortaxis will be measured and followed.
1.2
Non-measurable lesions
All other lesions, including small lesions (longest diameter < 10mmor 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 in not 
measurable by reproducible imaging techniques.  
1.3
Special considerations regarding lesion measurability
1.3.1
Bone lesions
Bone scan,PET scan or plain films are notconsidered adequate imaging techniques to 
measure bone lesions. However, these techniques can be used to confirm the presence or 
disappearance of bone lesions. 
Lytic bone lesions or mixed lytic-blastic lesions, with identifiablesofttissuecomponents, 
that can be evaluated by cross sectional imaging techniques such as CT or MRI can be 
considered as measurable lesions if the softtissuecomponentmeets the definition of 
measurability described above.
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Blastic bone lesions are non-measurable.
1.3.2
Cystic lesions
Lesions that meet the criteria for radiographically defined simple cysts should not be 
considered as malignant lesions (neither measurable nor non-measurable) since they are, by 
definition, simple cysts. 
‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable 
lesions, if they meet the definition of measurability described above. However, if non-
cystic lesions are present in the same subject, these are preferred for selectionas target 
lesions.
1.3.3
Lesions with prior local treatment
Tumorlesions situated in a previously irradiated area, or in an area subjected to other loco-
regional therapy, are usually not considered measurable unless there has been demonstrated 
progression in the lesion. 
1.4
Specifications by methods of measurements
1.4.1
Measurement of lesions
All measurements should be recorded in metric notation(mm). All baseline evaluations should 
be performed as close as possible to the treatment start and never more than 30 daysbefore the 
beginning of the treatment.
1.4.2
Method of assessment
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. Imaging based evaluation should 
always be done rather than clinical examination unless the lesion(s) being followed cannot be 
imaged but are assessable by clinical exam.
1.4.2.1
CT/MRI scan
CT/MRIis the best currently available and reproducible method to measure lesions selected for 
response assessment. Measurability of lesions on CT/MRIscanisbased on the assumption that 
CT/MRIslice thickness is 5mm or less. When CT scans have slice thickness greater than 5mm, 
the minimum size for a measurable lesion should be twice the slice thickness.
1.4.2.2
Chest X-ray
Chest CT is preferred over chest X-ray, particularly when progression is an important endpoint, 
since CT is more sensitive than X-ray, particularly in identifying new lesions. However, lesions 
on chest X-ray may be considered measurable if they are clearly defined and surrounded by 
aeratedlung.
1.4.2.3
Clinical lesions 
Clinical lesions will only be considered measurable when they are superficial and 10mm 
diameter as assessed using calipers. For the case of skin lesions, documentation by color 
photography including a ruler to estimate the size of the lesion is suggested. As previously noted, 
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when lesions can be evaluated by both clinical exam and imaging, imaging evaluation should be 
undertaken since it is more objective and may also be reviewed at the end of the study.
1.4.2.4
Ultrasound 
Ultrasound is notuseful in assessment of lesion size and should not be used as a method of 
measurement. If new lesions are identified by ultrasound in the course of the study, confirmation 
by CT or MRI is advised. 
1.4.2.5
Endoscopy, laparoscopy
The utilization of these techniques for objective tumorevaluation is not advised.
2
BASELINE DOCUMENTATION OF ‘TARGET’ AND ‘NON-TARGET’ 
LESIONS
2.1
Target lesions
When more than one measurable lesion is present at baseline all lesions up toa maximum of 
five lesions total (and a maximum of two lesions per organ) representative of all involved 
organs should be identified as targetlesionsand will be recorded and measured at baseline. 
Target lesions should be selected on the basis of their size (lesions with the longest diameter), be 
representative of all involved organs, andshould lend themselves to reproduciblerepeated
measurements.
A sumofthediameters(longest for non-nodal lesions, short axis for nodal lesions) for all target 
lesions will be calculated and reported as the baselinesumdiameters.If lymph nodes are to be 
included in the sum, then as noted below, only the shortaxis is added into the sum. The baseline 
sum diameters will be used as reference to further characterize any objective tumorregression in 
the measurable dimension of the disease.
2.1.1
Lymph nodes
Lymph nodesmerit 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 
15mm by CT scan. Only the shortaxis of these nodes willcontribute to the baseline sum. 
Nodes that have a short axis <10mm are considered non-pathological and should not be 
recorded or followed.
2.2
Non-target lesions
All other lesions (or sites of disease) including pathological lymph nodes should be identified as 
non-targetlesionsand should also be recorded at baseline. Measurements are not required and 
these lesions should be followed as ‘present’, ‘absent’, or in rare cases ‘unequivocal 
progression’.In addition, it is possible to record multiple non-target lesions involving the same 
organ as a single item on the case record form (e.g. ‘multiple enlarged pelvic lymph nodes’ or 
‘multiple liver metastases’).
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3
TUMOR RESPONSE EVALUATION 
3.1
Evaluation of target lesions
Complete Response (CR):Disappearance of all target lesions. Any pathological lymph nodes 
(whether target or non-target) must have reduction in short axis to <10mm.
Partial Response (PR):  At least a30% decrease in the sum of diameters of target lesions,
taking as reference the baseline sum diameters.
Progressive Disease (PD):  At least a 20% increase in the sum of diameters of target lesions, 
taking as reference the smallestsumonstudy(this includes the baseline sum if that is the 
smalleston study). In addition to the relative increase of 20%, the sum must also demonstrate an 
absolute increase of at least 5mm. (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.
3.1.1
Special notes on the assessment of target lesions
3.1.1.1
Lymph nodes
Lymph nodesmerit special mention since they are normal anatomicalstructures 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 
15mm by CT scan. Only the shortaxis of these nodes willcontribute to the baseline sum. 
Nodes that have a short axis <10mm are considered non-pathological and should not be 
recorded or followed.
3.1.1.2
Target lesions that become ‘too small to measure’  
All lesions (nodal and non-nodal) recorded at baseline should have their actual measurements 
recorded at each subsequent evaluation, even when very small (e.g. 2mm). If the radiologist is 
able to provide an actual measurement, that should be recorded, even if it is below 5mm.
However,when such a lesion becomes difficult to assign an exact measure to then:
if it is the opinion of the radiologist that the lesion has likely disappeared, the measurement 
should be recorded as 0mm. 
if the lesion is believed to be present and is faintly seen buttoo small to measure, a default 
value of 5mm should be assigned (note: in case ofa lymph node believed to be present and 
faintly seen but too small to measure, a default value of 5mm should be assigned in this 
circumstance as well). This default value is derived from the 5mm CT slice thickness (but 
should not be changed with varying CT slice thickness).   
3.1.1.3
Target lesions that split or coalesce on treatment
When non-nodal lesions ‘fragment’, the longest diameters of the fragmented portions 
should be added together to calculate the target lesion sum. 
As lesions coalesce, a plane between them may be maintained that would aid in obtaining 
maximal diameter measurements of each individual lesion. If the lesions have truly 
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coalesced such that they are no longer separable, the vector of the longest diameter in this 
instance should be the maximal longest diameter for the ‘coalesced lesion’.
3.2
Evaluation of non-target lesions
While some non-target lesions may actually be measurable, they need not be measured and 
instead should be assessed only qualitativelyat the time points specified in the protocol. 
Complete Response (CR):Disappearance of all non-target lesions.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) above the normal limits.
Progressive Disease (PD):  Unequivocalprogressionof existing non-target lesions. (Note:the 
appearance of one or more new lesions is also considered progression).
3.2.1
Special notes on assessment ofnon-target lesions
The concept of progression of non-target disease requires additional explanation as follows:
3.2.1.1
When the subjectalso has measurable disease
To achieve ‘unequivocal progression’ on the basis of the non-target disease, there must be 
an overall level of substantial worsening in non-target disease such that, even in presence 
of SD or PR in target disease, the overall tumorburden has increased sufficiently to merit 
discontinuation of therapy. 
A modest ‘increase’ in the size of one or more non-target lesions is usually not sufficient to 
quality for unequivocal progression status. 
3.2.1.2
When the subjecthas only non-measurable disease
To achieve ‘unequivocal progression’ on the basis of the non-target disease, there must be 
an overall level of substantial worsening such thatthe overall tumorburden has increased 
sufficiently to merit discontinuation of therapy. 
A modest ‘increase’ in the size of one or more non-target lesions is usually not sufficient to 
qualify for unequivocal progression status. 
Because worsening in non-target disease cannot be easily quantified (by definition: if all 
lesions are non-measurable) a useful test that can be applied when assessing subjects for 
unequivocal progression is to consider if the increase in overall disease burden based on the 
change in non-measurable disease is comparable in magnitude to the increase that would be 
required to declare PD for measurable disease: i.e. an increase in tumorburden 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 subjectshould be considered to have had overall 
PD at that point. 
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3.2.1.3
Tumor markers
Tumormarkers alonecannot be used to assess objectivetumorresponses.If markers are initially 
above the upper normal limit, however, they must normalize in order for a subjectto be 
considered as having attained acomplete response. 
3.3
New lesions  
The appearance of new malignant lesions denotes disease progression.The finding of a new 
lesion should be unequivocal: i.e. 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 subject’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 notscanned at 
baseline is considered a new lesion and will indicate disease progression. An example of this is 
the subjectwho has visceral disease at baseline and while on study has aCT or MRI brainscan
ordered which reveals metastases. The subject’s brain metastases are considered to be evidence 
of PD even if he/she did not have brain imaging at baseline.
If a new lesion is equivocal, for example because of its small size, continuedtherapy 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.
3.3.1
FDG-PET evaluation
While FDG-PET response assessments need additional study, it is sometimes reasonable to 
incorporate the use of the qualitative assessment 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: 
Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of PD 
based on a new lesion. 
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 positiveFDG-
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.
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4
RESPONSE CRITERIA
4.1
Time point response
Aresponse assessmentshould occurat each time point specified in the protocol.
For subjects who have measurable diseaseat baseline Table 4.1provides a summary of the 
overall responsestatus calculation at each time point.
Table 4.1.
Time point response: subjects 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 ornot 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, NE=not evaluable.
4.1.1
Missing assessments and not evaluabledesignation
When no imaging/measurement is done at all at a particular time point, the subjectisnot 
evaluable (NE)at that time point.If only a subset of lesion measurements are made at an 
assessment, the case is also considered NE at that time point, unless a convincing argument can 
be made that the contribution of the individual missing lesion(s) would not have changedthe 
assigned time point response.
4.1.2
ConfirmationScans

Verification of Response: Confirmation of PR and CR is required within 4 weeks to 
ensure responses identified are not the result of measurement error.
4.2
Best overall response: All timepoints
The bestoverallresponseis determined once all the data for the subjectis known.Itis the best 
response recorded from the start of the study treatment until the end of treatment taking into 
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account any requirement for confirmation.The subject’s best overall response assignment will 
depend on the findings of both target and non-target disease and will also take into consideration 
the appearance of new lesions. 
Best response is defined as the best response across all time points with subsequent confirmation. 
Complete or partialresponses may be claimed only if the criteria for each are met at a 
subsequent time point as specified in the protocol (generally 4 weeks later). 
In this circumstance, the best overall response can be interpreted asspecifiedin Table 4.2.When 
SD is believed to be best response, it must meet the protocol specified minimum time from 
baseline.Measurements must have met the SD criteria at least once after study entry at a 
minimum interval (in general not less than 6–8 weeks) that is defined in the study protocol.
Table 4.2.
Best overall response when confirmation of CR and PR ISrequired.
Overall 
response
Overall response
BEST overall response
First time point
Subsequent time 
point
CR
CR
CR
CR
PR
SD, PD or PRa
CR
SD
SD provided minimum criteria for SD duration met, 
otherwise, PD
CR
PD
SD provided minimum criteria for SD duration met, 
otherwise, PD
CR
NE
SD provided minimum criteria for SD duration met, 
otherwise NE
PR
CR
PR
PR
PR
PR
PR
SD
SD
PR
PD
SD provided minimum criteria for SD duration met, 
otherwise, PD
PR
NE
SD provided minimum criteria for SD duration met, 
otherwise NE
NE
NE
NE
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CR=complete response, PR=partial response, SD=stable disease, PD=progressive disease, NE=not evaluable.
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 subject had PR, not 
CR at the first time point. Under these circumstances, the original CR should be changed to PR and the best 
response is PR.
4.3
Duration of response
4.3.1
Duration of overall response
The duration of overall response is measured from the time measurement criteria are first met for 
CR/PR (whichever is first recorded) until the first date that recurrent or progressive disease is 
objectively documented (taking as reference for progressive disease the smallest measurements 
recorded on study).
The duration of overall complete response is measured from the time measurement criteria are 
first met for CR until the first date that recurrent disease is objectively documented.
4.3.2
Duration of stable disease  
Stable disease is measured from the start of the treatment (in randomized trials, from date of 
randomization) until the criteria for progression are met, taking as reference the smallest sum on 
study (if the baseline sum is the smallest, this is the reference for calculation of PD).
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APPENDIX 3
GUIDANCE ON CONTRACEPTION 
ACCEPTABLE METHODS FOR PROTOCOLS WITH A TERATOGENIC DRUG OR WHEN THERE 
IS INSUFFICIENT INFORMATION TO DETERMINE TERATOGENICITY
(CHOOSE ONE OF THE FOLLOWING 4OPTIONS)a
OPTION 1: Any TWO of the following methods
Hormonal methods of contraceptionb, c, d
IUDc, d,e
Vasectomyd,f
Tubal Ligationd
A Barrier method (Female or Male Condom with spermicide, Cervical Cap with spermicide, Diaphragm 
with spermicide)
OPTION 2:  Male condom (with spermicide) and diaphragmg
OPTION 3:  Male condom (with spermicide) and cervical capg
OPTION 4: Complete Abstinenceh
a The theoretical failure rate for any of the options listed is considerably less than 1% per year
b Excludes progestin-only pills
c Hormonal contraceptives may not be used for contraception unless a drug-drug interaction study has 
demonstrated that the pharmacokinetics of the hormone based contraceptive has not been adversely affected by 
the investigational drug in the protocol or there is compelling evidence to substantiate that investigational 
product(s) or con-meds will not adversely affect contraception effectiveness.  The PK scientist and MST chair 
must agree that the use of hormone-based contraception is safe and efficacious for WOCBP. The use of hormone-
based contraceptives is not otherwise restricted
d A highly effective method of birth control with a failure rate less than 1% per year
e IUDS used should have a failure rate lessthan 1% (highly effective method), such as Mirena and ParaGard
f Must be at least 90 days from date of surgery with a semen analysis documenting azoospermia
g These 2 barrier methods together are acceptable for a teratogenic drug
h   Complete abstinence is defined as the complete avoidance of heterosexual intercourse. Complete abstinence is an 
acceptable form of contraception for all study drugs and must be used throughout the duration of study and for the 
duration of time as specified in the protocol. It is not necessary to use a second method of contraception when 
complete abstinence is elected. Subjects who choose complete abstinence must continue to have pregnancy tests, as 
specified in the protocol.Acceptable alternate methods of highly effective contraception must be discussed in the 
event that the subject chooses to forego complete abstinence.
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UNACCEPTABLE METHODSOF CONTRACEPTION
No method
Withdrawal
Rhythm
Vaginal Sponge
Any barrier method without spermicide
Spermicide
Progestin only pills
Concomitant use of female and male condom
In countries where spermicideis not available or its use is not considered compatible with male 
condoms, use of a male condom without spermicide in conjunction with a hormonal method, 
IUD, or tubal ligation will be acceptable to fulfill this recommendation.  Any barrier method 
when used alone (without spermicide) or the concomitant use of a female and male condom, is 
not considered a sufficient method of contraception, as each carries a failure rate of >1%.
Women of childbearing potential (WOCBP) receiving BMS-936558 (nivolumab) will be 
instructed to adhere to contraception for a period of 23 weeks after the last dose of 
investigational product. Men receiving nivolumab and who are sexually active with WOCBP 
will be instructed to adhere to contraception for a period of 31 weeks after the last dose of 
investigational product.These durations have been calculated using the upper limit of the half-
life for BMS-936558 (nivolumab) (25 days) and are based on the protocol requirement that 
WOCBP use contraception for 5 half-lives plus 30 days and men who are sexually active with 
WOCBP use contraception for 5 half-lives plus 90 days after the last dose of BMS-936558 
(nivolumab).
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APPENDIX 4
NIVOLUMAB MANAGEMENTALGORITHMS
These general guidelines constitute guidance to the Investigator and may be supplemented by discussions with the 
Medical Monitor representing the Sponsor. The guidance applies to all immuno-oncology agents and regimens.
A general principle is that differential diagnoses should be diligently evaluated according to standard medical 
practice. Non-inflammatory etiologies should be considered and appropriately treated.
Corticosteroids are a primary therapy for immuno-oncology drug-related adverse events. The oral equivalent of the 
recommended IV doses may be considered for ambulatory patients with low-grade toxicity. The lower 
bioavailability of oral corticosteroids should be taken into account when switching to the equivalent dose of oral 
corticosteroids.
Consultation with a medical or surgical specialist, especially prior to an invasive diagnostic or therapeutic 
procedure, is recommended. 
The frequency and severity of the related adverse events covered by these algorithms will depend on the immuno-
oncology agent or regimen being used.
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